Pathology of Renal Neoplasms: Recent Advances

Transcription

1 Pathology of Renal Neoplasms: Recent Advances Jae Y. Ro, M.D., Ph.D. The Methodist Hospital Weill Medical College of Cornell University, MD Anderson Cancer Center, Houston, Texas Ewha Womans University Hospital Yonsei University Hospital, Seoul, Korea June 7, 2012

2 Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths By Sex, United States, CA Cancer J Clin 2012;

3 KIDNEY CANCER - CURRENT STATUS UNITED STATES, 2012 Including renal pelvis 64,770 (40,250, males; 24,520, females) New cases in ,570 (8,650, males;4,920, females)

4 Kidney Cancer with other GU Cancers 5-year Relative Survival Rates (%): Kidney Cancer is the Worst of GU Cancers 5-year Relative Survival Rates (%) 1975 to to to 2003 Kidney Bladder Prostate Testis Jemal A. et al. CA Cancer J Clin 2009;59:225-49

5 Male Female Stomach Colon Lung Liver Prostate Thyroid Bladder Pancreas Kidney Biliary tree ttree Thyroid Breast Stomach Colon Lung Uterine Cx Liver Biliary tree Pancreas ovary

6 Introduction Increased incidence of renal tumors More incidental and small tumors More partial nephrectomy More laparoscopic/robotic surgery Development of molecular targeted therapies (Sunitinib, Sorafenib, Bevacizumab, Temsirolimus )

7 Increasing of Cancers of Kidney /Renal Pelvis USA ( ) Data obtained from Cancer Statistics by American Cancer Society : 64,77 0

8 Surgical Treatment of Renal Tumor More smaller tumors are detected More incidental tumors More benign tumors More partial nephrectomy More laparoscopic/robotic surgery

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15 RCC Molecular Targeted Therapy No effective adjuvant therapy for RCC Molecular targeted drug approved by FDA All are active in cytokine refractory patients Sunitinib (Sutent) and Sorafenib (Nexavar) VEGF, PDGF Bevacizumab (Avastin) VEGF Temsirolimus (CCI-779) mtor Escudier et al. NEJM 2007;356:124. Motzer et al. NEJM Hudes et al. NEJM 2007

16 Histology and Classification

17 UICC/AJCC Consensus (1997) BENIGN MALIGNANT Oncocytoma Papillary adenoma Metanephric adenoma Clear cell RCC Papillary RCC Chromophobe RCC Collecting duct carcinoma RCC, unclassified

18 WHO Classification (2004) Clear cell RCC Multilocular cystic RCC Papillary RCC Chromophobe RCC Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma Xp11 translocation carcinomas Carcinoma associated with neuroblastoma Mucinous tubular and spindle cell carcinoma RCC, unclassified Papillary adenoma Oncocytoma

19 Kidney Histology

20 RCC marker Kidney specific cadherin

21 Kidney specific cadherin

22 Proximal tubules (85% -90%) Collecting Ducts (10% -15%) Intercalated cells (cortex) Collecting ducts (medulla) Clear cell RCC (3p-) Papillary RCC (+7, +17, -Y, others) Chromophobe RCC (-1, -Y ) (others -2, -10, -13 etc) Oncocytoma (-1, -Y) (Translocations chr 11) Collecting duct carcinoma (-1, -6, -14, -15, -22) LOH 8p and 13q

23 CRCC4 A B C D a b c d a b c d a b c d a b c d PRCC CHRCC OC

24 RCC Histology and Incidence (Selective large series and TMH data) Histologic Type Incidence (5 studies)* TMH (n=1147) Clear cell 68% % 77.2% Papillary 11% % 15.2% Chromophobe 4.3% - 6.5% 5.6% Collecting duct 0-1% 0.4% Unclassified 1% - 6.1% 1.4% * Ljungberg 1999 (n=186), Moch, 2000 (n=588), Amin 2002 (n=377), Cheville 2003 (n=2385), Kim 2004 (n=795)

25 Histology and Prognosis (Simplistic view ) Oncocytoma Chromophobe RCC Adenoma Type 1 Type 2 Papillary RCC Clear cell RCC Collecting duct Ca Low Malignant potential High

26 Contents 5: 5 types of malignant tumors 4: 4 (+4) newly defined entities 3: 3 benign tumors 2: 2 entities no longer exist 1: 1 (+1) most important prognostic factor

