Genitourinary Flashcards
Discuss the epidemiology for bladder/ureter cancer.
Incidence (Australian statistics)
- 3200 cases annually (2.1% of all new cancers)
- 11th most common malignancy, 4th most common in men
Marked male predominance (3:1)
Disease of the elderly -mean 70yo
Generally higher income nations & urban dwellers
5 year OS 50-60%
Trigone is most common site
75% of bladder cancers present as superficial disease
* 70% non-invasive papillary (Ta)
* 10% flat in-situ (Tis)
20% T1 invasive
* Previously TCC ○ Can involve urothelium from renal pelvis to urethra ○ Preinvasive/superficial disease > muscle invasive ○ Needs muscle in specimen to be certain of preinvasive/superficial disease ○ Can be further classified as non invasive vs invasive * General macro: ○ Most common sites: trigone (below VUJ), lateral and posterior wall, + bladder neck ○ Frequently multifocal dt field change and tumour seeding ○ Typically large infiltrative masses
Describe the risk factors for bladder/ureter cancer
Very rarely genetic, usually associated with exposure to carcinogens
1) cigarette smoking
* most important influence (3-5 fold increase in risk) (including SCC)
* 50-80% of bladder cancers are associated
* Critical with management od discuss smoking cessation with patient
* ?alcohol
2) industrial aryl amine (clothing dyes) & other industrial agents (e.g. paints, solvents), heavy metals
* 15+ year latency
4) cyclophosphamide exposure (TCC+SCC)
5) pelvic irradiation
6) reduced water intake
* Increasing intake may dilute carcinogens in urine –> reduce exposure
7) Chronic inflammation
* Chronic UTIs
* Chronic /long term IDC
* Bladder calculi
* Neurogenic bladder
8) Nephrolithiasis, anatomic anomalies eg. Horseshoe, duplicated renal pelvis (renal pelvis/upper tract SCC)
9) Bladder anatomical anomalies eg. diverticulum
Due to common risk factors, previous upper urinary tract carcinoma (ureter/renal pelvis) predicts for bladder cancer
Genetic
Slow acetylator – leads to impaired metabolism of amines
Lynch syndrome (esp MSH2) may be associated with increased risk (10%)
SCC RF: CHronic inflammation
schistosomiasis ○ Endemic in North Africa (esp Egypt) ○ Pathogenesis = parasitic worm--> organisms lay ova in epithelium --> chronic inflammation and metaplasia --> increased risk of bladder SCC (rather than TCC) * Chronic IDC –paraplegia, MVA. * Bladder stone, recurrent UTI * Cyclophosphamide
List the layers of the bladder.
i) Urothelium/epithelium– as above
ii) Lamina propria– separated from urothelium by thin basement membrane. Abundant connective tissue, loose stroma, blood vessels, thin bands of muscularis mucosa
iii) Muscularis propria (detrusor muscle)- surrounds lamina propria, thick irregularly arranged bands of detruser muscle. Smoothelin is a marker of terminally differentiated smooth muscle cells, specific for muscularis propria compared to muscularis mucosa so can be helpful in determining muscle invasion
Anchored to the abdominal wall by the urachus (embryological remnant)
iv) Serosa/Perivesical Fat – M propria is separated from perivesical fat by serosal layer.
Describe the pathogenesis for bladder cancer
1) papillary neoplasm
○ Chronic inflammation –cytokines, interleukin.
○ Gain of function mutations in FGFR3 and RAS pathways –> development of papillary NMIBC
○ Gain of further mutations which lead to muscle invasion (e.g. p53, RB)
▪ TERT, PI3K, other genetic instability
▪ Only 20% of lesions will progress to MIBC
2) carcinoma in-situ
○ Mutations in p53 +/- RB –> development of flat carcinoma in-situ within epithelium
▪ P53/RB mutations occur early in CIS
○ Gain of further mutations which lead to muscle invasion
▪ PTEN
▪ Much higher incidence of progression to MIBC
Discuss the theories for multifocality
The presence of a bladder or upper renal tract cancer strongly predicts for future disease
1) Field cancerisation Due to equal carcinogenic distribution, all areas are likely to have mutational damage ○ Therefore, high risk of further disease occurring elsewhere in bladder (50% recurrence after TURBT) ○ This also extends to risk of ureter/urothelial involvement Extensive disease involvement (or multiple recurrence) should indicate cystectomy as the preferred approach 2) Monoclonal seeding Malignant cells spread via intraluminal lymphatics and re-implant ○ A seemingly new tumour deposit takes shape Clinical evidence ○ If you have upper tract disease, you have 40% risk of bladder but 5% of contralateral upper tract
Describe the different types of non-invasive bladder histology
WHO classification
○ 2004/2022 update
○ G1/2/3 > PUNLMP > LG >HG
○ Aggressive subtypes: Micropapillary, nested, large nested
* Papilloma (1% of all bladder tumours) ○ Small and single causes haematuria ○ Benign ○ Exophytic papilloma = malignant progression rare (but possible) ○ Exophytic lesions w papillary fronds lined by urothelium lacking atypia. ○ Inverted papilloma = benign * Papillary urothelial neoplasm of low malignant potential (PUNLMP) ○ Papillae lined by thickened urothelium with ↑cell density. Mitoses rare. ○ Recurrence is reasonably frequent ○ Progression to malignancy is rare * Low-grade papillary urothelial carcinoma (non-invasive - Ta) ○ Slightly abnormal architecture in urothelium and low-grade atypia ○ Tendency to recur locally, but infrequently (10%) invade muscle ○ Rarely result in death as a result * High-grade papillary urothelial carcinoma (non-invasive - Ta) ○ Dyscohesive cells with irregular nuclei; frequent mitoses; disordered architecture ○ Markedly higher risk of progression to MIBC 65%. 10 year survival 40% ○ High risk of nodal and distant metastasis * Carcinoma in-situ ○ High grade lesion w cytologically malignant cells within a flat urothelium that have not invaded lamina propria. ○ Often asymptomatic, but may present with dysuria, urgency, haematuria. ○ MACRO – Irregularly hyperaemic mucosa. Commonly multifocal + may involve most of bladder surface, extending into ureters + urethra. ○ MICRO – severe cytologic atypia w nuclear anaplasia, loss of polarity, crowding, pleomorphism. Umbrella cell urothelium retained ○ If untreated >50% chance of progression to invasive malignancy
Describe the pathology for invasive urothelial carcinoma
- Invasive urothelial carcinoma (90%)
○ Classified by Papillary or flat, and high or low grade.
○ Depth of invasion is prognostic (and defines T-stage)
○ 80% of high grade lesions invade muscle
○ Ta, Tis and T1 are nonmuscle invasive.
○ Macroscopic Appearance
* Trigone, field changes, multifocality.
* Ranges from subtle bladder wall thickening, to obvious exophytic/ulcerated mass, esp trigoneMicroscopic Appearance * Cytologic appearance ○ Standard irregularities (high nuclear/cytoplasm ratio, irregular chromatin, hyperchromatic nuclei, bizarre mitoses) ○ Degree of changes indicates grade * Histology ○ Flat or Papillary: urothelium around fibrovascular cores ○ Neoplastic cells typically arranged in nests/sheets/cords ® Invading past Lamina propria ○ Can have single irregular cells within otherwise normal appearing structure ○ High grade hyperchromatic nuclei, enlarged, mitosis, necrosis mmunohistochemistry ○ POS = GATA3, CK7, CK20, p40, p63, HMWCK NEG = PSA & NKX3.1 & AMACR (prostate), PAX 8 (RCC)
List the rare subtypes of bladder TCC.
- Rare subtypes
○ Lymphoepithelial-like carcinoma
○ Microcystic carcinoma
○ Plasmacytoid carcinoma (impart poor prognosis) –> loss of E-cadherin (discohesive)
○ Micropapillary carcinoma (impart poor prognosis)
○ Sarcomatoid carcinoma (impart poor prognosis)
PMS is bad
Besides TCC what are other primary bladder tumour?
- Squamous Cell Carcinoma (SCC)
○ Epidemiology
§ Uncommon - 3-5% of bladder cancers
§ Incidence varies by geographic region, with higher prevalence (30%) in Egypt and Africa due to schistosomiasis
· Incidence is falling due to declining rates of schistosoma infection
§ Slight male predominance
○ Risk factors
§ Chronic inflammation
· Chronic catheter
· Neurogenic bladder
· Bladder stones
· Schistosomiasis
§ Smoking – x5 increased risk
○ Histopathology
§ Macro: Usually large exophytic tumours, some cases flat and ulcerating. Tan/white colour. Often necrotic with flaky keratin on surface
§ Micro: Irregular infiltrating nests or sheets of malignant cells with destructive stroma invasion. Keratin pearls/ intercellular bridges, often associated with SCC insitu.
§ If any focus of urothelial carcinoma is present, then tumour is defined as urothelial carcinoma with squamous differentiation- Adenocarcinoma
○ Rare
○ Associated with remnant urachus or in association with extensive intestinal metaplasia
○ More often secondary vs. primary (rectum, prostate, endometrium) - Small Cell Carcinoma
○ Rare
○ Aggressive natural history, associated with p53 or Rb mutations - Rhabdomyosarcoma
○ Exceedingly rare –> childhood cancer predominantly
Typically present with large masses protruding into lumen - Benign lesions:
§ Cystitis, metaplasia
® Infectious, iatrogenic, idiopathic
® Can form polyploid features
® Generally not premalignant
§ Malakoplakia: distinctive chronic inflammatory reaction
§ Nephrogenic adenoma: implantation of renal tubular cells into inflammaed urothelium
§ Urothelial papilloma: uncommon
Can invert and ivaginate into the lamina (no invasion)
- Adenocarcinoma
Describe the patterns of spread for bladder cancer.
Patterns of Spread
a) Local
* Often multifocal, can recur in previously uninvolved quadrants. May involve most of the bladder surface, ureters and urethra.
Multifocality due to 2 main reasons:
i) Tumour cells have ability of autotransplantation, hence multifocality.
ii) Field cancerisation, so recurrences are new tumours rather than true recurrences.
* Muscle invasion usually signifies high grade tumour + assoc w worse prognosis: 50% survival at 5yrs.
* Direct spread to pelvic side wall, vagina/uterus, rectum, prostate.
b) Lymphatic
* Drainage to perivesical LNs (1st ech)→ int + common iliacs. Some to ext iliacs.
* Macroscopically +ve LN generally v poor prognosis; precludes definitive treatment.
* However, some series evidence from radical cystectomy pts w pelvic LND, that 25% of pts w involved LN survive 10yrs. Also, pts who have a PLND have better survival than those that don’t, + pts w 10+ LNs dissected have better survival than <10 LNs (Case series)
* Note: TROG protocol- if ↑LNs on CT, then only eligible if LNs -ve on biopsy.
c) Haematogenous: Bone, lung + liver.
Discuss the recurrence risk factors and risk characterisation for non-muscle invasive bladder cancer.
Risk of Recurrence (superficial bladder cancer)
* 40-80% NMIBC recur within 6-12 months without additional therapy
* 10-15% will progress to MIBC, regional or met
* General:
○ Stage
○ Grade
○ Multifocality
○ Frequency of recurrence
○ Size
○ Presence of CIS
○ Variant histo
○ LVI
* Low-risk = all of: ○ solitary, primary (non-recurrent), low-grade Ta papillary carcinoma, <3cm ○ no CIS * Intermediate-risk ○ Not meeting either criteria = ○ Low grade papillary with some of multiple lesions, recurrent disease, >3cm * High-risk = any of: ○ CIS ○ High-grade Ta papillary carcinoma ○ T1 disease
Describe the prognostic factors for muscle invasive bladder cancer
Patient
* Age and performance status
* Co-morbidity (notably, renal function)
* Anaemia
* Smoking (impaired tumour control and worse toxicity)
* Ability to have surgery
Tumour
* T-stage is the most significant
○ T1 to T2 distinction most important
○ T2 50% survival at 5 years (75% T1, 20% T3)
○ Size is also relevant for outcome with CMT
* N-stage also important
○ N+ disease is considered metastatic
○ Risk of nodal increases w/ T stage (T1 – 5%; T2-3a – 30%; T3b – 50%; T4 – 60%)
* Histological grade, LVI
* Hydronephrosis
* Recurrent disease
* Various histopathological variants impart different prognosis
* Associated CIS - risk of MIBC 30% at 5 years
Treatment
* Concurrent chemotherapy (ideally cisplatin-based)
* Extent of TURBT (completeness of resection)
* Residual disease after TURBT
What factors should be considered when deciding on bladder preservation therapy.
- “Bladder Worth Preserving”
○ Continent
○ Good bladder capacity- Unifocal T2-3a disease only
○ In addition, lesions >5cm have worse prognosis - Maximal TURBT associated with improved outcome
- Absence of tumour associated hydronephrosis
Absence of extensive CIS (field cancerisation)
- Unifocal T2-3a disease only
Describe the history and examination for a patient with bladder cancer.
- History
○ HPI
§ Haematuria (painless in 80%) - micro or gross (usually gross)
□ Initial suggest urethral
□ Terminal suggests bladder neck or prostate
□ Continuous suggests bladder
§ Microscopic haematuria
□ –urologist/cystoscopy if age >40-50, smoker or gross haematuria
§ Bladder function
□ Irritative bladder symptoms: dysuria, frequency, urgency (especially in the absence of a UTI)
® Especially CIS
§ Suprapubic pain (direct tumour invastion/obstruction)
§ Pelvic pain
□ Obturator, hypogastric, rectal, presacral invasion or urogenital diaphgragm
§ Obstructive symptoms
□ Flank pain
□ LUTS if prostate/bladder neck (less common)
○ PMHx
§ Previous ureteric/bladder diagnosis (e.g. chronic cystitis)
§ Pelvic radiotherapy
§ Chemotherapy (esp cyclophosphamide)
§ Chronic UTIs–> chronic irritation of the bladder
○ Family History
§ Lynch syndrome
○ Social
§ Ethnic background (Africa/Egypt areas in which chronic infection with schistosoma has an association with chronic inflammation and SCC)
§ Smoking history (Most dominant risk factor- Increase RR x5)
§ Occupational exposures
□ Hair dyes
□ Paint
□ Petroleum
Describe the staging for bladder cancer.
