04/10/2018. What s new in renal tumor pathology what s important and why. Prognostic factors in RCC
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1 25th Annual Seminar in Pathology Pittsburgh, PA, April 26-29, 2018 What s new in renal tumor pathology what s important and why Kiril Trpkov, MD FRCPC Department of Pathology and Laboratory Medicine kiril.trpkov@cls.ab.ca Prognostic factors in RCC 1. Pathologic stage 2. Tumor WHO/ISUP grade 3. Morphologic type 4. Sarcomatoid-rhabdoid differentiation 5. Tumor necrosis (Lymphovascular invasion) Prognostic factors in RCC 1. Tumor WHO/ISUP grade 2. Sarcomatoid-rhabdoid differentiation 3. Tumor necrosis 4. Morphologic type 5. Pathologic stage 1
2 ISUP Consensus Meeting on Adult Renal Tumors Vancouver, March, 2012 Am J Surg Pathol Oct 2013 Nuclear grade (Fuhrman) G1 G2 Nuclear grade = Aggressivene ss G3 G4 Grade based on worst area 2
3 Nuclear grading issues Combination of nuclear size, shape and nucleolar size Size of worst area? Clear cell type vs. other types Nucleolar grading system (nucleolar size) Clear cell RCC only (G1-3) Worst area (x400) Delahunt B et al. Am J Surg Pathol 2011:135: WHO/ISUP grading system (1-4) 1: absent or inconspicuous nucleoli at x400 2: nucleoli distinctly visible at x400 (not at x100) 3: nucleoli distinctly visible at x100 4: extreme nuclear pleomorphism, multinuclear giant cells, and/or rhabdoid and/or sarcomatoid differentiation Note: validated for clear cell RCC and papillary RCC only! Delahunt B et al. Am J Surg Pathol 2013; 37: Am J Surg Pathol 2018;42:
4 Sarcomatoid dedifferentiation = WHO/ISUP grade 4 In any histologic type or unclassified (if pure) poor prognosis! (report %) Rhabdoid (rhabdoid-like) differentiation = WHO/ISUP grade 4 Tumor necrosis Macroscopic and microscopic necrosis should be recorded Except with presurgical embolization Focal, extensive (+) record % Independent prognostic f-r in Clear cell and Chromophobe RCC Controversial in Papillary RCC 4
5 ISUP Grading + Tumor necrosis (Clear cell RCC) ISUP Grading + Tumor necrosis ISUP Grading Delahunt B et al. Am J Surg Pathol 2013 Prognostic factors in RCC 5. Pathologic stage Metastatic breast carcinoma GATA3 PAX8 ER 5
6 PAX8 CA9 CK7 CD10 AMACR CD117 Vimentin Clear cell RCC /- - + Papillary RCC Chr RCC Oncocytoma Use as a guideline, not a gospel! Am J Surg Pathol 2014; 38: e35 e49 Immunohistochemistry should be used in conjunction with morphology for kidney tumor diagnosis ISUP Consensus Meeting on Adult Renal Tumors Vancouver, March, 2012 Am J Surg Pathol 2013; Oct 6
7 >95% <5% ISUP Consensus Meeting on Adult Renal Tumors Vancouver 2012 / WHO 2016 Clear cell renal cell carcinoma Multilocular clear cell renal cell neoplasm of low malignant potential Papillary renal cell carcinoma Type 1 Type 2 Chromophobe renal cell carcinoma Collecting duct carcinoma Renal medullary carcinoma MiT family translocation renal cell carcinoma Mucinous tubular and spindle cell carcinoma Tubulocystic renal cell carcinoma Acquired cystic disease associated renal cell carcinoma Clear cell papillary/tubulopapillary renal cell carcinoma Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma Succinate dehydrogenase (SDH) deficient renal carcinoma Renal cell carcinoma, unclassified Papillary adenoma Renal oncocytoma TABLE 1. Proposed New Renal Epithelial Tumors and Emerging/Provisional Tumor Entities New epithelial tumors Tubulocystic renal cell carcinoma Acquired cystic disease associated renal cell carcinoma Clear cell (tubulo) papillary renal cell carcinoma MiT family tra11slocation renal cell carcinoma (including t(6 II) re11al cell carcinoma) Hereditary leiomyomatosis renal cell carcinoma syndrome associated renal cell carcinoma Emerging /provisional entities Thyroid-like follicular renal cell carcino1na Succinic dehydrogenase B deficie11cy associated renal cell carcinoma ALK-translocation renal cell carcinoma 7