27 5 Malignant

28 Clear Cell RCC

29 Growth Patterns Classic (solid/acinar) Tubular Cystic Pseudopapillary Hemorrhagic Hyalinzed Cytomorphology Classic clear cell Granular Epithelioid Rhabdoid Spindle/sarcomatoid

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34 Clear Cell RCC Differential Diagnoses Morphologic variation of clear cell RCC Differential diagnosis Chromophobe RCC Papillary RCC type 2 Cellular or epithelioid angiomyolipoma Adrenal cortical carcinoma

35 Papillary RCC Common Gross Features: 1. More homogeneous 2. White tan 3. Friable, solid/cystic, punctuate chalky area 4. Better circumscription

36 Papillary RCC Growth Patterns Papillary Tubular Tubulopapillary Solid Cytomorphology Classic (basophilic) Eosinophilic Clear cell Mixed Sarcomatoid

37 Papillary RCC The second most common type RCC Cytogenetic changes: +7, +17, -Y Met protooncogene More frequent regional nodal metastasis Prognosis variable

38 Type 1 papillary RCC

39 Type 2 papillary

40 Type 2 papillary

41 PRCC, type 1 vs. type 2 Type 1 (n=102) 5-yr survival 65% vs. 47% p=0.017 Type 2 (n=48) Shen SS et al. Presented at USCAP 2008, Denver, Colorado

42 Foamy Macrophages

43 Type 2 PRCC macrophages

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45 Solid type

46 Type 1 papillary, solid

47 Papillary RCC is a Heterogeneous Group of Tumor Clear cell RCC can have pseudopapillary Papillary RCC can have clear cell changes Some papillary RCC can have features of both type 1 and type 2 Type 2 PRCC with low nuclear grade vs. oncocytic papillary RCC (same or different) Clear cell papillary RCC specific entity?

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49 Oncocytic Papillary RCC May be a distinct subgroup Kunju et al. (2008) Smaller tumor (mean 2.0 cm) IHC: CK7+ (7/7), CD10+ (7/7), AMACR+ (5/7) FISH: all trisomy 7, 17 No recurrence or metastasis in 22 months Park et al., (2009) Histology: nuclei polarized to surface of papillae IHC: AMACR+ (7/7), CK7+ (7/7), CD15+ (6/7) Cytogenetics: 3p+, 11q+, 17q+, 4q- No recurrence or metastases in 3 years

50 Chromophobe RCC Initially described by Thoenes et al in 1985 Two types described in 1988 Loss of multiple chromosomes (-1, -Y -2, -10, -13 etc.) Better prognostic group Association with oncocytoma (hybrid)?

51 Common Gross Features: 1. Homogeneous 2. Mahogany brown Chromophobe RCC 3. Solid 4. Well circumscription

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53 Chromophobe RCC Key Diagnostic Features Growth patterns Solid sheets, broad alveoli, tubular Broad fibrotic septae, thick-walled and hyalinized vessels, linear or parallel Cytologic features Cell types (mixed) Cytoplasmic quality (halo) Nuclear features (wrinkling, binucleation) Cytoplasmic membrane (prominent)

54 Chromophobe RCC Three Types of Cells Type 1: Eosinophilic cell with no perinuclear halo Type 2: Eosinophilic cell with perinuclear halo Type 3: Largest polygonal cells with voluminous, reticulated cytoplasm

55 Chromophobe RCC Morphologic Spectrum Typical: Easy to diagnose May be confused with clear cell RCC + Eosinophilic: + Predominant type 1 or type 2 cells; May be confused with oncocytoma

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62 Collecting Duct Carcinoma Rare (less than 1%) Major differential: TCC, metastasis, sarcomatoid RCC Histology: features of a high grade adenoca and TCC, desmoplasia Highly aggressive

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66 RCC, Unclassified Definition: tumor that does not fit into any known types by morphology or genetics RCC with mucin production? Composites of recognizable types? Unrecognizable cell types RCC with sarcomatoid change in which the epithelial elements cannot be assigned to one of the known categories

67 RCC with Mucin Production = Unclassified RCC Papillary RCC (20%~30%) Collecting duct carcinoma Invasive urothelial carcinoma Mucinous tubular and spindle cell carcinoma

68 Composite Recognizable Types = Unclassified? If low grade, better to diagnose as mixed subtypes If high grade,? RCC, unclassified

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70 Renal Cell Carcinoma, Unclassified Reserved for those truly unclassifiable based on adequate sampling of tumor Rule out metastatic tumor Consultation is advisable Immunohistochemical stains may be helpful Cytogenetic analysis?

