THE PATHOLOGY OF COMMON RENAL TUMORS. Victor E. Reuter, M.D Memorial Sloan Kettering Cancer Center

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1 THE PATHOLOGY OF COMMON RENAL TUMORS Victor E. Reuter, M.D Memorial Sloan Kettering Cancer Center A Practical Approach to Genitourinary Pathology Firenze, Italy May, 2016 Disclosures: none

2 1970 WHO classification: RENAL NEOPLASIA Landmarks in the pathological classification over the past 4+ decades Clear cell, Papillary, Granular, Sarcomatoid 1976: Oncocytoma (Klein and Valensi) Cancer 1976;38: : Papillary Renal cell carcinoma (Mancilla-Jimenez et al) Cancer 1976: 38: : Chromophobe RCC (Thoenes and Storkel) Virchow s Arch 1985;48:207 and J Pathol 1988;155: : Classification of RCC (Thoenes and Storkel) Pathol Res Pract 1986;181: : The Heidelberg classification 2004: WHO classification 2013: ISUP-Vancouver classification Am J Surg Pathol 2013;37: WHO classification : IGC, TCGA et al ; genomic classification of RCC

3 CLASSIFICATION OF RENAL EPITHELIAL TUMORS* Clear cell carcinoma Papillary carcinoma Chromophobe carcinoma Oncocytoma Multilocular cystic renal cell neoplasm Renal cell carcinoma with fibromuscular stroma Collecting duct carcinoma Medullary carcinoma Mucinous Tubular and Spindle Cell carcinoma MiTF-family translocation associated carcinoma BHD-associated renal tumor Tubulocystic carcinoma Clear cell papillary Hereditary leiomyomatosis renal cell carcinoma SDH related carcinoma TSC related carcinoma Circa 1985: Clear cell Papillary Granular cell Sarcomatoid

4 Heidelberg, 1995

5 Comprehensive molecular characterization of clear cell renal cell carcinoma: The Cancer Genome Atlas Network Nature Jul 4;499:43-9

6 Oostewijk et al Eur Urol, 2011;60:620

7 CLEAR CELL RENAL CELL CARCINONA 60% - 65% of renal epithelial neoplasms mean age at presentation: 6 th to 7 th decade - younger in hereditary cases M:F :1 Most are asymptomatic at presentation - triad (hematuria/ pain/ mass) in < 10% 10% multifocal, 3% bilateral VHL VHL is a tumor suppressor gene at 3p25.3 Well established role in CCRCC tumorigenesis Silencing via multiple mechanisms PBRM1 mutations (41%) SWI/SNF Inactivation of histone modifying genes

8 CLEAR CELL RENAL CELL CARCINONA Microscopic features: variable growth pattern, loosely related to grade - solid/acinar, delicate fibrovascular septa - sheet-like, pseudopapillary, rhabdoid, sarcomatoid fibrosis and hyalinization are common geographic necrosis and hemorrhage are common cell shape is variable, loosely related to grade cytoplasm is variable, loosely related to grade

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10 The many cytomorphologies of clear cell RCC

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12 Feature Score T stage: pt1 0 pt2 1 pt3 2 pt4 2 N stage: pnx or pn0 0 pn1 or pn2 2 M stage: pm0 0 pm1 4 Tumor size (cm): < Nuclear grade: Necrosis: Absent 0 Present 2 The SSIGN scoring algorithm SSIGN score % Estimated cancer specific survival 1-year 3-year 5-year 7-year 10-year The scores from each category in this table are added together and the total is used to determine survival Frank et al. J. Urol. 2005;.173: 48 51) International Journal of Urology 2010;18:20

13 49% 29% 8% 8% 6% Kapur P et al, Lancet Oncol. 2013;14:159 Hakimi AA et al Eur Urol Renal-call carcinoma: a step closer to a new classification Choueri et al, Lancet Oncol.2013;14:105

