Contemporary Outline Management of Renal • Epidemiology Masses • Differential Diagnosis • Evaluation • Imaging Geoffrey N. Box, MD • Role for Biopsy Vice Chair of Educational Affairs Assistant Professor • Treatment Direct, Laparoscopic Urologic Surgery • Surveillance Department of Urology • Surgery The Ohio State University Wexner Medical Center • Ablation James Cancer Hospital and Solove Research Institute • Follow-up

• Cases

Renal Mass • Increasing incidence with widespread use of cross-sectional imaging

• Renal lesions are seen in 15-25% of abdominal imaging studies ‒ Most are benign cysts

• Majority are detected incidentally.

● = <2 cm, ▲ = 2 – 4 cm, ○ = >4 – 7 cm, and ∆ = >7 cm

1 Renal Mass- Differential Diagnosis Renal Mass- Differential Diagnosis

Malignant Benign Inflammatory Renal Cell Carcinoma Simple cyst Abscess -Clear Cell Angiomyolipoma Focal pyelonephritis Malignant Benign -Papillary Oncocytoma Xanthogranulomatous -Chromophobe Metanephric adenoma pyelonephritis Renal Cell Carcinoma Simple cyst -Collecting duct Cystic Nephroma Tuberculosis -Clear Cell Angiomyolipoma Urothelial Based Mixed epithelial/stromal -Urothelial tumor -Papillary Oncocytoma carcinoma Reninoma -Chromophobe -Squamous cell Leimyoma -Adenocarcinoma Pseudotumor Sarcoma Wilms tumor Carcinoid Lymphoma Leukemia Metastasis

Is it Benign or Radiographic Assessment Malignant? • Ultrasound • The question at hand. • CT • This can frequently determined by • MRI radiographic assessment.

• Size Matters • Key Point: • Current trend is to biopsy more renal masses ‒ Need to determine enhancement <4cm.

2 Ultrasound CT Scan • Triple Phase (Renal Protocol)

• Reliable for ‒ Pre-contrast differentiation of ‒ Post-contrast (venous phase) a solid lesion Cyst ‒ Delayed (10 min) Tissue HU from fluid. Bone +1000 Blood 40 • Can establish Kidney 30 the diagnosis of Water 0 a simple cyst. • Hounsfield Units (HU) Fat -50 Solid Mass ‒ Represents the density of Air -1000 tissue

Enhancement CT-Enhancement

• Can only be determined if a contrast agent is used ‒ CT – iodonated contrast • Enhancing Lesion = Pre-contrast to Post-contrast change in HU >15-20

‒ MRI – Gadolinium Pre-contrast HU: 15 • Slightly more subjective Post-contrast HU: 55

3 MRI Risk of Contrast Agents

• Pre and Post Gadolinium • IV Contrast (CT) ‒ Contrast Allergy ‒ Nephrotoxicity • Avoid with severe renal impairment • Risk reduction: Hydration

• Gadolinium (MRI) ‒ No nephrotoxicity ‒ Risk of Nephrogenic Systemic Fibrosis in those with severe renal impairment (EGFR<30).

cG250 PET/CT: Radiolabeled Antibody Fat

• 124I-cG250 • Solid masses with areas (REDECTANE®) of negative HU (<-20) ‒ Binds carbonic indicate the presence of anhydrase IX fat and are diagnostic of ‒ Clear cell RCC AMLs. ‒ Radiographic diagnosis • AML = Angiomyolipoma

• No role for CT PET- • AML is a benign tumor. FDG with renal 18F-FDG tumors. 124I-cG250

Wilex AG, Munich, Germany

4 Renal Cysts: Bosniak Renal Cysts Classification Bosniak Class Description Cancer Risk Management • The kidney is one of the most common locations in the body for cyst formation. No enhancement Smooth Wall I No Septa 0% None • Renal cysts are cavities derived from renal tubules. No Calcifications No enhancement • Composed of a layer of epithelial II Hairline Septa Minimal None cells enclosing a cavity filled with Fine Calcifications urine-like liquid or semi-solid No enhancement material. Hyperdense lesion IIF Multiple Septa <10% Surveillance Thicker Calcifications • 20% by age 40 Thickened Wall with • 50% by age 60 III Enhancement 50% Surgery IV Enhancing Nodule 90% Surgery Adapted from Campbell-Walsh Urology 10th Ed.