71 4 Newly Defined RCC Entities Xp11 translocation carcinoma Mucinous tubular spindle cell carcinoma Multilocular cystic clear cell RCC Carcinoma associated with neuroblastoma

72 Xp11 Translocation Carcinomas A group of RCC with translocation involving Xp11.2, resulting TFE3 genes fusion Occur in children and young adult (~1.5%) Micro: papillary or nested growth with clear cytoplasm, psammoma bodies (common) IHC: TFE3/TFEB+ (nuclear) and RCCm, CD10, Pax-2+ Cytokertain -/weakly + Clinical outcome: may be more aggressive in adult

73 Xp11 Translocation Carcinomas TFE3 TFE3 Shen SS, Truong LD, Ayala AG, and Ro JY. Arch Pathol Lab Med :

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75 Mucinous Tubular and Spindle Cell Carcinomas Female predominance (4:1) Wide age range (17-82 yrs) Low grade indolent behavior? Multiple loss of chromosomes (1, 4, 6, 8, 9, 13, 14, 15, 22), lack of -3p Distinct entity or variant of papillary RCC?

76 Mucinous Tubular and Spindle Cell Carcinoma P504 RCCm CD15 Shen SS, Ro JY et al. Annals of Diag Pathol :13-21.

77 Multilocular Cystic Clear Cell RCC Composed of entirely cystic components Lined by layers of clear cells Low nuclear grade (G1 or G2) Lack of nodules of solid area of clear cells Excellent prognosis

78 Cortical cyst Cystic nephroma/mestk Multilocular cystic clear cell RCC RCC with cystic changes

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81 CA9 CK7 CD10 HMCK

82 RCC associated with neuroblastoma ~18 cases have been reported Male/female equally affected Neuroblastoma diagnosed, Age < 2 yrs RCC detected, 13.5 years (range 2 to 35) Tumor size: 4 cm (1-8cm) 1) solid/papillary with abundant eosinophilic cytoplasm; 2) clear RCC

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84 4 Newly described entities Tubulocystic carcinoma Thyroid-like follicular carcinoma Acquired cystic disease associated RCC Clear cell papillary RCC

85 Tubulocystic RCC Also known as low grade CDC < 60 cases reported Strong male preponderance 7: (mean 60yo) Closely related to papillary RCC type 1 +CK7, AMACR, CD10, CK19

86 CK7 AMACR H&E RCC, low grade papillary RCC, tubulocystic RCC, high grade papillary Yang XJ, Zhou M, Hes O, Shen SS et al AJSP 32:177;2009, 33:1840

87 Thyroid Follicular Carcinoma-like Tumor of Kidney Jung SJ, Chung JI, Park SH, Ayala AG, and Ro JY. Am J Surg Pathol : The tumor with follicular architectures containing luminal inspissated colloid-like material; no recognizable RCC Strongly positive for CK (AE1/AE3), CD10, Focal cytoplasmic stain for CK35βH11 and vimentin Negative for TTF-1 and thyroglobulin, CK7, CK19, CK20, CK34βE12, CEA, EMA, and CD15. CGH showed gains of 7q36, 8q24, 12, 16, 17p11- q11, 17q24, 19q, 20q13, 21q22.3, and Xp and losses of 1p36, 3, and 9q These findings are dissimilar to previously classified renal neoplasm

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89 Thyroid Follicular Carcinoma-like Renal Tumor: A Case Report Sterlacci WS et al. Virch Arch. 2008;412:91-5; Amin MB et al, Am J Surg Pathol 2009;33: Follicular structures with abundant eosinophilic colloidal material and focal papillary differentiation by light microscopy. Positive for PAX2, CK-7, CK-20, CAM 5.2 and vimentin. Negative for CD-10, CD-117, TTF-1, and thyroglobulin FISH showed chromosomal losses of 1, 3, 7, 9p21, 12, 17, and X This is an uncommon variant