○ NMIBC (70%): Superficial low-grade tumors (Ta, T1).
○ Of those, 70% are confined to mucosa (Tis/Ta). 30% are confined to submucosa (T1).
○ 15-20% develop MIBC after diagnosis.
○ MIBC (25%): Invasion of the detrusor muscle. Around 50% will develop metastases, even with local therapy.
○ 4% with mets at diagnosis.
Risk of nodal involvement
○ Overall 24% LN+.
○ Lymph nodes for T0-1 / 2 / 3a / 3b-4
○ of 5→ 18→ 26→ 50%
○
TNM Staging (8th edition)
Ta-T1 = superficial
>=T2 = MIBC
Describe the work up for bladder cancer.
Work-Up
- Urine cytology (12-60% sensitive; high specificity) (not if catheter) ○ If high-index of suspicion, proceed to cystoscopy ○ If cystoscopy negative, urine cytology to exclude upper tract malignancy - Bloods (pre-surgical/pre-chemotherapy) ○ FBC, EUC, CMP, LFT - Urine MCS - exclude UTI, exclude haematuria mimics by seeing RBC ○ Prior to cystoscopy ○ Prior to intravesical therapies - Imaging: ○ Renal tract USS often in initial workup § Can miss small tumours, especially if less than 10mm § False positives with inflammation or underfilling ○ CT CAP –good for bladder masses. Only 70% sensitive for nodes. § Used for initial imaging where possible ○ CT IVP for renal pelvis and ureter lesion - exclude synchronous § Prioritises the excretory phase and contrast is timed to best image the kidney and ureters § At least 3 phases with delayed excretory phase (IVP) □ 87% sensitivity, 99% specificity § Good for upper tract abnormalities and potential met disease § Not good for muscle invasion § Contrast timing is less intentional for imaging the urinary tract ○ Bone scan ○ MRI to assess tumour extent § Not rebated § Suitable for contrast allergy § Distinguish T1 from T2; also better for T3 § Needs to be done before TURBT ○ FDG-PET (rare cancer MBS item) § Changes management in 10% - EUA + Cystoscopy ○ EUA first - assess for fixation, if so - not resectable ○ Biopsy (aim TURBT) 4 quadrants + urethra § Urethra involvment = contraidindication for intravesical therapy. § Usually piecemeal, en bloc resection better - limited by size (needs to be able to come out with c'scope) § Cold cup biopsy -no diathermy, then diathermy after to stop bleeding § Resectascope -loop resection with plasma arc -cuts/coagulates □ Need 3 way catheter after to stop clot -dilutes with saline § Generally will put in stent at time of TURBT ○ § Risks - □ Anaesthetic, bleeding, clots, UTI, pain □ Damage to bladder, Ureter (obstruction from ureter) □ Incomplete resection □ Seeding of infection ○ Bilateral Ureter cytology ○ Fluorescence: instilled 1 hour before. More sensitive for tumour § Improves recurrence free survival § Good for CIS ○ Need muscle present in biopsy specimen ○ Important to assess for CIS: o If present, increased risk of MIBC o Assoc with aggressive disease o Less likely to have durable response to BCG ○ Important to assess for hydronephrosis: o Associated with MIBC in 90% cases o Assoc with 70% extravesical spread o Less likely to achieve CR - FU after TURBT should biopsy TURBT site.
Describe the general initial management for bladder cancer.
- Patients should all have a cystoscopy with maximal TURBT (including non-MIBC)
○ TURBT full thickness biopsy to full depth of detrusor muscle
§ Resect all visible disease to muscle and margin
§ After first resection -scarring thickens bladder make second resection safer
○ Allows best T-staging
§ Approx 30% of apparent T1 tumours understated by TURBT
□ Repeat 4-6 weeks to assess recurrence for all >=T1 and high grade Ta, even if initial resection thought to be complete
○ Cyto-reduction is important before trimodality therapy- Hydronephrosis management options:
§ Patients with VUJ obstruction should have stenting performed prior to treatment commencement
○ Stenting
§ Plastic, silicone, reinforced. Can be solid
□ Works by urine tracking along outside of stent (hard stent vs soft tissue), unless cancer surrounds stent and hardens.
® Reinforced stents are harder (cancer takes longer to het as hard)
□ Changed between 3-12months -get brittle and encrusted (stones)
® Inability to remove
§ Stent colic pain ?from distention or muscle spasm
® Treat with alpha blockers/cholinergics/NSAID to relax muscle
® Hurts when urinate -urine refluxes up ureter
§ Stent bleeding -expected from stent
□ Rubs/irritates urothelium in renal pelvis/bladder
□ Esp clopidogrel causing clot retention
§ Does not seed tumour
○ Perc nephrostomy (bridge to treatment, not good palliation as frequent admission)
○ Reimplantation nephrectomy (doesn’t work post RT)
○ Observation - Consider maintenance of Hb > 100g/L (if concurrent chemoRT)
- Recommend smoking cessation (increases risk of progression and recurrence)
- Hydronephrosis management options:
Discuss management options for muscle invasive bladder cancer.
- Radical cystectomy remains the gold-standard therapy (traditionally the cornerstone of curative treatment removal of bladder, prostate, seminal vesicles, pelvic lymph node dissection and reconstruction of the urinary tract)
○ No randomised trial to suggest otherwise
○ Radical cystectomy is associated with significant perioperative mortality and morbidity risk
○ Open or laparoscopic- Trimodality therapy is a reasonable alternative (bladder preservation approach with maximal TURBT followed by chemoRT)
○ Comparative cure rates are similar (in carefully selected cohorts)
§ No direct RCTs comparing RC vs. BCT
§ TMT tends to be reserved for pt not fit for surgery
○ 5 yr OS 50%, bladder preservation rate 70%
§ Main modality of failure is distant (up to 80%)
§ ~67% cCR after induction
○ Toxicity and QoL implications are generally better
§ More tolerable for elderly or medically co-morbid patientsD
- Trimodality therapy is a reasonable alternative (bladder preservation approach with maximal TURBT followed by chemoRT)
Discuss cystectomy for bladder cancer.
Cystectomy
- Remains the standard of care for patients fit for extensive surgery for MIBC (cT2-T4a) with: - Neoadjuvant platinum-based chemotherapy is also the standard of care ○ Neoadjuvant preferred as pt frail postop. ○ Metanalysis: 5% improved overall survival ○ 3x MVAC protocol (MTX, vinblastine, doxorubicin, cisplatin) § ECOG 0-1, Cr clearance >60, good hearing/peripheral nerves, no heart failure § Given dose dense 2 weekly with growth factor support ○ Alternative Cisplatin+gemcitabine (v slightly worse outcome but better tolerated) - Neoadjuvant immuno -ongoing RCT trial
Cystectomy:
- Preferred: (also see candidates for tri-modality)
○ Widespread CIS
○ Multifocality
○ Residual/recurrent disease following TUBRT
○ Poor baseline function
○ Relative contraindications to chemo/radiotherapy
○ Variant pathology
○ Location
○ Ureter involvement
○ Acceptability of stoma
- Also excellent local palliation
- Vs partial cystectomy
○ Want radical cystectomy but unfit, or for organ preservation
○ Partial cystectomy probably good enough control of solitary MIBC, not near trigone (eg. Near urachus)
- The procedure entails: ○ As soon after recovery from NAC as possible ○ Open or minimally invasive ○ Resection of bladder and adjacent organs en-bloc § Prostatectomy/SV/vas/proximal urethra § If required: Hysterectomy + 1/3 vagina +- BSO ○ Bilateral pelvic lymphadenectomy if M0 § At minimum EI, II, obturators § More nodes = better outcomes, at least 10 ○ Formation of: § 90% Abdominal stoma (continent or incontinent) □ Ileal conduit 15cm § Or Neobladder (sbowel connected to urethra) 50cm of ileum - □ For young nonsmokers, Not for multifocal disease □ 30% work well, 60% poor quality of life -incontinence, self IDC, mucus washout, frequency ○ 30% of patients experience complications within 3 months of surgery § Sexual dysfunction § Nocturnal incontinence § Urinary retention § Serious complications in 3-5% (urethro-enteric anastomotic stricture, intestinal obstruction) □ Ileus, dehiscence, infection, lymph leak, urine leak. 2-3 weeks in hospital § Perioperative mortality is 2-5%, 1-2% for well selected younger patients ○ Late □ Recurrent urosepsis □ Hernia, ueteroileal stricture, stoma issues, □ SBO □ Lymphocele □ 35% develop CKD3 - Open vs. Minimally invasive/ Robotic ○ Less invasive, less blood loss, faster recovery ○ Most benefitial in frail, elderly, obese ○ Reduction in ureter/hernia complications ○ Can have sexual function preserved ○ Good QoL
Role of bladder preservation chemo/radiotherapy
- Selection
- Tumour: T2/3a, <5cm, CIS, unifocal
- Patient: nil hydro (understaging) good bladder and renal function , ECOG
- Treatment max TURBT
- Outcomes
○ 5yr OF 50%, bladder preservation 66%
○ 30% G3/4 acute tox, 5% late tox
Recurrence after CR: 30% CIS, 15% invasive, 15% N=
Partial cystectomy = indications
- Major: indications for radical, but unfit for radical cystectomy on physiologiocal grounds
- Minor/weak: localised solitary, urachal, partial preference, location - technically easier if distant from UO/bladder neck, diverticulum tumour
Discuss adjuvant management after cystectomy for bladder cancer.
- Consider adjuvant chemo if NAC was not given in pT3+ or N+ (generally pts not fit, poor renal function)
○ EORTC 30994
○ 5yr PFS benefit (48 >32%) without improvement in OS (54 >48%)
○ Chemo included Gemcitabine/Cisplatin, MVAC, or ddMVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)- Adjuvant Radiotherapy (limited use)
○ Consider adjuvant chemo or PORT for pT3-pT4a, SM+, ECE, or < 10 LN removed.
○ pT3-4, SM+ or ECE: Pelvic nodes to 45-50.4 Gy and cystectomy bed (if SM+) to 54-60 Gy.
○ LR after RC: 45-50 Gy to pelvic nodes, 60-65 Gy to gross LR with CDDP. - Adjuvant Nivolumab for high risk patients -on PBS
○ patients are considered at high risk of recurrence if pathological stage pT3, pT4a, or pN+ (for patients not eligible/declined adjuvant cisplatin-based chemotherapy) or pathological stage ypT2 to ypT4a or ypN+ (for patients who received neoadjuvant cisplatin)
RCT CHECKMATE: HR 0.7 (15% absolute) Improved DFS, especially >1% PDL.
- Adjuvant Radiotherapy (limited use)
Describe tri-modality therapy for bladder cancer.
- Comprised of
○ Maximal TURBT in any bladder preservation case
§ Pool RTOG analysis suggested cCR in 50% for incomplete TUBRT vs 70%
○ Definitive radiotherapy (64Gy/32F or 55Gy/20F)
§ Split course (two phases, UTD/EviQ)
□ 50Gy/25Fx, assessment with cystoscopy, then Further 14Gy/7Fx to primary
□ No trials comparing the two approaches, institutional dependent
○ Concurrent chemotherapy (Cisplatin or MMC + 5-FU or low dose gemcitabine
§ RCT: Improved locoregional control, reduced salvage cystectomy
§ Cisplatin 100 mg/m2 q3w, or Cisplatin 35mg/m2 q1w
§ Cisplatin doublet:
□ CDDP 15 d1-3,8-10,15-17 + Paclitaxel 50 d1,8,15.
□ CDDP 15 d1-3,8-10,15-17 + 5-FU 400 d1-3,8-10,15-17
§ MMC (12mg/m2 d1) + 5-FU (500mg/m2/d d1-5, d16-20). (week 1 and 4)
§ Concurrent low dose gemcitabine is also an option (twice weekly)- Selection for patients appropriate (EUA/AUA/EviQ/FROGG/NCCN)
○ Good bladder function and capacity (a bladder worth salvaging)
○ cT2-T3a urothelial carcinoma
○ No CIS
○ Unifocal disease
○ Non variant histology
○ Preferably <3cm, not more than >6cm
○ Maximal TURBT achieved/essential
○ No hydronephrosis or ureteral obstruction (increased risk of incomplete response and LR)
○ Compliance/reliable with surveillance
○ FROGG prefers if
§ Increased perioperative mortality/morbidity
§ Patient preference to conserve bladder - There is no clearly proven benefit to adjuvant chemotherapy following TMT
If metastatic nodal disease, will require chemotherapy
- Selection for patients appropriate (EUA/AUA/EviQ/FROGG/NCCN)
Describe elective nodal irradiation in bladder cancer and also management of node positive disease.
- Elective nodal irradiation is controversial/optional in node negative patients
○ Common in USA, not done in UK/AUS
○ Data
§ BC2001 & TROG trials have shown nodal recurrence of <10%
○ Rationale for avoiding
§ Chemotherapy will address some risk
§ Marked increase in toxicity
§ No evidence supporting its use
○ FROGG management recommendations (Table 10, FROGG 2020 guideline)
§ Node positivity = poor prognostic factor, 5yr OS 29%
§ If confined to pelvis BCT may be offered as a treatment option
§ Involved nodes - treat to prescribed dose given to GTV, respecting OARs
§ cN0 - ENI increases toxicity, no evidence improves outcomes (as above)
Node positive bladder cancer -series data only
Neoadjuvant chemo, cystectomy and dissection
CRT
Chemo alone, clinical trial
ASTRO 2022 conference: retrospective analysis CRT 2.4 years median survival, cystectomy 2.1 years Consider -metastasis risk (high if >3 nodes involved), location/number size of nodes (RT toxicity re bowel proximity)
Describe palliative management of muscle invasive bladder cancer.
- Radiotherapy alone
○ ~30-50% 5 year LC, underestimated as pt w/ DM less likely to undergo bladder surveillance
○ Up to 50% of MIBC may harbour occult DM
○ Consider 36/6 as palliative approach if pt not good candidates for CCRT, 21Gy/3#, 8Gy/1#, 50Gy/20#, 35Gy/10#
§ 90% improvement in haematuria, 80% frequency, dysuria 70Gy, nocturia 64Gy
§ 21Gy/3# if prognosis 6 months or very elderly.
