30 Bladder Carcinoma

1. GROSS DESCRIPTION

Specimen — urine cytology/bladder washings/cystoscopic biopsy/transurethral resection bladder (TURB)/ cystectomy/cystourethrectomy/cysto- prostatectomy (including seminal vesicles)/cystoprostatourethrec- tomy/anterior or total exenteration (including uterus and adnexae ± rectum). — weight (g) and size (cm). ⎯ length (cm) of ureters and urethra. ⎯ bladder cancer commonly presents with symptoms of painless haema- turia and investigation is by urinary cytology, cystoscopy and biopsy. Cytology is good at designating high-grade papillary, in-situ and inva- sive urothelial neoplasia but poor at separating low-grade papillary lesions from reactive atypia and cellular changes associated with calculi, in-dwelling catheters, recent instrumentation and post- therapy changes. Biopsy is with “cold” cup forceps or a small diathermy loop, the advantage of the former being good preservation of histological detail. Flexible cystoscopy is easier for the patient and allows a wide field of vision but rigid cystoscopy with a larger lumen allows instrument access for transurethral resection of superficial bladder tumours with diathermy to the base (TURBT). Deep biopsy of the muscularis propria is important staging information in inva- sive tumours and may be submitted separately by the urologist. Further staging is by a combination of endoluminal ultrasound, CT and MRI scan. Carcinoma in situ is usually treated by topical chemotherapy (mitomycin) or immunotherapy (bacille Calmette– Guérin (BCG) therapy) or resected by TURB if localized. Widespread disease may necessitate radical surgery. Superficial urothelial cancer confined to the mucous membrane is resected transurethrally with submission of multiple fragments and follow-up by cystoscopy. Adjuvant intravesical therapy is used for high-grade or recurrent disease. Muscle-invasive tumours require radical surgery with cystec- tomy ± in continuity prostatectomy/urethrectomy and regional lym- phadenectomy, and in the female cystourethrectomy or an anterior exenteration. 314 HISTOPATHOLOGY REPORTING

Tumour

Site — fundus/body/trigone/neck/ureteric orifices. — anterior/posterior/lateral (right or left). — single/multifocal. — diverticulum.

Size — length × width × depth (cm) or maximum dimension (cm).

Appearance — papillary/sessile/ulcerated/mucoid/keratotic/calcification. — bladder mucosa: erythematous/oedematous (carcinoma in situ).

Edge — circumscribed/irregular.

2. HISTOLOGICAL TYPE

Transitional cell (urothelial) carcinoma — 90% of cases. ⎯ usual type: papillary or sessile. variants with deceptively benign features: — microcystic type: intraurothelial microcysts containing protein secre- tions mimicking cystitis cystica. — nested type: uniform cell nests in the lamina propria mimicking florid Von Brunn’s nests but with an irregular margin and look for muscle invasion. Potentially aggressive. — micropapillary type: resembles ovarian serous papillary carcinoma. Associated with stromal retraction artefact mimicking lymphovascu- lar invasion. Also shows true LVI and is a high-grade tumour. — inverted type: architecturally similar to inverted papilloma but has WHO II/III cytology. Look for muscle invasion. — also clear cell, plasmacytoid, lipid cell, with pseudosarcomatous stroma (see below), trophoblastic cells (HCG positive) or prominent lymphoid infiltrate (lymphoepithelioma) variants.

Squamous cell carcinoma — 5% of cases. — classical/verrucous/basaloid/sarcomatoid, i.e. the same range of tumours as encountered in the upper aerodigestive tract. — old age and associated with calculi, schistosomiasis or diverticulum and chronic infection. Prognosis is poor with a 13–35% 5-year survival and two-thirds are pT3/pT4 at presentation. 30. BLADDER CARCINOMA 315

Adenocarcinoma — the common cloacal embryological origin of bladder and rectum high- lights the range of glandular differentiation that can be seen in the bladder mucosa. — 2% of bladder malignancy. — enteric, mucinous (colloid), signet ring cell, clear cell (mesonephroid), ex villous adenoma, or adenocarcinoma not otherwise specified (NOS). — can arise either from intestinal metaplasia/cystitis glandularis (60%), extrophy, diverticulum or bladder dome wall urachal remnants (30%). Usually muscle invasive and of poor prognosis (particularly signet ring cell carcinoma).

