Ureter, Urinary Bladder, and Kidney

Ureteritis Cystica

• Von Brunn nests (small nests of normal urothelial cells within lamina propria) with central lumens (cystic dilatation) lined by urothelial cells

Ureteritis Glandularis

• Von Brunn nests with central lumens lined by columnar cells

Urothelial Hyperplasia

• Increase in number of layers of urothelial cells

• Does not show nesting of urothelial cells

Von Brunn Nests

• Lacks formation of central cystic dilatation

Grading of Urothelial Carcinomas

• To simplify the World Health Organization (WHO) (1973) system and avoid an intermediate cancer grade group (grade II), the WHO (2003)/International Society of Urological Pathology (ISUP) system classifies papillary urothelial carcinomas into only two grades:

  • Low-grade papillary urothelial carcinoma (LG-UC)

  • High-grade papillary urothelial carcinoma (HG-UC)

Inverted Papilloma

• Urothelial cords and trabeculae with uniform thickness, peripheral palisading, and central spindling and streaming

• Minimal cytologic atypia and low mitotic activity

• Lacks invasion into the muscularis propria

Fibroepithelial Polyp

• Typically solitary with a short, thin stalk

• Consists of a polyp of loose fibroconnective and fibrovascular tissue covered by normal-appearing urothelium

Clinical Features

• Inflammatory condition caused by impaired intraphagosomal digestion

• Most commonly found in the bladder; may be seen in the ureter, renal pelvis, testis, gynecologic tract, gastrointestinal tract, and lung

• Typically found in women; peak incidence in fifth decade

• Rarely seen in children

• Most patients present with typical symptoms of urinary tract infection

• Often culture Escherichia coli or other bacteria from the urine

Gross Pathology

• Multiple, soft, yellow-white, nodular plaques measuring less than 2 cm

• Involves mucosal surface

Histopathology

• Accumulation of histiocytes with abundant eosinophilic granular cytoplasm (von Hansemann histiocytes) in the superficial lamina propria, typically underlying an intact urothelial layer ( Figure 10.2 )

  

• Michaelis-Gutmann bodies (small round basophilic intracytoplasmic or extracytoplasmic laminated structures with a bull’s eye appearance) are found within histiocytes as well as within the interstitium

• Michaelis-Gutmann bodies are formed by precipitation of calcium or iron on bacteria or bacterial fragments

• Extensive fibrosis or marked acute and chronic inflammation may be seen

Special Stains and Immunohistochemistry

• Von Kossa calcium and Perl’s Prussian blue: Michaelis-Gutmann bodies are positive

• Periodic acid-Schiff (PAS): Von Hansemann and Michaelis-Gutmann bodies are positive

Other Techniques for Diagnosis

• Electron microscopy: Michaelis-Gutmann bodies consist of a dense core surrounded by a homogeneous zone composed of myelin figures; measure 5 to 10 μm in diameter

Differential Diagnosis

Polypoid Cystitis

• Small polypoid mucosal lesions (may mimic bladder carcinoma)

Follicular Cystitis

• Mucosa showing erythematous gray-white nodules

Giant Cell Cystitis

• Usually a subtle finding; erythematous bladder mucosa may be seen

Polypoid Cystitis

• Broad fronds covered by benign-appearing urothelial cells

• Lamina propria is edematous with chronic inflammation and congested blood vessels

Follicular Cystitis

• Lamina propria contains scattered lymphoid follicles, usually with germinal centers

Giant Cell Cystitis

• Atypical large stromal cells with bipolar or multipolar tapering eosinophilic processes and enlarged hyperchromatic nuclei (degenerative atypia); cells often contain multiple nuclei; mitoses are absent or rare ( Figure 10.3 )

  

Bacterial Cystitis

• Inflammatory component consists of acute inflammatory cells

• Bladder culture may yield positive results

Low-Grade Papillary Urothelial Carcinoma

• May be confused with polypoid cystitis

• Typically shows branching delicate papillae rather than broad fronds

• Papillae are covered by atypical urothelial cells, which is much more pronounced than that seen in polypoid cystitis