90 CK PAX2

91 Acquired cystic disease associated RCC Most common subtype of RCC in endstage kidneys, especially with acquired cystic disease Incidence of cystic disease (>90% at 10 years or more) RCC: 3-7% in patients with end-stage kidneys Micro: tumor cells with eosinophilic cytoplasm, sieve-like/cribriform appearance and oxalate crystals Clear cell papillary, papillary, clear cell, chromophobe RCC may occur (AMACR+, CD10, RCCm +: CK7- or focal +)

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94 AMACR CK7 focal +

95 AMACR CK7-

96 Clear cell papillary RCC Both end stage renal disease and also seen in non-endstage setting Unicentric and occasionally multicentric Most are small pt1 with rare pt3 No LN or other sites metastasis Clear cells with low NG; papillary/tubular-acinar; nuclei in linear arrangement away from basal aspect of cells AMACR, RCCM & CD10-; PAX8, CK7, CA9 and HMCK + Cytogenetically, no -3p, no +7, +17

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99 CK7 + in both papillary and tubular areas

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110 No VHL mutation No HMB45

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112 ---this neoplasm appears to have both epithelial and mesenchymal components. The epithelial portion has some tubular and solid areas compatible with low grade clear cell RCC and the mesenchymal component reminds me of angiomyoliopma Is it a renal angioadenomyomatous tumor?

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114 3 Benign

115 Metanephric Adenoma

116 Metanephric Adenoma

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120 Morphologic Overlapping Metanephric Adenoma (MA) and Papillary RCC Papillary Pattern Glomeruloid Pattern Solid Pattern Psammoma Bodies Macrophages MA 6/8 (75%) 4/8 (50%) 8/8 (100%) 6/8 (75%) 1/8 (13%) PRCC 11/11 (100%) 4/11 (36%) 7/11 (64%) 1/11 (9%) 7/11 (64%) Moore B. Dance et al CAP Poster

121 Papillary RCC Metanephric Adenoma

122 Metanephric Adenoma vs. Papillary RCC RCCm AMACR WT-1 PAX2 0% 0% 100% 100% MA 90% 100% 0% 73% prcc Moore B. Dance et al CAP Poster

123 Papillary Adenoma Baby (<0.5 cm) low grade papillary RCC Incidental findings Often associated with end stage renal D Associated with papillary RCC Frequently multiple

124 Papillary Adenoma

125 Papillary Adenoma

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128 Oncocytoma Most frequent benign renal neoplasm Benign behavior Cytogenetic: normal or losses of -1, -Y Close relation with chromophobe RCC

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138 Oncocytoma: Atypical Features Focal nuclear atypia (~10%) Hemorrhage Fat invasion (rare) Vascular invasion (rare) Large size

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142 2 Entities no longer exist

143 Granular RCC

144 Granular Cell RCC Granular cell RCC is not a specific entity Differential diagnoses include: Clear cell RCC Chromophobe RCC, eosinophilic variant Papillary RCC type 2 Oncocytoma Epithelioid angiomyolipoma

145 Clear Cell RCC with Granular Cells Very common Granular cell in clear cell RCC often have higher nuclear grade Keys to the diagnosis of clear cell RCC Component of classic clear cell Typical vascular pattern Exclude other histologic types

146 Clear Cell RCC with Granular Cells All clear cells 12.3% Mixed clear /granular cell 67.1% All granular cell 20.6% Data modified from Victor Reuter s USCAP Long Course 2008

147 Issues of Granular RCC Chromophobe RCC Oncocytoma Angiomyolipoma Clear cell RCC

148 Granular RCC Not a specific entity Think about clear cell RCC first Be familiar with chromophobe RCC Keep angiomyolipoma in mind

149 Sarcomatoid RCC

150 Sarcomatoid Changes Occur in All Types of RCC # Cases # Sarcomatoid (%) Clear cell (5.4) Papillary (4.5) Chromophobe 60 1 (1.7) Collecting duct 6 4 (66.7) Unclassified 15 6 (40) Total (6) (TMH Unpublished Data)

151 Sarcomatoid Changes Spindle cell area with at least moderate cytologic atypia Report the percentages of sarcomatoid and tumor necrosis Attempt to identified RCC histologic type

152 Sampling is important

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155 Is this sarcomatoid?