○ Decide based on burden of distant metastasis
Salvage surgery -cystectomy: bleeding, pain, obstruction
Ablating all urothelium helps with pain.
Describe management of non-muscle invasive bladder cancer.
Non-MIBC (Ta, Tis, T1) - 75% of all bladder Ca
- All should have cystoscopy with a TURBT in the first instance - Further therapy is based on the pathology and risk grouping - risk calculator Essentially add adjuvant intravesical BCG unless low grade papillary (single chemo)
Radiotherapy +/- chemotherapy
- Can be used in NMIBC, generally multiple TURBT but poor bladder function so limited role of RT
○ Concern re understaged NMIBC
- Retrospective study (Weiss, J Clin Onc 2006); 141 pt T1, 60% HG, (RT=28, RT+ chemo=113) ○ cCR 88% ○ Rates of tumour progression 5 yr 19%, 10yr 30% ○ CSS 5yr 82%, 10yr 73% ○ 80% bladder preservation
NMIBC Pembrolizumab post TURBT (not on PBS)
Describe intravesical therapy for Non-muscle invasive bladder cancer.
- Bacillus Calmette-Guerin (BCG)
○ Standard for high-grade T1, Tis, or T1 tumours after TUBRT
○ Live attenuated mycobacterium bovis,
§ local immune response
§ Induction of mononuclear cell infiltrate, predominantly CD4 T cells and macrophages
§ Increased expression IFNg > inc expression of MHC class II
§ Elevated urinary cytokine levels
§ Direct suppression of tumour growth in dose-dependent manner
○ Toxicity: polyuria, cystitis, fever, haematuria; can be severe
○ Course used in all high risk disease
§ Also for select intermediate risk
§ MA: consistently decreases the risk of recurrence and progression c/w chemotherapy when at least 1 year administered- Single shot chemo, not shown to be superior ; CHEMO RARELY USED IN AUSRTALIA (chemo precautions, perforation)
- Mitomycin
○ Usually given as a single administration following resection of low risk NMIBC
○ MA (2007): reduces recurrence by 17%
§ Better if given within 24 hours vs. 2 weeks
○ 6x weekly courses if low grade and recurrent - Gemcitabine
○ Similar to MMC, better toxicity profile
Discuss indications for cystectomy in non-muscle invasive bladder cancer.
- Cystectomy should be considered if:
○ Extensive multifocal disease (TURBT not feasible)
○ Multiple recurrences/ residual disease despite multiple repeat TURBTs
○ T1 + LVI present
○ Adverse pathology
§ Pure SCC or adenocarcinoma
§ Micropapillary or sarcomatoid malignancy
§ Small cell (usually after neoadjuvant chemotherapy)
○ CIS involving prostatic ducts
○ T1 HG + CIS, >3cm, multiple; Better CSS with early RC
Consider bladder preservation with chemoRT for high grade cT1 (Weiss paper)
Describe management of upper urinary tract cancer and metastatic bladder cancer.
Upper tract urothelial cancer
Low risk – endoscopic laser ablation
High risk:
Neoadjuvant chemo -small benefit
Nephrouureteroectomy
Gold standard -remove ureter, kidney and cuff of bladder -en block resection
1-2 day admission
IDC for 2 weeks
Metastatic Bladder cancer
First line: chemo ddMVAC or 3 weekly MVAC (OS ~1 year) Cisplatin gemcitabine -well tolerated If can't have cisplatin, Carbo instead. Single agent chemo no use Immuno -not on PBS New Trial: EV + pembro 1st line improved overall survival (on PBS) Progression or Maintenance immuno (after 4-6 months chemo) Pembrolizumab (on PBS) 3rd line: on PBS Enfortumab vedotin -antibody drug chemo Nectin 4 antibody (urothelial surface), Chemo attached (MMAE) Improved survival vs chemo Se: neuropathy, occular, rashes, hyperglycaemia
Discuss the evidence to support trimodality therapy in bladder cancer.
Summary:
- Tri-modality therapy is a reasonable treatment option with high rates of local control and survival
- Hypofractionation is a reasonable non-inferior approach with comparable or better outcomes
Zlotta 2023 Retrospectibe matched analysis TNT (TURBT+ CRT) vs cystectomy – 1119 patients, T2-3N0 no difference in 5 year DFS, OS favoured TNT 30% had salvage cystectomy Multi-institutional Matched Comparison (Efstathiou, ASTRO 2022, Lancet 2023) ○ Retrospective 722 pt MIBC cT2-T4aN0M0 treated 2005-2017 in 3 centres § RC 440, TMT 282; all pt solitary, <7cm, no hydro, no extensive CIS □ 60% NACT in cystectomy arm § 5y MFS ~75%. 5y DFS ~74%. 5y pelvic nodal-failure free survival ~95%. § 5y CSS ~81→ 84%. 5y OS 66→ 73%. (favours TMT) § Local failure after TMT □ 20% NMIBC □ 11% MIBC □ 13% Salvage cystectomy § Limitations: retrospective, high volume centres ?generalisability, 60% NACT only ○ Similar dutch study Bruck 2023 BC2001 (James, 2012) ○ 360 patients with MIBC cT2-T4a were randomised to § Definitive RT (55/20 36%, 64/32 64%) +/- chemotherapy (MMC + 5-FU) □ PTV: Outer empty bladder wall + 1.5 cm. Extravesicular disease + 2 cm. ® Ant anterior and 2 lateral fields used to encompass PTV in 95% isodose. § Despite no extra- perivesicular nodal coverage - rates of pelvic nodal failure <10% □ Recall: Only ~25% will have nodes, 70% of which are perivesicular. 1.5 cm margin covers it. ○ Outcomes § Improved DFS in the chemoRT arm (67% vs 54%; HR 0.68; p=0.03) □ 5 year 63% (95% CI 54–71%) in the cRT group versus 49% □ 5 year Locoregional recurrence of 21% vs 36% (HR 0.57) ® Invasive control 79% vs 64% ® Noninvasive control § No improvement in 5 year OS (48% vs 35%; HR 0.82; p=0.16) □ No chemo ~10% less § Reduction in rate of cystectomy at 5 years (14% vs 22%) □ Most for disease recurence, 1% had cystectomy for late se § Acute G3-4 36% (21% GU, 10% GI), late G3-4 ~ 8-9% with CCRT. § QOL: chemo no impact RTOG Pooled Analysis (Mak, 2014) ○ 468 patients from 6 phase II or III trials were pooled § All investigating the role of chemoRT § Phase 1 treatment included radiation therapy to approximately 40 Gy, then re-staged patients with cystoscopy before proceeding to either cystectomy (non-complete response) or phase 2 consolidative radiation therapy up to 64 Gy (if complete response). ○ Outcomes § Clinical CR was achieved in 69% § 5yr OS = 57% whilst 10yr OS = 36% § 5yr CSS = 71% whilst 10yr CSS = 65% § Of patients who survived 5 years, 80% avoided cystectomy (intact bladder preserved) ○ Failure patterns: § Non-muscle invasive LF 5 /10 yr: 31 >36% § Muscle invasive LF 5/ 10yr : 13 > 14% § Nodal failure 5/10 13>16% § DM 5/10 yr 13 > 35% § Ie. 50% will have LF, 2/3 non-invasive; most within the first 5 years UK Meta-analysis (Choudhury, 2021) ○ 782 patients across two trials (BC2001 and BCON trials) § Both trials assessed chemoradiotherapy § BC2001 (n=456): RT ± 5-FU and MMC. 360 pts. Only 36% received 55/20. § BCON (n=326): RT ± hypoxia modifying therapy. Majority (70%) received 55/20. § Either 64Gy/32F (2Gy/#) or 55Gy/20F (2.75 Gy/#) were allowed as per physician choice § Add 1.5 cm to the bladder and 2 cm to extravesicular disease to PTV for coverage. ○ Outcomes § Hypofractionation was associated with trend of LR benefit- not significant (HR 0.91) § No difference in OS § Similar toxicity profiles in both arms □ with difference in G3-4 late bladder or rectum symptoms of -3.37% (-11.85-5.10). □ 5y late bladder/rectal toxicity (G3-4 on LENT-SOMA scale) ~32%. § Note that there was LC and OS advantage to the use of a radiosensitiser (BCON)
Discuss the evidence for neoadjuvant treatment and cystectomy in bladder cancer.
Summary:
- Neoadjuvant platinum-based chemotherapy is the standard of care
- No role for neoadjuvant RT (LC benefit only)
Neoadjuvant chemotherapy
Meta-analysis (ABCMC, 2003) ○ 2688 patients from 10 RCTs § Examination of the role of neoadjuvant chemotherapy prior to cystectomy § Platinum-based ○ Outcomes § Neoadjuvant chemotherapy associated with improved 5 year OS (HR 0.81; 5% absolute; p=0.016) § Combination chemotherapy superior to single-agent cisplatin
Neoadjuvant radiotherapy
Retrospective single-institution trial (Cole, 1995) ○ 570 patients with MIBC were treated with cystectomy § Some had neoadjuvant radiotherapy (~50Gy) and some did not ○ Outcomes § Improved local control with neoadjuvant radiotherapy (91% vs 72%) § No difference in OS (52% vs 40%; not significant)
Open vs Minimally Invasive
Retrospective review (Raza, 2015) ○ Retrospective review of 702 patients undergoing robotic cystectomy ○ Outcomes § 5 year OS = 50% § 5 year CSS = 75%
Discuss the evidence to support palliative RT in bladder cancer
HYBRID (2009-2014) [Hafeez IJROBP ‘17]: Phase II. 36/6 q1w.
○ 36Gy/6#: standard plan vs plan of the day
○ Hypofractionated RT delivered weekly with a “plan of the day” approach offers good LC and acceptable toxicity.
○ 65 pts. T2-T3a Nx M0-1. Median age 86y. 3D planning. Not suitable for RC or CCRT.
§ Local control 92%.
§ Local progression at 1 / 2y of 7→ 17%.
§ 1y OS 63%.
§ Acute G3 GU 18%. Acute G3 GI 4%. G3 late toxicity ~5%.
○ 2021 update
Discuss the side effects for bladder RT.
Acute:
-Fatigue
-Irritative or obstructive urinary symptoms - Bladder spasms, dysuria, nocturia, frequency, incontinence, urgency, retention.
-Proctitis - Including diarrhoea, increased bowel frequency, rectal urgency, pain and bleeding.
-Toxicity relating to chemotherapy
-Sexual function - female Vaginitis, vaginal mucositis, dyspareunia/stenosis.
-Sexual function - male Sexual and erectile dysfunction.
Late:
-Fatigue
-Cystitis/urethritis - Includes haematuria.
-Bladder dysfunction - New or ongoing.
-Urinary incontinence
-Radiation induced small bowel obstruction - Rare.
-Proctitis
-Faecal incontinence
-Radiation induced rectourethral fistulas - Rare.
-Lymphoedema
-Sexual dysfunction - male Including erectile dysfunction, impotence, dry and/or painful ejaculation, haematospermia and reduction in ejaculate. Patients should be offered sexual counselling to manage potential late effects related to sexual function.
-Sexual dysfunction - female Including dyspareunia, vaginal dryness and vaginal stenosis.
-Premature ovarian failure/menopause - If ovaries present.
-Impaired fertility or infertility Fertility preservation should be discussed prior to commencement of treatment.
-Second malignancy
- Pooled RTOG analysis [Efstathiou JCO ‘09]: Late effects of bladder preservation do not appear prohibitive.
No radical cystectomies were performed due to late treatment-related toxicity.
○ 285 pts. RTOG 8903, 9506, 9706, 9906.
○ 5y late G2 10% (9.6% GU, 1.9% GI).
○ 5y late G3 7% (5.7% GU, 1.9% GI). No G4 events, no pts req’d RC due to treatment related toxicity.
§ Median duration of late G3 pelvic toxicity of 7.1 months. Time to late G3 of ~2 years. - Quality of life [Zietman JoU ‘03]: Normal bladder fxn preserved in most pts w ~20% having persistent bowel sx.
○ 71 pts alive and w native bladders. 49 pts participated, but only 31 came in for urodynamic study. Median f/u 6.3y.
○ Of those that did UDS, 24/32 (75%) with normally functioning bladders.
§ Decreased compliance in 7 pts (22%).
§ Bladder HSN, involuntary detrusor contractions and incontinence in 2 women.
○ > 85% no bothersome urinary symptoms.
§ 6% flow sx, 15% urgency, and 19% control problems.
○ Bowel sx in 22% (e.g. rectal urgency), with 14% recording any level of distress.
○ 50% normal erectile function. - BC 2001, James et al
Acute G3-4 36% (21% GU, 10% GI), late G3-4 ~5% with CCRT.
Describe the radiation technique for definitive bladder cancer treatment.