14 WILL THE FURHMAN NUCLEAR GRADING SYSTEM SURVIVE? Virtually nobody applies strict size criteria Follow-up data does not support 4 risk groups Four tiered grading schemes suffer from reproducibility issues Furhman Nuclear Diameter Nuclear Shape Nucleoli G1 10 μm Round, uniform Absent G2 15 μm Subtle irregularities Visible at 400X G3 20 μm Obvious irregularities Visible at 100X G4 20 μm, bizarre, spindle

15 WILL THE FURHMAN NUCLEAR GRADING SYSTEM SURVIVE? Delahunt et al, AJSP, 2011;35:1134 Nucleolar grade is superior to nuclear grade in clear cell RCC Difference between nucleolar grade 2 & 3 is magnificationdependent Delahunt et al, AJSP, 2013;37:311 Novel grading system for clear cell carcinoma incorporating necrosis Nucleolar (ISUP) grade Coagulative necrosis Sarcomatoid or rhabdoid morphology

16 NUCLEOLAR GRADE 100X magnification Grade 1 Grade 2 Grade 3 Grade 4: Rhabdoid, Sarcomatoid

17 THE IMPORTANCE OF THE RENAL SINUS AND ITS VESSELS IN PREDICTING TUMOR PROGRESSION Bonsib SM et al Am J Surg Pathol, 2000;24:451 Leibovich BC et al, J Urol, 2005;73:716 Bonsib SM, Am J Surg Pathol, 2004;28:1594 Thompson RH et al Am J Surg Pathol, 2007;31:1089 Bonsib SM, Mod Pathol, 2007;20:44 The end result is modification of the AJCC/UICC staging classification (2010, 7 th ed) where Renal Vein Invasion below the diaphragm and Invasion of Muscular Branches of the Renal Vein are both pt3a

18 ANATOMY OF THE KIDNEY

19 CLEAR CELL CARCINOMA Feifer A, et al. J Urol. 2011;185:35-42

20 CLEAR CELL RENAL CELL CARCINONA Differential diagnosis: Papillary RCC Chromophobe RCC Epithelioid AML RCC with fibromuscular stroma Translocation-associated RCC Adrenal cortical carcinoma Metastatic disease

21 TUMORS COMPOSED PREDOMINANTLY OF CLEAR CELLS Tumor type CA IX CK7 CD 117 Cathepsin-K HMB45 Clear cell RCC Clear cell papillary RCC Chromophobe RCC, classic Epithelioid AML MiTF-TFE tumors Xp11 family t (6;11) Positive, diffuse membranous Positive, cuplike Negative Negative Negative Negative Negative Positive Negative Negative Negative Positive, cytoplasmic Positive, membranous Negative Negative Negative Negative Positive, cytoplasmic Variable but focal Variable but focal Negative Negative Positive (50%), cytoplasmic Negative Negative Positive, cytoplasmic Negative Positive, cytoplasmic Negative * Positive (always focal)

22 Immunohistochemistry for classification General comments (isuporg.org) Over a dozen entities to deal with Dozens of antibodies have been evaluated in at least one publication Nothing better than level II or Level III evidence (no validation studies) Inter-laboratory variability clone, methodology Most studies do not focus on hard to classify tumors but rather classic cases Best applied as Ab panels, taking into consideration a differential diagnosis tumors with clear cell cytology tumors with a predominant papillary pattern of growth high grade tumors with pleomorphic features

23 Clear cell RCC Vimentin CA IX EMA

24 PAPILLARY RENAL CELL CARCINOMA 13% to 18% of renal epithelial neoplasms M:F :1 mean age at presentation in the 6 th -7 th decade - earlier in hereditary cases most cases are asymptomatic

25 Therapeutic approach to selected type 1 papillary RCC HGF Met receptor Tyrosine kinase inhibition Activating mutation

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27 PAPILLARY RENAL CELL CARCINOMA Microscopic features: broad morphologic spectrum - papillary, papillary/tubular, papillary/solid classic features -discrete papillary fronds with central fibrovascular core - cuboidal, columnar or polygonal cells - cytoplasmic basophilia, amphophilia or eosinophilia - psammoma bodies, foamy macrophages - geographic necrosis

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29 PAPILLARY RENAL CELL CARCINOMA