156 Is this sarcomatoid?

157 Is this sarcomatoid??

158 1 RCC Staging

159 TNM Stage of RCC, 2010 T1 T1a T2 T3 T3a T3b T3c T4 < 7 cm, limited to kidney < 4 cm and T1b > 4 cm > 7 cm, limited to kidney T2a >7- <10 and T2b >10cm invades major veins, perinephric fat, but not beyond Gerota s fascia renal vein, perirenal, renal sinus fat vena cava below diaphragm above diaphragm, invades vena cava wall invades beyond Gerota s fascia, ipsilateral adrenal involvement

160 T stage 1978 AJCC 1987 AJCC 1997 AJCC 2002 AJCC 2009 AJCC pt1 RCC Staging an Evolving Topic pt1a Small tumor <2.5 cm <4 cm pt1b 2.5 to 7 cm 4 to 7 cm pt2 >7 cm >7 cm >7 cm pt2a pt2b pt3 Large tumor 7-10 cm >10 cm pt3a Perirenal/adrenal gland extension pt3b Perirenal spread RV involved RV/VC below diaphragm pt3c VC below diaphragm VC above diaphragm RV inv./ renal fat ext. VC below diaphragm VC above diaphragm or VC wall invasion pt4 pt4a pt4b Adjacent organ or abdominal wall Beyond Gerota s fascia VC above the diaph. Ext. beyond Gerota s fascia Beyond Gerota s fascia and/or ipsilateral adrenal

161 T stage 1978 AJCC 1987 AJCC 1997 AJCC 2002 AJCC 2009 AJCC pt1 RCC Staging an Evolving Topic pt1a Small tumor <2.5 cm <4 cm pt1b 2.5 to 7 cm 4 to 7 cm pt2 >7 cm >7 cm >7 cm pt2a pt2b pt3 Large tumor 7-10 cm >10 cm pt3a Perirenal/adrenal gland extension pt3b Perirenal spread RV involved RV/VC below diaphragm pt3c VC below diaphragm VC above diaphragm RV inv./ renal fat ext. VC below diaphragm VC above diaphragm or VC wall invasion pt4 pt4a pt4b Adjacent organ or abdominal wall Beyond Gerota s fascia VC above the diaph. Ext. beyond Gerota s fascia Beyond Gerota s fascia and/or ipsilateral adrenal

162 T stage 1978 AJCC 1987 AJCC 1997 AJCC 2002 AJCC 2009 AJCC pt1 RCC Staging an Evolving Topic pt1a Small tumor <2.5 cm <4 cm pt1b 2.5 to 7 cm 4 to 7 cm pt2 >7 cm >7 cm >7 cm pt2a pt2b pt3 Large tumor 7-10 cm >10 cm Perirenal/adrenal gland extension pt3a pt3b Perirenal spread RV involved RV/VC below diaphragm pt3c pt4 pt4a pt4b Adjacent organ or abdominal wall VC below diaphragm Beyond Gerota s fascia VC above the diaph. VC above diaphragm Ext. beyond Gerota s fascia RV inv./ renal fat ext. VC below diaphragm VC above diaphragm or VC wall invasion Beyond Gerota s fascia and/or ipsilateral adrenal

163 T stage 1978 AJCC 1987 AJCC 1997 AJCC 2002 AJCC 2009 AJCC pt1 RCC Staging an Evolving Topic pt1a Small tumor <2.5 cm <4 cm pt1b 2.5 to 7 cm 4 to 7 cm pt2 >7 cm >7 cm >7 cm pt2a pt2b pt3 Large tumor 7-10 cm >10 cm pt3a Perirenal spread Perirenal/adrenal gland extension pt3b RV involved RV/VC below diaphragm pt3c VC below diaphragm VC above diaphragm RV inv./ renal fat ext. VC below diaphragm VC above diaphragm or VC wall invasion pt4 pt4a pt4b Adjacent organ or abdominal wall Beyond Gerota s fascia VC above the diaph. Ext. beyond Gerota s fascia Beyond Gerota s fascia and/or ipsilateral adrenal

164 Tumor size T2 tumors T3a tumors RCC Staging Issues Perirenal fat invasion Sinus fat invasion Vascular invasion

165 Size Matters Largest dimension (3 dimension?) Multiple tumors Cut-off criteria for staging T1a vs. T1b (4 cm T1 substage) T2 (>10 cm substage, th AJCC)

