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RCC in ADPKD / CKD / ESRD
FOIU 2018 David A. Goldfarb, MD,FACS
Professor of Surgery,
Cleveland Clinic Lerner College of Medicine
Glickman Urological and Kidney Institute
Cleveland Clinic, Cleveland, Ohio
Disclosure
• No financial disclosures
• Discussion of off label use of mTOR inhibitors
2017 Annual Data Report
Volume 1 CKD, Chapter 3 3
vol 1 Figure 3.1 Unadjusted and adjusted all-cause mortality rates per 1,000 patient-years at risk for Medicare patients
aged 66 and older, by CKD status and year, 2003-2015
(a) Unadjusted
Data source: Special analyses, Medicare 5% sample. January 1 of each reported year, point prevalent Medicare patients aged 66 and older. 1b adjusted for age/sex/race and 1c adjusted for age/sex/race/comorbidities. Standard population Medicare 2014 patients. Abbreviation: CKD, chronic kidney disease.
2017 Annual Data Report
Volume 1 CKD, Chapter 3 4
vol 2 Table 5.4 Expected remaining lifetime (years) by age, sex, and treatment modality of prevalent dialysis patients and transplant patients,
and the general U.S. population, 2013
ESRD patients
2013
General U.S. population
2013
Dialysis Transplant
Age Male Female Male Female Male Female
0-14 23.8 23.1 59.3 60.3 70.7 75.4
15-19 21.8 19.1 47.6 48.7 59.7 64.4
20-24 18.8 16.1 43.4 44.5 55.0 59.5
25-29 16.2 14.1 39.4 40.7 50.3 54.6
30-34 14.1 12.6 35.1 36.6 45.7 49.7
35-39 12.6 11.5 31.1 33.0 41.0 45.0
40-44 11.0 10.3 27.2 28.9 36.5 40.3
45-49 9.3 8.8 23.3 25.2 32.0 35.6
50-54 7.9 7.7 19.9 21.8 27.7 31.1
55-59 6.6 6.6 16.7 18.4 23.7 26.8
60-64 5.5 5.7 13.9 15.4 19.9 22.6
65-69 4.6 4.8 11.4 12.7 16.2 18.6
70-74 3.8 4.0 9.4 10.3 12.8 14.8
75-79 3.2 3.5 7.6a 8.6a 9.8 11.4
80-84 2.6 2.9 7.1 8.4
85+ 2.1 2.3 3.8 4.4
Data Source: Reference Table H.13; special analyses, USRDS ESRD Database; and National Vital Statistics Report. “Table 7. Life expectancy at selected ages, by race, Hispanic origin, race for non-Hispanic population, and sex: United States, 2013 (2016).” Expected remaining lifetimes (years) of the general U.S. population and of period prevalent dialysis and transplant patients. aCell values combine ages 75+. Abbreviation: ESRD, end-stage renal disease.
Acquired Renal Cystic Disease
• Common in CKD / ESRD
• Associated with RCC
• Etiology??
Epidemiology of ESRD and Renal Cancer How you sample drives the incidence
• Autopsy: dialysis population - Dunhill 1977: ARCD (47%), RCCa (20%)
- Miller 1989: ARCD(58%), AD(16%), RCCa(2%)
• US screening - Terasawa 1994:RCCa(2.6%) (1603 dialysis pts)
- Gulanikar 1998:ARCD (31%), RCCa(3.8%)
• Nephrectomy at Tx (selected ESRD /CKD population study, 260 kidneys)
- Denton 2002: ARCD 85/260 (33%), AD 35/260 (14%), RCC 11/260 (4.2%)
Incidence of Renal Cancer
• Assymptomatic General Population* – 0.045%
• ESRD / dialysis – 2-8%
*Tosaka, J Urol, 146:618, 1991
0.045 x 100 = 4.5%
Associations with ARCD
• Age
• Dialysis duration
• Male
• AA vs. Caucasian
• HD vs. PD
• Diagnosis: GN, DM
Pathology of RCCa in ESRD 52 ESRD pts., 66 kidneys, 261 tumors
• ~40% tumors are classic papillary(15%), clear cell(18%), chromophobe(8%)
• ~60% are new histological classifications - Acquired renal cystic disease associated RCCa
(ARC-RCC) 36%
- Clear cell tubulo-papillary RCC 23%
Tickoo, Am J Surg Path, 2006
Acquired Renal Cystic Disease Associated Renal Cell Carcinoma
• Abundant eosinophilic cytoplasm
• Clear cytoplasmic vacuoles giving ‘sieve’ like appearance
• Large nuclei, prominent nucleoli
• Oxalate crysstals
Acquired Renal Cystic Disease Associated Renal Cell Carcinoma Pryzbycin et al, Am, J Surg Path, 2018
• 40 pts, 1990-2015, multi-institutional
• 90% dialysis, mean duration 80 mos.