30 PAPILLARY RENAL CELL CARCINOMA GROWTH PATTERN CYTOPLASMIC FEATURES Pure papillary 27 (32.5%) > 50% papillary* 36 (43.4%) < 50% papillary* 20 (24.1%) * also tubular, solid, spindled, glomeruloid Eosinophilic 10 (12.0%) Amphophilic 13 (15.7%) Basophilic 4 ( 4.8%) Mixed 56 (67.5%)

31 Amin et al. Am J Surg Pathol. 21:621,1997.

32 Type 1 PRCC Type 2 PRCC

33 Delahunt et al. Hum Pathol. 32:590,2001 Sukov et al. J Urol 187:54; Furhman grade superior to tumor type Delahunt et al. AJSP 37:311; ISUP nucleolar grade but not necrosis

34 PAPILLARY RENAL CELL CARCINOMA HISTOLOGIC SUBCLASSIFICATION Type Cell size Cytoplasm Grade Molecular classification 1 small pale and 2A small and large pale and eosinophilic A large eosinophilic B large eosinophilic Yang, X. J. et al. Cancer Res 2005;65:

35 Type 1 Type 2a Type 2b

36 Current state of papillary renal neoplasia It s a mess Type 2 papillary RCC is not an entity How many morphologic, clinical and molecular entities are included is yet to be defined Type 1 papillary RCC is better defined but needs fine tuning Some papillary RCC have morphologic features of both type 1 and type 2 tumors

37 Papillary Renal Cell Carcinoma Morphologic continuum? Grade related?

38 MSKCC study on Type 1 Papillary RCC We investigated the clinicopathological features, including cancer specific (CSS) and progression free survival (PFS), of PRCC with any type 1 component, based on the premise that the presence of even focal typical type 1 morphology would define the tumor classification 199 cases of PRCC with the WHO-defined type 1 features, diagnosed at our institution from 1995 to Tumors with type 2 features were included if any identifiable type 1 areas were present. The type 2 areas were quantified in tumors with mixed histology. Various pathological features were evaluated. Clinical features and follow up information were obtained from an IRB-approved annotated clinical database. Murugan P et al, USCAP 2015

39 0% 2% 4% 6% 8% 10% 12% Probability of Cancer-Specific Mortality 0% 2% 4% 6% 8% 10% 12% Type 1 Papillary RCC Study There were 10 patients who died of disease and 12 who recurred. The median follow-up time among those who did not die of disease was 7.8 years (IQR: 5.7, 10.0). Figure 1: Probability of a recurrence Figure 2: Probability of cancer-specific mortality Years since Nephrectomy Years since Nephrectomy Number at risk Number at risk The Kaplan Meier estimated probability of recurrence at 15 years of follow-up was 7% (95% CI 4%, 11%) and for cancer-specific death was 6% (95% CI 3%, 10%). Murugan P et al, USCAP 2015

40 MSKCC phase 1 study on Type 1 Papillary RCC 95 tumors (48%) contained some type 2 component; the median amount of type 2 morphology was 25% (IQR: 10%, 70%). PFS and CSS showed no significant association with the presence of type 2 morphology in the tumor (p=0.2 and 0.2, respectively) or its percentage (p=0.052 and 0.13, respectively). Associations with cancer specific survival (CSS) rates: Tumor size (p=0.003) Mitotic rate (<0.0001) Circumscription (0.0002) Lymphovascular invasion (LVI) (<0.0001) (6/6 pts DOD) Sarcomatoid and solid architectures (<0.0001, and 0.014) Murugan P et al, USCAP 2015

41 MSKCC phase 1 study on Type 1 Papillary RCC conclusions PRCC with any component of type 1 morphology, regardless of presence or amount of type 2 features, have excellent long-term outcome. Both predominant Fuhrman and ISUP nucleolar grades are significantly associated with clinical outcome, but focal high grade nuclear or nucleolar features are not. Tumor size, mitotic rate, tumor circumscription, lymphovascular invasion, sarcomatoid and solid architectures are significantly associated with outcome in type 1 papillary RCC. Murugan P et al, USCAP 2015