Transitional cell (urothelial) carcinoma with mixed differentiation — squamous cell carcinoma/adenocarcinoma components are seen in 20–30% of high-grade invasive transitional cell carcinomas empha- sizing a capacity for divergent differentiation.

Spindle cell carcinoma — “sarcomatoid carcinoma” or carcinosarcoma. — old age. Large and polypoid with a poor prognosis (50% dead within 1 year). There may be a recognizable in-situ or invasive epithelial (transitional, glandular, squamous or undifferentiated) component and cytokeratin/vimentin positive spindle cells with varying stromal differentiation, from non-specific fibrosarcoma-like to specific heterologous, mesenchymal differentiation, e.g. rhabdomyosarcoma, chondrosarcoma, osteosarcoma.

Small cell carcinoma ⎯ primary or secondary from lung. CAM5.2/synaptophysin/CD56 posi- tive. Aggressive with early metastases to nodes, liver, bone and peri- toneum. May be pure or mixed with other in-situ or invasive bladder cancer subtypes and there is coexistent prostatic disease in 50% of cases. ⎯ large cell neuroendocrine carcinoma also occurs rarely.

Undifferentiated carcinoma — no specific differentiation and a high-grade tumour.

Malignant melanoma — primary or secondary (commoner). — note there can be spread to bladder from a primary urethral lesion.

Metastatic carcinoma — metastases should be considered in any bladder tumour with unusual histology, e.g. adenocarcinoma or squamous cell carcinoma. Knowl- edge of a previous positive history and comparison of morphology are crucial. Metastatic disease in the bladder is usually solitary. 316 HISTOPATHOLOGY REPORTING

— direct spread from adjacent pelvic organs (>70% of cases): prostate, cervix, uterus, anus, rectum, colon. To distinguish primary adenocar- cinoma from secondary colorectal carcinoma look for an origin at the dome from mural urachal remnants, or areas of adjacent mucosal intestinal metaplasia/cystitis glandularis in a primary lesion. A previ- ous positive history on cervical smear/biopsy or endometrial sampling raises the possibility of a primary gynaecological tract malignancy. Prostatic cancer is PSA/PSAP positive but CK7/CK20/34βE12 negative, which is the converse of bladder cancer. Note that some poorly differen- tiated or metastatic prostate cancers stain more strongly with polyclonal rather than monoclonal PSA with the potential for a false-negative result using only the latter. — distant spread: breast, malignant melanoma, lung, stomach.

