Bladder Cancer & Urothelial Neoplasms: Types, Risks, Path...

DISORDERS OF THE LOWER URINARY TRACT — PART 2 --- 3. NEOPLASMS OF THE URINARY BLADDER Overview: Bladder cancer = 9th most common cancer worldwide 95% of bladder tumours are of epithelial origin Urothelial neoplasms = by far the most common type, followed by squamous and glandular neoplasms Classification of Bladder Tumours: Urothelial (transitional) tumours — noninvasive and infiltrating Squamous cell carcinoma Adenocarcinoma Mixed carcinoma Small-cell carcinoma Sarcomas --- A. UROTHELIAL NEOPLASMS Overview: Represent ~ 90% of all bladder tumours Range from small benign lesions that never recur → aggressive fatal cancers Many are multifocal at presentation Can arise anywhere urothelium exists — from renal pelvis to distal urethra Two Distinct Precursor Lesions to Invasive Urothelial Carcinoma: Noninvasive papillary tumours — originate from papillary urothelial hyperplasia; most common precursor Flat noninvasive urothelial carcinoma in situ (CIS) — cytologically malignant cells confined to epithelium; no basement membrane invasion; always considered high grade ⚠️ In ~50% of invasive bladder cancer cases, the tumour has already invaded the bladder wall at presentation — precursor lesion destroyed by the high-grade invasive component. Prognostic Key: Invasion into lamina propria → worsens prognosis Invasion of muscularis propria (detrusor) → major survival drop → 30% 5-year mortality --- Epidemiology: Male-to-female ratio = 3:1 Higher incidence in high-income nations and urban dwellers ~80% of patients aged 50–80 years Rarely familial Risk Factors: Cigarette smoking — increases risk 3–7× depending on duration and type of tobacco use; single most important risk factor Industrial aryl amine exposure — particularly 2-naphthylamine ; cancer appears 15–40 years after first exposure Schistosoma haematobium — 70% of associated cancers are squamous; remainder urothelial or glandular Long-term analgesic use Heavy/long-term cyclophosphamide exposure Irradiation --- Pathogenesis — Two Molecular Pathways: Pathway 1 — Non-muscle-invasive papillary cancers: Gain-of-function alterations → ↑ signalling through growth factor receptor pathways Common mutations: FGFR3 tyrosine kinase receptor gene amplifications + activating mutations in RAS and PI3-kinase These tumours frequently recur but progress to muscle-invasive cancer in only ~ 20% of cases Pathway 2 — Muscle-invasive cancers (via flat CIS): Majority develop by progression from flat CIS p53 and RB mutations prevalent in all muscle-invasive cancers p53/RB mutations occur early in CIS development but later in papillary cancer progression High somatic mutation burden — comparable to lung cancer and melanoma (underscoring carcinogen exposure role) --- Morphology: Papillary lesions: red, elevated excrescences; <1 cm up to 5 cm; often multiple discrete tumours Papilloma (Exophytic): Represents ≤ 1% of bladder tumours; seen in younger patients Small (0.5–2 cm); delicate; attached to mucosa by a stalk Finger-like papillae with central fibrovascular core covered by histologically normal urothelium Recurrences and progression rare but possible Inverted Papilloma: Completely benign Inter-anastomosing cords of cytologically bland urothelium extending into the lamina propria ⚠️ Simulates an invasive process histologically — do not confuse Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP): Similar to papilloma but with thicker urothelium and greater cell density Larger than papillomas on cystoscopy; may be indistinguishable from papillary cancers Recurrent tumours usually show same morphology Progression to higher grade: rare Low-Grade Papillary Urothelial Carcinoma: Orderly architecture; low-grade cytologic atypia Cells evenly spaced (maintain polarity) and cohesive Scattered hyperchromatic nuclei; infrequent mitoses (predominantly basal); slight nuclear size/shape variation May recur and infrequently invade Rarely life-threatening High-Grade Papillary Urothelial Carcinoma: Dyscohesive cells with large hyperchromatic nuclei, irregular chromatin, prominent nucleoli Some cells highly anaplastic Frequent mitoses including atypical mitoses Architectural disarray + loss of polarity Much higher rate of progression to muscle-invasive cancer Significant potential for metastasis → regional lymph nodes, liver, lung Carcinoma In Situ (CIS) / Flat Urothelial Carcinoma: Cytologically malignant cells within a flat urothelium — no invasion Ranges from full-thickness cytologic atypia → scattered malignant cells in otherwise normal urothelium ( pagetoid spread ) Shared feature with high-grade papillary carcinoma: lack of cohesiveness → malignant cells shed into urine Extensive shedding → few CIS cells left clinging to a denuded basement membrane Cystoscopy: mucosal reddening, granularity, or thickening — no intraluminal mass Commonly multifocal ; may involve most of bladder + extend into ureters and urethra ⚠️ If untreated: 50–75% progress to invasive cancer Invasive Urothelial Carcino