8 ISUP Vancouver Classification of Renal Neoplasia Proposed new entities Tubulocystic RCC Acquired cystic disease RCC Clear cell (tubulo)papillary RCC Translocation RCC (MiT family) Hereditary leiomyomatosis associated RCC Tubulocystic RCC Tubulocystic carcinoma (note prominent nucleoli!) 8
9 Tubulocystic RCC Low gr. collecting duct RCC ( Bellinian epithelioma ) Rare (<100) M:F > 7:1 Low stage (indolent) Similarities with Papillary RCC: IHC Array CGH Cytogenetics Tubulocystic RCC Acquired cystic disease associated RCC 9
10 Acquired cystic disease associated RCC Calcium oxalate crystals Acquired cystic disease associated RCC Dialysis or renal failure ACD (25% with tumors) ACD-RCC (Papillary, Clear cell) Some aggressive 10-20% with MS IHC: CK7 (-), AMACR (+) Cytogenetics: Gains of chr. 1,2,3,6,7,16 and Y Array CGH with papillary RCC 1 IJ""Ii" pi lip"+ 1l 1p11" f 1r 11pmp11fTTTITilnp1:1Jn1q:n1 :
11 Clear cell (tubulo)papillary RCC Clear cell (tubulo)papillary RCC End-stage kidney or sporadic Incidence ~1% Benign or indolent IHC: CK7 (+), AMACR (-), CD10 (-) CAIX (cup-shaped +) Cytogenetics: Different from Clear cell and Papillary RCC Clear cell (tubulo)papillary RCC CA 9 11
12 t(6:11)(p21;q12) Translocation RCC TFEB Col IV Translocation type RCC (Xp11) Translocation type RCC (Xp11) 12
13 Translocation type RCC (Xp11) 34PE I... FISH for TFE3 or TFEB necessary for diagnosis! t(6;11) and Xp11 RCC similar MiT family translocation RCC Xp11: 39% MS or DOD (>25 years old) t(6;11): 21% with MS or DOD Wide age range (30 mean) IHC: Cytokeratin poor Some HMB45/Melan A (+) Cathepsin K + (TFEB all; TFE3 ~60%) 13
14 Hereditary leiomyomatosis associated RCC (HLRCC) Architectural patterns (n=40): Papillary 25 (63%) Tubulo-papillary 8 (20%) Tubular 2 (5%) Solid 1 (2%) Mixed 4 (10%) Hereditary leiomyomatosis RCC Autosomal Dominant Cutaneous and uterine leiomyomas (M > F) 50% hysterectomy (< 35y) Resemble PRCC type 2 or collecting duct-like RCC Fumarate hydratase germline mutations (1q42) Abnormal succination = 2SC Aggressive! up to 50% MS at Dx 14
15 FH deficient RCC previosly labelled as Unclassified, high grade Papillary type 2 Tubulocystic with dedifferentiated foci Collecting duct carcinoma (CDC) FH deficient RCC 15
16 FH FH deficient RCC 2SC FH retained RCC Am J Surg Pathol 2016;40: IHC of Unclassified RCC detected 24 (19%) RCC associated with FH deficiency FH and 2SC IHC done on: 124 RCC whole slide sections (multiple institutions): - unclassified, high grade or unclassified with papillary pattern - at least focal prominent nucleoli In addition, 3 TMA with 776 renal neoplasms evaluated: Tumor type Clear cell RCC Papillary RCC Chromophobe RCC Oncocytoma Other RCCs Urothelial Ca No. Cases
17 IHC Screening of Unclassified RCC detects FH deficient tumors H&E FH negative 2SC positive TMA detected case ( papillary type 2, with prominent nucleoli ) Papillary (74%) + other patterns! Tubulocystic (41%) and tubular (26%) 17
18 Solid (44%) and sarcomatoid (15%) Am J Surg Pathol 2016; 40: IHC by FH and 2SC detected 24/29 (83%) FH deficient RCC Am J Surg Pathol 2018; Jan 5. [Epub ahead of print] 25% (13/51) cases previously diagnosed as CDC reclassified as FH-deficient RCC upon review and IHC for FH and 2SC 18
19 JO I. $.' ScitiP. 1:75, _ Ocean N o r r h P a c i f i c I t C f' tl ' \ 1 M MDUCO( - ""' N o r t h At Ian t i c. Ocean i A tib n t i c Ocean Ind i an I N D 0 N \ I Nort/1 I. P a c i f i c fioijp: d (. ; n(f f.,. ; 04/10/2018 FH d eficie nt RCC Summary Negative FH on IHC strongly correlates with: - FH gene alterations and morphology compatible with HLRCC - Aggressive behaviour (but often without the stigmata) Negative FH IHC - screening for additional genetic testing Negative FH - more specific and equally sensitive compared with 2SC " I---l " I 1l. I -\."'. f - f - ".,. I s 0 u [h... Oc edll..,, la.lav[:.?r...:t I Oc ean , = - Prognostic factors in RCC 5. Pathologic stage 19
