Patozone

Ureter

Bladder

Urothelial carcinoma

Urothelial (transitional cell) tumors

• Squamous differentiation
• Glandular differentiation
• Papilloma
• Inverted papilloma
• PUNLMP
• Papillary urothelial carcinoma
• Carcinoma in situ
• Invasive urothelial carcinoma

Fibroepithelial Polyp

Almost exclusively in males, B9, Rare, tend to occur in kiddos and adolescents, rarely in adults, usually presents c urinary retention, bladder outlet obstruction and/or hematuria

- usually seen in the ureter or urethra, rather than the bladder

Gross: polypoid excrescence

Micro: "clover leaf-like" projections, lined by normal-appearing urothelium

Tx/Px: do not recur after excision, not assoc c cancer

DDx: urothelial papilloma (does not have lining of normal epithelium) - misdiagnosing a fibroepithelial polyp in a younger pt as a urothelial papilloma in a younger pt would subject them to years of unnecessary close surveillance

- may also consider florid cystitis cystica et glandularis, polypoid / papillary cystitis, and inverted papilloma

Reference:

http://apps.pathology.jhu.edu/sp/week-1-case-1-1112/

Urothelial Ca

How to differentiate Urothelial ca from Prostate ca?

A panel of PSA, HMWCK, and p63 was optimal for separating

95% PCa (PSA+/HMWCK and/or p63–)

vs 97% UCa (PSA–/HMWCK and/or p63+)

The majority of PCa cases retain PSA

Negative PSA with positive HMWCK and/or p63 establishes a diagnosis of UCa.

CK7/CK20 coexpression was noted in 50% of UCa cases, whereas 86% of PCa cases were negative with both

Radiation Cystitis

May be misinterpreted as SCC

- may develop decades after radiation tx

Micro: Fibrin deposits assoc c hemorrhage and reactive epithelial prolif into lamina propria

- nests can have squamoid appearance and nuclear pleomorphism

Malakoplakia

Can be seen in any part of the GU tract, most commonly in the urinary bladder

- means "soft plaque" in Greek

Gross: Solitary or confluent yellow mucosal nodules or plaques

Micro: Mixed inflam; Epithelioid histiocytes with eosinophilic cytoplasm.

Michaelis-Guttman bodies - Basophilic, targetoid cytoplasmic inclusions, are lysosomes c degradation products of E. coli.

Michaelis-Gutmann bodies - large numbers of epithelioid histiocytes c abundant eosinophilic cytoplasmic inclusions, concentric laminated bodies that are PAS+

- concentrically laminated structure on EM

Nephrogenic adenoma

Clinical: Wide age range of presentation (usually middle-aged men) , ~1/5 occur in peds and some after kidney transplant

- Majority of cases associated with a history of genitourinary procedure, trauma, or calculi. Not a true neoplasm.

- Represents a metaplastic process

Micro: Composed of cuboidal cells with tubulo-cystic and papillary growth pattern. Scant cytoplasm

- lined by single layer columnar or cuboidal hobnail or flattened cells

- Minimal nuclear atypia and mitotic activity. In contrast, clear cell carcinomas have solid and diffuse growth pattern, ample portions of clear cytoplasm (positive for glycogen on PAS stain), significant

nuclear atypia and increased mitotic activity.

IHC: (+) PAX8, P504 (AMACR)

Px: may recur, but malignant transformation has not been seen

Postoperative spindle cell nodules/

pseudosarcomatous fibromyxoid tumor

Can be seen throughout the GU tract, including urinary bladder and prostate. May be seen spontaneously or following GU instrumentation or trauma. Represents a reparative/reactive process

Micro: Composed of a proliferation of (myo)fibroblasts. Uniform nuclear features. Variable mitotic activity.

DDx:: leiomyosarcoma.

Urothelial neoplasms [WHO classification]

1) Flat lesions

• Urothelial carcinoma in situ: variety of growth patterns including clinging and cancerization/pagetoid involvement

2.) Papillary neoplasms

a. Includes papilloma, inverted papilloma, papillary neoplasm of low malignant potential, low-grade and high-grade papillary carcinoma.

b. Noninvasive versus invasive. If the latter is present, the extent of invasion has therapeutic implication, ie, lamina propria versus muscularis propria.

c. Variants of invasive TCC include sarcomatoid (carcinosarcoma), microscystic and micropapillary

Urothelial Carcinoma -- Two Phenotypes?

Non-muscle invasive BC (NMIBC) 70-80%

Muscle Invasive BC (MIBC) 20-30%

Reactive Urothelial Atypia

• Acute or chronically inflamed urothelium

• Vesicular uniformly enlarged nuclei with central

prominent nucleoli.

• Mitotic figures may be common.