166 T2 Tumors Are Uncommon T Stage # Cases % T % T % T % T4 18 2% Total % Form TMH RCC database ( )

167 Fat Invasion and Staging Perirenal fat invasion Sinus fat invasion Extent of fat invasion

168 Renal Sinus Fat Invasion pt3a : directly invades perinephric tissue including sinus fat, direct adrenal invasion (Bonsib et al. AJSP 2000)

169 Renal Sinus vs. Perirenal Fat Invasion Worse 5 yr survival Perirenal fat inv. 51% Sinus fat inv. 26% No difference SF = Sinus fat inv. PF = Perirenal fat inv. (n=70) (n=96) (n=199) Thompson RH et al. J of Urol 2005 Margulis V. et al. J of Urol 2007

170 Extent of perirenal fat invasion (focal vs. extensive) Jung SJ, Ro JY, Truong LD, Ayala AG, and Shen SS. Human Pathol :

171 Extent of Perirenal Fat Invasion Jung SJ, Ro JY, Truong LD, Ayala AG, and Shen SS. Human Pathol :

172 Adrenal Invasion Direct adrenal invasion : pt3a (AJCC, 2002) T4 in th AJCC staging More aggressive behavior than fat invasion (Han et al. J Urol 2003)

173 Adrenal Invasion Group 2-year 5-year Log Rank 1 (n=118) 80% 63% Vs. 2 p< (n=66) 55% 32% Vs. 3 p= (n=14) 31% 21% Vs. 1 p=0.001 Fat inv. Renal vein inv. Adrenal inv. Jung SJ, Ro JY, Truong LD, Ayala AG, and Shen SS. Human Pathol :1689

174 Renal Vein Invasion Combine renal vein invasion with Perirenal fat invasion as T3a (2010)

175 K-M Survival analysis of pt2/pt3 RCC T2 Fat Inv. Groups p value T2 vs Fat Inv Fat vs RV Inv Renal Vein Inv.

176 Grading

177 Fuhrman s Nuclear Grade Nucleolus visible with 10x objectiveyes No G1 or G2 G3 or G4 Nucleolus visible with 40x objective or visible chromatin detains No G1 (Nucleus 10µm) Yes G2 (Nucleus 15µm) Pleomorphis m No Yes G3 G4 (Same nuclear size 20µm)

178 Nuclear Grade and Prognosis (n=721) G2 (n=379) G1 (n=73) G3 (n=213) G4 (n=56)

179 40x Grade 1 40x Grade 2 40x Grade 3 40x Grade 4

180 Fuhrman s Nuclear Grade Two distinct nuclear grades in RCC are not uncommon finding Grading is based on the worst area Take adequate sections of tumor Used for all RCCs Value for chromophobe not clear, most of them are grade 2-3

181 Nucleolar Grade In papillary RCC Only nucleolus change Not considered these factors Nuclear size Nuclear shape

182 Sika-Paotonu, Delahunt, et al AJSP. 2006;30:1091-6

183 Chromophobe RCC, Grade No effective grade for ChRCC Delahunt et al (AJSP 2007:31;957-60) is based on assessment of nuclear crowding & anaplasia: 3-tier (Paner and Amin 2010:34; )

184 Gr 1 Gr 2 Gr 3

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186 Chromophobe RCC, Grade Univariate associations with CS survival included 2010 TNM stage, sarcomatoid differentiation, coagulative tumor necrosis, chromophobe RCC grade, and nucleolar grade (all P<0.001). (Not FN grade) Nonsarcomatoid TNM stage groupings I and II chromophobe RCC, only stage grouping (I vs. II) was significantly associated with CS survival (P=0.03). Cheville et al AJCP 2012 Feb 24. [Epub ahead of print]

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188 Ancillary Tests

189 USE of IHC DDX of renal vs. non-renal neoplasms

190 USE of IHC DDX of renal vs. non-renal neoplasms Histologic subtyping of renal cell carcinoma

191 IHC of RCC Clear Cell RCC +: Vimentin, AE1/AE3, CD10, RCCM, PAX2, PAX8, CAIX - : HMWCK, CK7, CK20, CD117, Ksp-cadherin, Parvalbumin Papillary RCC and MTSCC +: Vimentin, AE1/AE3, CK7, AMACR, RCCM, PAX2 and PAX8 - : CD117, Ksp-cadherin, and Parvalbumin. Chromophobe RCC/Oncocytoma +: E-cadherin, Ksp-cadherin, Parvalbumin, CD117, AE1/AE3, CK7 strong/diffuse for chromphobe RCC - : Vim, CK7 (or weak for oncocytoma), CAIX, and AMACR

