RCC in ADPKD / CKD / ESRD Goldfarb b.pdfRCC in ADPKD / CKD / ESRD FOIU 2018 David A. Goldfarb, MD,FACS Professor of Surgery, Cleveland Clinic Lerner College of Medicine Glickman Urological

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