Definitive Chemoradiotherapy
Patients
1) MIBC
Pre-simulation
MDT discussion
Maximal TURBT upfront
Consider ureteric stenting prior to RT
Fertility discussion
Smoking cessation
Simulation
Supine with arms on chest
Vacbag, knee-block and ankle-stocks
Bladder empty
Empty rectum
Generous CT (2mm without contrast)
- Diaphragm to below ischial tuberosity (include entire kidneys)
Fusion
MR fusion (if available)
Dose prescription
Single Dose Level
- 64Gy/32F prescribed to the PTV
- 55Gy/20F prescribed to the PTV
2-phase bladder only:
- 50Gy/25Fx + 14Gy/7Fx to tumour area with margin, usually treated with full bladder to minimise bowel dose
- (not used in AUS as far as I can tell)
Two Dose Level (SIB)
- 64Gy/32F to the primary + 60-64Gy to involved nodes
- 54Gy/32F to the elective nodes (EQD2 50)
- 55Gy/20F primary and involved, 45Gy/20F to the nodes
Concurrent chemotherapy
- Cisplatin at 35mg/m2 (weekly)
- MMC at 12mg/m2 & 5-FU at 2500mg/m2 over 5 days (q3wk)
VMAT technique
10 days per fortnight
Volumes
Primary
- GTV
○ Residual disease (if present)
- CTV
○ Entire bladder
○ GTV + 5mm (to account for extravesical)
○ Consider:
○ Include prostate/prox urethra if - bladder neck/trigone involved, multiple tumours or CIS
○ Prostate if invasion
○ Include 1cm distal ureter if VUJ is involved
- PTV
○ CTV + anisotropic margin
○ Sup = 1.5cm (may need less if small bowel)
○ Ant/Post/Lat = 1.5cm
○ Inf = 1cm
Nodal (if node positive)
- GTV64
○ Involved nodes - CTV64
○ GTV + 7mm - PTV64
○ CTV + 7mm - CTV54
○ Internal iliac, External iliac and obturator nodes, consider presacral, common iliac - PTV54
○ CTV + 7mm
Target Verification
Daily CBCT
Consider adaptive approach
OARs
Small Bowel
- ALARA (avoid hotspots)
- V45 < 195cc
Rectum
- 64Gy/32#= V50 < 50%
- 55Gy/20#= V44Gy <50%
Femoral Heads
- 64Gy/32#= V50Gy <10%
- 55Gy/20#= V44Gy <10%
Spinal Cord/Cauda Equina
- Dmax < 45Gy
Describe the palliative radiation technique for bladder cancer
Palliative
Patients
1) Symptomatic disease
Pre-simulation
MDT discussion
Fertility discussion
Smoking cessation
Consider ureteric stenting prior to RT
Simulation
Supine with arms on chest
Vacbag, knee-block and ankle-stocks
Generous CT (2mm without contrast)
- Diaphragm to below ischial tuberosity (include entire kidneys)
Fusion
N/A
Dose prescription
Single Dose Level (multiple options)
- 50Gy/20F
- 36Gy/6F (weekly)
- 37.5Gy/15Fx
- 21Gy/3F (weekly)
- 8Gy/1F
VMAT technique
9 days per fortnight
Volumes
- GTV
○ Residual disease (if present)
- CTV
○ Entire bladder
○ GTV + 5mm (to account for extravesical)
- PTV
○ CTV + anisotropic margin
○ Sup = 2cm
○ Ant/Post/Lat = 1.5cm
○ Inf = 1cm
Target Verification
Daily CBCT
Discuss the prognosis and follow up for muscle invasive bladder cancer with tri-modality therapy
MIBC (with tri-modality therapy)
RTOG pooled data
- 5 year OS = 50-60% (old crumbly pts)
- 5 year CSS = 60-75%
○ Recurrence in nodes in 12%, Metastasis in 30%
- 5 year LC = 70-80%
○ Clinical complete response 70-80% (50% if no chemo)
○ Muscle invasive recurrence 15%
○ NMIBC recurrence 30%
- Bladder preservation 80% @ 5 years
Yuvnik ph2 newcastle talk
TMT
5 year OS 50%
Bladder preservation 66%
30% acute g3-4 toxicity, 5% late toxicity
Recurrence: local 15%
Node 15%
Distant 30%
Follow-Up
MIBC After Tri-modality Therapy
- Clinical review every three months for the first two years ○ Cystoscopy every three months ○ Urine cytology every six months ○ Bloods including urine function every six months ○ CT CAP every six months § Or MRI q6-12m - Clinical review every six months for years 3-5 ○ Cystoscopy every six months CT CAP every twelve months
Discuss the prognosis and follow up of non-muscle invasive bladder cancer after TURBT
Non-MIBC -after TURBT
- Up to 50% recur within 6-12 months ○ Up to 20% will be MIBC at recurrence - Low grade <5% progress to invasion; 50-70% recurrence - High grade 15-40% progress to invasion; 50-80% recurrence - CIS 50-75% progress to invasion without any treatment - Risk factors for recurrence ○ Stage (T1 is worst) ○ Grade ○ Multifocality ○ Size (>3cm)
Follow-Up
With High-Risk Non-MIBC
- Clinical review every three months for the first two years ○ Cystoscopy every three months ○ Urine cytology every six months - Clinical review every six months for years 3-5 ○ Cystoscopy every six months
No role for routine CT imaging
No role for routine bloods
Describe the management of metastatic bladder cancer
Cisplatin was mainstay of treatment up until 2024
Now ddMVAC if fit as this is where evidence is (vs cis/gem) ->if stable or good response ->Maintenance with Avelumab (continuous) as per Javelin trial
It not fit for chemo, then can use pembrolizumab upfront (Keynote –052 for 24 months total. OS 11.3months
* Enfortimab vedotin –antibody-drug conjugate –Second line –can have long term survivial ○ Median survival time - 12.8months ○ Target is Nectin 4 SE of peripheral neuropathy and pruritic/ rash
Discuss the epidemiology for renal cancers.
Incidence (Australian statistics):
- 4193 cases annually
- 7th most common malignancy in Australia (2% of total cancer incidence)
Incidence is rising (early detection does not fully explain this observation)
Male predominance (2:1)
Disease of the elderly (generally 60yo+)
- Exception is Wilm’s tumour (disease of children)
RCC = 80-95% of primary renal cancers
Mostly adenocarcinoma (cc)
65% localised, 16% regional nodes, 15-25% metastatic disease: Lung, bone, brain or retrograde venous spread to ovary/testes
Most common in high socioeconomic countries
- Common in North America + Scandinavia
Less common in Asia and South America
Discuss the risk factors for renal cancers
Convincing risk factors:
1) Smoking (RR <1.5)
a. Smoking also associated with advanced presentation
2) Obesity, high dietary fat
a. Obesity associated with earlier stage and low grade disease
3) HTN
4) Acquired kidney diseases (RR up to 30)
a. End-stage renal failure (ESRF) of any cause
b. Cystic kidney disease
c. Renal stones (RR 2)
5) Occupational exposures
a. Asbestos
b. Lead and cadmium (heavy metals)
c. Petroleum materials
d. Thorotrast (old-school radiological contrast)
6) Prior radiotherapy or cytotoxic chemotherapy
7) Genetic causes (see below)
8) Analgesic abuse nephropathy ↑ risk of collecting duct tumours/TCC of renal pelvis.
9) Dialysis patients (6% develop RCC)
Protective factors:
- Alcohol consumption
- Exercise
Genetic Causes
1) Von Hippel-Lindau (VHL) syndrome: 3p25 a. 50% of sporadic RCC has silencing VHL mutation b. Autosomal dominant inheritance, 1/36000 c. With high lifetime risk of RCC (50-70%) --> predominantly clear cell d. VHL --> Implicated in the physiological hypoxia & angiogenesis pathway i. Part of Ubiquitin ligase that turns off HIF e. Retinal/CNS haemangioblastoma, Pancreatic NET and phaeochromocytomas i. Ongoing surveillance: annual BP, eye, UA, second yearly hearing, MRI brain+spine, abdo 2) Hereditary leiomyomatosis and RCC syndrome a. Autosomal dominant mutation of the FH gene (fumarate hydratase --> Kreb's cycle) i. ?similar to IDH mutation. Induces glycolysis/lactate b. Presents with cutaneous & uterine leiomyomatous tumours c. Also presents with aggressive papillary carcinomas (RCC) with high metastatic risk 3) Hereditary papillary renal carcinoma a. Autosomal dominant mutations in the MET (TK gene) proto-oncogene b. Presents often with multiple bilateral RCC with papillary appearance 4) Birt-Hogg-Dube syndrome (BHD) a. Autosomal dominant mutation of the BHD gene (responsible for folliculin expression) b. As well as RCC (various types), can present with skin lesions/pulmonary cysts/Pneumothorax c. Renal tumours: Clear cell, Oncocytomas d. Penetrance of 30% 5) Tuberous sclerosis a. TSE1/TSE2 b. Increased risk of angiomyolipomas (AML) and RCC i. Multiple hamartomas (benign CNS, renal, liver, lung, skin lesions, eye), intellectual delay, autism, c. Only 5% risk of RCC
List the histological subtypes of primary renal cancer.
Malignant Histological Subtypes
1) Clear cell (75-80%) 2) Papillary or chromophilic (10-15%) 3) Chromophobic (5-10%) 4) Oncocytic (3-5%) 5) Collecting duct (very rare) - Typically arise in upper pole. Often invade renal vein +/or collecting duct.
Describe the pathology for clear cell RCC.
Clear cell RCC
- worse than papillary or chromophobe
- Macroscopic
○ Well-defined lesion with pseudocapsule; white to yellow coloration
○ Common to have haemorrhage or necrosis associated
○ Tends to invade the renal vein
- Microscopic
○ Round or polygonal cells
○ Characterised by cells with abundant cytoplasmic lipid & glycogen (hence “clear cell”)
○ Generally, nuclei are close to normal (WD)
○ Delicate branching vasculature (chicken-wire)
- Arise in the proximal tubule epithelium ○ Usually solitary in presentation - Typically present with a deletion in chromosome 3p (98%) - Linked with VHL mutation (both sporadic or germline/familial) - IHC: RCC ma (specific antibody) positive, Vimentin positive, PAX 2/8 positive, CA9 positive, Ck7/20 neg, c-KIT neg
Describe the pathology for papillary/chromophilic RCC
Papillary/chromophilic RCC
- Macroscopic
○ Well circumscribed tumour with pseudocapsule (often associated haemorrhage)
○ Tan to light brown in colour
○ Often multifocal or bilateral
- Microscopic
○ Cuboidal or low columnar cells in papillary pattern (fibrovascular core)
○ Psammoma bodies present (calcification)
○ Foamy macrophages often present
- Also arise from proximal tubule - Two key types: Type 1 is low grade with better prognosis than type 2 high grade (larger nuclei, more cytoplasm ○ Type 1 = favourable prognosis § Associated with hereditary papillary RCC (MET mutation) ○ Type 2 = poor prognosis, more agressive § Advanced stage at presentation ie. N+ and/or mets § Associated with leiomyomatosis and RCC syndrome (FH mutation) IHC: RCC ma (specific antibody) positive, CK7 positive, PAX 2/8 positive, c-KIT positive
Describe the pathology for chromophobic RCC
Chromophobic RCC
- Better DFS than clear cell
- Arise from intercalated cells of collecting ducts
Chromophobe cell - light coloured pale cytoplasm (flocculant), perinuclear halo, bi-nucleated, thick distinct cytoplams.
Eosinophilic cells – dark nuclei with prominent deep pink cytoplasm.
- Macroscopic ○ Well circumscribed; tan to light brown in colour ○ Occasionally have central scar - Microscopic ○ Lack the abundant lipid and glycogen classic of most RCCs ○ Prominent cell membranes with pale eosinophilic cytoplasm (halo around nucleus - koilocytic) ○ Wrinkled nuclei (raisinoid) ○ Arranged in solid sheets concentrated around vessels - Associated with upregulation of KIT oncogene - Good prognosis relative to clear cell variant - IHC: RCC ma (specific antibody) variable, Ck7 positive, PAX 8 positive, CA9 negative
Describe the pathology for Collecting duct RCC
Collecting Duct RCC
- 1% of RCC (rare), from distal collecting ducts. Poor prognosis
- 2/3 men, age 50-60yrs, but can occur in younger pts
- Associated with analgesic nephropathy
- MICRO: hobnail cells with a desmoplastic stroma and cystic tubular structures.
- Frequently demonstrate and aggressive disease course
- Medullary carcinoma is a common variant (arise from cells in renal medulla)
IHC: RCC ma negative, PAX8 positive, Vimentin Positive
Describe the RCC Fuhrmann/WHO-ISUP grading
- Relates to visibility/prominence of nucleoli
- Fuhrmann was old -based on nuclei. New is WHO Nucleioli
- – based on nuclear characteristics and nucleoli. Grades 1-3 based on nucleolar prominence, while grade 4: highly pleomorphic tumor giant cells or the presence of sarcomatoid and/or rhabdoid morphology○ Grade 1 = nucleoli absent at 400x magnification
○ Grade 2 = nucleoli prominent at 400x magnification
○ Grade 3 = nucleoli prominent at 100x magnification
○ Grade 4 = extreme nuclear pleomorphism (giant cells, sarcomatoid/rhabdoid change)
Most relevant for clear cell (less relevance for other subtypes)
Describe common benign renal lesions.
Relevant Benign Lesions (less common – 40% of tumours <1cm)
Oncocytoma
- Mimic renal cell carcinoma
- Macroscopic
○ Well circumscribed lesions; tan to mahogany brown
○ Central stellate scar often present
- Microscopic
○ Well circumscribed without capsule
○ Consist of a pure population of large WD neoplastic cells characterised by dense mitochondria
○ Few mitoses, no necrosis
- May progress to chromophobe RCC if it develops p53 mutations
- Benign natural history (rarely metastasise despite large size) - Arise in the intercalated cells of the collecting system - Associated with tuberous sclerosis and BHD syndrome
Papillary renal adenoma
- Small, discrete adenomas arising from the tubular epithelium
○ Benign, do not require management
- Microscopic ○ Generally <1.5cm in diameter ○ Frequently papillary in appearance ○ Cut section = Generally pale yellow-to-grey with well circumscribed edge (no capsule) - Microscopic ○ Complex, branching, papillomatous structures with numerous fronds ○ Cuboidal to polygonal cells with scanty cytoplasm ○ Small regular centrally-located nuclei - Histologically, very similar to low-grade papillary carcinoma (type 1) ○ Size < 3cm is defining distinction ○ Metastasis is rare below this size
Angiomyolipoma (AML)
- Benign mesenchymal tumours consisting of vascular, smooth muscle and fat tissue
○ Arise from perivascular epithelioid cells
- Macroscopic ○ Well-circumscribed tumours with pushing border (no capsule) ○ Variable appearance depending on dominant component (red = vascular; white/grey = muscle; yellow = fat) ○ Generally unilateral and single ○ Fat content gives classic radiological appearances (esp MR) - Microscopic ○ Triphasic appearance with spindle cells, adipose tissue and dysmorphic thick-walled vessels - An epithelioid variant also exists (fat-poor) ○ Addition of epithelioid cells in the tumour ○ Loss of fat makes radiological diagnosis difficult (needs biopsy) ○ Increased chance of malignant transformation (still unusual) - Whilst benign, are associated with haemorrhage (when lesions are large) - Associated with tuberous sclerosis (25-50% of patients will develop AML)
Ddx:
Renal pelvis Transitional cell
Neuroendocrine
Describe the prognostic factors for renal cancer.
