BLADDER, URETER, URETHRA AND PENIS PATHOLOGY
URETERS
NORMAL
3 narrowing
Ureteropelvic
Crossing iliac vessels
Before getting into bladder
CONGENITAL ANOMALIES
Congenital anomalies and complications***
Diverticula (congenital or acquired)à stasis and infections
Bifid uretersà join distallyà no significance
Ureteropelvic junction obstruction[1]à hydronephrosis
Hydroureter (congenital or acquired)
Major causes of ureteric obstruction
SCLEROSING RETROPERITONEAL FIBROSIS
Define*
Fibrous proliferation arising over sacral promontoryà encases retroperitoneal structures (abdominal aorta) and uretersà hydronephrosis
Clinical
Mid to late age
Etiology: secondary causes. Primary aka?
Drugs: ergot derivatives, β-blockers
Inflammation: diverticulitis, Crohn, vasculitis
Malignancies: lymphoma, TCC
Idiopathic: 70% (Ormond disease)
Micro: type of inflammation
Fibrosis with lymphocytes
Germinal centers
Plasma cells, eosinophils, +/-granulomas
Necrosis in fat possible
Related diseases
Riedel fibrosing thyroiditis
Mediastinal fibrosis
Sclerosing cholangitis
URETERITIS
Types*
Ureteritis follicularis: lymphoid follicles in LPà granular surface
Ureteritis cystica: urothelial lining
TUMORS
Benign tumors*
FEP
Leiomyomas
Malignant tumors of ureters*
TCC
?
URETERS CLASSIFICATION
URINARY BLADDER
NORMAL
What protein in apical plaque on top of umbrella cells?
Uroplakin
What are normal layers?
Epithelium: transitional urothelium (can have both squamous and glandular differentiation)
Mucosa, LP, MP (thick bundles, organized only in bladder neck), serosa
Can have fat in the muscularis
No submucosa?
MM: ill-defined, only wisps of SM
METAPLASIA
Types
Squamous (trigone)à secondary to estrogen
Intestinal metaplasia in cystitis glandularis
Proliferative changes: von Brunn’s nests, cystitis cystica, cystitis glandularis
2 types of squamous metaplasia. Which one is worse?
Keratinizing worse than non-keratinizing
CONGENITAL ANOMALIES
Congenital anomalies in bladder*
Diverticula (acquired or congenital)à risk for infections, lithiasis, cancers (SCC and adenocarcinoma)
Exstrophyà bladder protrudes inside out through open anterior wall like popcornà risk for infections, intestinal and squamous metaplasiaà adenocarcinoma of bladder and of colon
Vesicoureteral reflux:
Urachusà between umbilicus and bladderà risk for infections, urachal cystsà adenocarcinomas
Congenital fistula
3 complications of bladder diverticula
UTI
Stones
VUR
Why tumors in diverticulum more dangerous?
Diverticulum has thin wall
CYSTOCELE
What’s that? Consequence
Bladder protruding into vagina
No emptying during micturition
CYSTITIS
RF
Females
Bladder stones
Urinary obstruction
DM
Instrumentation
Immunosuppression
Types of cystitis
Acute
Chronic: chronic infectionà thickening of MPà decreased bladder elasticity
Infectious: KEEPS (Klebsiella, E coli, Enterobacter, Proteus, S?), TB (always secondary to renal TB), Candida, Cryptococcus (immunosuppressed), Schistosomiasis (hematobium), viruses (adenovirus), Chlamydia, Mycoplasma
Polypoid: chronic irritation such as Foleyà confused with TCC
Hemorrhagic: chemotherapy (cyclophosphamide, busulfan) or radiation
Eosinophilic: associated with allergic disordersà submucosal eosinophils, fibrosis, +/-some giant cells
Xanthogranulomatous: malakoplakia without MGB
Interstitial (Hunner ulcer): mast cells, lymphocytes, macrophages, ulcer, hemorrhage, granulation tissue
Malacoplakia: yes, it’s one type of cystitis
Follicular: secondary to Foley, BCGà often confused with TCC
Ulcerative
Granulomatous
Causes of granuloma
| TB | |
| BCG | |
| Post-cautery | Peculiar central fibrinoid necrosis (necrobiotic center) |
| Xanthogranulomatous | |
| Sarcoid | |
| Infections | Adenovirus, Chlamydia, Mycoplasma |
| Fungi | Candida, Cryptococcus |
| Parasites | Schisto, leprosy |
| Chemoradiation | Cyclophosphamide, busulfan |
| FB | |
| Neoplastic | Hodgkin |
Note: can get pseudosarcomatous inflammatory changeà ulcer surrounded by normal spindle cells.