Renal Cysts – Bosniak Classification Case- Simple Renal Cyst I II

• Pictures of each III IV

5 Imaging Interpretation Role for Biopsy • Enhancing renal masses are most likely malignant. • Historically, renal masses have not been biopsied. • Simple Cysts (Bosniak Type I): ‒ Most are malignant ‒ Can be diagnosed by U/S or CT. ‒ Do not need follow-up. ‒ Issues with accuracy/non-diagnostic rates • AMLs are benign and can be followed ‒ Fear of needle tract seeding ‒ >4cm = greater risk for spontaneous ‒ High reported complication rates bleeding • Selective angioembolization vs. surgery

AML = Angiomyolipoma

Role for Biopsy Role for Biopsy

• Contemporary results of renal mass • Current role for biopsy is expanding biopsy: ‒ Especially for masses <4cm ‒ Diagnostic rate: 92%. • RCC Subtype Concordance: 80-100% • Updated date on biopsy results are much • Fuhrman Grade Concordance: 50-70% improved.

‒ Complications: <5% • Hematoma most common

Marconi et al. Eur Urol 2015

6 Indications: Indications: Renal Mass Biopsy Renal Mass Biopsy • R/o non-renal primary (mets or lymphoma) • R/o non-renal primary (mets or lymphoma)

• +/- R/o benign lesions • +/- R/o benign lesions

• Confirm diagnosis and histologic subtype in • Confirm diagnosis and histologic subtype in patients with metastases or unresectable patients with metastases or unresectable lesions lesions

• Confirm diagnosis: • Confirm diagnosis: ‒ Prior to ablative therapy ‒ Prior to ablative therapy ‒ In patients considering observation when ‒ In patients considering observation when surgery is high risk surgery is high risk

Indications: Renal Mass Biopsy Tumor Size and Pathology

• R/o non-renal primary (mets or lymphoma) Tumor Size RCC Benign* High Grade

• +/- R/o benign lesions ≤2.0 75% 25% 4% Biopsy only if it will change management • Confirm diagnosis and histologic subtype in 2.1-3.0 80% 20% 5% patients with metastases or unresectable lesions 3.1-4.0 84% 16% 25% • Confirm diagnosis: ‒ Prior to ablative therapy *Oncocytoma and AML – 75% ‒ In patients considering observation when surgery is high risk

J Urol 2006; 176:896

7 Renal Cancer 2015 Renal Cell Carcinoma – • Incidence Risk Factors ‒ 61,560 new cases • Tobacco Exposure ‒ 14,080 deaths ‒ May account for ~20% of cases • Obesity • Peak incidence 5th-7th decades ‒ May account for ~40% of cases in US ‒ Risk increases ~30% for every 5kg/m2 increase in BMI • Men > Women • Hypertension

• Lifetime Probability of Developing Renal Cancer: • Low socioeconomic status and urban background ►1 in 49 male (#7) • More than 100 chemicals have been investigated ►1 in 84 female (#10) but none have been definitively established as

American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015 causative in RCC

Renal Cancer – Mortality Renal Cancer – Presentation and Survival

Site Incidence/yr Deaths 2015 Stage at Prostate Cancer 220,800 27,540 (12%) Diagnosis Distribution 5-yr Survival Localized 61% 91% Bladder Cancer 74,000 16,000 (22%) Regional 17% 63% Kidney Cancer 61,560 14,080 (23%) (lymph nodes) Distant 18% 11% (metastatic)

American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015 Seer Database

8 Clinical Presentation Paraneoplastic syndromes • 80% incidental • “Internist’s Tumor” • Elevated ESR 55% • HTN 38% • Flank pain • Anemia 36% • Gross hematuria • Cachexia 35% “Classic Triad” <10% • Pyrexia 17% • Palpable mass • Elevated LFTs 14% • Microhematuria • Hypercalcemia 5% • Polycythemia 4% • Paraneoplastic syndromes (10-20%) • Neuromyopathy 3%

Campbell-Walsh Urology 10th Ed.