3. DIFFERENTIATION/CYTOLOGICAL GRADE Flat, papillary and invasive urothelial neoplasia are graded separately. There are several classification options, although in the UK the WHO 1973 scheme remains in favour rather than the more recent WHO/ISUP 1998 consensus and WHO 1999 classifications due to concerns about their reproducibility. In general, they are based on the degree of cytoarchitec- tural abnormality characterized by increasing nuclear atypia, hyperchro- masia and crowding with up-regulated proliferative and mitotic activity. Flat urothelial neoplasia: comprises urothelial dysplasia (mild/moder- ate/severe) on a spectrum with, and severe dysplasia equating to, carci- noma in situ (CIS). Urologists will follow up a diagnosis of dysplasia but initiate treatment for CIS which may entail BCG immunotherapy, intrav- esical chemotherapy or surgery. Dysplasia and CIS (syn: low- and high- grade intraurothelial neoplasia, respectively) are to be distinguished from urothelial hyperplasia and regenerative atypia which can be encountered in a range of conditions, e.g. cystitis, calculi, an indwelling urinary catheter or post chemo-/radiotherapy. In addition to morphological clues, dysplasia/CIS overexpresses p53 and Ki-67 with strong, diffuse CK20 staining, whereas non-neoplastic urothelium tends to show only basal layer proliferative activity and CK20 staining of surface umbrella cells. Papillary urothelial neoplasia: papillary urothelial lesions with a spec- trum of minimal to marked cytoarchitectural abnormalities ranging from the very rare benign transitional cell papilloma covered by normal urothelium to the commonplace transitional cell carcinomas WHO I/II/III (G1/G2/G3). A WHO I/G1 carcinoma is the least disordered, being a low-grade lesion with <5% risk of progression to invasion. A WHO III/G3 tumour is the most anaplastic, being high-grade with a 15–40% risk of progression. Thus a papillary neoplasm is typed, graded and assessed for the presence of underlying invasion with comment on the absence or presence of dysplasia or CIS in the represented flat mucosa in the rest of the sample. A comparison of the classifications is given in Table 30.1. 30. BLADDER CARCINOMA 317 alities. Transitional † WHO III/G3 † of low malignant potential(PUNLMP) carcinoma of low malignant potential(PUNLMP) WHO I/G1 WHO II/G2 WHO III/G3 WHO 0/G0 WHO I/G1* WHO II/G2 Classification of papillary urothelial neoplasms Low-grade disease. High-grade disease. Table 30.1 Table WHO 1973WHO/ISUP 1998 cell papilloma Transitional Urothelial papillomaWHO 1999 Papillary urothelial neoplasm Low-grade urothelial Urothelial papilloma∗ † High-grade urothelial carcinoma Note that the columns are not discrete categories or directly transferable but represent a spectrum of cytoarchitectural abnorm Papillary urothelial neoplasmcell (urothelial) papilloma can be exophytic or inverted in type. Urothelial carcinoma cell carcinoma Transitional 318 HISTOPATHOLOGY REPORTING

Invasive urothelial neoplasia: well/moderate/poor, or WHO I/II/III (G1/2/3). Note that WHO III invasive urothelial carcinoma often assumes a squamoid appearance in addition to actual mixed squamous or glan- dular differentiation (20–30% of cases).

Non-urothelial invasive neoplasia: well/moderate/poor/undiffer- entiated, or Grade 1/2/3/4. For squamous cell carcinoma based on keratinization, cellular atypia and intercellular bridges, and, for adenocarcinoma, on the tumour percentage gland formation (well/G1: >95%; moderate/G2: 50–95%; poor/G3: <50%). Signet ring cell adeno- carcinoma is high grade (G3).

4. EXTENT OF LOCAL TUMOUR SPREAD Border: pushing/infiltrative. Lymphocytic reaction: prominent/sparse. The TNM classification applies to urinary bladder carcinomas (non- invasive and invasive) and also papillary urothelial (transitional cell) neoplasm of low malignant potential (see above). pTis carcinoma in situ: potential multifocal urinary tract field change pTa papillary non-invasive pT1 invasion of subepithelial connective tissue pT2a invasion of superficial muscle (inner half) pT2b invasion of deep muscle (outer half) pT3 invasion of perivesical fat: a. microscopically b. extravesical mass (macroscopically) pT4 invasion of: a. prostate, uterus, vagina b. pelvic wall, abdominal wall. Direct invasion of distal ureter is classified by the depth of greatest inva- sion in any of the involved organs. Invasive bladder cancer with associated in-situ change extending into prostatic urethra or duct epithelium is classified according to the depth of bladder wall invasion and comment on the in-situ changes noted by use of a suffix, e.g. pT2b (ispu) for prostatic urethral involvement. Involvement of prostatic urethra or stroma by invasive disease is pT4a, as is small or large intestine, peritoneum covering the bladder and seminal vesicles. Superficial tumours are regarded as either pTa or pT1 and are often his- tological grade I or II. Formal substaging of pT1 bladder tumours is not usually done but comment should be made on the degree of invasion, e.g. focal or extensive, above/at/below muscularis mucosae (pT1a: cores of papillae; pT1b: lamina propria; pT1c: below muscularis mucosae). Deeply (muscle) invasive tumours are pT2 or pT3 and more often grade III. They are prognostically adverse, requiring more radical treatment and assessment of invasion of the detrusor layer of muscularis propria is of crucial importance in their designation. As well as invasion of the 30. BLADDER CARCINOMA 319 wall pT4b Pelvic wall, abdominal wall, Pelvic pT4a vagina Prostate, uterus, Prostate, pT3b Adjacent Adjacent structures mass D pT3a Macroscopic extravesical Macroscopic Microscopic pT2b pT2a The surface component may be exophytic/papillary or sessile be exophytic/papillary surface may The component pT1 A pTa pTis Superficial bladder cancer = pTa/pT1: deep cancer = muscle invasive disease = muscle invasive deep cancer Superficial = pTa/pT1: bladder cancer Radial Margin the Circumferential (mm) to D = tumour distance fat. of the perivesical (CRM) of excision serosa by is also covered fat fundal perivesical The Urinary bladder carcinoma. 30.1. Inner 1/2 Outer 1/2 Outer Epithelium Submucosa Perivesical fat Perivesical Lamina propria IGURE Muscularis propria F Muscularis mucosae 320 HISTOPATHOLOGY REPORTING bladder wall, urothelial cancer can extend into the bladder neck, prostate, urethra and seminal vesicles. Because of this, urethral biopsy is done in staging patients with CIS or high-grade invasive disease and en bloc prostatourethrectomy favoured at the time of cystectomy.