DDx: TCC with sarcomatoid change (HMK useful)
Sarcomas (eg. LMS)
Clinical triad of cystitis
Frequency
Pain
Dysuria
INTERSTITIAL CYSTITIS (Hunner ulcer)
Presentation
Women with pain, dysuria (due to fibrosis and inflammation of all bladder layers!) and hematuria
Characteristic endoscopic finding
Fissuring and punctate hemorrhages (glomerulations)
Etiology
Unknown
Micro
Early: nonspecific submucosal hemorrhage
Late: ulcers* (Hunner ulcers!), inflammation and fibrosis of all bladder layers. Mast cells* characteristic (>20 /1 mm2)
MALAKOPLAKIA
What’s this?
A form of chronic bacterial cystitis
Gross
Soft yellow plaques of 3-4cm diameter (quite large)*
Micro*
Lymphocytes, foamy histiocytes, MGC
Michaelis Gutmann bodies inside and outside macrophages (note retraction artifact around MGB)
IHC: what stains MGB?
PAS: due to ingested membranes
Ca
Fe+
Mechanism.
E. coli (#1), Proteus (#2)à inability to degrade bacterial products
More commonly immunosuppressed pts (transplant), but not exclusively
Where else?
Orifices: GI, lungs, GU, bones
PROLIFERATIVE/REACTIVE CHANGES
Name some
Von Brunn nests: nests of transitional epithelium growing downward into LP
Cystitis cystica: transitional lining
Cystitis glandularis: cuboidal or columnar lining
Cystitis glandularis with intestinal metaplasia (goblet cells)*
Squamous metaplasia (intracytoplasmic glycogen, trigone, female, estrogen responsive)
Nephrogenic metaplasia
Is intestinal metaplasia risky?
Controversial probably very slight if any
Cystitis glandularis vs intestinal metaplasia
Goblet cells
NEPHROGENIC ADENOMA
Etiology
Shedding of tubular epithelium in response to injury
Post-transplant
Micro: 2 components, how deep?
Papillae lined by cuboidal epithelium on surface
Tubular proliferation in LP and superficial detrusor muscle
Prominent mixed chronic inflam infiltrate
Where else can it occur?
Prostate
IHC: name one stain.
PAX2+
Racemase+
DDx
Prostate adencoca (male)
Clear cell carcinoma of ovary (female)
Metastatic adenocarcinoma
INFECTIONS
SCHISTOSOMIASIS
Which type in bladder?