• F/U 32 pts - 24 (67%) Alive, NED, 27 months
- 4 died of other causes
- 4 adverse events: local recurrence, metastasis, DOD
• Unique pattern local recurrence
• Distinct entity in 2016 WHO classification
New Categorization of RCCa in ESRD / ARCD
ARD – RCC
• Differences in histology, molecular markers and genetic markers suggests the possibility of a different biology (oncogenesis and natural history) from conventional histological types
ADPKD and Renal Cell Cancer
• Literature sparse
• A clear association never shown
• No clinical epidemiological or molecular data to demonstrate increased risk
• Several studies now support an association
ADPKD / RCCa Hajj et al, Urology, 74:631, 2009
• Surgical path, 1982-2003, 79 pts / 89 Nx’s
• 50/79 (63%) on HD, or Tx x 1 year
• 11/89 (12.3%) with cancer, 5 Nx’s due to mass
• All pT1a, mean size=1.8cm
• 58% clear cell, 42% tubulopapillary
• Surgical path, 2000-2010,177cases, 6 cases ADPKD
• 2 cases RCCa (clear cell), 1 papillary adenoma
Lane et al, Open J Urology, 1:11, 2011
ADPKD / RCCa Jilg et al, Nephron Clin Practice, 123:13, 2013
• Surgical path, 301 kidneys/891 registry pts
• Indication: Tx, symptoms, mass
• 16 malignancies – 5.3%
• 66.7% of those on dialysis
• Histology: Papillary 63%, Clear cell 31%
• Suprisingly high incidence of RCCa
RCC in ADPKD
• The role of dialysis and the confounding influence of ARCD is unknown
• Surgical series can underestimate the incidence as it is driven by radiologic dx.
• Activation of mTOR pathway, favor renal tubular cell proliferation
Imaging Challenges for CKD / ESRD: US, CT, MRI
US
CT
MRI
Imaging in ESRD • US for screening – low resolution
• CT +/- contrast, nephrotoxicity, allergy
• MRI – warning for GBCA and NSF
• Potential new technologies - Lanzman, Radiology, 265:799, 2012
• Arterial spin labelling, noncontrast MRI
- Taouli, Radiology, 2009 251:388, 2009 • Diffusion weighted MRI -Tumors with lower ADC than cyst
Transplantation for Renal Cell Carcinoma: Wait Time Penn. Transplantation. 55:742, 1993
Goldfarb et al, Transplantation,12:1726, 1997
High Risk Low Risk
High stage ( T2) Low stage ( T2)
Extensive disease Low volume disease
Synchronous B/L Nx Nephron sparing surgery
Symptomatic Incidental / screening
Waiting Period No Waiting Period
Wait Time: Contemporary Assessment
• Predictive tools to calculate outcomes based on pre- and post-op findings
• Kutikov, JCO, 2010 – competing risks calculator
• Kutikov, J Urol, 2012 – competing risk calculator adjusted for comorbidity
• Cancernomogrms.com
Survival on Dialysis is the Better Comparator – USRDS
Varies by age, dialysis modality, diagnosis, era,
race, gender
USRDS 5yr
survival
66yo=0.27
USRDS 5yr
survival
46yo=0.44
Modality
Survival
Probability
at 5yrs
Dialysis 0.35
Transplant 0.73
2 patients – 5 year predictions Using Competing Risks
• 46 yo
• Male
• Dialysis
• 2.5cm mass
• Kutikov 2010 nomo - RCCa 1%
- Other 3%
• 66 yo
• Male
• Dialysis, PTCA/stent
• 7cm mass
• Kutikov 2012 nomo - RCCa 7.7%
- Other 20.1%
Proof of Principle Preemtive Transplant in VHL with Tumor
Can be low risk for recurrence
• 40 yo , man , VHL
• Angioma, stable CNS
• R radical, L partial
• Unresectable recurrence
• eGFR 32-47
• L NX with LUD Tx
• Multifocal T1a
• Clear cell, Fuhrman 2
• IL2/FK/MMF/Pred
• Creat 2
• mTor switch at 6 mos
• Creat 1.7 @ 3 yrs
Transplant in RCCa - Limitations
• 30 yo, female, VHL
• CNS hemangioblastoma
• eGFR 25
• B/L Nephrectomy
• Clear cell / papillary
• Fuhrman 2
• Venous invasion
• pT3a
• Wait time needed