Malignant Lymphoma

• Must be distinguished from follicular cystitis

• Lymphomatous infiltrate typically shows a diffuse rather than follicular architecture

Sarcoma

• Must be distinguished from giant cell cystitis

• Sarcomatous stromal cells have a higher degree of nuclear atypia; mitoses are commonly found

Granulomatous Cystitis Secondary to Bacillus Calmette-Guerin Therapy (Bacillus Calmette-Guerin Cystitis)

• Partially or entirely denuded bladder mucosa

Radiation Cystitis

• Hyperemic and edematous bladder mucosa with thickened mucosal folds

Hemorrhagic Cystitis

• Hemorrhagic and edematous bladder mucosa

Bacillus Calmette-Guerin Cystitis

• Superficial lamina propria shows discrete noncaseating granulomas containing epithelioid histiocytes and multinucleated giant cells

• Granulomas are associated with intense lymphocytic infiltrate

• Urothelium may show nonspecific reactive atypia or be denuded

Radiation Cystitis

• Lamina propria shows edema, hyperemia, and dilated blood vessels with fibrin ( Figure 10.4 )

  

• Proliferation of urothelial nests within lamina propria “hugging” ectatic vessels

• Surface urothelium may shows desquamation, superficial ulceration, and atypical cytologic features mimicking CIS; however, atypia is degenerative and nuclear-cytoplasmic (N:C) ratio is low

• Bizarre giant cells and multinucleated cells are often present

• The stroma contains extravasated erythrocytes, inflammation, and hemosiderin deposition

• Late changes include collagenization of the lamina propria, myointimal proliferation or hyalinization of the arteriole’s media, and often ulceration with fibrinous exudate

Hemorrhagic Cystitis

• Lamina propria shows hemorrhage and congested blood vessels

• Urothelium shows regenerative changes including nuclear pleomorphism

• Healing may result in hyperplastic urothelium with papillae formation

• Repeated bouts may result in a fibrotic, contracted bladder

Bacterial Cystitis

• Inflammatory component consists of acute inflammatory cells

• Bladder culture may yield positive results

Urothelial Carcinoma in Situ

• Cytologic atypia and architectural distortion are more pronounced and mitoses are frequently found

Nonulcerative or Early Disease

• Multiple microhemorrhages are present within the lamina propria (glomerulations)

• Classic phase (Hunner ulcer)

• Single or multiple patches of reddened, ulcerated, or denuded bladder mucosa with fibrinous exudate often seen admixed with chronic inflammatory cells, including lymphocytes, plasma cells, and mast cells

• Characteristic feature is increase in mast cells within the mucosa, lamina propria, and muscularis propria

• Hemorrhage, edema, congestion, and fibrosis are also seen

• Occasionally there is no ulceration of the mucosa; only chronic inflammation, edema, hemorrhage, and granulation tissue are seen

Flat Urothelial Carcinoma in Situ

• Denuding CIS exhibits ulceration, vascular congestion, and inflammation resembling interstitial cystitis

• Multiple tissue sections should be examined to search for atypical cells

Bacterial Cystitis

• Inflammatory component consists of acute inflammatory cells

• No increase in mast cells

• Bladder culture may yield positive results

Noninfectious Cystitis

• Features of polypoid cystitis, follicular cystitis, giant cell cystitis, or hemorrhagic cystitis

• No increase in mast cells

Cystitis Cystica

• Small submucosal cysts filled with clear yellow fluid

Cystitis Glandularis

• May not always be grossly visible

• Occasionally see irregular nodular mucosa

Cystitis Cystica

• Von Brunn nests within the lamina propria showing central cystic dilatation with spaces lined by urothelial or low cuboidal epithelium ( Figure 10.5 )

  