20 ISUP Consensus Meeting on Adult Renal Tumors Vancouver 2012 Trpkov K et al. Am J Surg Pathol 2013; 37: Bonert M, Kuo-Cheng H, Trpkov K. Diagnostic Histopathology 2016;22(2):
21 Stage pt3a pt3 Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota s fascia pt3a Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system, or invades perirenal and/or renal sinus fat but not beyond Gerota s fascia Renal tumor stage summary of changes - AJCC/TNM 8 th edition Definition of Primary Tumor (pt): T3a disease Word grossly was eliminated from the description of renal vein involvement Muscle containing - omitted as descriptor for segmental veins Invasion of the pelvicalyceal system was added Renal tumor stage Key prognostic parameter Used in prognostic nomograms 7 th edition (2009) 8 th edition (2017) Robson CJ et al. J Urol 1969; 101:
22 Handling of renal tumors Goals: Thorough gross examination Adequate sampling Pathologist Reporting of stage and other important prognostic parameters Specimen received in the lab Identify and sample: Adrenal gland Vascular margins Ureter Ureteral stump opened and examined 22
23 Ureteral invasion Initial section of specimen along long axis (lateral or medial) Probes in collecting system or in largest hilar veins Initial section of specimen along long axis (lateral or medial) Consider additional parallel sections 23
24 Radical and partial nephrectomies should be inked Complete Localized Selective (resection margin) Renal tumor measurement (greatest dimension) Measure any tumor invading into extracapsular tissue Do not measure tumor invading into renal/caval vein Stage T1 and T2 Tumor limited to kidney! TNM 2009 (7 th edition) same in AJCC/TNM 2017 (8 th edition) 4cm > 7cm > 4 but 7cm T2a (>7 cm but 10 cm) T2b (>10 cm) 24
25 TNM Descriptors m - multiple tumors in a single site - pt(m)nm y - during or following initial multimodal therapy - yptnm r - recurrent tumor after a disease-free interval - rptnm a - stage determined at autopsy aptnm Residual tumor (R) - residual tumor after curative therapy X - can t be assessed; 0 - no; 1 - microscopic; 2 - macroscopic How many blocks should you submit for examination? Important to assess tumor relationship with: Renal capsule (perirenal fat) Renal sinus Adrenal gland Renal pelvis Areas of different appearance or consistency! Sarcomatoid differentiation, necrosis etc. Sampling of renal tumor for examination One block per cm, minimum of 3 blocks (subject to modification) 25
26 Multiple renal tumors Hereditary: Sporadic: about 5% Von Hippel Lindau disease Papillary RCC - more common bilateral Birt-Hogg Dubbé Sy Hereditary papillary carcinoma Tuberous sclerosis Oncocytosis Index and satellite tumors mostly identical Discordant TU 17-26% (clear cell + papillary) Likely local recurrence if nephron-sparing surgery Measurement of multiple tumors Measure and report tumor dimensions for all tumors, up to a maximum of 5 Sampling and staging of multiple tumors Minimum of 5 largest tumors (if smaller look similar) If uncertain about histologic type or adverse findings in remaining tumors, do additional sampling Largest T used label with (m) pt(m) Different subtype separate stage 26
27 Stage pt3a pt3 Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota s fascia pt3a Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system, or invades perirenal and/or renal sinus fat but not beyond Gerota s fascia Pushing border, even if beyond normal kidney, NOT diagnostic of fat invasion Invasion: lost smooth interface, or irregular nodules protruding into fat Assessment of perinephric fat invasion (pt3a) Multiple perpendicular sections of tumor fat interface 27