5. LYMPHOVASCULAR INVASION Present/absent. Intra-/extratumoral. Invasion into the lamina propria may result in prominent retraction artefact spaces around tumour cells and nests mimicking lymphovascu- lar invasion. This phenomenon is particularly prominent in micropapil- lary carcinoma. For true vascular involvement identify an endothelial lining with adherent tumour and red blood cells. Endothelial markers (CD31, CD34) may be of use. Vascular invasion is associated with an increased rate of recurrence.

6. LYMPH NODES Site/number/size/number involved/limit node/extracapsular spread. Regional nodes: pelvic nodes below the bifurcation of the common iliac arteries. pN0 no regional lymph nodes metastasis pN1 metastasis in a single regional node ≤ 2cm pN2 metastasis in a regional node > 2cm but ≤ 5cm or multiple regional nodes each ≤ 5cm pN3 metastasis in a regional node > 5cm. Nodal metastases are present in 25% of invasive TCCs. Common sites of distant metastases are lungs, liver, bone and CNS.

7. EXCISION MARGINS Distances (mm) to the limits of the urethra, ureters, circumferential perivesical fat margin and fundal serosa, and the inferior resection limit of the bladder wall in a partial cystectomy. Note also the presence of any dysplasia/CIS at the ureteric and urethral limits.

8. OTHER PATHOLOGY Diagnostic criteria for TCC Carcinoma in situ (CIS) — flat urothelium of variable thickness (3–20 layers). — marked cytological abnormality of usually (but not always) the whole epithelial thickness of either large cell (±pleomorphism) or small cell types. — note unusual patterns such as the Pagetoid variant, or clinging CIS resulting from dyscohesion and shedding of cells. — CIS equates to severe dysplasia and is by its nature a high-grade lesion. — present adjacent to invasive carcinoma in 50–60% of cases. — beware of overcalling dysplasia or in-situ change, as normal urothe- lium often partially denudes on biopsy, leaving a thin covering of basal cells which can then appear hyperchromatic. 30. BLADDER CARCINOMA 321

— note that a biopsy diagnosis of dysplasia with no previous history may progress to CIS or invasive malignancy in up to 19% of cases over the course of several years.

Papillary TCC — >7 cell layers thick. — papillae with fine stromal cores which are not true lamina propria (a distinguishing feature from the broad oedematous cores of polypoid cystitis). — variable nuclear grade of abnormality.

Growth pattern

Papillary, exophytic — the vast majority of cases.

Sessile — tends to be associated with high-grade lesions.

Endophytic and non-invasive, or invasive — differentiate from inverted papilloma (covering of normal urothelium, no atypia or mitoses, inversion of the epithelial layers). ⎯ non-invasive lesions have an intact, round basement membrane and no desmoplastic or inflammatory stromal response and often repre- sent a complex crypt pattern to the lesion base or extension of malig- nant epithelium into Brunn’s nests. Invasive endophytic lesions can have a rounded deep border with no inflammatory reaction, making assessment of invasion difficult—look for atypical urothelium present in relation to muscularis propria.