Clinical Presentation - RCC Renal Cell Carcinoma: Histologic Subtypes • Local Tumor Growth ‒ Hematuria ‒ Flank Pain ‒ Abdominal Mass

• Metastasis ‒ Persistent Cough ‒ Bone Pain ‒ Cervical Lymphadenopathy ‒ Constitutional Symptoms Type: Clear cell Papillary Chromophobe Oncocytoma • Obstruction of IVC ‒ Bilateral Lower Extremity Edema Freq (%): 75 15 5 5 ‒ Right-sided Varicocele (or nonreducing Varicocele)

9 Hereditary RCC VHL: Renal Cell Carcinoma

Gene • RCC occurs in 50% of VHL Disease (chromosome) Histology Frequency patients von Hippel-Lindau VHL (3) Clear Cell 75% ‒ Males=females in VHL ‒ 4th to 5th decade (39) HLRCC* FH (1) Papillary Type 2 10% ‒ Now most common cause of death Multiple Renal Cysts Chromophobe/Onc Containing RCC Birt-Hogg-Dube BHD (17) 10% ocytoma Hereditary Met (7) Papillary Type 1 5% papillary RCC

*HLRCC = Hereditary Leiomyomatosis Renal Cell Carcinoma Sporadic Inherited Clear Cell RCC

Renal Cell Carcinoma: Treatment Options Staging • Surveillance Stage Tumor Lymph Nodes Metastasis • Surgical Excision I T1 (<7cm) N0 M0 Gold Standard ‒ Radical Nephrectomy ‒ Partial Nephrectomy II T2 (>7cm) N0 M0 T1 or T2 N1 • Needle Ablation III M0 T3 (vein/fat) N0 or N1 ‒ Cryoablation or Radiofrequency Ablation T4 (outside Any N Any M IV Gerota’s) Any N M1 • RCC does NOT respond to chemotherapy or Any T radiation

10 Decision Making Active Surveillance (AS)

• Tumor Characteristics: • Incidentally detected tumors: ‒ Size ‒ Small size (<4cm) ‒ Location ‒ Elderly ‒ Appearance ‒ Patients with significant comorbidity unfit for surgery • Patient Characteristics ‒ Comorbid disease ‒ Life expectancy • Opportunity to observe the natural history ‒ Patient desire of these small tumors.

Tumor Size and Pathology Active Surveillance

• Tumors <3cm Tumor Size RCC Benign* High Grade ‒ Risk of developing metastasis in 3 ≤2.0 75% 25% 4% years is ~1% • Average growth rate ~0.3cm/yr 2.1-3.0 80% 20% 5% • Most studies only have limited follow-up 3.1-4.0 84% 16% 25% • Follow-up protocol is not defined *Oncocytoma and AML – 75% ‒ Repeat imaging every 6-12 months

J Urol 2006; 176:896

11 Active Surveillance Risk-adapted Management

• Biopsy can be helpful • AUA Guidelines: ‒ “AS is a reasonable option for • More favorable histology: patients with a limited life ‒ Papillary type 1 expectancy or for those who are ‒ Chromophobe unfit for or do not desire intervention.” ‒ Low grade: • Fuhrman grade 1 and 2.

Risk-adapted Management Surgery • 5 yr Cancer specific survival: ‒ Fuhrman Grade (clear cell RCC): • Approach? • I: 94% ‒ Open vs. Laparoscopic vs. Robotic • II: 88% • III: 63% • Radical vs. Partial Nephrectomy? • IV: 39% ‒ Nephron preservation

• Low (I&II): 90% • High (I&II): 61%

Becker et al. Eur J Surg Oncol 2015

12 PARTIAL NEPHRECTOMY Chronic Kidney • Partial nephrectomy oncologically Disease (CKD) equivalent to radical nephrectomy. 2 Leibovich et al. J Urol 2004; 171:1066 • GFR <60 ml/min/1.73m for at least 3 Breau et al. J Urol 2010; 183:903 months • L/S PN equivalent to Open PN with less morbidity. • Important consideration with significant • Technical obstacles associated morbidity and mortality • MIS- more likely to have radical nephrectomy Gill et al. J Urol 2007; 178:41 • RCC patients are NOT donor • More attention has been given to the nephrectomy patients significant morbidity associated the chronic kidney disease (GFR<60). ‒ Often have HTN and/or DM • Surgical vs. Medical Go, et al: NEJM 2004; 351: 1296 • Nephron-preservation • Median survival after starting dialysis is 2-2.5 years

Renal Cancer – Is the tumor amenable to a Nephron Preservation partial nephrectomy?

CKD Stage Death Any (Estimated GFR from Any Cardiovascular Any (ml/min/1.73m2)) Cause Event Hospitalization CKD III (30-44) 1.8 2.0 1.5 CKD IV (15-29) 3.2 2.8 2.1 CKD V (<15) 5.9 3.4 3.1

Go et al: NEJM 2004;351:1296.