Patient Factors
* Age and performance status * Symptomatic disease (e.g. anaemia, hypercalcaemia, weight loss) ○ Imparts worse prognosis * Renal function ○ Suitability for nephrectomy * presence of paraneoplastic syndromes, (St4- ↑LDH, ↑Ca, ↓Hb)
Tumour Factors
* Stage at Dx most important * T-stage ○ Size (i.e. T1 vs T2) ○ Invasion of collecting system or perinephric fat are important prognostic checkpoints ○ Invasion of vasculature (renal vein or IVC) is also highly relevant * N-stage & M-stage * Fuhrman/WHO histological grade * Histological subtype (controversial) ○ Clear-cell carcinoma may be worse * Other histological features ○ Necrosis ○ Sarcomatoid/rhabdoid subtype * Solitary lesion * Lung mets alone do better than other mets
Treatment Factors
* Suitability for nephrectomy
NOTE: positive surgical margins do not necessary predict recurrence (no clear impact on prognosis)
List the factors to consider when considering a patient for upfront management of metastatic renal cancer
Suitability for Upfront Treatment of Metastatic Disease
IMDC Score (Heng score)
- Karnofsky score < 80
- Time from diagnosis < 1 year
- Hb below LLN
- Ca elevated above ULN
- Absolute neutrophil count elevated above ULN
- Plt elevated above ULN
0 factors = low-risk
1-2 factors = intermediate-risk
3+ = high-risk
Discuss the history and examination for RCC
- History
○ HPI
§ Majority are incidental on imaging (25-40%)
§ Classical triad (10%)
□ Haematuria (in 40%)
□ Abdominal pain
□ Renal flank mass
§ Scrotal varicocoele (due to gonadal vein obstruction
○ Paraneoplastic syndromes
§ RCC is the great ‘mimic’ due to paraneoplastic syndromes of:
□ Hypercalcaemia (due to lytic bone mets, PTHrP production or prostaglandin prodn causing bone resorption), Cushings (prednisone secretion), HTN, polycythaemia, masculinisation, feminization, cachexia.
§ Anaemia (normocytic, normochromic)
§ Hepatic dysfunction in absence of metastases (Stauffer syndrome)
§ Fevers
○ PMHx:
§ Benign kidney disease (e.g. ESRF)
§ Previous radiotherapy
○ Family History
§ Genetic syndromes include
□ Von Hippel Lindau
□ Birt-Hogg-Dube
□ Tuberous Sclerosis
○ Social
§ Smoking
§ Occupational exposures (e.g. heavy metals)
○ 25% metastasis at presentation (Mostly lung and bone, then brain)- Examination
○ General Appearance
○ Abdominal examination
§ Including renal flank
○ Urine MCS
- Examination
Discuss the work up for RCC.
- Imaging
○ CT AP +/- US urinary tract
§ Good to assess size and complexity of any cystic mass
§ Assess local extent and LN invovlement
§ DDx: simple cyst, tumour, abscess
○ CT chest for mets
○ WBBS, MRI brain if indicated
○ MR kidney
§ Particularly good at evaluating fat content and vascular involvement- Bloods
○ FBC, EUC, CMP and LFT
§ Assess for key paraneoplastic syndromes
○ LDH (prognostic) - Renal DMSA scan
○ If planning for surgical management - Histopathology
○ NO role for biopsy
Proceed directly to partial/total nephrectomy if suspicion is sufficient
- Bloods
Discuss solid renal masess and also the bosniak score for cystic renal masess.
Solid renal masses
- Larger the renal mass, the more likely malignant
- Most solid renal masses > 1.5cm are RCCs. Differentials are oncocytoma, angiomyolipoma or renal cortical adenoma.
- Imaging alone cannot reliably distinguish between benign tumour + RCC.
- When imaging suggests solid renal mass > 1.5cm, tissue normally obtained by total or partial nephrectomy. i.e. diagnosis is usually presumptive for tumours > 1.5cm.
For lesions < 1.5cm, no defined method of Mx. Active surveillance is reasonable.
Bosniak Score for Cystic renal masses
- Scoring system to estimate risk of malignancy for cystic renal masses ○ Based on CT alone - Bosniak I ○ Benign simple cyst § Thin wall § No septae or solid components - Bosniak II ○ Minimally complex benign cyst § Few hairline thin septae - Bosniak IIF ○ Minimally complex cyst § Multiple thin septae § Presence of calcification ○ Requires follow-up (5% risk of malignancy) - Bosniak III ○ Indeterminant cyst § Thickened walls with septae ○ Requires surgical resection (55% risk of malignancy) - Bosniak IV ○ Malignant mass § Enhancing soft tissue components Requires oncological management (100% risk of malignancy)
Describe staging for renal cancers
Describe surgical management for RCC
Surgical resection is the only curative therapy option
- Partial nephrectomy is favoured where possible (nephron-sparing), usually up to T1b disease
○ Multiple RCC syndrome
○ At risk for chronic renal impairment
○ Decreased overall mortality
○ Preserve renal function
- Total radical nephrectomy is required if: (complex) ○ Large primary (T2 >7cm), as role for partial nephrectomy in T2 tumours is contradictory ○ Locally-advanced disease (including nodal) - LR after nephrectomy is ~5%, therefore limited role for adj RT or chemo ○ Higher LR for R1/2 or N+
Lymphadenectomy should be adjusted for risk of involvement
- If low-risk –> renal hilum only
- If higher-risk –> extended retroperitoneal dissection
○ pT3 or pT4
○ G4 or sarcomatoid
○ Coagulative necrosis
Discuss adjuvant treatment for RCC.
Adjuvant Systemic Therapy
2024: None on PBS
Traditionally, there was no role for any adjuvant therapy
- Sunitinib has demonstrated a DFS benefit only and not reproduced
- This does not outweigh the lack of OS and increase in toxicity
New data suggests that adjuvant pembrolizumab may be appropriate for higher-risk patients
- Risk groups
○ High-intermediate –> pT2 & grade 4 pathology OR pT3
○ High-risk –> pT4 OR node positive
- KEYNOTE 564 trial
○ Pembrolizumab was associated with improved DFS and OS compared with observation
§ High-intermediate or high risk patients only
○ Note increased G3+ toxicity (19% vs 1%)
Adjuvant Radiotherapy
- There is no clear role for adjuvant radiotherapy following nephrectomy ○ Retrospective and poorly designed randomised studies ○ Likely a LC benefit, inconsistent OS benefits - Particularly in the era of TKIs and ICIs, adjuvant radiotherapy should not be delivered
Keynote-564 (Choueiri, 2021)
- 496 patients with resected clear cell RCC were randomised to
○ Pembrolizumab for 1 year
○ Surveillance
- Outcomes
○ Improved OS (HR 0.54)
○ Improved 24mo DFS (77.3% vs 68.1%; HR 0.68; p=0.002)
Describe non-surgical management for RCC
Definitive Radiotherapy
- SABR remains an option for patients who are ineligible for surgery and: ○ Tumour < 10cm ○ Minimal bowel contact ○ Reasonable eGFR (>30) - results in a moderate reduction in EGFR ○ Good for perihilar tumours (can't ablate due to heatsink), large tumours - Available preliminary retrospective data suggests high-rates of local control ○ Local control > 90% - FASTRACK I/II protocol ○ Dose is dependent on tumour size § 26Gy/1F (if tumour <4cm) § 42Gy/3F (if tumour >4cm) ○ Baseline mean eGFR reduced by -10.6mL/min 1 yr, -14.6mL/min 2 yr; plateaued thereafter ○ 100% local control and cancer specific survival - SABR also can be used as salvage if failure post nephron sparing surgery or thermal ablation
Other modalities
- Percutaneous thermal ablation can be considered if complete ablation can be reliably achieved - RCC <3 cm - thermal ablation - If RCC >3cm cryoablation or microwave ablation preferred, as create a larger ablation area than RFA Centrally located cryoablation reduces urothelial damage
Active Surveillance:
- Consider in ○ Mass <2cmL high rate benign tumours, low metastatic potential ○ T1a (<=4cm) and predominanly cystic component ○ cT1 masses, signficiant competing risks of death/morbidity from intervention - Process ○ Surveillance imaging with timely intervention ○ Should include periodic metastatic survey (blood work, chest imaging)
Describe systemic management of metastatic RCC.
Metastatic Disease
Systemic Therapy
Clear cell: Not responsive to traditional chemo
Systemic therapy is selected following assessment of:
- Patients should be prognosticated as per the IMDC/Heng criteria
- Burden of disease should be assessed
○ Includes volume of disease, rate of progression, symptomatology and life-threatening metastases
Agents:
Historical: cytokines
Pathophysiology: Often VHL mutation which promotes growth pathways: VEGF, PDGF, MTOR, HIF TKI work faster than immuno Skin toxicity -severe blistering rashes, mucositis Sunitinib, axinitib, sorafenib, Pazotinib (VEGFR, PDGFR) Levatinib (FGFR, VEGFR, PDGFR Cabozantinib (Cmet, AXL, VEGFR) Everolimus (MTOR) HIF2a inhibitor -Belzutifan Immune therapy 1st line: doublet immuno -ipi + nivo No biomarkers re immuno reponse (PDL not good) vs TKI response Prognostic score below (based on pts failing sunitinib) Immuno and TKI 1st line Improved survival vs TKI alone (Doublet immuno + TKI very toxic)
Discuss the Heng criteria for RCC and associated management options
- KPS < 80
- Time from original diagnosis < 1 year
- Hb < ULN
- Neutrophils > ULN
- Platelets > ULN
- Calcium > ULN
FAVOURABLE = 0 factors
INTERMEDIATE = 1-2 factors
POOR = 3+ factors
Discuss cytoreductive nephrectomy for metastatic RCC
Cytoreductive Nephrectomy
Data supporting this approach was very clear in the older cytokine therapy era
- OS advantage to cytoreductive nephrectomy
This is less clear in the TKI/ICI era, where systemic responses are improved
- Randomized trials do not support this approach
○ CARMENA trial –> sunitinib alone was non-inferior to addition of nephrectomy
§ ? Due to more surgical complications and/or delays in initiating systemic therapy
○ SURTIME trial –> OS was improved in those who had deferred nephrectomy vs upfront
- Retrospective data is in contrast with this approach
○ There is apparent suggestion of OS advantage in low-risk groups
It is reasonable to consider cytoreductive nephrectomy if:
- 0-1 risk factors (favourable risk)
- <65 years old
- No adverse histology (e.g. non-sarcomatoid clear cell)
Consider deferral of cytoreductive nephrectomy until after initial systemic therapy to ensure no inherent resistnace to systemic therapy, as pt selection is key
Or consider SBRT - avoids all surgery issues, does not delay systemic therapy known to provide OS benefit
Summary:
- Should not be offered to Intermediate or High risk patients
- Can be considered in favourable risk patients
CARMENA trial (Mejean, 2018) ○ 450 patients with metastatic clear cell RCC were randomised to sunitinib +/- cytoreductive nephrectomy § Heng groups = intermediate and high only § Median mets 2 (1-5), most commonly lung; untreated brain excluded. ○ Outcomes § Sunitinib was non-inferior to addition of nephrectomy □ Median OS = 18mo vs 14mo ® Apparent NS survival detriment ® Surgical issues, delays to systemic therapy □ No difference between intermediate and high risk groups Retrospective analysis (Bakouny, 2020 - ASCO) ○ >4000 patients with denovo metastatic RCC were reviewed § Patients with nephrectomy vs ICI or TKI alone ○ Outcomes § Improves OS with the cytoreductive nephrectomy group (2yr OS 69% vs 41%) § Patients were more likely to receive nephrectomy if: □ <65 years old □ Heng score 0-1 □ No adverse histology (e.g. non-clear cell; sarcomatoid)
Discuss Metastasis directed therapy for RCC.
Metastasectomy
- Complete metastasectomy can be considered if: ○ Oligometastatic (1-3 metastases) ○ Expected survival is >12 months ○ If metachronous metastases, long disease-free interval (>12mo) - If this occurs, patients should be observed for recurrence before initiation of systemic therapy - Majority of data is with surgical management ○ No clear evidence that it can be extrapolated to SABR ○ If unresectable, then SABR is a reasonable approach (using SABR-COMET & meta-analysis data) - Bone mets: radiation if symptomatic Brain mets: surgery or RT; no optimal systemic therapy
Classical retrospective series (Kavolius, 1998)
- 278 patients with metastatic RCC were analysed
○ 141 patients underwent curative metastasectomy
- Outcomes
○ If all lesions resected curatively, 5 year OS was 44%
○ Favourable features (with 5yr OS)
§ Disease-free interval of >12mo (55% vs 9%)
§ Solitary vs multiple (54% vs 29%)
§ Age < 60 years (49% vs 35%)
Updated retrospective data in TKI era (Takagi, 2020)
- 51 patients with metastatic RCC were analysed
○ Majority were favourable/intermediate risk
- Outcomes
○ Median relapse free survival was 22mo
○ 5 year CSS = 82%
○ Unfavourable features
§ 2+ metastatic sites (HR 4.5)
§ Sarcomatoid pathology (HR 11.5)
SABR ORCA meta-analysis (Zaorsky, 2019)
- 28 stuies with 1602 patients
○ Patients with oligometastatic RCC who underwent SABR
- Outcomes
○ 1 year LC = 90%
○ 1 year OS = 86% (49% for intracranial)
G3+ toxicity was < 1%
Discuss the evidence for SABR in RCC.
