EAU Guidelines recommendations on upper tract urothelial carcinoma. Oliver Hakenberg Department of Urology Rostock University Germany

Transcription

1 EAU Guidelines recommendations on upper tract urothelial carcinoma Oliver Hakenberg Department of Urology Rostock University Germany

2 Urothelial carcinoma 6% 2% 90% 2%

3 Evidence-based guidelines

4 Upper tract urothelial carcinoma (UUT) 5-10% of all urothelial carcinoma cases incidence 2/ /3 are multifocal renal pelvis UUTs are 2-3 times more common than ureteral UUTs 60% of renal pelvis UUTs are invasive

5 UUT 1% are synchronous bilateral metachronous bilateral occurrence 2-6% relation to bladder UC: 17% have synchronous bladder UC in 2-6% occurrence after bladder UC in 22-47% bladder UC occurs after UUT Cosentino M et al, World J Urol 2012 Novara G et al, Int J Urol 2009 Margulis v et al, Cancer 2009

6 Upper tract urothelial carcinoma 60% are invasive at diagnosis compared to 15-25% of bladder UC age peak years male: female = 3:1 Cosentino M et al, World J Urol 2012 Novara G et al, Int J Urol 2009 Margulis v et al, Cancer 2009

7 hereditary syndromes of UTUCs Lynch Syndrome II colon cancer without polyposis but with extra-colonic tumours, e.g. UTUC mean age 55 years, more common in females Muir-Torre syndrome Cancer Family syndrome familial transitional cell carcinoma syndrome Lynch et al, J Urol 1990 Frischer et al, J Urol 1985 Orphali et al, Urology 1986

8 HNPCC = Lynch syndrome hereditary non-polyposis colorectal carcinoma familial/hereditary UTUC HNPCC hereditary non-polyposis colorectal carcinoma (Lynch Syndrom) suspect if patient < 60 years with history of an HNPCC-associated cancer 1rst degree relative < 50 years with HNPCC-associated cancer or twoo 1rst degree relatives with 1.Grades HNPCC-associated cancer then DNA sequencing for the identidification of hereditary casers that have been misclassified as sporadic cases close follow-up + genetic counselling Rouprêt M et al Eur Urol 2008 Audenet F et al, BJU Int 2012

9 EAU guidelines 2015

10 Are there differences between upper and lower tract UC? bladder and ureter urothelium from different embryological structures differ in uroplakin content and keratin expression pattern differences in extracellular matrix proteins hypermethylation and microsatellite instability are more common in UTUC invasive disease more common in UTUC

11 Molecular biology of UTUC UTUC has some common risk factors and molecular characteristiocs in common with bladder UC but is not identical some genetic polymorphisms are associated with increased incidence and faster progression of UTUC two identifdied polymorphisms with increased risk: variant allele, SULT1A1*2, reduced sulfotransferase activity on T allele of rs on chromosome 8q24 Rouprêt M et al, J Urol 2012 Rouprêt M et al, Cancer Epidemiol Biomarkers Prev 2007

12 Histological variants of UTUC 65% plain urothelial carcinoma 25% mixed form, always high grade (mostly renal) micro-papillary clear cell neuro-endocrine lympho-epithelial < 10% squamous cell carcinoma associated with inflammation, urolithiasis, etc. < 1% adenocarcinoma rare: small cell cancer very rare: sarcoma colecting duct carcinoma: very similar Olgac S et al, Am J Surg Pathol 2004 Perez-Montiel D et al, Mod Pathol 2006

13 2004 WHO PUNLMP - papillary urothelial neoplasia of low malignant potential low-grade carcinoma high-grade carcinoma

14 Symptoms of UTUC most common symptom: hematuria macroscopic or microscopic (70-80%) flank pain: 20-40% flank tumour: 10-20% incidental on follow-up after bladder UC Inman BA et al, Cancer 2009 Raman JD et al, Urol Oncol 2011

15 UTUC diagnosis CT urography is the gold standard (grade A, EAU guidelines) sensitivity 96% for 5-10 mm 89% for up to 5 mm 40% for under 3 mm MRI sensitivity > 75% for UTUC of 2 cm Cowan NC. Nat Rev Urol 2012 Dillman JR et al, Abdom Imaging 2008 Vrtiska TJ et al, AJR Am J Roentgenol 2009