42 PAPILLARY RENAL CELL CARCINOMA Differential diagnosis: Clear cell RCC with pseudopapillary areas Clear cell papillary RCC Metanephric adenoma Translocation-associated RCC Metastatic carcinoma ACDK-associated RCC Hereditary leiomyomatosis PRCC syndrome

43 TUMORS WITH A SIGNIFICANT PAPILLARY COMPONENT CAIX CK7 AMACR Cathepsin-K 4A4 TFE3/TFEB Clear cell RCC with papillary growth Papillary RCC type I Papillary RCC type II Clear cell papillary RCC MiTF-TFE trans-assoc Positive, membranous Negative Negative Negative Negative Negative Negative Positive Positive Negative Negative Negative Negative +/- positive Positive Negative Negative Negative Positive, cup-like Variable but focal Positive, diffuse Negative Negative Negative Negative Negative Positive Positive (50%) Negative Positive* Collecting duct Ca Negative Positive +/- positive Negative Positive Negative

44 Papillary RCC CK7 AMACR Vimentin CAIX

45 Metanephris adenoma Type 1 PRCC (solid) Wilms tumor WT-1 + CD57 + BRAF + CK7 + AMACR + WT-1 +

46 Papillary adenoma Definition (WHO 2016) Size: 15 mm or less Papillary, tubulo-papillary or solid Fuhrman grade 1-2 Nucleolar grade 1-2 No peritumoral pseudocapsule

47 CHROMOPHOBE RENAL CELL CARCINOMA 6% to 11% of renal epithelial neoplasms M:F :1 mean age at presentation in the 6 th -7 th decade 10% multifocal, 3% bilateral asymptomatic in 58% hematuria in 19%, palpable mass in 30%

48 MICROSATELLITE ANALYSIS IN CHROMOPHOBE CELL RENAL CARCINOMA CASE: = LOH = No LOH NI= Not informative Bugert et al. Lab Invest 76: ,1997.

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50 CHROMOPHOBE RENAL CELL CARCINOMA Microscopic features: dominated by large round-to-polygonal cells with well defined cell borders and amphophilic to basophilic reticulated cytoplasm smaller number of polygonal cells with eosinophilic cytoplasm larger cells with abundant foamy cytoplasm hyperchromatic nuclei with irregular membranes binucleate cells are common bizarre nuclei (degenerative atypia) in up to 50%

51 CHROMOPHOBE RENAL CELL CARCINOMA

52 CHROMOPHOBE RENAL CELL CARCINOMA May be confused with clear cell RCC. Alternatively some clear cell RCC may have chromophobe-like areas

53 Kidney TCGA Unsupervised clustering of DNA copy number profiles KICH TCGA early data

54 Clear cell RCC - TCGA Case Outliers* Pathology review** Category Number Clear cell/likely clear cell 18 Clear cell papillary 4 Chromophobe/likely chromophobe 15 Oncocytoma/likely oncocytoma 2 Not clear cell or chromophobe 6 Not reviewed 16 Total 61 *Outliers: Chomo-like genotype wtvhl No 3p loss ** Pathologists Satish Tickoo (MSKCC) Pheroze Tamboli (MDACC) Maria Merino (NCI) Sabina Signoretti (DFCC) Victor Reuter (MSKCC)

55 CHROMOPHOBE CARCINOMA Predictors of Aggressive Behavior on multivariate analysis Predictor Relative Hazard ratio (p) 95% CI Sarcomatoid change 4.7 (0.013) 1.4, 16.0 Microscopic necrosis 3.5 (0.020) 1.2, 10.0 pt stage (3,4 vs 1,2) 3.4 (0.025) 1.1, 9.7 Tumor size (>7.5cm) 1.0 (0.75) 0.9, 2.2 Amin et al. Am J Surg Pathol. 2008