Meta-Analysis (Correa, 2019)
- 26 studies with 372 patients
○ Primary RCC which was biopsy confirmed in 79%
○ SABR was delivered, with most common fractionations being 40Gy/5F and 26Gy/1F
- Outcomes
○ Pooled LC = 97.2%
○ G3+ toxicity = 1.5%
FASTRACK (Siva, 2017)
- 37 patients with unresectable RCC
○ Histology confirmed in 92%
○ SABR dose dependent on tumour size (26Gy/1F vs 42Gy/3F)
- Outcomes
○ LC was 100% at two years
○ 1 patient had grade 3 toxicity (3%)
○ eGFR reduced by 10mL/min at 2 years
FASTRTRACK 2 2022 (Siva, 2023 ASTRO)
- 70 pt, primary RCC, solitary lesion, ECOG 2, medically inoperable, high risk or declined surgery
- T1a 33%, MFU 42 months
- (26Gy/1F for <=4cm, vs 42Gy/3F >4cm),
○ ITV (<1cm free or DEBH) to PTV 5mm
- LC 100%, (short MFU)
- 3 yr OS 82%
- eGFR loss 15ml/min @ 2 years (10ml@1year)
- G3 AE 10%, no G4-5
Transient N/V
Discuss the prognosis and follow up for RCC
Prognosis
5 year OS Stage I >90% Stage II 80% Stage III 60% Stage IV 20%
Local Control After SABR (primary or metastasis)
- >90%
Follow-Up (fast track II protocol)
- Clinical review every six months for the first two years
○ CT CAP every visit
§ Consider MR for surveillance if ablation only
○ Bloods every visit
- Clinical review every twelve months for years 3 to 5 ○ CT CAP every visit § Consider MR for surveillance if ablation only ○ Bloods every visit
Post SABR
-can see pseudo-progression if post treatment scanning to early (.ie prior to 6months)
-in general more likely to have contrast enhancement post treatment, regardless of actual response
- Consider more frequent review if has not undergone nephrectomy (i.e. ablation only)
Describe the radiotherapy technique for RCC SABR
SABR (FASTRACK protocol)
Patients
1) Non-metastatic RCC
2) Unsuitable for surgical resection
Pre-simulation
MDT discussion
Pre-treatment eGFR
DMSA study
Smoking cessation
Simulation
Supine with arms above head
Vacbag, knee-block and ankle-stocks
Generous CT (2mm with IV contrast)
- Mid chest to below ischial tuberosity
Expiratory vs Inspiration breath hold vs 4DDCT freebreathing
Fusion N/A
Dose prescription
Small Tumours (<4cm)
- 26Gy/1F prescribed to the 100% isodose
Large Tumours (>4cm)
- 42Gy/3F prescribed to the 100% isodose
- 40Gy/5F prescribed to the 100% isodose
VMAT-based SABR technique
- Avoid entering via contralateral kidney
Alternate days
Volumes
GTV = gross tumour
ITV (free breathing only)= GTV on each respiratory phase
PTV = ITV + 5mm
- If in breath hold consider adding additional sup and inf to account for drift during breath hold
Consider 2-3mm PRV on bowel etc
Target Verification
Daily CBCT
Match to target, secondary to OARs
Mid treatment CBCT
Dose Quality Criteria Coverage
- D99% = 100% (dose to 99% of PTV must be 100% of prescription)
Dmax
- 125% to 143%
OARs
26Gy/1F
Spinal Canal
- Dmax 0.03cc < 15Gy
Small Bowel (circumferential)
- Dmax < 12.5Gy
Large Bowel
- Dmax 1.5cc < 12.5Gy
Stomach
- Dmax 1.5cc < 15.4Gy
Liver
- ALARA
Ipsilateral Kidney (minus ITV)
- ALARA
Contralateral Kidney
- V10Gy < 33%
Describe the epidemiology and natural history of testicular cancer.
Information is for Germ Cell Tumours (GCTs) –> 95% of testicular tumours
Incidence (Australian statistics)
- 980 cases annually = 1% male cancers
- 11th most common malignancy in males overall
○ Most common solid malignancy for age group 15-45
§ 50% seminoma, 50% mixed germ cell
- Rising incidence (unclear cause)
Predominantly impact young adults (15-40 years old)
- Biphasic (at 2yo then 25-40yo)
Predominance in Caucasian populations (especially Scandinavia/Europe)
- Uncommon in Africa and Asia
30’s: seminoma, NSGCT
Pediatrics: Yolk-sac Tumour, rhabdomyosarcoma, teratoma, gonadal stromal tumour
60yo -spermatocytic, DLBCL, melanoma mets
Natural history
-Seminoma –indolent growth, long natural history. Late recurrences common
1st echolon Nodes: L paraortic near renal vein (bilateral for R testes)
Pulmonary mets
-Nonseminoma
Frequent haematogenous mets eg. Lungs, brain, bones, liver.
Aggressiveness depends on subtye eg choriocarcinoma
Describe the risk factors for testicular cancer.
Key risk factors
1) Cryptorchism (undescended testis) 5-10x
a. Seen in 10% of all testicular GCTs
b. ?pathophysiology: abnormal development, differences in hormone,, increased temperature, endocrine disruptors
c. Orchidopexy before puberty reduces risk (never returns to baseline)
2) Environmental Exposures
a. Inferred from migration data, no clear cause found
b. Possibly implicated: pesticides, non-steroidal oestrogens (e.g. in utero DES exposure)
3) History of other genital issue
a. Gonadal dysgenesis
b. Impaired fertility
c. Testicular microlithiasis (controversial)
d. Hypospadia
e. Prior contralateral testicular cancer
4) Genetic cause
a. Strong family history link (8-10 times higher if affected brother)
i. Can have germline mutations in KIT & BAK
b. Small increase risk of non-GCTs = Peutz-Jeghers syndrome (GIT polyps) & Carney complex (MEN with benign skin neoplasms)
c. Kleinfelters (47XXY = tall, weak, no sperm), Down (47 21x3)
d. 46XY -DSD, ambiguous genitalia
5) Race/ethnicity
a. White, American Indian, native Alaska men are several times more likely to get testicular cancer than black, Asian or pacific islander.
Less definitive correlations:
- Testicular trauma (controversial –> likely detection bias)
- Obesity
- Immunosuppression
- HIV infection
List the histological types of primary testicular cancer
Normal
- Round tubular structures, lots of cells
- Increasing differentiation to centre
- Sperm in the middle
Key Pathological Groups
Germ-cell tumours of testis (95%)
- Seminoma (50%)
- Non-Seminoma GCTs
○ Embryonal carcinoma
○ Yolk-sac tumour
○ Choriocarcinoma
○ Teratoma
NOTE: NSGCTs often present as mixed non-pure tumours
Non-GCTs of Testis
- Sex cord-gonadal stromal tumours (<5%)
○ Leydig cell tumour
○ Sertoli cell tumour
NHL
Describe the pathology for seminoma.
Seminoma
- Pure seminomas account for 50% of GCTs
○ 20% of other GCTs are mixed (contain seminomatous component)
○ Uncommon in pre-pubertal males
- Macroscopic ○ Bulky masses much larger than normal testis ○ Well demarcated from remainder of testis ○ Cut-surface = homogenous, pale/lobulated cream/grey-white devoid of haemorrhage/necrosis - Microscopic ○ No sperm/spermatids ○ Fried egg appearance. ○ § Well-defined cell membrane (round to polyhedral) § Centrally-located nuclei with prominent nucleoli § Angled/polygonal nuclear membranes § Clear cytoplasm (glycogen) ○ Sheets of uniform cells divided by delicate fibrous septae § Less cohesive cells than in other GCTs ○ Often contains a lymphocytic infiltrate - Immunohistochemistry ○ PLAP IHC highlights neoplastic germ cells, normal seminiferous tubule negative for PLAP ○ POS = OCT3/4, c-KIT, NANOG, D2-40 (podoplanin), PLAP, SALL4 § +-BHCG (low level from syncytiocytoblasts) ○ NEG = CK and CD30; vimentin; AE1/AE3 § AFP neg, - BHCG - bHCG may be elevated (15% giant syncytiotrophoblasts), but not a prominent feature - AFP not elevated
Describe the pathology for embryonal carcinoma of the testes
Embryonal Carcinoma
- Generally present a little earlier than seminoma - More aggressive disease course - Macroscopic ○ Tend to invade through tunica albuginea and spermatic cord ○ Cut-surface § Soft tan-white tumour § Poorly marginated/circumscribed § Variegated appearance with foci of haemorrhage/necrosis (pomegranate) - Microscopic ○ Epithelial appearing cells (large and anaplastic; quite pleomorphic) § Quite cohesive ○ Hyperchromatic nuclei with prominent nucleoli ○ Indistinct cell membranes ○ Frequent mitotic figures ○ Necrosis ○ ABSENCE of fibrous septae - Immunohistochemistry ○ POS = CD30, OCT3/4, SALL4, PLAP, cytokeratin ○ NEG = KIT & D2-40 (podoplanin) CK7 and 20 - Modest AFP & bHCG elevation is expected More significant elevation should trigger suspicion of other component
Describe the pathology for choriocarcinoma of the testes.
Choriocarcinoma
- Highly-malignant form of GCT (early haematogenous metastasis) ○ Rare in pure form (generally as part of mixed tumour) ○ In mixed form, its presence does not impart worse prognosis ○ From trophoblastic tissue - Macroscopic ○ Primary tumours are generally small (<5cm) ○ Haemorrhage/necrosis are extremely common - Microscopic ○ Diagnosis = two juxtaposed cells (syncytiotrophoblasts & cytotrophoblasts) § Syncytiotrophoblasts are large multinucleated cells (bHCG in cytoplasm) § Cytotrophoblasts are more regular and tend to be polygonal with clear cytoplasm § Abundant haemorrhage - Immunohistochemistry ○ POS = GATA3, PLAP, CK, bHCG (of limited use) ○ NEG = OCT3/4, NANOG, D2-40, CD30, CKIT, SOX2 - bHCG is often markedly elevated - No AFP elevation
Describe the pathology for yolk-sac tumour of the testes.
Yolk-sac Tumour
- Pure yolk-sac tumours are the most common GCT in children (<3 year) ○ Generally only a component of mixed tumours in adults - Good prognosis in this age group - Macroscopic ○ Pre-pubertal § Homogenous grey-yellow lobulated mass, gelantinous § Minimal haemorrhage/necrosis ○ Post-pubertal (adult) § Poorly demarcated white to tan tumours § Haemorrhage/necrosis common - Microscopic ○ Most morphologically variable of all GCTs § Hyaline-type globules and Schiller-Duval bodies (50%) can be seen § Reticular network of medium-sized cells (cuboidal to spindled) § Typically low-grade (minimal atypia) - Immunohistochemistry ○ POS = AFP, AE1/AE3, SALL4, CK ○ NEG = OCT3/4, cKIT, PLAP, D2-40, NANOG, SOX2
Associated with marked elevations in AFP
Describe the pathology for Teratoma.
Teratoma
- Characterised by having multiple components from difference germ layers ○ Ectoderm = CNS & skin (e.g. hair) ○ Mesoderm = muscle, bone + connective tissue ○ Endoderm = gut - Adult and child teratoma are biologically different ○ Pure teratoma is more common in children (benign course) (prepubertal) ○ Mixed is more common in adults (more aggressive course) - Macroscopic ○ Heterogenous appearance (depending on components present) ○ Can have cystic components ○ Lobulated, with cysts of mucinous, gelatinous or serous material - Microscopic ○ Collections of differentiated cells and organ structures § Highly variable (neural tissue, muscle tissue, cartilage, squamous epithelium, intestinal wall, etc.) ○ Elements may be mature or immature (resembling embryonic tissue) § Mature teratoma (prepubertal) -differentiated cells/organoid morphology, including hair follicles § Immature teratoma (postpubertal) § -Any type of tissue may be present, eg embryonic tissue § Teratoma with malignant transformation (Teratoma with somatic type malignancy ) * Teratoma + resembles another cancer (SCC, adeno, sarcoma) * Frequent mets ○ Chromosome 12p amplification present in postpubertal teratomas - bHCG and AFP are not secreted ○ However, may be elevated (indicates presence of other GCT components) Somatic type malignancies Eg rhabdo, embyronic neuroectodermal (PNET), adenocarcinoma Retains 12p chromosome mutation Chemo resistant
Describe the pathology for Leydig cell tumour of the testes.
Leydig Cell Tumours
- Note that Leydig tumours are derived of the stroma (Leydig cells are endocrine cells that secrete testosterone), while Sertoli tumours are derived from the sex-cord.
* Tumours of testicular stroma. Rare, between 20-60 yrs old
* Clinical presentation – testicular swelling, gynaecomastia, feminisation. In children, precocious puberty (due to ↑oestrogen production). Produces testosterone and or estrogen. Testosterone can be converted to estrogen by aromatase.
* Can be associated with hereditaory leiomymatosis/RCC (FH deficiency)
Most are benign, 10% are malignant and may metastasize. MACRO: ○ Circumscribed nodules < 5cm, distinct golden-brown homogenous cut surface MICRO: ○ Large round malignant cells with abundant eosinophilic cytoplasm with round central nucleus. ○ IHC: androgen and steroid hormone post
Describe the pathology for Sertoli cell tumour of the testes.
Sertoli Cell Tumours
- Tumours of sex-cord. Derived from sertoli cells which form part of the supporting substrate within seminiferous tubules for spermatogenesis.
- May produce either estrogens or androgens, but rarely in sufficient quantities to cause precocious masculinisation or feminisation. Occasionally present with gynaecomastia.
- Associated with familial adenosis polyposis, Carney’s syndrome
90% benign, 10% invasive.
MACRO:
○ Firm small nodules with homogenous white/yellow cut surface.
MICRO:
* Cord-like structures resembling immature seminiferous tubules.
* Well organized cuboidal-columnar epithelium
IHC: Vimentin, CD99 post
Describe the features of a testes synoptic pathology report.
Subtype and % of histologic component
Size for pure seminoma (esp 3-4cm)
Invasion or rete, epididymus, tunica vaginalis, sperm cord, scrotal wall, tunica albuginea
LVI (metastasis for NSGCT) Fibrosis -(regressed component) Syncytiotrophoblast cells (produce bHCG) Presence of GCN in situ Leydig cell hyperplasia Testicular atrophy D
Describe the prognostic factors and risk stratification for seminoma
Prognostic Factors (for seminoma GCTs)
Patient Factors
- Age and performance status (fitness for therapy)
- Previous inguinal surgery (orchidopexy, inguinal hernia)
○ Diverted lymphatics
Tumour Factors
- T-stage
○ Invasion through tunica vaginalis imparts worse prognosis
○ Size > 4cm is also predictive of occult metastasis
○ Invasion of rete testes
- N-stage
- M-stage
○ Lung metastases better prognosis than other sites
- Pure seminoma has better prognosis than other subtypes
- Lack of bHCG & AFP elevation indicates better prognosis
○ Presence indicates mixed GCT (treat as NSGCTs)
Treatment Factors
- Post-operative serum markers (bHCG & AFP)
- Presence of positive margins
International Germ Cell Cancer group risk stratification (for seminoma)
- Good risk = all of: ○ Any primary site ○ No metastases ○ Normal AFP - Intermediate risk = all of: ○ Any primary site ○ Metastases confined to LN and lungs ○ Normal AFP - No poor risk group
Describe the prognostic features and risk stratification for non-seminoma.