Hematobium (central spine)
NODULES
POSTOPERATIVE SPINDLE CELL NODULE
Diagnosis
3 months or less after surgery
Intersecting fascicles of spindle cells
High mitoses
Delicate network of capillaries
Scattered acute and chronic inflammation
Small foci of hemorrhage
Mild to moderate edema
Focal myxoid change
No marked atypia
Locations
Bladder, prostate
DDx
Myxoid sarcoma
Sarcomatoid carcinoma of prostate or bladder
Sarcomatoid TCC
SFT
| PSCN | LMS |
| Myxoid
Mitoses Atypia |
|
| History of recent surgeryà most useful hint | |
| Prominent delicate capillary network | Less |
| MFB on EM | SM on EM |
| Sometimes impossible to differentiateà recommend excision and follow-up with re-biopsy | |
INFLAMMATORY PSEUDOTUMOR
Is this neoplastic? Relationship with IMT? (USCAP)
Not neoplastic
Not same as IMT (neoplastic, more in kids)
Micro
Spindle cells separated by vascular, myxoid, somewhat basophilic stroma
IHC
ALK1
CD43+ in lung
TUMORS
UROTHELIAL PAPILLOMA
Demo
Younger patients
Micro: identical to normal urothelium (therefore bland)
Any consequences
May recur although rare
Variant and describe*
Inverted: anastomosing cords
PUNLMP vs papilloma
Thicker urothelium or diffusely enlarged nuclei
How to manage?
Same as LGPUC
| LGPUC | HGPUC |
| Cohesive always | Maybe discohesive |
| Maintained polarity (even spacing) | May be lost |
| Mild atypia
Scattered dark nuclei Only mild size variation |
More atypia
Larger nuclei |
| Rare mitoses (limited to base) | Mitoses, some atypical |
CIS
Gross
Granular, slightly raised, red
Micro: Partial or full thickness, HG atypia, mitoses, discohesive
Special spread pattern?
Pagetoid
% progression if untreated?
50-75%
Treatment
BCG
TCC
Progression risk for preinvasive lesions
| Urothelial papilloma | <2% |
| PUNLMP | <2% |
| LGPUN | <10% |
| HGPUN | Up to 80% |
| TIS | 50-75% |
Precursor lesions (2) and give progression risk
Noninvasive papillary tumors
CIS: HG by definition.
Classify papillary urothelial lesions and lay out treatment for each
Papillary HP: excision
Papilloma (inverted variant): excision
PUNLMP: excision
LGUPC: excision
HGUPC: excision and BCG
TIS: excision and BCG
LP invasion: excision and BCG
MP invasion: cystectomy
How TCC spreads?
Early: invades adjacent structures and LN
Late: hematogenous dissemination (liver, lungs, marrow), especially anaplastic tumors.
What’s similar epidemiologically between TCC and lung cancers?
Males, industrial country cancer, urban disease
RF*
Smoking: cigarette>> cigars, tobacco
Chemical exposure: arylamines, 2-naphthylamine
Schistosoma hematobium: causes both SCC and TCC
Cyclophosphamide: must be prolonged exposure
Radiation: TCC
2 pathogenetic pathways***
9p/9q deletions (p16)à superficial papillary TCCà 17p deletion (p53)à invasion
17p deletion (p53)à CISà 9p/9q deletions (p16)à invasion[2]
13q deletion (Rb loss) in invasive tumors
Pathogenesis for TIS and invasive tumors
14q deletionsà unknown gene
Are multifocal tumors clonal?
Yes, most often
IHC
CK7+
CK20+
HMK+
CEA+
CD15+
CDX2 can be positive!
Prognosis*: give 2 most important
Stage[3]
Grade
Multifocality
Size (not included in staging)
Prior recurrence rate
Indications for BCG
CIS
HGPUC (LGPUC requires only TURBT)
Multifocal
History of rapid recurrence
LP invasion (T1)
Indications for cystectomy
Detrusor invasion
CIS or HGPUC refractory to BCG
CIS extending into urethra or prostatic ducts
Indications for chemotherapy
Advanced stage
Should we grade invasive TCC?
Yes, based on which component (invasive or surface component?)
Which variants have worse prognosis?
Nested
Micropapillary
Invasion
Single, nested
Paradoxical maturation
Retraction artifact
Chance of survival when MP invaded
50%
Sequence of spread
LN first, then hematogenous (liver, lung, marrow)
Variants*
Lymphoepithelioma-like
Small cell carcinoma
SCC
Mixed or pure more frequent?*
Often mixed
RF for SCC (hint: SCC)
Schistosis, stones
Cyclophosphamide
Catheter
What pattern is never see in SCC?
