요로종양병리 학습목표병리학교실 조 남훈

1. 방광 및 요로 상피세포의 조직학적 특징을

이해한다.

2. 방광암의 타종양과 차이점을 이해한다.2. 방광암의 타종양과 차이점을 이해한다.

3. 방광암의 육안 및 조직학적 유형 4가지를 이

해하고 각 유형별 가장 흔한 대표적인 유전

자 변이를 알아본다.

4. 방광암의 T0 개념을 포함한 병기를 이해하며

CIS의 진단방법을 알아본다.

Normal Histology

• 2-3/3-5/5-7 cells thick from pelvis to ureter/bladder/urethra

• Umbrella cell-Uroplakin-CK 20

• Discontinous muscularis mucosa

vs. detrusor muscle proper

Physiology and microanatomy of Normal Urotheliumto be characterized by Urine-Blood Barrier

• Surface epithelium covered by umbrella cell

• Umbrella cell surface: plaque with intermediate flexible segment acting as hinge, plaque-forming

membrane called asymmetric unit membrane (AUM)

• AUM is produced by Golgi app. and forming oblong cytoplasmic vesicle with a role in vehicle for

intracellular transport of AUM

• Incorporated to the surface membrane during the process of distention, and eventually increasing the • Incorporated to the surface membrane during the process of distention, and eventually increasing the

surface areas and maintaining the structural integrity.

: One flat border in cytology

: Multinucleation

: DNA polypolidy

: Uroplakin +

• Tight junction in surface cells and deep urothelial cells: impermeable to urine

• AUM can be partly or wholly replaced by symmetrical unit membrane lining finger-like projections

(microvilli) in case of cancer transformation

Uroplakin as AUM markerA B

C D

A B

C D E

Sclerosing retroperitoneal fibrosis

• Uncommon ureteral obstructive disorder characterized by

- fibrous proliferative inflammatory process

- encasing the retroperitoneals tructures

- causing hydronephrosis

- by drug, adjacent inflammation, malignancy- by drug, adjacent inflammation, malignancy

i.e, lymphoma, urothelial ca or idiopathic (Ormond ds)

- systemically associated with similar lesions in other

sites probabaly by autoimmune disorder• Mediastinal fibrosis

• Sclerosing cholangitis

• Riedel fibrosing thyroiditis

Special Forms of Cystitis-1

• Interstitial cystitis (Hunner ulcer)

– Menopausal women

– Unknown etiology, Autoimmune theory

– Acute phase (non-ulcer/non-classic); glomerulation (punctate hemorrhage)

– Chronic (classic, ulcerative)– Chronic (classic, ulcerative)

– Increased mast cell in intermuscular tissue-controversial as pathognomonic finding (toluidine blue metachromasia)

• Polypoid cystitis – Inflammatory condition resulting from irritation to the bladder mucosa,

most commonly indwelling catheter

– Marked submucosal edema

– D/Dx: papillary urothelial ca

Special Forms of Cystitis-2

• Malakoplakia– Soft, yellowish mucosal plaque (3-4 cm)

– Von-Hansemann histiocytes

– Michaelis-Gutmann body

•Laminated, mineralized concretion in enlarged phargosomes

– Defect in phargocytic or degradative

function of MФ overloading E-coli, proteus

MGB

vHH

Metaplastic Lesions

1. Cystitis glandularis and (et) cysticaOften coexist

Intestinal metaplasia in case of goblet cells

2. Squamous metaplasia2. Squamous metaplasiaResponse to injury

Physiologically glycogenated vaginal-type of

squamous epithelium in woman at trigone-

no sq metaplasia

3. Nephrogenic metaplasia (adenoma)Papillary pattern lined by cuboidal cells and

tubular proliferation, ca mimicker

Epidemiology of Urothelial Ca

• Cigarette somking

• Industrial exposure– 2-naphthylamine

– 15-40 yrs after the first exposure

• Schistosoma haemoatobium

• Analgesics abuse

• long-term exposure to cyclophophamide– hemorrhagic cystitis

• Prior exposure of bladder to radiation

PAPILLARY UROTHELIAL NEOPLASMS(1973 WHO/ISUP Consensus)

[2004 WHO adopt]

• Papilloma

• Papillary urothelial neoplasm of low malignant potential (PUNLMP) -TCC G1 (1973 WHO)