Prognostic Factors (for non-seminomatous GCTs)
Patient Factors
- Age and performance status
○ Fitness for therapy
○ For some subtypes, children have favourable natural history (e.g. teratoma, yolk-sac)
- Previous inguinal surgery (orchidopexy, inguinal hernia)
○ Diverted lymphatics
Tumour Factors
- T-stage
○ Invasion through tunica vaginalis imparts worse prognosis
- N-stage
- M-stage
○ Lung metastases better prognosis than other sites
- Histological subtype
○ Choriocarcinoma has worst prognosis
○ Embryonal carcinoma imparts higher risk of recurrence
- LVI on histopathology
- Lack of bHCG, AFP or LDH elevation indicates better prognosis
Treatment Factors
- Post-operative serum markers (bHCG & AFP)
International Germ Cell Cancer group risk stratification (for non-seminoma GCT)
- Good risk = all of: ○ Testicular or retroperitoneal primary ○ Metastases confined to LN and lungs ○ Serological markers § AFP < 1000ng/mL § bHCG < 5000 mIU/mL § LDH < 3x ULN - Intermediate risk = all of: ○ Testicular or retroperitoneal primary ○ Metastases confined to LN and lungs ○ Serological markers § AFP 1000 to 10000 ng/mL § bHCG 5000 to 50000 mIU/mL § LDH 3 to 10x ULN - Poor risk = any of: ○ Mediastinal primary ○ Metastases other than LN and lungs ○ Serological markers § AFP > 10000 ng/mL § bHCG > 50000 mIU/mL § LDH > 10x ULN
Describe the history, examination and work up for testicle cancer.
Consultation
- History ○ HPI § Typically a painful ipsilateral testicular mass § Up to 25% will have signs of epididymitis § Symptoms of metastases □ SCF LN □ Back pain (retroperitoneal LN) □ Bone pain ○ PMHx § Cryptorchidism § Any scrotal or abdominal surgery ○ Family History § Testicular cancer (strong familial association) - Examination ○ General appearance ○ Testicular examination § Size, firmness and tenderness (relative to contralateral) § Discrete palpable masses § Transillumination ○ Inguinal nodal examination ○ Abdominal inspection (scars)
Work-Up
- Bloods (prior to orchidectomy)
○ Pre-chemotherapy = FBC, EUC, CMP, LFT
○ Tumour markers = bHCG & AFP
§ bHCG –> choriocarcinoma
§ AFP –> yolk sac tumour
○ Serum LDH (prognostic)
- Scrotal US
- Histology
○ Diagnostic and therapeutic orchidectomy
- Staging Imaging for everyone (after histologic confirmation)
○ CT CAP
○ Consider MR Brain (if extensive visceral metastases)
Discuss the non-neoplastic differential diagnosis for testicular cancer.
Nonneoplastic Differential diagnosis
* Infection: Epididymitis/orchitis, Syphilitic gumma
* Infarction: Testicular torsion
* Fluid collection: Hydrocoele, Varicocoele, Haematoma, Spermatocoele
* Hernia
Discuss the tumour markers for testicular cancer.
Serum Tumour Markers
* AFP is major serum protein of early fetus, secreted by yolk sac tumours.
* B-HCG is normally synthesized + secreted by placenta, secreted by choriocarcinoma.
* Both markers ↑ in 80% of mixed NSGCT.
* LDH useful to assess tumour burden, hence ↑ not specific for testicular ca.
* Markers are useful for:
i) Evaluation of testicular mass
ii) Staging – after orchidectomy, persistent ↑ indicates adv dx.
iii) Assess tumour burden – esp. LDH related to tumour mass, a PF.
iv) Monitor response to therapy
v) Surveillance for relapse
βhCG
* Serum t½ 24 hrs (normalisation within 1wk- 5t½)
* False +ve can occur in hypogonadal states, marijuana use.
* Values > 10,000 mIU/ml only in GCT, pregnancy or GTD (women).
* 15% of seminomas produce
AFP
* Normally produced by foetal yolk sac, should be undetectable in serum of men.
* 10,000 ng/ml almost exclusive to NSGCT + HCC.
* AFP production in yolk sac tumours, (sm amount in embryonal ca).
* 80% mediastinal NSGCTs associated with ↑AFP, regardless of histo subtype.
* Serum t ½ 5d, should normalise by 25d.
* False +ve: HCC, liver damage (cirrhosis, hepatitis, chr drug/alcohol abuse).
LDH
* ↑ in 30-80% with pure seminoma, 60% NSGCT.
* Produced in every tissue in bodu
* Less sens/specific marker for NSGCT, but may be only marker ↑ in pure seminoma.
* Used pre orchidectomy and repeated post surgery if raised
* LDH- prognostic factor in pure seminoma, but not reliable marker of relapse.
Describe the staging for testicular cancer.
Stage I – confined to the testis- T1-4N0M0S1-3 (1a=pT1; 1b=pT2-4)
Stage II – regional LNs (infradiaphragmatic)- N1,2,3, S0-1
IIA= LN < 2cm
IIB = LN 2-5cm
IIC = LN > 5cm
Stage III – Supradiaphragmatic LNs + extralymphatic mets, S2-3
Stage IV – none
Describe the management of Stage 1 seminoma.
General Management
- All patients should have cryopreservation of sperm discussed - All patients should proceed to radical orchidectomy ○ Diagnostic and therapeutic (no biopsy) - Inguinal approach preferred to scrotal approach ○ Need to cover scrotum with adjuvant radiotherapy if contaminated
Stage I Seminoma (node negative)
- Post-orchidectomy surveillance is preferred ○ Rationale § 85% of men are cured with orchidectomy alone § Salvage chemotherapy on recurrence is extremely successful (risk of death is 0.1%) ○ Protocol (ANZUP) § Clinical review + tumour markers --> 6 monthly review for 2 years, then annual thereafter § CT AP --> 6 monthly for 2 years, then at 36 months and every second year - Alternatives if men are unable to proceed with surveillance ○ Radiotherapy § 20Gy/10F to a para-aortic strip alone ○ Chemotherapy § Single cycle of carboplatin § Often preferred to radiotherapy due to favourable late toxicity profile - Risk factors for recurrence (consider upfront adjuvant) ○ Large tumour size (>4cm) ○ Epididymal invasion or rete testis invasion ○ LVI
Describe the management of stage two seminoma.
General Management
- All patients should have cryopreservation of sperm discussed - All patients should proceed to radical orchidectomy ○ Diagnostic and therapeutic (no biopsy) - Inguinal approach preferred to scrotal approach ○ Need to cover scrotum with adjuvant radiotherapy if contaminated
Stage II Seminoma (node positive)
- Stage IIA (node < 2cm) ○ Adjuvant radiotherapy is preferred § 30Gy/15F boost with 20Gy/10F to the elective region § Hockey-stick with boost ○ Chemotherapy is a reasonable alternative - Stage IIB & IIC (nodes >2cm) ○ Chemotherapy is favoured due to bulk of disease § 3x BEP (bleomycin, etoposide & cisplatin) § 4x EP
Describe the management of advanced stage seminoma/non-seminoma germ cell tumour
Advanced Stage (both seminoma and NSGCTs)
- Stratify as per IGCCCG risk staging ○ Low-risk --> Intermediate risk --> Poor risk ○ Factors § LDH, bHCG and AFP § Primary location (testis vs mediastinum) § Location of metastases (pulmonary vs distant) - If low risk disease ○ 3x BEP chemotherapy - If intermediate or high-risk disease ○ 4x BEP chemotherapy ○ If lung toxicity is a concern, consider 4x VIP chemotherapy (etoposide/ifosfamide/cisplatin)
Describe the post orchidectomy management of Stage 1 and Stage 2 non-seminoma germ cell tumour.
Stage I NSGCTs
- Stratify into low or high risk based on presence of any of: ○ LVI ○ Embryonal component ○ pT3/pT4 primary - If low risk ○ Active surveillance is preferred ○ Alternatives include § RPLND § Chemotherapy (1-2 cycles of BEP) - If high risk ○ RPLND is preferred ○ Chemotherapy is a reasonable alternative (1-2 cycles of BEP)
Stage II NSGCTs
- Clinical Stage IIA (nodes < 2cm) ○ Should undergo RPLND § Diagnostic and therapeutic (80% of men require no further therapy) ○ Further therapy is guided by pathology § If <2cm and <4 LN involved --> active surveillance § If >2cm or >4 LN involved --> 2x BEP chemotherapy ○ If patient declines RPLND, treat as per Stage IIB - Clinical Stage IIB or IIC (nodes > 2cm) ○ Should proceed to 3x BEP chemotherapy - Residual LN masses following initial chemotherapy ○ Require RPLND § Residual cancer is uncommon § Many will have a teratoma component ○ If any residual high-grade component § 2 cycles of VIP chemotherapy
Describe the evidence to support active surveillance for stage 1 seminoma.
Stage 1 Seminoma
Active Surveillance
Very reasonable default option to spare patients toxicity for treatment
- Dependent on active surveillance and salvage of recurrence (20% of patients)
Risk factors including size, LVI or epididymal invasion may influence this risk and may necessitate adjuvant therapy
Danish retrospective study (Mortensen, 2014) ○ Retrospective review of 1954 patients with stage I seminoma managed with surveillance only § Followed for median of 15 years ○ Outcomes § 5 year relapse rate was 18.9% □ Late relapse is rare (only 5% of all relapses) § Disease specific survival at 15 years was > 99% § Predictors of relapse □ Tumour size □ LVI Epididymal invasion
Describe the evidence to support radiotherapy and chemotherapy in stage 1 seminoma.
EORTC RCT 30Gy vs 20 GY (Jones, 2005)
Dose de-escalation RT
No difference in relapse rates
30GY/15F –> 20GY/10F as standard of care
The favoured radiotherapy approach is
- 20Gy/10F
- PA strip only (unless scrotal surgery)
UK MRC TE10 trial (Fossa, 1999) ○ 478 patients with stage I pure seminoma were randomised to § 30Gy/15F via PA strip vs classic dog-leg ○ Outcomes § No significant difference in relapse rates between arms □ Slightly increased rates of pelvic relapse in the PA strip group § OS is unchanged between arms (100% vs 99.3%) § Improved spermatogenesis in the PA strip group UK MRC TE18 trial (Jones, 2005) ○ 625 patients with stage I seminoma were randomised to § 30Gy/15F vs 20Gy/10F § All received a PA strip field as standard (add dog-leg if scrotal surgery) ○ Outcomes § No difference in relapse rates (HR 1.11; p=0.81) § Higher-grade acute toxicity in the 30Gy arm
Chemotherapy
Single-agent carboplatin is a reasonable alternative as adjuvant therapy
EORTC/UK MRC TE19 trial (Oliver, 2011) ○ 1447 patients with stage 1 seminoma were randomised to § Adjuvant chemotherapy (1 cycle of carboplatin) § Adjuvant radiotherapy (PA strip; 30Gy vs 20Gy was an optional randomisation) ○ Outcomes § No difference in relapse rates (HR 1.25; p=0.37)
Describe the radiotherapy technique for stage I seminoma.
Stage I Seminoma
Patients
1) Stage I seminoma (opting not to pursue AS)
Pre-simulation
MDT discussion
Fertility discussion +/- sperm banking
Smoking cessation
Establish history of abdominal/inguinal surgery
Simulation
Supine with arms by side
Vacbag, knee-block and ankle-stocks
Generous CT (2mm with IV contrast)
- Mid chest to below ischial tuberosity (include entire kidneys)
Testicular clam shell for shielding
Fusion
N/A
Dose prescription
Single Dose Level
- 20Gy/10F prescribed to the PTV
AP/PA technique
10 days per fortnight
Volumes
Field-based
* Paraaortic strip
* T11-L5, 10cm width
* Superior = Top of T11/T12
* Inferior = L5/S1 (bottom of L5)
* Lateral = lateral processes of vertebrae (~10cm wide)
Volume-based
* CTV
○ Volume aorta and IVC
○ 2cm inferior to top of kidneys
○ Bifurcation
○ Expand IVC by 1.2cm and aorta by 2cm
○ Clip to anatomy
* PTV
○ CTV + 0.7cm
Exceptions
If left-sided testicular tumour
- Include left renal hilum
If scrotal invasion/violation or previous abdominopelvic surgery
- Include scrotum, inguinal nodes and iliac nodes
Target Verification
Daily CBCT
OARs
Kidney
- Mean < 5Gy
ALARA (avoid hotspots in bowel or cord)
Describe the evidence to support management of stage II seminoma.
SWENOTECA (Tandstad, 2011)
○ 1384 men with stage I-II seminoma were treated as per the following protocol
§ Stage I = AS, RT or chemotherapy
§ Stage IIA = RT (dog leg to dose of 27Gy/15F)
§ Stage IIB-C = 4x EP chemotherapy
○ Outcomes
§ Stage I
□ 14% of patients on surveillance relapsed
□ Radiotherapy had improved relapse risk compared with chemotherapy (HR 4.7; p=0.03)
§ Overall CSS was 99.6% at 5 years
Describe the radiotherapy technique for Stage II seminoma.