Never papillary growth
Good or bad?
Bad
ADENOCARCINOMA
Name 4 RF
Intestinal metaplasia
Exstrophy
Schistosomia
Urachus
Name premalignant lesion
Adenoma (same as colonic)
Micro
Same as colorectal adenocarcinoma
Can mix with TCC
Variants*
Signet-ring
Mixed with TCC
Diagnostic criteria for urachal adenocarcinoma
Dome or anterior wall
Not in continuity with urothelium
No in situ component
Exclude metastatic source
| Bladder adenocarcinoma | CDX2+ (therefore not reliable), prostatic markers-, TCC markers+ (CK7+/CD20+, thrombomodulin+) |
| Colonic mets | CK7-/CD20+ |
| Nephrogenic adenoma | Smaller, uniform, after GU surgery |
SMALL CELL NE CARCINOMA
Why searching carefully in micro?
Often coexists with other cancers
What important to know about IHC?
TCC markers- (thrombomodulin, HMK, uroplakin all-)
CK20-
NE markers+
TTF1+
CK+
DDx
Lymphoma
Lung mets: TTF1 useless, better use imaging, no concomitant TTC, often submucosal,
MESENCHYMAL TUMORS
Most common benign and malignant mesenchymal tumors in bladder*
Leiomyoma
RMS in kids
LMS in adults
METASTASIS
Sources
Cervix, uterus, prostate, rectum
Lymphoma
URETHRA
DIFFERENTIALS
Types of polyps in urethra
Inflammatory polyp
Caruncle
Nephrogenic adenoma
Urothelial papilloma
Squamous papilloma
Prostatic urethral polyp
Malakoplakia
Cystitis glandularis
INFLAMMATION
Name infectious agents*
Gonococcal
E coli and other enteric
Chlamydia
Mycoplasma
Accompanying cystitis and prostatitis
Reiter’s syndrome
Urethritis, conjunctivitis, arthritis
TUMORS
| Benign | Malignant* |
| Squamous papilloma | SCC in distal |
| Urothelial papilloma | TCC in proximal |
| Inverted papilloma | Adenocarcinoma (rare) |
| Condyloma |
PROSTATIC URETHRAL POLYPS
Micro (hint: surface vs core)
Surface: urothelium
Core: prostatic glands + stroma
DDx
Nephrogenic adenoma
Edematous urethral mucosal folds
Papillary urothelial HP
FE polyps
URETHRAL CARUNCLE
Presentation*
Painful friable red mass at external urethral meatus (either inside or outside) in female patient
Can ulcerate and bleed
Micro*
Highly vascular young fibroblastic connective tissue
Heavily infiltrated by leukocytes
Transitional or squamous lining
PENIS
Name 3 congenital malformations in the penis
Hypospadias (#1)à risk for urinary obstruction and abnormal ejaculation
Epispadias
Phimosisà small orifice preventing prepuce retractionà risk for infection, cancer and paraphimosis
Hypertrophy
Duplication
Hypoplasia
Aplasia
Implications with hypo/epispadias
Association with undescended testes
Urinary obstruction
Implications with phimosis
Infections
SCC
INFLAMMATION
BALANOPOSTHITIS
Infectious agents
Candida
Anaerobes
Gardnerella
Pyogenic
RF*
Phimosis
Non circumcision (smegma)
TUMOURS
5 lesions associated with HPV (hint: same as in cervix)
Condyloma acuminatum
Bowen disease: crusty white plaque, associated with visceral cancer in 1/3 cases!
Erythroplasia of Queyrat (red velvety plaque)
Bowenoid papulosis: multiple, young sexually active adults, pigmented papules (grossly mistaken for condyloma but histologically mistaken for Bowen), spontaneous regression in most
Invasive SCC
SCC
RF
No circumcision with smegma accumulation
HPV association
Smoking
Which LN?
Inguinal and iliac
Variants
Verrucous*