• History of instrumentation, infection, stones, therapy

- Overuse of the diagnosis “mild dysplasia”

 Mild staining and fixation alterations

 Normal vs. mild dysplasia

 Urologists desensitized to the diagnosis of

dysplasia

 Do not use the term “mild dysplasia” – diagnose

as “normal or reactive”

Urothelial Papilloma

Usually solitary lesions, 1-2% of papillary lesions, present c hematuria (gross or microscopic), MC in young adults

- can have extensive multifocal involvement of mucosa, called diffuse papillomatosis

- papillomas are diploid and have frequent FGFR3 (3/4) mutation

• Discrete papillary growth with a central fibrovascular core lined

by urothelium of normal thickness and cytologic features

• No need to count cell layers (7)

• Very rare lesion

Micro: exophytic papillary neoplasm lined with normal appearing urothelium, lacking significant atypia

- architecturally are slender with minimal branching

- superficial umbrellas can be prominent and can have vacuolization and large multinucleated cells

Tx: excision

Px (Magi-Galluzzi et al. Am J Surg Pathol 2004)

•34 de novo papillomas

•Mean age 58 years

•24 males; 10 female

• F/U in 26 pts (mean 29 months)

• 3/34 (8.8%) recurrence rate

• 3/34 (8.8%) progression to LG UrCa or PUNLMP

• No progression to invasive UrCa (pT1 or pT2)

3) Urothelial Dysplasia

• Preneoplastic atypia short of CIS

M>F, avg age 60 yo, presents c irritation or obstructive sx or hematuria;

- rare, Relatively uncommon diagnosis – most cases

either normal or significant atypia (CIS)

- strong risk factor for CIS and invasive ca (~15%)

- secondary dysplasia assoc c concurrent or prior hx of urothelial ca, and is risk for recurrence

- Without qualifier, equals “moderate dysplasia”

Micro: abnormal architectural and cytologic changes that fall short of unequivocal CIS

- see altered polarity of superficial cells and cytoplasmic clearing is common

- cells vary in size and shape and nuclei c irreg granular chromatin and wrinkled nuclear membranes

- nuclear crowding and hyperchromasia

- long axis of nuclei are parallel to BM, lack prominent nuclei or atypical mits

Grading of dysplasia is NOT recommended

Management of Urothelial Dysplasia

• In someone with h/o of CIS, indicates the disease is

recurring. May be treated with intravesical therapy

• In someone with de novo diagnosis of dysplasia,

often patients followed more closely for CIS

4) Urothelial CIS

Elderly men (60-70 yo), 10M>1F,  usually assoc c concurrent of prior UC, presents c irritative or obstructive sx or hematuria

- can masquerade as interstitial cystitis

- cystoscopy can show nonspecific or velvety erythematous lesion c granular or cobblestone appearance

- usually in trigone and base of bladder

Presence of cytologically malignant cells regardless of

quantity

Micro: Full thickness invovement is NOT a prerequisite

- disordered prolif of malig urothelial cells c loss of polarity and dec cellular cohesion

- high NC, nuclear pleomorphism, hyperchromasia,, irreg nuclear membranes and irreg mits

• No need to be full thickness

• Pagetoid cells

• Spectrum of atypia and cell size

• Umbrella cell layer may still be present

• CIS cells 5x size of stromal lymphocytes, compared to normal

cells which are 2x size of lymphocytes

• Enlarged & hyperchromatic ON 10X OBJECTIVE

• Dyscohesive : “denuding cystitis”

• Prostatic Urethra: Caution !

Variants: large and small cell, denuding (frequently missed! Loses cell adhesion molecules), Pagetoid, Sq, glandular, micropapillary, microinvasion (CISmic)

Genes: p53 and RB genes are the MC altered genes

Nested urothelial carcinoma

- variant of urothelial ca originally recognized by its ability to mimic b9 conditions like proliferating von Brunn nests, esp in small bx's

- however, has a propensity to invade deep into bladder wall despite its low-grade morphology

- may be assoc c carcinoma in situ or conventional urothelial ca

- IHC: similar to typical UC (+ CK7 and p63, often CK20+)

Inverted papilloma

Rare, b9 urothelial tumor, presents c hematuria and irritative sx

- 7M.1F, usually ~50 yo

- usually trigone and bladder neck

- b9 and not related to urothelial carcinoma

• Most commonly seen in the trigone region

• Usually solitary (3%

• Polypoid /sessile on cystoscopy , smooth surface

• Size: wide range

• Can be associated with urothelial carcinoma, yet not

thought to be directly related

Micro: smooth surface covered by normal urothelium and endophytic growth of urothelial cells aroborizing extensively from surface urothelium to lamina propria

- anastomosing cord, columns and thin trabecula

- peripheral pallisading with spindly nuclei

- no atypia or mits

- no exophytic component

- may see squamous morules

- may show non-keratinizing squamous metaplasia

DDx: inverted urothelial carcinoma

Inverted Papilloma Comparison to Urothelial Carcinoma

• Lacks cytological atypia

• Mitotic activity limited to basal cell layer

• Lacks inflammation and reactive stroma

• Squamous metaplasia lacks keratin formation

• Lacks muscularis propria invasion

Px: recurrence ~1%

Urothelial Papillary Proliferation of Undetermined Significance

(UPUMP)?

