OncologyTier 2Disease (DEADMAN)

Malignancies - genitourinary malignancies

Description

Three distinct diseases grouped by organ system. Prostate has its own note: prostate cancer.

Renal cell carcinoma

Subtype	%	Genetics
Clear cell	~75%	VHL loss in 50-90% (3p) -> HIF stabilisation -> inc VEGF, PDGF
Papillary type 1/2	~10-15%	MET (type 1, HPRC); FH (type 2, HLRCC)
Chromophobe	~5%	Birt-Hogg-Dube (FLCN)
Collecting duct / medullary	<1%	Medullary: sickle cell trait

*Chemotherapy and hormonal therapy have essentially no activity* - historically IL-2/interferon, now TKI + checkpoint inhibitors

Bladder / urothelial carcinoma

Urothelial (transitional cell) ~90% in developed countries
Squamous - commonest type worldwide, schistosomiasis and chronic catheter/stone irritation
Adenocarcinoma - urachal remnant, treated like a GI adenocarcinoma
Field change disease - synchronous/metachronous tumours anywhere in the urothelium (renal pelvis to urethra)
Split by the only question that matters: muscle-invasive or not

Testicular germ cell tumour

	Seminoma	NSGCT
Age peak	30s-40s	20s-30s
AFP	*Never* (AFP -> non-seminomatous component present)	Yolk sac, embryonal
beta-hCG	May be raised	May be raised (choriocarcinoma - very high)
LDH	Bulk marker	Bulk marker
Radiotherapy	Sensitive	Not sensitive

NSGCT subtypes: embryonal, yolk sac, choriocarcinoma, teratoma (mature teratoma is chemoresistant - resect residual masses)
Most curable solid malignancy, even metastatic

Epidemiology

RCC

~2% of adult cancers; M:F ~2:1; peak 60-70
>50% found incidentally on imaging (the classic triad of flank pain, haematuria and mass is now rare and means advanced disease)

Bladder

M:F ~3:1; median age ~73
75% present as non-muscle-invasive

Testicular

Commonest solid cancer in men 18-40; ~1,000/yr AU
Incidence rising; >95% cure overall

Aetiopathogenesis

RCC risk factors

Smoking, obesity, hypertension
End-stage kidney disease / acquired cystic disease on long-term dialysis
Hereditary: VHL (clear cell, bilateral/multifocal, + phaeochromocytoma, haemangioblastoma, retinal angioma), HLRCC (fumarate hydratase - aggressive papillary type 2 + cutaneous/uterine leiomyomas), Birt-Hogg-Dube (chromophobe + lung cysts/pneumothorax, fibrofolliculomas), hereditary papillary (MET), tuberous sclerosis
Trichloroethylene, cadmium

Bladder risk factors

Smoking - ~50% of cases
Occupational aromatic amines (aniline dyes, rubber, printing, painting) - latency 20-30 years, ask an occupational history
Cyclophosphamide (acrolein) - also causes haemorrhagic cystitis
Pelvic radiotherapy, chronic infection/stones/catheter (SCC), Schistosoma haematobium
Phenacetin, arsenic
Lynch syndrome -> upper tract urothelial carcinoma (renal pelvis, ureter)

Testicular risk factors

Cryptorchidism (risk persists after orchidopexy, and in the contralateral testis)
Hypospadias, testicular dysgenesis, impaired spermatogenesis/infertility
Prior contralateral germ cell tumour, family history
Klinefelter (mediastinal GCT), HIV
Isochromosome 12p in most germ cell tumours

Diagnosis

RCC

CT abdomen with contrast (corticomedullary + nephrographic phases) - enhancing solid renal mass
Biopsy not always needed if imaging is characteristic and surgery planned; biopsy before systemic therapy or ablation
Staging CT chest; bone scan/brain imaging only if symptomatic
Paraneoplastic: polycythaemia (EPO), hypercalcaemia (PTHrP), Stauffer's syndrome (non-metastatic hepatic dysfunction), hypertension (renin), amyloid

Bladder

Visible haematuria = cystoscopy + upper tract imaging (CT urogram) in everyone, regardless of anticoagulation
TURBT provides diagnosis, staging (detrusor muscle must be in the specimen) and treatment
Urine cytology - useful for high grade/CIS, insensitive for low grade
MRI for local staging of muscle-invasive disease; CT C/A/P

Testicular

Scrotal ultrasound first; tumour markers AFP, beta-hCG, LDH before and after orchidectomy
Radical inguinal orchidectomy - never trans-scrotal biopsy (seeds the scrotal lymphatics)
CT C/A/P; retroperitoneal nodes are the first landing site
MRI brain if: beta-hCG >5,000, AFP >10,000, choriocarcinoma histology, visceral metastases, or neurological symptoms
Marker half-lives after orchidectomy: beta-hCG 1-3 days, AFP 5-7 days
- Failure to fall as predicted -> residual disease
Discuss sperm banking BEFORE orchidectomy or chemotherapy

Management

A. Renal cell carcinoma

Localised

Partial nephrectomy where feasible (T1); radical nephrectomy for larger/central
Ablation (RFA/cryo) or active surveillance for small masses in the elderly/comorbid
Adjuvant pembrolizumab 1 yr for high-risk resected clear cell (KEYNOTE-564 - OS benefit)

Metastatic - stratify by IMDC risk (Karnofsky <80, <1 yr from diagnosis, anaemia, hypercalcaemia, neutrophilia, thrombocytosis)

