Case 1 - 60 year old male with bladder tumor

       Scroll down to see the final diagnosis and discussion

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DIAGNOSIS: High grade invasive urothelial carcinoma

MICROSCOPIC DESCRIPTION:

The pictures above show thickened transitional epithelium composed of disorganized malignant cells with pleomorphic nuclei. Occasional mitoses can be seen. Note the loss of maturation and absence of umbrella cells that are seen in an otherwise normal bladder. Invasion (not shown here) was identified in another section.

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High yield information on urothelial cancer

Clinical features

• Typically seen in patients over the age of 50 years

• More common in males (M: F ratio is 3:1)

• Environmental factors include petrochemical industries, cigarette smoking, arylamines, aniline dye, auramine, phenacetin, and cyclophosphamide.

• Schistosoma haematobium can be a cause.

• Common sites in bladder: lateral wall, posterior wall, trigone, ureteric orifice, dome, and anterior wall.

• Most common presenting symptom is painless hematuria,

• Flank pain and obstructive symptoms can be seen

Gross pathology

• Invasive tumors can arise from both papillary and sessile precursors • Low-grade tumors show a typical papillary architecture seen as multiple finger-like fronds over the bladder mucosa • Higher-grade tumors generally lack papillary architecture and show nodular, polypoid, or sessile pattern. • Bladder wall is characteristically thickened, firm, and gray-white

Types of specimens encountered:

A. Biopsy specimens.

Obtained by cautery (“cold-cup”) and should be instantly immersed in formalin. Three hematoxylin and eosin (H&E)-stained slides should be prepared, with 3-4 levels on each slide.

B. Transurethral resection of bladder specimens (TURBT)

Obtained by thermal cautery.

Usually all tissue is submitted to ensure tissue with deep muscle is examined for invasion, which is important for correct staging of Urothelial carcinomas.

C. Partial cystectomy specimens.

• Indicated in minority of bladder cancer patients.

• Sheet-like portion of tissue - should be pinned down and fixed overnight.

• Gross tumor is sampled and margins assessed (these can be shaved off or sampled by perpendicular sections, depending on their relationship and proximity to the tumor).

• Frozen section of the mucosal margin may be requested.

What are the indications of a partial cystectomy ?


- Solitary tumor with no associated carcinoma in situ 
- Localized tumor to bladder dome 
- Tumors that can be removed with 2cm margin of resection, away from ureteral orifice and bladder neck

D. Total cystectomy and cystoprostatectomy specimens.

What are the indications for a radical cystectomy ?


- Muscle invasion or locally advanced disease T2-T4a
- Non-muscle invasive bladder cancer that has high risk features (multiple, recurrent, large CIS)
- Cases that are refractory after cystoscopic resection, intravesical chemortherapy or immunotherapy

Brief anatomy of bladder and relations to other organs:

STEP 1 : ORIENTATION

STEP 2 : IDENTIFY THE URETERS AND URETHRA

• Identify the ureters (here only one is identified as patient had previous left uretectomy)

• submit distal ureteric and urethral margins margins

STEP 3 : INK THE SPECIMEN

STEP 4 : PROBE THE URETHRA AND OPEN ALONG PROBE OR CATHETER IF PRESENT

STEP 5 : OPEN THE BLADDER AND INSPECT FOR TUMORS/LESIONS

STEP 6 : Serially slice the bladder from distal to proximal and place them in order

• Submit sections of the tumour to demonstrate its maximal depth of invasion and relationship of tumour to the bladder mucosa

• Sections from trigone, dome, anterior wall, posterior wall, left and right lateral wall (2 each).

• Transverse sections from ureter and longitudinal sections from ureteral orifices, sections from prostate and lymph node if any.

Microscopic Pathology

• Variable sized irregular aggregates, small clusters, or single cells irregularly dispersed in the lamina propria, and in the muscularis propria if invasion • Epithelial pattern can be noted in form of trabeculae, cords and discrete nests. • Tumor cells are medium sized with moderate amount of pale to slightly eosinophilic cytoplasm. In some cases, the cytoplasm is more abundant and may be clear or typically eosinophilic. Cytologic atypia is moderate or marked, but in rare cases, mild cytologic atypia can also be seen. • Crucial point to look for is the depth of invasion. • Variants: IUC with squamous differentiation, IUC with glandular differentiation, IUC-nested variant, IUC-large nested variant, IUC- micropapillary variant, IUC- lymphoepithelioma variant, sarcomatoid (spindle cell, metaplastic) variant, and plasmacytoid variant

Staging and grading:

Pathologic Stage Classification (pTNM, AJCC 8th Edition)

Primary Tumor (pT)