13 Indications for Nephron Partial Nephrectomy Sparing Surgery • GOALS ‒ Cancer Control • Absolute/Imperative: To prevent anephric state • Margins ‒ Anatomic/Functional solitary kidney • CSS ‒ Bilateral RCC ‒ Preservation of renal function • Relative: Contralateral kidney is threatened by • Technical ability to perform NSS local, systemic, genetic conditions that may • ↓ Warm Ischemia time affect function • Selective/no ischemia

‒ DM, HTN, stones, RAS, VHL ‒ ↓ Complications • Elective: NSS with a normal contralateral kidney ‒ ↓ Convalescence • Robotics facilitates very difficult partial Uzzo: AUA Review Course nephrectomies

Partial Nephrectomy RAPN - Nationwide Inpatient Sample

• Open

• Laparoscopic

• Robotic

• Approach is not as important as preserving nephrons  partial nephrectomy

14 OSU Partial Nephrectomy Robotic Partial Nephrectomy

Robotic Open

Robotic Partial Nephrectomy

LEFT

HEAD FEET HEAD FEET

15 RIGHT ROBOTIC PARTIAL NEPHRECTOMY Margin Assessment

ROBOTICS –RAPN -Solitary Kidney -BMI: 48 -Pre-op Cr: 2.03 (eGFR-37) -Post op Cr: 2.10

Posterior Segmental A

RA

16 ROBOTICS – Partial Nephrectomy RAPN with unexpected venous thrombus video

17 Laparoscopic Renal ablative techniques Radical Nephrectomy • Potential for less morbidity/complications

• Allows treatment of older patients who are not good surgical candidates

• Potential for similar efficacy to partial Laparoscopic nephrectomy for select masses surgery is the preferred approach for most tumors

Indications for ablation of renal masses Ablative Modalities • Solid renal lesion <3cm (T1a) ‒ Not good candidates: • Tumor deep in the renal sinus • Radiofrequency Ablation (RFA) • Adjacent to the renal hilum or ureter • Anterior tumors with adjacent bowel • Cryoablation • Best suited to treat renal lesions in patients with comorbidities that preclude a major surgical procedure • Generally performed percutaneously with ‒ i.e. elderly, severe COPD, CV disease CT, MRI or U/S guidance. • Renal insufficiency • Solitary kidney • Multifocal/Recurrent tumors secondary to VHL, BHD etc

Leveilee R, Wingo M. Ablation technologies for renal cell carcinoma: Oncology spectrum 1(2)

18 Percutaneous cryoablation Laparoscopic cryoablation

Laparoscopic cryoablation Post-ablation imaging

2 weeks 6 weeks 3 months

19 Treatment Options: Treatment Options - Summary LOCAL RECURRENCE FREE SURVIVAL

Treatment Survival Tumor Size (cm) F/U (mo) • Surgery • Gold Standard RFA 87.0% 2.7 19 • Suitable for tumors of all sizes • Nephron-sparing when possible Cryo 90.6% 2.6 18 • Minimally invasive approaches available LPN 98.4% 2.6 15 • Needle Ablation OPN 98.0% 3.1 47 • Tend to have higher local recurrence LRN 99.2% 4.6 18 rates ORN 98.1% 4.8 58 • Active Surveillance • Long term outcomes unknown RFA=radiofrequency ablation; Cryo=cryoablation; • Not best for younger/healthier patients LPN=laparoscopic partial nephrectomy; OPN=open partial nephrectomy LRN=laparoscopic radical nephrectomy; ORN=open radical nephrectomy

Adapted from Campbell-Walsh Urology 10th Ed.

Advanced Disease Robotic Nephrectomy with IVC Thrombectomy • Surgery remains an integral part of the management of these patients. IVC

‒ Tumor thrombus in IVC ‒ Regional Lymphadenopathy IVC ‒ Metastatic disease

• Surgery is the only treatment that offers the opportunity for cure IVC

20 Robotic Nephrectomy with Robotic Nephrectomy with IVC Thrombectomy IVC Thrombectomy

IVC

IVC

IVC

21 Metastatic Renal Cell Carcinoma Case: • Cytoreductive nephrectomy Simple Renal Cyst

Median Survial 13.6 mo vs. 7.8 mo

J Urol 2004; 171:1071

Case: Case: 2 cm Enhancing Renal Mass Left 9 cm Renal Mass & 4 cm Adrenal Mass

22 Conclusion • Renal masses are typically found incidentally

• A simple renal cyst can be diagnosed by U/S or CT and does not need follow-up

• Most solid renal masses represent renal cell carcinoma

• Nephron-sparing surgery should be perform when technically feasible.

• Most surgery can be performed in a minimally invasive fashion (laparoscopic/robotic)

23