Management of Incidentally Detected Small Renal Masses: A Primary Care Guide Alon Z. Weizer, MD, MS Associate Professor of Urology University of Michigan

Disclosures Advisory Board for Summus eConsult platform

Learning Objectives Define Small Renal Mass Determine when referral is needed Understand How Management is determined based on patient and tumor factors Understand the role of the primary care physician in longitudinal management

Outline Case presentation Definition small renal mass Epidemiology of renal masses Determining management of small renal masses Treatment options/outcomes Surveillance/survivorship

Case presentation 53 yo man incidentally discovered 4 cm renal mass on CT obtained for elevated LFTs PMH: Type 2 diabetes, hypertension, treated hepatitis C, obesity (BMI 38) PSH: knee arthroscopy Social history: married, employed, 2 adult children, works at water treatment facility FH: no kidney disease or masses Medications: lisinopril, HCTZ, metformin, OTC ibuprofen, MVI All: none Labs, CXR normal Next steps….

What is a small renal mass? Cystic or solid lesion of the kidney measuring less than 4 cm Refers to primary kidney tumors, not urothelial or metastases Usually incidentally detected Certain patients should be managed differently: Multiple masses in one or both kidneys Family history of kidney tumors

Epidemiology Incidence: 63,000 new cases; 14,000 deaths 2:1 ratio (men: women) Occurs most frequently in 6th to 8th decade of life (rare < 40 yo) Racial differences exist with increasing incidence in AA

Epidemiology: RCC is increasing Largely attributed to increased use of cross-sectional imaging Mortality decline subtle Most renal masses detected are small with good outcomes Patients with locally advanced/metastatic disease continue to have poor survival (although TKIs have improved outcomes)

Epidemiology: Risk Factors Clinical observations from UM Median BMI 38 Trend toward decreasing age at diagnosis (17 years old youngest primary RCC) Association with Hepatitis C Chow et al, Nat Rev Urol, 2010

Epidemiology: Familial Syndromes

Appropriate Management of SRMs? Historically all SRMs are treated (biopsy considered non-informative) Arguments to avoid intervention: many tumors are benign Will not affect survival of patient Our treatments have side effect (“Do no harm”) We have tools that can give us information about how to manage SRMs (biopsy)

Management Considerations Understanding the tumor: Character (Cystic versus solid) Size Location Number of lesions Extent of disease Understanding the patient: Medical comorbidities Age Prior surgical history Family history Symptoms Understanding Risk of Interventions

Management: Tumor Characteristics Imaging goals: Determine whether the tumor is cystic or solid Size of tumor Location of tumor in reference to vascular, collecting system anatomy Assess for loco-regional disease/metastases

Cystic Lesions/Bosniak Classification

Cystic Lesions/Bosniak Classification

Size Matters in SRM Mgmt Kunkle, J Urol, 2008 N=2770 Frank, J Urol, 2003

Location/Complexity of tumors: Nephrometry Score Nephrometry.com

Number of lesions/Extent of Disease Multifocal disease warrants different evaluation Referral to tertiary center with Urologic Oncology and genetic evaluation All patients with renal masses/cysts < 40 years old are recommended to be evaluated by genetics Staging work-up can include: Labs: CBC/comp Chest imaging Abd/pelvis imaging Bone scan not indicated unless Ca, Alkaline phosphatase elevated or symptoms Brain imaging not indicated unless symptoms Risk of metastasis rare with tumors < 2 cm so imaging work-up should also be influenced by diagnosis and management

Management: Patient Factors Medical comorbidities Age Prior surgical history Family history Symptoms

Chronic Kidney Disease is an Important Consideration in How We Manage Small Renal Masses

Why does this matter for our patients with kidney cancer? CKD is actually more common than we think among patients with renal cortical tumors Baseline GFR may be associated with long-term survival Nephron sparing approaches (partial/ablation) associated with a decreased risk of post-operative chronic kidney disease and adverse renal health outcomes BUT STILL RISK WITH NS approaches

Health Implications of Chronic Kidney Disease Adverse CV Events Death An independent, graded association was observed between a reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization in a large, communitybased population. These findings highlight the clinical and public health importance of chronic renal insufficiency. Go et al, NEJM, 2004

Quantifying competing risks in RCC Age-specific mortality from kidney cancer showed relative stability within size strata; cancer-specific mortality varied inversely with tumor size.: 5.3% at 5 years for patients with tumors <= 4cm vs 18.1% for patients with tumors > 4 cm. Competing cause mortality increased with patient age, estimated at 28% at 5 years for patients 7 and older at the time of diagnosis. Hollingsworth et al, CANCER, 2007

Even Nephron Sparing approaches have potential side effects IMPORTANCE Even Nephron Sparing approaches have potential side effects