Microinvasion — characterized by single cells, irregular spicules or nests of atypical urothelium budding into or lying separately in the superficial lamina propria often associated with stromal oedema, retraction artefact or a loose fibroblastic response. Deeper invasion comprises irregular cell nests separated by variably desmoplastic submucosa or detrusor muscle bundles. Histological interpretation can be partially compro- mised by TURBT diathermy distortion.

Pathological predictors of prognosis — number of tumours/multifocality: both within the bladder and extra- vesical, e.g. ureters and renal pelvis. — size of tumour. — depth of invasion. — histological grade. — coexistent carcinoma in situ/dysplasia adjacent to or away from the tumour are markers of higher risk for recurrence and progression. — progression of grade and stage with time. — poor initial response to chemo-/radiotherapy. 322 HISTOPATHOLOGY REPORTING

Additional comments

Biopsies Assess material from: the base (for pT stage), and adjacent and distant mucosa (for pTis). Clear distinction between superficial and deep muscle cannot be made on biopsy material (unless submitted separately by the cli- nician), so that muscle-invasive carcinoma should be reported as at least pT2a in depth. The muscle bundles should be coarse indicating the detru- sor layer or muscularis propria rather than the fine fibres of the poorly defined lamina propria. Note that fat may also be present in the lamina propria and between muscle coat bundles and does not necessarily mean invasion of perivesical tissue. This designation is reserved for complete assessment of the cystectomy specimen. Biopsies from other lesions that can mimic a papillary neoplasm are polypoid cystitis, nephro- genic adenoma, follicular cystitis, cystitis cystica, malakoplakia, villous adenoma and inverted papilloma. Although the latter is benign, a small minority can be multifocal and recurrent and difficult to distinguish from urothelial carcinoma with an inverted pattern. Mimics of a solid urinary neoplasm are previous biopsy site reaction, inflammatory pseudotumour, amyloid, endometriosis, sarcoma, extrinsic and metastatic carcinoma.

Resection blocks — urethral limit: transverse section. — ureteric limits: transverse section. — prostate, seminal vesicles: not infrequently there is concurrent, undi- agnosed prostatic adenocarcinoma which requires separate typing, Gleason score and TNM staging. — normal bladder: lateral walls, dome, trigone. — tumour and wall: one section per cm of tumour diameter to show the deepest point of mural invasion.

Post-operative necrobiotic granuloma — post-TURP fibrinoid necrosis with palisading histiocytes. Biopsy site reaction to previous TURB often shows prominent neofibrotic gran- ulation tissue, focal dystrophic calcification and a foreign body giant cell response which may be associated with diathermy coagulum. The giant cells can be epithelioid and “pseudocarcinomatous” in appear- ance and cytokeratin/CD68 staining may be necessary to help distin- guish from residual invasive urothelial carcinoma.

Post-operative spindle cell nodule and inflammatory myofibroblastic tumour (IMFT)/pseudosarcomatous fibromyxoid tumour These are myofibroproliferative processes histologically resembling sarcoma. Spindle cell nodule is small (5–9mm) and has a history of recent genitourinary tract instrumentation. It comprises a proliferation of cytologically bland spindle cells in which normal mitoses are readily seen and it occurs at the operative site. IMFT occurs de novo, can be several centimetres in diameter or larger and forms a polypoid mass. The atypical myofibroblastic proliferation is associated with prominent 30. BLADDER CARCINOMA 323 inflammation and granulation tissue-type vasculature. Mitoses can be seen, but are not prominent or abnormal. Both lesions are usually benign and must be distinguished from sarcoma, although some cases of IMFT have been reported to recur and even progress with local infiltration. Cytokeratin is positive in spindle cell nodule but often negative in IMFT (a useful discriminator from spindle cell carcinoma); actin and desmin are variably positive (40–80%). IMFT can be ALK positive. Diverticulum ± calculus: squamous cell carcinoma.