56 Table 2. Cox regression to evaluate predictors of disease-free survival following nephrectomy for chromophobe renal cell carcinoma, adjusted for age at surgery Characteristic Hazard Ratio 95% CI P Value adjusted for age Gender (Female vs Male) , Tumor size (cm) , T stage, 2010 AJCC classification T2a/b vs T1a/b , 2.76 T3a/b, T4 vs T1a/b , Nodal status at presentation NX vs N , 2.40 N1 vs N , Microscopic necrosis (yes vs no) , Gross necrosis (yes vs no) , Sarcomatoid differentiation (yes vs no) , Mitotic count (> 1/10 HPF vs 1/10 HPF) * * * Vascular invasion (yes vs no) , Capsular invasion (yes vs no) , Renal sinus invasion Yes vs No , 3.13 Not interpretable vs No , cases Median f/u: 6.1 yr Mets at presentation: 5 Progression after surgery: 8 Renal sinus vessel invasion Yes vs No , 5.78 Not interpretable vs No , Przybycin Am J Surg Pathol 2011;35:962

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61 CHROMOPHOBE RENAL CELL CARCINOMA Differential diagnosis: Clear cell RCC Oncocytoma Epithelioid (pleomorphic) AML Hybrid oncocytic tumors (HOCT) Oncocytosis/Birt-Hogg-Dubé Tuberous sclerosis complex (TSC)-associated Succinate Dehydrogenase (SDH)-associated

62 RENAL ONCOCYTOMA Peak incidence in 6 th to 7 th decade 5%-10% or renal epithelial tumors M : F = 2:1 Most are asymptomatic No consistent genetic abnormalities - loss of chromosomes 1and Y - rare translocations (chr 11) - mitochondrial DNA defects Well circumscribed, mahogany brown Central scar in 30% No necrosis Hemorrhage (20%)

63 RENAL ONCOCYTOMA Microscopic features: compact nests, acini, tubules or microcysts hyalinized hypocellular stroma round to polygonal epithelial cells densely eosinophilic cytoplasm round, regular nuclei with dispersed chromatin and central nucleoli

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67 RENAL ONCOCYTOMA Acceptable findings: degenerative cytologic atypia peri-renal or sinus fat invasion vascular invasion Non-acceptable findings: more than an isolated mitotic figure tumor necrosis overt papillary architecture true cytologic atypia

68 Benign Our contemporary study on renal oncocytoma Renal oncocytoma: a clinicopathologic study of 70 cases. Perez-Ordonez B, Am J Surg Pathol 1997;21: Considerable controversy regarding the definition of renal oncocytoma RCC unclassified (oncocytic, at worst low grade malignant) Renal oncocytic neoplasm Hybrid oncocytic tumor Renal cell carcinoma with oncocytic features In general, because we aim to keep this a benign entity the morphologic criteria applied by most pathologists are extremely rigorous However, even within our own institution, thresholds vary. VER and SKT agree it is oncocytoma VER and SKT agree it is NOT oncocytoma VER and SKT disagree whether it is oncocytoma or not

69 Agree yes Disagree Agree no Agree no

70 Our contemporary study on renal oncocytoma 183 patients with oncocytic neoplasms resected at our institution from All non-oncocytoma (like) tumors were excluded from the study Cases put into one of three groups 1. definite oncocytoma [102 (53%)] 2. disagreement between pathologists whether oncocytoma or not [56 (29%)] 3. definite not oncocytoma [35 (18%)] Morphologic features described within each group Clinical follow-up information was interrogated Median f/u of 60 months (5 d-166 mo) No metastases of tumor-related deaths in any of the 3 groups Conclusions: 1. Renal oncocytoma or oncocytoma-like tumors all have excellent long-term prognosis 2. Atypical morphologic features are likely unduly overemphasized in excluding the diagnosis of renal oncocytoma

71 ONCOCYTOMA Differential diagnosis: Eosinophilic variant of Chromophobe RCC Epithelioid (oncocytic) AML Hybrid oncocytic tumor (HOCT) Oncocytosis/Birt-Hogg-Dubé Tuberous sclerosis complex (TSC)-associated Succinate Dehydrogenase (SDH)-associated