• Cysts are often filled with pale eosinophilic fluid

Cystitis Glandularis

• The epithelial lining of von Brunn nests undergoes glandular metaplasia

• Glands are lined by cuboidal to columnar cells without anaplasia

• Cells may contain mucin and occasionally goblet cells are present

• If the epithelium acquires intestinal-type goblet cells, this variant is called cystitis glandularis with intestinal metaplasia (if diffuse without urothelial cells: colonic metaplasia)

Urothelial Carcinoma, Nested Variant

• Florid von Brunn nest 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

Adenocarcinoma

• Rare bladder neoplasm

• Atypical glands lined by stratified, pleomorphic cells with infiltration into the muscular layer

• Signet ring cells may be seen

Prostatic and Clear Cell Adenocarcinoma

• Not typically associated with other clinical conditions

• Tubules with prominent nucleoli sometimes situated within muscle bundles

• Usually much larger

• Shows greater cytologic atypia and high mitotic rate

Low-Grade Papillary Urothelial Carcinoma

• Papillae are covered by neoplastic urothelial cells rather than benign-appearing cuboidal cells

• Nested or microcystic variant of urothelial carcinoma exhibits greater atypia and increased mitoses at the deep invasive fronts

Capillary Hemangioma

• Negative for CK7 and positive for endothelial markers, such as CD31

Clinical Features

• Rare benign urothelial lesion; it may be seen in the flat mucosa adjacent to a low-grade papillary urothelial lesion

Gross Pathology

• Noncontributory

Histopathology

• Markedly thickened urothelial mucosa without cytologic atypia

• Rather than requiring a specific number of cell layers, marked thickening compared with the adjacent normal urothelium is needed to diagnosis flat hyperplasia

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Frequent deletions of chromosome 9 detected by fluorescence in situ hybridization (FISH) have been reported in urothelial hyperplasias found in patients with papillary bladder cancer

Differential Diagnosis

Clinical Features

• Typically discovered on routine follow-up cystoscopy for papillary urothelial neoplasms

Gross Features

• Benign focally elevated lesion identified at cystoscopy, described as papillary, raised, sessile, or bleblike

Histopathology

• Undulating urothelium arranged into mucosal narrow papillary folds of varying heights; no detached papillary fronds

• The urothelium within papillary hyperplasia and the adjacent flat mucosa are often thicker than normal

• The cytologic findings are similar to those characteristic of normal urothelium

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Typically found in elderly individuals with a mean age older than 65 years

• More frequently seen in men M:F = 3:1

• Associated with tobacco smoking, many toxic chemicals (including nitrosamines), drugs (phenacetin, cyclophosphamide), infections ( Schistosoma hematobium )

• Most common presenting symptom is painless hematuria

• Patients may have flank pain and obstructive symptoms

Gross Features

• Tumors usually involve the lateral or posterior bladder walls; occasionally involve the bladder dome

• Low-grade tumors typically have a papillary architecture appearing as multiple finger-like fronds over the bladder mucosa (see Noninvasive LG-UC)

• Higher-grade tumors often lack papillary architecture and show nodular, polypoid, or sessile pattern (see Noninvasive HG-UC); focal remnants of papillary architecture may persist

• Bladder wall is typically thickened, firm, and gray-white

• Ulceration and hemorrhage are often seen in the high-grade tumors

Histopathology

Special Stains and Immunohistochemistry

• Cytokeratin (high molecular weight, CK7, CK20), p63, and CD15: positive

• CEA: positive (especially in high-grade tumors)

• GATA3: positive

Other Techniques for Diagnosis

• Cytogenetic studies: deletion of chromosome 9p is associated with superficial disease; abnormalities involving chromosome 17p are associated with disease progression; aneuploidy involving chromosomes 3, 7, and 17

Differential Diagnosis

Well-Differentiated Adenocarcinoma of the Colon or Bladder

• Degree of cytologic atypia similar to analogous colonic lesions

• Invasion into lamina propria

Nonurachal Adenocarcinoma

• Typically an exophytic, papillary, ulcerating mass arising from the bladder mucosa