16 UTUC diagnostic work-up cystoscopy - mandatory (grade A, EAU guidelines) ureteroscopy allows direct visualization + biopsy + grading flexible ureteroscopy can reach all calyces in 95% of cases valid bioptic diagnosis possible in 90% of cases (10% false-negative!) Messer J et al, BJU Int 2011 Johannes JR et al, J Urol 2010 Chen AA et al, J Endourol 2008

17 Urine cytology and FISH positive urine cytology with negative cystoscopy = highly suspicious for UTUC sensitivity of cytology and FISH for UTUC lower than for bladder UC selective urine sampling before contrast media

18 Ureteroscopy diagnosis selective urine cytology biopsy electroresection/ -coagulation for conservative treatment

19 Tanaka et al, Urol Int 2015 PET/CT

20 Risk of contralateral metachronous UUT Novara et al, Int J Urol 2009

21 EAU guidelines 2015 EAU guidelines: diagnosis

22 Molecular tissue markers: prognosis from retrospective series cell adhesion (E-cadherin, CD24), cell differentiation (snail, EGFR) angiogenesis (hypoxia-inducible Faktor-1α, metalloproteinases), proliferation (Ki67), epitheliale-mesenchymal transition (snail), mitosis (aurora-a), apoptosis (Bcl-2, survivin) vascular invasion (récepteur d origine nantais RON, c-met protein MET) none of these can be used clinically as yet micro-satellite instability (MSI) is an independent prognostic factor; indicates mutations with potential heredity. Eltz S et al, BJU Int 2008 Comperat E et al, J Urol 2008 Scarpini S et al, Urol Oncol 2012

23 Margulis et al, Cancer 2009 Survival after treatment

24 Age and survival probability after RNU for UTUC Shariat et al, BJU Int 2009

25 Prognosis of UTUCs stage + grade muscle-invasive 5-year DSS < 50% for pt2/pt3 < 10% for pt4 positive lymph nodes with extranodal extension lymphovascular invasion synchronous CIS sessile vs papillary localization ureteral and multifocal tumours have worse prognosis Lehmann J et al, Eur Urol 2007 Fajkovic H et al, J Urol 2012 Ouzzane A et al, Eur Urol 2011

26 Predictors of muscle-invasion or non-organconfined UTUCs Favaretto et al, BJU Int 2012

27 A nomogram: prediction of non-organ-confined UTUC n= 1453 UTUC cases with nephroureterectomy Margulis V et al, J Urol 2010

28 Survival probability: TALL score TALL score (1 7) sum of T ( T1 = 1, T2 = 2, T3 = 3 and T4 = 4), A (papillary = 0 and sessile = 1), LVI (absent = 0 and present = 1), L (LAD = 0 and no LAD = 1). Youssef et al, World J Urol 2015

29 EAU guidelines 2015 Prognostic factors for survival

30 EAU guidelines 2015 Risk stratification for treatment

31 Standard treatment recommendation: radical nephrouretereectomy with bladder cuff EAU guidelines 2015

32 EAU guidelines 2015 UTUC conservative treatment

33 EAU guidelines 2015 Management flow chart

34 EAU guidelines 2015 Recommendations for follow-up

35 Rostock

36 risk factors for UTUC tobacco (risk increase 2.5-7fold) aromatic amines (benzidine, β-naphthalen) OR banned since 1960s (phenacetin) banned since 1970s aristolochic acid (d-aristolactam causes p53 mutation) endemic Balkan nephropathy chinese herbs (aristolochia fangchi, a. clematis) high incidence in Taiwan (arsenic exposure in drinking water) Colin P et al, BJU Int 2009 Grollman AP et al, Proc Natl Acad Sci USA 2007 Nortier JL et al, N Engl J Med 2000

37 Follow-up of UTUC after radical nephroureterectomy: minimum 5 years non-invasive UTUC cystoscopy + urine cytology after 3 months, then every year CT every year invasive tumour cystoscopy + urine cytology after 3 months, then every year CT urography after 6 months for 2 years, then yearly after organ-sparing treatment for at least 5 years urine cytology and CT urography after 3 and 6 months, then yearly cystoscopy + ureteroscopy + cytology after 3 months, then every 6 months for 2 years, then yearly European Association of Urology Guidelines 2015