• pTX: Primary tumor cannot be assessed • pT0: No evidence of primary tumor • pTa: Noninvasive papillary carcinoma • pTis: Urothelial carcinoma in situ: “flat tumor” • pT1: Tumor invades lamina propria (subepithelial connective tissue) • pT2: Tumor invades muscularis propria • pT2a: Tumor invades superficial muscularis propria (inner half) • pT2b: Tumor invades deep muscularis propria (outer half) • pT3: Tumor invades perivesical soft tissue • pT3a: Tumor invades perivesical soft tissue microscopically • pT3b: Tumor invades perivesical soft tissue macroscopically (extravesical mass) • pT4: Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall • pT4a: Extravesical tumor invades directly into prostatic stroma, uterus, or vagina • pT4b: Extravesical tumor invades pelvic wall, abdominal wall Regional Lymph Nodes (pN) • pNX: Lymph nodes cannot be assessed • pN0: No lymph node metastasis • pN1: Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac or sacral lymph node) • pN2: Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac or sacral lymph node metastasis) • pN3: Lymph node metastasis to the common iliac lymph nodes Distant Metastasis (pM) • pM1: Distant metastasis • pM1a: Distant metastasis limited to lymph nodes beyond the common iliacs • pM1b: Non-lymph node distant metastases

Histologic Grading

For urothelial carcinoma, other variants, or divergent differentiation: • Low grade • High grade

Special Stains and Immunohistochemistry

• Reactive: CK7, CK20, high-molecular-weight cytokeratin p63, and CD15. • Reactive in high grade tumor: Carcinoembryonic antigen (CEA). • GATA3 shows nuclear staining.

Molecular pathology

• Mutation of the fibroblast growth factor receptor gene FGFR3 (60%–80%) or HRAS gene (15%–30%) • Chromosome 9q deletion • TSC1 (tuberous sclerosis complex 1), PTCH (patched homolog) and DBC1 (deleted in bladder cancer 1). • PI3KCA gene mutation is present in 10%–27% of cases.

Prognosis

Pathologic stage is the most potent predictor for survival. 5-year survival rate of approximately 75% in patients with no more than lamina propria invasion at the time of cystectomy, 50% and 20%, for tumors infiltrating muscularis propria or perivesical fat respectively

Differential diagnosis

Florid von brunn nests • Nested and large nested urothelial carcinoma variants give similar appearance • Lobulated architecture with flat, noninvasive base • Urothelial nests are of uniform size and shape and often associated with cystitis cystica et glandularis • No significant cytologic atypia Polypoid cystitis • Must be differentiated from low-grade papillary transitional cell carcinoma • Usually wider papillary structures with edema in stroma • Urothelium can show reactive atypia but less dysplastic in comparison to transitional cell carcinoma Nephrogenic adenoma • Must be differentiated from glandular component of urothelial carcinoma with glandular differentiation • Classic histologic pattern is that of small tubules resembling kidney tubules • Papillary architecture confused with urothelial carcinoma • Papillae and tubules are lined by benign cuboidal cells • PAX2 and PAX8 positive, P63 and GATA3 negative Inverted papilloma • Minimal cytologic atypia and mitosis • Absence of invasion into muscularis propria Low-grade papillary urothelial carcinoma with inverted growth pattern • Must be distinguished from large nested variant of urothelial carcinoma • Absence of invasive appearance and invasion into the muscularis propria • Rounded nests uniform in size with crowded appearance Squamous cell carcinoma • Pure squamous lesions lack in situ and invasive urothelial component • If urothelial component is noted, should be classified under urothelial carcinoma with squamous differentiation Lymphoma • Should be distinguished from lymphoepithelioma-like variant of urothelial carcinoma • High-grade epithelial cell islands are absent • Leukocyte common antigen (LCA) is diffusely positive and cytokeratin negative Prostatic adenocarcinoma • Poorly differentiated bladder cancer has to be differentiated from Prostatic adenocarcinoma • Biopsy in these cases is from the trigone or bladder neck • p63, GATA3, and thrombomodulin are negative • Prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), prostate specific membrane antigen (PSMA), p501s (prostein), and NKX3.1 are positive

How to sign out the case

Procedure •Radical cystoprostatectomy Tumor Site •Trigone Histologic Type •Urothelial carcinoma, invasive Histologic Grade •High grade Tumor Extension •Tumor invades muscularis propria Margins (Ureteral margin, Urethral margin, Soft tissue margin) •Involved/uninvolved by invasive carcinoma Lymphovascular Invasion •Present/ absent Regional Lymph Nodes •If submitted, mention involved or uninvolved by tumour

References

Surgical Pathology Dissection: An Illustrated Guide 2nd edition Rosai and Ackerman’s Surgical Pathology, 11th edition Mills, Stacey E. Sternberg’s Diagnostic Surgical Pathology Differential diagnosis in surgical pathology, Third edition 2015 https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates

Compérat, E., Varinot, J., Moroch, J.et al.A practical guide to bladder cancer pathology.Nat Rev Urol15,143–154 (2018). https://doi.org/10.1038/nrurol.2018.2