Types of Complications: Ablation Collecting system / Ureteral injury Hemorrhage Adjacent organ injury Pain/Neuromuscular injury Tumor seeding Grounding pad burns Infection Pneumothorax Cryoshock (theoretical)

Complications- Nephron Sparing Surgery Variable Partial Nephrectomy Approach Mean % (range) Laparoscopic Laparoscopic-RP Robotic Open N 11505 255 1055 9947 Acute Kidney Injury 0.7 (0.6-0.9) Not reported 3.5 (0.5-13) Death 0.3* 0.5* Nephrectomy 1.8 (0.5-4) 3.6 (1.6-7.7) Clavien 3+ 11 (0-36) 4.5* 4.9 (0-8.2) 5 (4-6.7) Embolization 1.7 (0.5-4) 0.9* 1.7 (1-2.6) 3* Urine leak 3.4 (1-8) 0-1.8 3.9 (1-16.8)** 2.5 (0.6-5.5) Blood transfusion 6.3 (1.6-12.5) 2.7-5.1 4.2 (0-7.1) 8.2 (5.1-11) Readmission 11 (10.4-11.1)* 11.9*

How Do We Balance Tumor, Patient Factors, and Risks to Help Patients Make Informed Decisions About Management of SRMs?

Observation of Renal Masses Observation of small renal masses Often used in elderly/multiple medical comorbidities Advantages Determine natural history of mass Avoid unnecessary intervention Disadvantage Risk of disease progression?

Results: most grow slowly Combined Uzzo J Urol 2005

Renal Mass Biopsy- A Christmas Carol Remix Renal Mass Biopsy at UM Past Present Future

Renal Mass Biopsy: Past The ancient past: no renal mass biopsy The more recent past at UM…

78/204 patients underwent RMB Patient factors predicting biopsy: 2009-10 Patient factors predicting biopsy: Non-Caucasian Family history Anatomic factors: Juxta-hilar tumors Increasing BMI High complexity Nephrometry score

Biopsy directed management Biopsy performed in a greater proportion of patients undergoing radical nephrectomy (identification of aggressive pathology-papillary type II) Biopsy directed management Active surveillance more common in patients with benign or low risk histology Intervention more frequent for aggressive histology Take home message- biopsy was often used to avoid intervention for technically difficult surgeries

Renal Mass Biopsy-Present What drives active surveillance?

Similar population: 73 of 204 patients underwent active surveillance Patient factors: distance from the hospital, ECOG performance status Tumor factors: tumor size, endophytic, multifocality Surgeon factors: minimally invasive surgeons more likely to operate Interestingly, biopsy did not play a major role in selecting active surveillance over treatment

Renal Mass Biopsy-Future OR the Death of Unecessary Surgery?

SRM Active Surveillance Protocol Eligibility criteria Inclusion Incidental sporadic solid renal mass 2 kidneys < 4 cm mass Percutaneous renal mass core biopsy No lymphadenopathy or metastatic disease Exclusion Hereditary syndrome ECOG > 2 Concerns over compliance Unable to obtain adequate imaging to perform surveillance

SRM Active Surveillance Protocol Histology definitions Benign – AML, adenoma, … Favorable – oncocytic, chromophobe, gr 1 pap type 1 / Intermediate – gr 2 pap type 1 / clear cell Unfavorable – pap type 2, gr 3-4 clear cell, … Indeterminate – any non-diagnostic histology

Individualizing SRM Management Renal Mass Biopsy Indeterminate Treat per histology Repeat Biopsy F/u per MD Benign F/u per MD Treat Unfavorable Intermediate Favorable

151 patients underwent renal mass biopsy and surgery over 10 years for mass < 4 cm We used this data to see if RMB would help characterize the appropriate treatment based on algorithm Biopsy diagnostic in 133 cases

36 patients assigned to surveillance based on algorithm 11 patients initially assigned to surveillance should have undergone treatment based on final pathology (issue with grade especially for clear cell) No patients went from treatment to surveillance After moving any clear cell to intermediate risk Accuracy 97%, NPV 86%, PPV 100%

How Many People Remain on AS? .2 .4 .6 .8 1 Cum. Survival 6 12 18 24 30 36 Time How Many People Remain on AS?

Renal Mass Biopsy: The Real Future? Need to use Renal Mass Biopsy to better characterize risk Grade continues to be difficult Does biopsy represent true biology of tumor? Can we learn more from RMB to refine algorithm? IHC Omics?

Small Renal Masses: Treatment Strategies

Small Renal Masses: Treatment Strategies

Take Home Message Discuss imaging with Urologist prior to referral (minimize unnecessary/unhelpful imaging) Help Urologist understand the competing medical co-morbidities of your patient Discourage direct referral to radiology if they do not partner with a Urologist Consider referral to tertiary center for young patients/multifocal disease Re-assure patients that outcomes of SRMs are good and that they have time to understand options