72 TUMORS WITH ONCOCYTIC FEATURES CD117 CK7 Ksp-cadherin HMB-45 Parvalbumin Oncocytoma Positive, membranous Negative Positive Negative Positive Chromophobe RCC, eosinophilic Positive, membranous Positive but variable +/- positive Negative Positive Oncocytic papillary RCC Negative Positive but focal Not known Negative Unknown Oncocytic AML Negative Negative Negative Positive, focal Negative Other Abs said to differentially expressed on oncocytomas and chromophobe RCC Positive in Oncocytoma, negative in Chromophobe Negative in Oncocytoma, positive in Chromophobe EABA, S100A1 MOC31, EpCam, Caveolin-1, CD82

73 Tumor Size (cm) Median Tumor Size Renal Cortical Tumors Nephrectomy Year Incidental detection 80.0% 70.0% 60.0% 50.0% 40.0% Lee et al. Urol Oncol 2002;7: % 20.0% 10.0% 0.0% MSKCC Case Year MSKCC

74 HISTOLOGICAL SUBTYPE IN 2,675 PATIENTS TREATED SURGICALLY FOR A RENAL MASS Tumors Number of tumors (%) Benign 311 (11.6) Oncocytoma 232 (74.5) Angiomyolipoma 35 (11.2) Metanephric adenoma 8 ( 2.6) Other 36 (11.6) Malignant 2,675 (88.4) Clear cell 1,679 (71.0) Papillary 341 (14.4) Chromophobe 239 (10.1) Collecting duct 7 ( 0.3) RCC unclassified 98 (4.1) Thompson RH, et al J Urol 2009;181: MSKCC

75 BENIGN TUMORS vs RCC ACCORDING TO SIZE IN PATIENTS TREATED SURGICALLY FOR A RENAL MASS Size (cm) No. Benign (%) No. RCC (%) Less than 1 6 (37.5) 10 (62.5) 1 to less than 2 56 (19.2) 236 (80.8) 20.2% 2 to less than 3 77 (16.5) 391 (83.5) 3 to less than 4 58 (13.0) 390 (87.0) 4 to less than 5 30 (8.7) 315 (91.3) 5 to less than 6 23 (10.0) 206 (90.0) 6 to less than 7 13 (6.6) 183 (93.4) 7 or greater 48 (7.1) 633 (92.9) 16.1% Thompson RH, et al J Urol 2009;181: MSKCC

76 CHROMOPHOBE RENAL CELL CARCINOMA 4 cm or less Cases: 74 Follow-up (mos): 73.5 (median) Outcome: NED: 73 AWD: 1 (1.4%) DOD: 0 Przybycin Am J Surg Pathol 2011;35:962 MSKCC

77 TREATMENT OF SMALL RENAL MASSES Treating blindly - Surgery - Ablation Active surveillance - Life expectancy - Co-morbidities - Tumor biology Cost

78 Gellert et al, USCAP 2012 Cases (N) Adequate material (%) Correct Diagnosis on H&E alone Clear Cell (84) 75 (89) 64 (85) 68 (91) Papillary (18) 18 (100) 17 (94) 18 (100) Chromophobe (14) 13 (93) 8 (62) 12 (92) Oncocytoma (11) 6 (55) 4 (67) 6 (100) Total (127) 112 (88) 93 (83) 104 (93) Al-Ahmadie et al, Am J Surg Pathol 2011;35:949 Tumor type Total Ablation Nephrectomy Chemotherapy Correct Diagnosis with IHC Active Surveillance Clear cell RCC (16%) Papillary RCC (29%) LG oncocytic neoplasm Chromophobe (44%) oncocytoma (67%) 63% NOS (100%) Clear cell papillary RCC (75%) Angiomyolipoma (100%) Misc* (0%) Total (33%)

79 SUMMARY Renal tumors are not a single histologic, clinical or molecular entity Proper molecular and morphological classification of tumors is of clinical importance for risk stratification Further molecular and morphologic dissection of renal neoplasms will lead to more appropriate therapies of both primary and metastatic disease In vivo classification of tumors is desirable and possible in the majority of cases Judicious use of antibody panels can be useful to arrive at a proper diagnosis MSKCC

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