Stage II Seminoma
Patients 1) Non-bulky Stage II seminoma (stage IIa)
Pre-simulation
MDT discussion
Fertility discussion +/- sperm banking
Smoking cessation
Establish history of abdominal/inguinal surgery
Simulation Supine with arms by side
Vacbag, knee-block and ankle-stocks
Generous CT (2mm with IV contrast)
- Mid chest to below ischial tuberosity (include entire kidneys)
Testicular clam shell for shielding
Fusion MR and FDG-PET fusion (if available)
Dose prescription Two Dose Levels (sequential)
- Elective = 20Gy/10F prescribed to the PTV
- Boost = 10Gy/5F prescribed to the PTV (16gy if >2cm)
AP/PA technique
10 days per fortnight
Volumes
Volume-Based
* CTVelect (modified dog-leg field)
○ Para-aortic strip
○ Volume aorta and IVC
§ 2cm inferior to top of kidneys
§ Bifurcation
○ Expand IVC by 1.2cm and aorta by 2cm
○ Clip to anatomy
○ Upper pelvis
○ Volume ipsilateral common/external/internal iliac vessels
§ Extend to acetabular roof
○ 1.2cm expansion
○ Clip to anatomy
* PTVelect
○ CTV + 0.7cm
* GTVboost
○ Involved nodes
* CTVboost
○ GTV + 7mm
* PTVboost
○ PTV + 7mm
Exceptions
If left-sided testicular tumour
- Include left renal hilum
If scrotal invasion/violation or previous abdominopelvic surgery
- Include iliac nodes
Target Verification
Daily CBCT
OARs
Kidney
- Mean < 5Gy
ALARA (avoid hotspots in bowel or cord)
Describe the prognosis and follow up for testicular cancers.
Prognosis
Seminoma
- OS is excellent regardless of stage
○ Stage I to II –> 5 year OS = >98-99%
○ Advanced Stage –> 5 year OS = >90%
- On active surveillance, relapse rate in stage I disease is 15-20%
Non-seminoma
- OS is generally worse than seminoma
- Advanced stage –> 5 year OS = 70-90% (depending on risk group)
Follow-Up
- As per the ANZUP protocol ○ Clinical review and examination every six months for the first two years § CT CAP at each visit § Tumour markers at each visit ○ Clinical review every year thereafter to 10 years § CT CAP at years 3 and 5 § Tumour markers at each visit ○ Serum endocrinology (testosterone and FSH/LH) § 6 months, 24 months and 5 years ○ Protocol suggests more frequent follow-up in the non-seminomatous group
Describe the epidemiology and risk factors for penile cancer.
Incidence (Australian statistics)
* 103 cases annually
* Rare cancer (<1% of all cancers)
Predominantly impacts men > 50 years old (mean 60 years of age)
-most common histology is SCC w HPV link
* Marked HPV correlation, need to account for latency
Most common in developing world
* Incidence is up to 10+% of all male cancers
Aetiology
1. HPV infection ○ Present in 30-50% of cases ○ High-risk types (16, 18 --> 6) 2. Socioeconomic status ○ Increased risk of HPV infection ○ Poor global hygiene 3. Other factors related to the penis (mix of HPV infection and chronic inflammation) ○ Warts (OR 7.6) ○ Circumcision reduces risk ▪ Rare in circumcised populations (Jews & Muslims) ▪ Early circumcision reduces risk compared with late ○ Phimosis (OR 7-10) ○ Penile tear/injury ○ Lichen sclerosis 4. Immunosuppression ○ HIV infection 5. Smoking (OR 3-4) 6. PUVA therapy (psoralens + ultraviolet A photochemotherapy)
Factors with no proven link
* Sexual orientation
Describe the pathogenesis for penile cancer.
HPV dependent or independent pathways
HPV related
HPV infection implicated in ~50% of cases
* Majority are HPV 16 & 18
* Others include HPV 6
Mucosal break (e.g. coital/penile injury) allows penetration of virus into basal epithelial layer
HPV viral integration results in transcription of pathogenic E6 & E7 proteins
* E6 –> binds to p53 which promotes degradation
○ Allows uncontrolled cell-cycle progression
○ Impairs DNA repair pathways
○ Upregulates telomerase, leading to cellular immortality
* E7 –> binds to Rb which promotes degradation
○ Allows uncontrolled cell-cycle progression
○ Impairs DNA repair pathways
Chronic Inflammation
Exposure to chronic inflammatory stimuli
* p53 mutation
* Upregulation of cyclin D1
Describe pre-malignant and primary invasive histologies for penile cancer.
Pre-Malignant Lesions
Refers to umbrella group Penile Intraepithelial Neoplasia (PeIN)
* Undifferentiated PeIN (HPV infection)
○ Bowen disease
▪ Solitary thickened grey-white plaque
▪ Dysplastic squamous epithelium with large hyperplastic nuclear
▪ 10% transform to invasive disease
○ Bowenoid Papulosis
▪ Younger age of presentation
▪ Multiple reddish brown papular lesions
▪ Virtually never transforms to malignancy and resolves spontaneously
* Differentiated PeIN (non-HPV) ○ Balanatis xerotica obliterans ▪ Retains squamous maturation ▪ Impacts older patients
Invasive Disease
Key subtypes
* SCC (95%)
○ Usual type (50-60%)
○ Papillary (15%) –> HPV related
○ Warty/condylomatous (10%) –> HPV related
○ Basaloid (10%) –> HPV related
○ Verrucous (5%)
○ Sarcomatoid (<5%)
* BCC
* Kaposi sarcoma
* Melanoma
Describe the pathology for warty and verrucous SCC of the penis
Warty SCC
* High-rate of HPV involvement
* Tends to be slow growing with low risk of mortality
○ Intermediate –> between verrucous & usual SCC
* Macroscopic ○ Exophytic mass arising from glans (usually) ○ Verruciform and cobblestone external surface ○ Endophytic cut surface * Microscopic ○ Typical features consistent with warty carcinomas of vulva, cervix and anus ▪ Acanthosis (thickening of epidermis), hyperkeratosis and parakeratosis (retention of nuclei in the stratum corneum) ▪ Conspicuous koilocytosis (large nuclei, irregular nuclear contour – raisinoid, hyperchromasia, perinuclear halo) * Immunohistochemistry ○ POS = HMWK, p16, p40, p63
Verrucous SCC
* Slow-growing and low risk of metastasis
* Usually HPV negative
* Macroscopic ○ Broad-based grey-white exophytic lesion with cauliflower appearance * Microscopic ○ Very well differentiated with keratinisation (intercellular bridges) ○ Hyperkeratosis but no koilocytosis * Immunohistochemistry ○ NEG = usually p16 neg
Describe the prognostic factors for penile cancer.
Key Prognostic Factors
Patient Factors
* History of genital warts/condylomata
* Smoking (poorer outcome)
* Immunosuppression (including HIV)
Tumour Factors
* TNM stage
○ Bilateral or multiple LN imparts worse prognosis
* Histologic grade
* Depth of invasion (including structures invaded)
* LVI
* PNI
* Histological subtype
○ Verrucous tumours are rarely metastatic
○ Basaloid and sarcomatoid types do poorly
* HPV status (may impart better prognosis – uncertain significance)
Treatment Factors
* Suitability for radical therapy
* Clear surgical margins
Describe the history, examination and work up for penile cancer.
Consultation
- History ○ HPI § Painless mass in the penis (typically on glans) § Cutaneous abnormality § Bleeding or balanitis (uncommon) § Inguinal lymphadenopathy ○ PMHx: § Immunosuppression § Benign penile injury (phimosis, tear, warts, lichen sclerosis) ○ Medications § Immunosuppressants ○ Social: § Socioeconomic status § Hygiene practices § Smoking - Examination ○ Penile examination § Extent of disease (? Nodular extension) § Depth of invasion (i.e. into corpus cavernosum) § Nature of disease § Examine entire penis ?presence of skip lesions ○ Palpate inguinal lymph nodes
Work-Up
- Biopsy ○ Including HPV status - Imaging ○ US penis ○ MR penis (with artificial erection) § Uncomfortable ○ CT CAP
Very high rate of microscopic nodal involvement
Describe the staging for penile cancer.
Describe the nodal assessment in penile cancer
Lymph Node Assessment
- Management is dependent on ○ Clinical Nodal Evaluation ○ Risk Factors § Low-risk = pTis, pTa, pT1a □ Higher risk factors (i.e. pT1b) = LVI, PNI, grade 3 or sarcomatoid § High-risk = pT1b or more - CT Abdo/Pelvis should be performed prior to any surgical technique ○ Exclude presence of pelvic nodal disease
Clinically Node Negative (cN0)
In patients with clinically node-negative groins, a non-randomised controlled trial (RCT) observed that early LN surgery:
1) Led to a 3-year survival rate of 84% compared to 35% in those receiving delayed LN surgery
2) ENE incidence of 20% compared to 95% in the early vs. delayed surgery groups.
Therefore, detecting lymphatic spread as early as possible is a crucial element in penile cancer management.
3) Clinically node negative patients still have 20-25% risk of occult mets
Inguinal US, FNABx and/or SLBx still recommended in clinically node negative patients, unless very low risk
Surgical staging is recommended in high risk tumours
-T1 with high grade + LVSI
-T2-4 any grade
Surgical staging= Sentinel LN biopsy or radical inguinal LN dissection (in specialised centre)
Describe lymph node management in penile cancer
Describe the management of the primary tumour in penile cancer in surgical candidates.
Describe the management of the primary tumour in non-operative penile cancer
Organ Sparing
Definitive EBRT
- 66-70Gy at 2Gy/F
○ Consider concurrent chemotherapy
○ Use a wax-block/Plexiglas approach
- If no surgical nodal management/staging
○ If cN0 –> 50Gy prophylactic to inguinal and pelvic LN
○ If cN+ –> boost to 60Gy
Definitive brachytherapy
- Continuous LDR
○ 60Gy at 50cGy/hr (over 5 days)
- Fractionated HDR
○ 54Gy/18F (BD for 9 days)
○ 6-9 needles
Discuss adjuvant treatment for penile cancer
Adjuvant Therapy
Radiotherapy
Can request circumcision with surgeon to reduce phimosis rates
-
- Should consider adjuvant RT to primary site if
○ Positive margin
- Adjuvant RT to nodal regions is controversial ○ No evidence available (to support or deny benefit) ○ Adjuvant chemo better - Should be consider to both inguinal and pelvic nodal regions if: ○ Patient declines surgical management ○ Extranodal extension, 2 nodes, >4cm node ○ Disease in bilateral nodal regions ○ Patients who decline adjuvant/neoadjuvant chemotherapy ○ 56gy ene, 50gy, 45gy uninvolved - Dose ○ 50Gy/25F EBRT with boost to 60Gy for any macroscopic disease - Volume ○ Include lower pelvic nodes if not surgically staged - Addition of concurrent chemotherapy is an option (not widely accepted) ○ Cisplatin
Chemotherapy
- Should be considered if: ○ Pelvic nodal involvement ○ Extranodal extension ○ Bilateral nodal involvement ○ More than 3 LN involved
4 cycles of TIP chemotherapy
Discuss the evidence for management in penile cancer.
There is very sparse literature for penile cancer
- Very rare disease
Any evidence available are retrospective series
Much of the evidence is therefore extrapolated from vulval cancer
- Especially the approach to nodal management
Role of adjuvant RT after inguinal lymphadenectomy
No clear evidence for benefit in the specific penile setting
Meta-analysis (Robinson, 2018) ○ 1605 men from 7 retrospective series § Men received adjuvant inguinal radiotherapy § Indications included 3+ LN or ECE ○ No clear benefit associated with adjuvant radiotherapy § Acknowledge poor evidence base available ○ Cannot recommend it as standard therapy without evidence of benefit
Describe the EBRT technique in penile cancer
Radiotherapy +/- chemotherapy (EBRT)
Patients
1) Resected primary with adverse features
1. Close/positive margins
2) Node positive (after LN dissection)
1. Any macrometastases
3) Unresectable disease
Pre-simulation
MDT discussion
Fertility discussion
Smoking cessation
Circumcision
Simulation
Supine with arms on chest
Vacbag, knee-block and ankle-stocks
Plexiglas bivalve case for penis (bolus)
Generous CT (2mm with IV contrast)
- L2 to mid thigh (include entire kidneys)
Fusion
MR and FDG-PET fusion
Dose prescription
Primary Dose
- Resected + close/microscopically positive margins = 50Gy/25F
- Resected + macroscopic disease = 60-66Gy
- Definitive RT = 66Gy/33F
Nodal Dose
- Resected = 50Gy/25F
- Macroscopic disease = 60-66Gy
Concurrent chemotherapy (consider, no clear role)
- Cisplatin at 40mg/m2 weekly
Chemo only required if:
- node positive
- macroscopic positive margins/unresected
Technique
- Laterals for penis
- VMAT technique for nodes
10 days per fortnight
Volumes
GROSS DISEASE BOOST
* GTV
○ GTVp = primary penile disease (CT/PET/MR)
○ GTVn = involved nodal disease (CT/PET/MR)
* CTVp Boost
○ GTVp + 10mm
* PTVp Boost
○ CTVp Boost + 7mm
* Ctv entire penis
- CTVn Boost
○ GTVn + 3mm - PTVn Boost
○ CTVn Boost + 7mm
ELECTIVE / ADJUVANT
* CTVp Elective
○ Close/Positive margins = Surgical Bed + 15mm
○ Treat full thickness of penis
- CTVn Elective (not routine)
○ If declines surgical management:
○ Inguinofemoral nodes
○ If an inguinal node is positive & no pelvic surgery, include lower pelvic nodes
○ Internal and External Iliacs
○ Obturators - PTV = CTV + 7mm
Target Verification
Daily CBCT
OARs
Bladder
- V45 < 50%
Rectum
- V40 < 60%
Small Bowel
- V45 < 195cc
- Dmax < 50Gy
Kidneys
- Mean < 10Gy
Femoral heads
- Dmax < 50Gy
Spinal Cord
- Dmax < 45Gy
Describe the brachytherapy technique for penile cancer.
Brachytherapy
Patients
1) cT1-T2 N0 penile SCC (ideally <4cm lesion)
Pre-simulation
Need circumcision prior
Simulation
General anaesthetic
IDC inserted
Template affixed
6-9 needles passed
- Paris dosimetric system
- 12-15mm separation
Lead baseplate should be positioned to shield testes
Dose prescription
HDR Single Dose Level
- 38/12# BD
- 54Gy/18F
- BD over 9 days
LDR Single Dose Level
- 60Gy at 50cGy/hr
- Continuous over 5 days
Volumes
* GTV = gross tumour
* CTV = GTV + 10mm
Discuss the prognosis and follow up for patients with penile cancer.
Follow-Up
- Clinical examination every three months for the first 2 years ○ CT CAP every six months - Clinical examination every six months for years 3-5 ○ CT CAP every twelve months § Every six months if N2-N3 disease