Immunophenotype Transitional cell carcinoma is positive for cytokeratins 7, 8, 18 and 20, CEA, uroplakin III, CA19-9, Leu M1 and Lewis X antigen. Overexpres- sion of p53 correlates with the likelihood of progression in superficial disease. A useful panel is 34βE12/CK7/CK20/p53 positive: PSA/PSAP negative with the converse for poorly differentiated prostatic carcinoma, which helps to clarify the nature of poorly differentiated carcinoma at the bladder base. Treatment of bladder TCC is usually by transurethral resection and cys- toscopic follow-up. High-grade (pT1G3) or refractory superficial disease (i.e. confined to the mucous membrane) may also need radiotherapy and/or intravesical chemotherapy/BCG. The latter are also useful for TCC in situ. Non-responsive superficial or deep (muscle-invasive) cancer necessitates surgery. In follow-up, note that intravesical agents such as mitomycin lead to urothelial atypia and these changes must not be con- fused with dysplasia or carcinoma in situ. The nuclei are focally enlarged and have a “smudged” chromatin appearance rather than the angular, ink blank hyperchromasia of in-situ change. BCG often results in inflam- mation and superficial non-caseating granulomas but bacilli are usually not seen. A range of other post-therapy changes can be seen with sys- temic chemotherapy, radiotherapy, laser and photodynamic therapy. Urachal-related adenocarcinoma at the bladder dome may be considered for a partial cystectomy with resultant preservation of urinary function.

Prognosis Muscle-invasive cancer often starts as carcinoma in situ or a flat/sessile rather than a papillary lesion and relates strongly to histological grade (WHO I = 2% invasive; WHO III = 40% invasive). Invasive cancer will develop in up to 30–50% (or more) of patients with untreated carcinoma in situ but 85–90% 5-year survival rates can be achieved by radical surgery which is also targeted at multifocal field change in the urothe- lium (bladder, prostatic ducts, urethra, ureters, seminal vesicles). Up to 80% of urothelial carcinomas are non-invasive at the time of presenta- tion and although tumour recurrence is common (single lesion 30–45%, multiple 60–90%), tumour progression (10%) relates strongly to histo- logical grade, tumour size, non-tumour dysplasia of bladder mucosa and depth of invasion. Overexpression (>20% of tumour cells) of Ki-67, p53 and Her-2 may also be other prognostic indicators. Five-year survival rates also vary according to these parameters: 324 HISTOPATHOLOGY REPORTING

Transitional cell carcinoma Superficial invasion Grade I 70% Grade III 60% Deep muscle invasion 40–55% Squamous cell carcinoma 15% Adenocarcinoma 15–35%

As can be seen, squamous cell carcinoma and adenocarcinoma are of worse prognosis.

9. OTHER MALIGNANCY

Lymphoma/leukaemia — usually secondary to systemic disease. ⎯ primary lymphoma varies from low-grade MALToma with indolent behaviour to diffuse large B-cell lymphoma. Leukaemic involvement is seen in 15–30% of cases.

Carcinoid tumour — rare.

Phaeochromocytoma — young women. Paragangliomatous nested pattern of cells with eosinophilic cytoplasm and variable nuclear features. Chromogranin positive with S100 positive sustentacular cells. — local recurrence and metastases can occur in about 10% of cases. Histology does not reliably predict behaviour.

Leiomyosarcoma — commonest sarcoma in adults, bladder dome, infiltrates muscle. — nuclear atypia mitoses and tumour necrosis: some are extensively myxoid. ⎯ desmin/h-caldesmon positive.

Other sarcomas — rhabdomyosarcoma, malignant fibrous histiocytoma, osteosarcoma: all rare and must exclude sarcomatoid carcinoma (carcinosarcoma).

Rhabdomyosarcoma — embryonal variant in children, sarcoma botryoides. — cellular subepithelial cambium layer with a loose myxoid zone and cellular deep zone ± rhabdomyoblasts. Desmin/myo D1/myogenin positive.

Choriocarcinoma and yolk sac tumour — choriocarcinoma: exclude urothelial carcinoma with trophoblastic differentiation. — yolk sac tumour: rare; childhood.