• Usually involves the trigone or posterior bladder wall

• Often shows infiltrative margins

• May be sessile and cause a diffuse thickening of the bladder wall (resembles linitis plastica of the stomach); overlying bladder mucosa may be intact, leading to negative biopsies (signet ring cell variant)

Urachal Adenocarcinoma

• Most form discrete masses over the dome of the bladder

• It may involve urachal remnants, forming a large mass in the anterior abdominal wall

• Overlying bladder mucosa may be intact or ulcerated

• Cut surface of the mass often shows abundant mucin

Urachal and Nonurachal Adenocarcinomas

• Mucinous carcinoma with pools of mucin containing single and groups of neoplastic cells (often resembles colonic adenocarcinoma)

• Neoplastic glands with an infiltrative growth pattern

• Glands are lined by large, pleomorphic cells with vesicular chromatin and prominent nucleoli; nuclear stratification is also common

• Signet ring cells may be seen

• CIS or intestinal metaplasia may be seen in nonurachal adenocarcinoma

Urachal Adenocarcinomas

• Criteria to classify a tumor as urachal adenocarcinoma

  • Location in the dome or anterior wall of the bladder

  • Sharp demarcation between tumor and normal surface epithelium

  • Lack of urothelial carcinoma

  • Typically adjacent mucosa lacks prominent cystitis glandularis

  • Bulk of tumor is in the bladder wall rather than luminal

  • Exclusion of primary adenocarcinoma located elsewhere that has spread secondarily to the bladder

Cystitis Cystica et Glandularis

• Small submucosal cysts with benign cytologic features

• Typically small lesions without deep infiltration

Nephrogenic Adenoma

• About 50% of cases found following genitourinary surgery

• Composed of small uniform tubules resembling proximal tubules of the kidney

• Usually much smaller than adenocarcinoma

Endometriosis

• Composed of endometrial glands and stroma

• Hemosiderin-laden macrophages often seen

Metastatic Adenocarcinoma

• Presence of primary adenocarcinoma at distant site must be ruled out

Urothelial Carcinoma with Squamous Differentiation

• If urothelial component is present, the tumor should not be classified as a squamous cell carcinoma

• Urothelial CIS may be seen; it would never be seen in a pure squamous cell carcinoma

Metastatic Squamous Cell Carcinoma

• Presence of squamous cell carcinoma from local (cervix) or distant site must be ruled out

Squamous Papilloma

• Lack of cytologic atypia and invasion

Condyloma

• Presence of koilocytic cells

Metastatic Small Cell Carcinoma

• Clinical correlation is needed to exclude presence of primary small cell carcinoma at distant site

• Identification of urothelial component, including urothelial CIS, supports a bladder primary

Malignant Lymphoma

• Consists of atypical lymphoid population

• Positive staining for LCA

• Negative staining for cytokeratin, synaptophysin, and chromogranin

Sarcomatoid Urothelial Carcinoma/Carcinosarcoma

• Consists of malignant epithelial and malignant mesenchymal components

• Numerous mitotic figures

• Lacks inflammatory background

• Lacks network of thin-walled blood vessels

Leiomyosarcoma

• Overall, rare; however, it is the most common bladder sarcoma in older adults

• Usually shows infiltrative margins

• Typically shows cytologic atypia and increased mitotic activity with atypical mitotic figures

• More commonly shows immunohistochemical evidence of smooth muscle differentiation

Sarcomatoid Carcinoma (Carcinosarcoma)

• Consists of malignant epithelial and malignant spindle cell components

• Islands of cells with epithelial differentiation are seen

• Cytokeratin positivity in the epithelial component

Inflammatory Myofibroblastic Tumor

• Background usually contains a sparse inflammatory component

• Prominent network of thin-walled blood vessels in an edematous or myxoid stroma

• Mitotic figures may be present and even frequent, but they are not atypical

• ALK-1 protein expression