First line is now a doublet in essentially everyone
- Ipilimumab + nivolumab - intermediate/poor risk (CheckMate 214; durable responses, plateau)
- IO + TKI - pembrolizumab + axitinib or lenvatinib, nivolumab + cabozantinib (higher response rate, all risk groups)
- Single-agent sunitinib/pazopanib is no longer standard first line
Later lines: cabozantinib, lenvatinib + everolimus, belzutifan (HIF-2alpha inhibitor, esp. VHL disease), tivozanib
Cytoreductive nephrectomy selectively (not routine); metastasectomy for oligometastatic disease
TKI class toxicity (axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib)
- Hypertension, fatigue, hand-foot skin reaction, diarrhoea/mucositis/stomatitis, dysphonia, hypothyroidism, hair depigmentation, transaminitis, proteinuria
- Sunitinib: hypertension + diarrhoea. Pazopanib: hepatotoxicity + leucotrichia
mTOR inhibitors (everolimus, temsirolimus) - pneumonitis, hyperglycaemia, hyperlipidaemia, mucositis, oedema, infection

B. Bladder cancer - the axis is muscle invasion

Non-muscle-invasive (Ta, T1, CIS)

TURBT + single immediate intravesical dose (gemcitabine or mitomycin C) within 24 h
High-grade or T1 or CIS -> intravesical BCG: 6 weekly induction + maintenance up to 3 yr
- BCG stimulates a local Th1 immune response
- *Do not give with macroscopic haematuria, traumatic catheterisation, or bacteriuria* - risk of disseminated BCG ("BCGosis"), treated as mycobacterial infection with rifampicin/isoniazid/ethambutol +/- steroids
BCG failure -> intravesical gemcitabine/docetaxel, pembrolizumab, or cystectomy
Lifelong cystoscopic surveillance

Muscle-invasive (>=T2)

Neoadjuvant cisplatin-based chemotherapy (ddMVAC or gem/cis) then radical cystectomy - ~5% absolute survival gain; better evidenced than adjuvant
Trimodality therapy (maximal TURBT + chemoradiation) for bladder preservation in selected patients or where cystectomy is not feasible
Adjuvant nivolumab if high-risk residual disease at cystectomy

Metastatic

First line: enfortumab vedotin (Nectin-4 ADC) + pembrolizumab - median OS ~31.5 vs 16.1 months vs chemotherapy (EV-302); has displaced platinum doublet
- EV toxicity: hyperglycaemia, peripheral neuropathy, skin toxicity (rarely SJS/TEN), ocular
Platinum doublet (gem/cis) if EV+P unavailable; avidumab/avelumab maintenance after platinum response
Cisplatin-ineligible if: ECOG >2, CrCl <60 mL/min, grade >=2 hearing loss or neuropathy, NYHA >=III heart failure
Later: erdafitinib (FGFR3 altered), sacituzumab govitecan

C. Testicular germ cell tumour

Radical inguinal orchidectomy in all
Stage I
- Surveillance alone cures ~80% of seminomas, ~70% of NSGCT - preferred, avoids overtreatment
- Adjuvant single-dose carboplatin (seminoma) reduces relapse ~2/3
- Adjuvant BEP x1 (high-risk NSGCT, LVI)
Stage II-III -> BEP x3-4 (bleomycin, etoposide, cisplatin), by IGCCCG risk group
- Seminoma stage IIA also treatable with radiotherapy
Residual mass after chemotherapy
- NSGCT: resect if >1 cm (may be teratoma - chemoresistant, can transform)
- Seminoma: FDG-PET at >=6 weeks; resect only if PET-positive
BEP toxicity
- Bleomycin -> pulmonary fibrosis (~10%), organising/hypersensitivity pneumonitis; cumulative dose limit; high FiO2 during anaesthesia may precipitate it - flag it to anaesthetists for life
- Cisplatin -> nephrotoxicity (hydrate), ototoxicity, peripheral neuropathy, magnesium wasting, emesis, late cardiovascular risk
- Etoposide -> myelosuppression, secondary AML (topo-II, 11q23, short latency)
Sperm banking before treatment in every patient

Associations

RCC

VHL disease - haemangioblastoma, phaeochromocytoma, retinal angioma, pancreatic NET
HLRCC, Birt-Hogg-Dube, tuberous sclerosis
Dialysis-associated acquired cystic kidney disease
Paraneoplastic: polycythaemia, hypercalcaemia, Stauffer's syndrome, AA amyloid

Bladder

Smoking, aromatic amine exposure, cyclophosphamide, schistosomiasis
Lynch syndrome - upper tract urothelial carcinoma
Field cancerisation - synchronous/metachronous urothelial tumours

Testicular

Cryptorchidism, hypospadias, infertility, testicular dysgenesis syndrome
Klinefelter (mediastinal germ cell tumour)
Down syndrome
Contralateral germ cell neoplasia in situ

Natural history & complications

RCC

5-yr survival: localised >90%, metastatic ~15-25% (improved with IO doublets)
Late relapse characteristic - can recur >10 years after nephrectomy
Metastasises to lung, bone (lytic, vascular), liver, brain; classic cannonball lung metastases
Highly vascular metastases - consider pre-embolisation before spinal surgery

Bladder

Non-muscle-invasive: recurrence 50-70%, progression to muscle-invasive 10-20% (higher with T1 high-grade/CIS)
Muscle-invasive: 5-yr survival ~50% after cystectomy; metastatic ~15% (better with EV+P)

Testicular

Cure >95% overall; >70-80% even with metastatic disease
Long-term survivorship burden - the reason follow-up matters more here than the cancer
- Second malignancy: ~2.6x with sub-diaphragmatic radiotherapy, ~2.1x with etoposide/cisplatin (esp. leukaemia)
- Cardiovascular disease and metabolic syndrome
- Hearing impairment, tinnitus, peripheral neuropathy (cisplatin)
- Hypogonadism (~15%) - check morning testosterone
- Subfertility, Raynaud phenomenon
- Nephrotoxicity, psychological morbidity

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