• Papillary urothelial carcinoma, low grade-TCC G1-2

• Papillary urothelial carcinoma, high grade-TCC G 3

PapillomaG1 G2 G3

PUNLMP LG HG

WHO 1973

WHO 2004

Ureteric Urothelial Carcinoma- Renal Pelvis and Ureter-

Renal Pelvis

Tumor

Urothelial Bladder Cancer

• 95% urothelial origin tumor

• Over 90% malignancy

– Unpredictable px

– Gross configuration/grade/stage

• Multiplicity

– Clonal theory>fileld theory

• Recurrent

– Increased atypism at each recurrence

Pathogenesis of Urothelial Ca

• 9 deletion: superficial PTCC– 9p21: p16 (INK4a, MTS1)

– 9q: unknown

• 17p deletion: high grade TCC, invasive/CIS– P53 loss

• 13q deletion: high grade TCC, invasive/CIS– pRb loss

• 14q del: non-papillary TCC

9p del 13q/17p del

GI >>

GII/III

II/III>I

13q/17p/14q delIII>IIII/III>>I

Carcinoma in situ

Urothelial Papilloma

• Exophytic papilloma, typical papilloma

• Small lesion , < 50 yrs

• A papillary tumor with a delicate fibrovascular stroma covered by urothelium indistinguishable from that of the normal bladder.

• Discrete frond with occasional branching but without fusion

Urothelial LMP vs. Urothelial ca- low grade

Urothelial CarcinomaLow grade vs. High grade

Bladder Cancer-Divergent differentiation to adeno/squamous type

Urothelial Carcinoma In SituNonpapillary Noninvasive TCC, Grade III

1-5% of CIS occurs in the absence of other pattern of cancer- primary CIS. If untreated, 50-75% of CIS progress to invasive ca.

Pagetoid CIS

Clinging CIS

Historical Overview of Urine Cytology• One of the first branch in medicine• Ancient era

– Soul substance to protect against evil– Rain-urine of god (deity)-exposure to rain is soul-healing.– Bathing for beauty and mouthwash for caries/ Cheese flavor, tobacco leaf, bakery leavening

• Hippocrates (Greek)– Foamy urine-serious and first invented biomarker – Colic, suppuration, hematuria: triad for urologic ds (stone, Tbc, cancer)

• Galen (Roman, AD 130-200)– Renal physiology and urine mechanism

• Avicenna (Persian, AD 980-1037)– Urinalysis (color, density, sediment, odor)-true biomarker

• Brian (1637)- urine examination alone in the absence of patient (Pisse-prophet)• Hooke (1665)-crystal figure in “Micrographia”• Rees (1836)- scientific urinalysis description in textbook

• Lambl (1856)-first documents on urothelial ca in urine cytology (On cancer of bladder)– 6 bladder tumors, 1 uterine ca to bladder, 1 papilloma in a girl, 2 inflammation

• Beale (1864)- urine cell type description • Papanicolaou (1945)-”urine cytologic evaluation of cancer” published in Science

– True + 88.8%, true – 60%

• Stewart (1942)-Carcinoma in situ (Dr. J. Ewing’s urine)• Koss-integrate urine cytology

Superficial vs. Myoinvasive• Topical immunotherapy (BCG installation-immediately postop)

– High risk group: CIS, multifocal, TaHG, Hx of rapid recurrence, LP invasion (T1)

• Radical cystecomy Ix– MP invasion (T2+)

– CIS refractory to BCG, CIS extending to prostatic urethra and ducts

• Once muscle invasion- 50% 5-yr mortality

Urothelial Carcinoma of the Urinary Bladder

Recurrence vs. Progression

• Recurrence

– Subsequent tumor at different sites from the original lesions

– New tumor or shedding/implantation of the original tumor cells

– Recurrence-free survival factors

• Size, multifocality, stage, grade, prior recurrence rate, a/w CIS• Size, multifocality, stage, grade, prior recurrence rate, a/w CIS

– 98% of 10-yr survival in LG UC vs. 40% survival in HG UC

• Progression

– Staging progression (no applied on grading progression: recurrence)

– Progression-free survival factors

• grade

• presence of lamina propria (pT1 stage)

• associated carcinoma in situ

Urachal Cancer• Obliterated Median umblical ligament

• Persistent/patent urachus anomaly

• Subsequent malignant transformation

– Bladder dome/anterior wall

– Arising within the wall, not from mucosa– Arising within the wall, not from mucosa

– Mucinous/signet ring cell ca

Bladder calculi and trabeculation-outlet obstruction