28 Perinephric fat invasion (pt3a) - micro Tumor touching fat Tumor extending as irregular tongues into fat (with or without desmoplasia) Problematic perinephric fat invasion (pt3a) Renal sinus Central perinephric fat compartment no fibrous capsule Between pelvicalyceal system and renal parenchyma Main lymphovascular supply of kidney 28
29 Renal sinus invasion (pt3a) Principal route for extrarenal extension: Clear cell RCC, but also other types >90% of clear cell RCCs 7 cm invaded renal sinus Bonsib SM. J Urol. 2005;174: Invasion into sinus worse prognosis than into perinephric fat Renal sinus invasion - sampling If sinus invasion grossly evident, or obviously absent, (e.g. small peripheral tumor): When uncertain if sinus invasion present: Sample only 1 block to confirm sinus invasion present or absent Sample at least 3 blocks of tumor - sinus interface Renal sinus invasion present on micro if tumor seen in: Direct contact with sinus fat In loose connective tissue beyond renal parenchyma Any endothelial lined space within sinus, regardless of size 29
30 Renal vein invasion AJCC 8 th edition Renal vein invasion (pt3a): tumor (grossly) extends into renal vein or segmental branches Renal vein invasion Tumor attached to the vessel wall or Tumor fills and distends vessel lumen Vein invasion in the renal sinus = pt3a 30
31 Vein invasion in the perinephric tissues = pt3a Renal vein and margin sampling Submit actual margin Renal margin negative retraction of vein after fixation + Additional sections of tumor thrombus, if grossly suspected to be adherent to vein wall Renal vein margin positivity Renal margin positive only if tumor adherent at actual margin, confirmed microscopically 31
32 Invasion into pelvicalyceal system = pt3a (new in AJCC 8 th edition) Vena cava invasion Tumor into vena cava below or above diaphragm Vena cava invasion pt3c Tumor grossly extends into vena cava above diaphragm or invades wall of vena cava 32
33 Specimen submitted as caval thrombus Include 2 or more sections to search for adherent caval wall tissue and possible invasion Tumor invades the wall of vena cava (pt3c) Adrenal gland involvement Contiguous spread (pt4) Metastasis (pm1) Prognostic significance! Direct adrenal gland involvement - pt4 Direct invasion into adrenal pt4 disease Associated with significantly worse prognosis than perinephric fat invasion! Matches pt4 tumors (invasion into adjacent organs) 33
34 Metastatic adrenal gland involvement M1 Assessment of hilar lymph nodes Restrict evaluation to palpation and dissection of hilar fat only Nodes found in less than 10% of cases Nodes rarely identifiable! Assessment of hilar lymph nodes Grossly visible hilar nodes positive in 80% of cases Microscopic nodes found in only 25% of cases = all benign! Searching for occult nodes not practical! Mehta V et al. Arch Pathol Lab Med 2013; 137:
35 Regional lymph nodes N1 Single or multiple regional nodes involved Examine all submitted separately Renal hilar Caval (pre-, para-, retro-, interaortocaval) Aortic (pre-, para-, retro-) Sampling uninvolved renal parenchyma Adjacent to tumor, as well as distant from tumor Routine assessment for concurrent glomerular, tubulointerstital and vascular kidney disease Diabetic nephropathy (KW nodules) Hypertensive vascular disease 35
36 Eur Urol 2010; 58: It is expected that AJCC 8 th edition staging for renal cancer will perform (at least) as well as the 7 th AJCC/TNM edition Take home messages Utilize the new WHO/ISUP grading system (and educate clinicians!) Recognize the expanding spectrum of novel renal tumors AJCC 8 th edition introduces some (minor) staging changes and refines some definitions, but retains most of the 7 th edition parameters Stage remains key to prognostication of renal cancer patients Trpkov Kiril Uropathology St Cyril 36
37 Hope you don t feel like this now! Thank you 37
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