• Tented or undulated thickened urothelium WITHOUT

SIGNIFICANT ATYPIA

• Base with dilated capillaries

• No discrete papillary fronds

• UPMP is frequently associated with prior or concurrent low

grade papillary neoplasms:

- papilloma

- PUNLMP

- low grade papillary urothelial carcinoma

• De novo diagnosis: close follow up

• Follow up for papillary tumors: could represent shoulder

lesion of recurrent tumor

Papillary Urothelial Neoplasms of Low Malignant Potential (PUNLMP)

Described in 2004 WHO as papillary neoplasm c feature bwt b9 papilloma and low-grade papillary utoherlial carcinoma

- show minimal mits and minimal nuclear atypia

- architectural complexity low

- may have minimal nuclear atypia and thickening

• Orderly arrangement

• Thicker than papilloma

• No atypia , at most nuclear enlargement

• At most rare mitoses at base

• Not associated with invasion

Px: have low but real risk of recurrence, and require clinical surveillance

Involvement of FGFR-3 and HRAS are important for the development of low-grade carcinomas

- p53 and RB are involved in progression to high-grade neoplasms and carcinoma in situ

-- p16 may be involved, typically as a deletion of the locus in FISH assays

punlmp

Papillary urothelial carcinoma

Terminology of Papillary Tumors (LASOP Netto lecture 2021)

• Non invasive papillary carcinoma, Low grade

• Non invasive papillary carcinoma , High grade

• Do Not use: “In situ papillary urothelial carcinoma”

• Non invasive papillary urothelial carcinoma

• Invasive papillary urothelial carcinoma

• Grade by the worst component

• •? HG component <

- Low grade: appears orderly with a thicker lining than papillomas c a little nuclear atypia and few mits

--- ~10% invade

- assoc c Fibroblast growth factor receptor 3 (FGFR3), esp in non-muscle invasive tumors

- High grade: marked atypia, dyscohesive, large hyperchromatic nuclei, lots of mits

~80% invade

Non Invasive Papillary Carcinoma, Low Grade

• Overall orderly arrangement with minimal variation in polarity

(clonal)

• On low power looks “pink” due to low N/C ratio

• Mild atypia consisting of scattered enlarged hyperchromatic

nuclei

• Scattered mitotic figures some at levels higher than base layer

• Inconspicuous nucleoli

Non Invasive Papillary Carcinoma, High Grade

• Overall disorderly arrangement with irregularly

clustered cells, fused papillae

• Marked atypia analogous to CIS

• Numerous mitotic figures including atypical forms at

all levels

• Dyscohesive single cells

• Prominent nucleoli

Invasive urothelial carcinoma

Must be staged:

Noninvasive, papillary = Ta; CIS = Tis; Lamina propria invasion = T1; Invasion of adjacent structures = T4

Lamina Propria Invasion

Inverted growth vs true invasion:

 Small nests

 Retraction artifact

 Paradoxical differentiation/maturation

Substaging

 Focal vs. extensive

 Depth relative to muscularis mucosae (LAM1 vs. LAM2)

 Micrometer (1.5 MM)

Maximum length of invasive foci

Terminology - Muscle

• Muscularis propria (detrusor muscle) invasion

• Muscularis mucosae invasion (do not report?)

• Do not use “superficial muscle” or “deep

• Do not use “superficial bladder

Muscularis Propria (MP) Invasion

• Infiltration of thick muscle bundles

• If uncertain MP vs. MM indicate uncertainty to urologist

• Do not attempt to substage MP invasion

• Fat seen at all levels, such that does not

indicate extension out of the bladder

Micropapillary variant of invasive urothelial carcinoma asspc c high pathologic stage and lymph node mets 2/2 inc rate of lymphovascular invasion

*** CAVEAT: non-invasive papillary urothelial carcinomas can have a micropapillary-like pattern, and these tumors have a clinical course and prognosis similar to HG-noninvasive papillary urothelial ca. Thus the designation of "micropapillary" variant should be restricted to only INVASIVE carcinomas to avoid unnecessary tx [2]

Plasmacytoid Variant Urothelial Carcinoma

Micro: Malignant cells dyscohesive with eccentric nuclei and glassy eosinophilic cytoplasm and signet-ring morphology

Px: assoc c extensive spread through bladder wall and abdominal cavity compared to other variants of urothelial ca

- thus has uniformly poor px with advanced stage at presentation and metastatic dz progession

Adenocarcinoma

Malignant tumor making up to 1/50 bladder tumors

- M>F, assoc c nonfunctional bladder or exstrophy usually presenting c hematuria

Micro: malignant-looking glands that make mucin

- can be subclassified into mucinous, enteric or signet ring varieties

IHC: similar to colonic AC, (+) CK20, p63, CK5/6, B-catenin (cytoplasmic)

- variable CK7 and CDX2

- B-catenin is NUCLEAR positive in colonic ac and CYTOPLASMIC in the bladder, can be an important differentiation!

To differentiate urothelial carcinoma and prostate carcinoma, urothelial carcinoma is usually positive for HMWK and nuclear p63, while these markers are positive in basal cells of b9 prostate glands, their expression is lost in prostatic adenocarcinoma

Urothelial carcinoma is negative for PAX-8

Tx: surgery, rads and chemo depending on stage

Px: poor