192 IHC of RCC Collecting Duct Carcinoma +: p63, HMWCK; Some + for PAX2 and PAX8 - : RCCM, CD10, CD117, KSP, and Parvalbumin Xp11.2 Translocation Carcinoma +: CD10, RCCM, TFE3, PAX2 or 8, and Cathepsin-K - : CK (usually or weak) Clear Cell Papillary RCC +: CK7, PAX2 and PAX8 - : AMACR, RCCM, CD10

193 Vim RCC Marker AMACR

194 USE of IHC DDX of renal vs. non-renal neoplasms Histologic subtyping of renal cell carcinoma Diagnosis of rare primary renal neoplasm

195 USE of IHC DDX of renal vs. non-renal neoplasms Histologic subtyping of renal cell carcinoma Diagnosis of rare primary renal neoplasm Diagnosis of core biopsy of renal tumor

196 USE of IHC DDX of renal vs. non-renal neoplasms Histologic subtyping of RCC Diagnosis of rare primary renal neoplasm Diagnosis of core biopsy of renal tumor Diagnosis of metastatic RCC

197 Renal tumors with clear/light-staining cytoplasm Antibody Clear Cell RCC Chromophobe RCC MITF/TFE Family XP11.2 Carcinoma Clear Cell Papillary RCC Epithelioid Angiomyolipoma CK7 - + (diffuse, occasionally patchy) - + (diffuse, almost 100% tumor cells) CD10 + (membranous) -/(rarely +) + (but often in TFEB carcinoma) - - Vimentin + -/(rarely +) -/+ + + Ksp-cadherin No Data - CD (diffuse, often peripheral membranous accentuation - No Data - AMACR - (rarely focal +) - + (usually) - - EMA/MUC (rarely focal +) + - PAN-CK(AE1/AE3) (rarely focal +) + - CAIX + (diffuse membranous) - (+ perinecrotic areas) - (+ in some cases) + (diffuse membranous) TFE3/TFEB Parvalbumin Melan-A(MART-1) in TFEB carcinoma, rarely + in TFE3 HMB in TFEB carcinoma, rarely + in TFE3 MiTF in TFEB carcinoma, rarely + in TFE Actin-sm /- - -

198 Renal tumors with papillary or Tubulopapillary Architecture Antibody Papillary RCC Collecting Duct Carcinoma Metanephric Adenoma CK (may be + in branching tubules or papillary structures) CD10 + (often luminal pattern) Mucinous Tubular and Spindle Cell Carcinoma /+ (focal) - RCC Variable -/+ AMACR + - -/+ + - EMA/MUC (may be + in branching tubules or papillary structures) + + WT HMCK(34 E12) - +/- - -/+ + Clear Cell Papillary RCC CD57 - No Data + - No Data INI1 + + (lost in renal medullary carcinoma) Ulex No Data CAIX - (+ perinecrotic areas and papillary tips) -/+ (perinecrotic area) No Data No Data +

199 Antibody Renal tumors with Granular/Eosinophilic Cytoplasm Clear Cell RCC, Eosinophilic Chromophobe RCC, Eosinophilic Oncocytoma MiTF/TFE Family Translocationassociated Carcinoma Vimentin +/- - (rarely +) - -/+ + CD Pax (rarely +) + Variable - RCC + -/+ -/+ + - CK7 - +/ Epithelioid Angiomyolipoma CD10 + -/+ + + in TFE3 carcinoma, often (-) in TFEB - K 네 -cadherin Variable - Parvalbumin No Data - EpCAM/BER-EP4 Variable + - (occasionally focal or patchy +) Variable - TFE3/TFEB Melan-A(MART-1) in TFEB carcinoma, rarely + in TFE3 HMB in TFEB carcinoma, rarely + in TFE3 MiTF in TFEB carcinoma, rarely + in TFE Actin-sm /- HMCK(34 E12) - - (rarely focal +) - - (occasionally focal +) - EMA/MUC1 + + (occasionally only focal +) + (occasionally only focal +) - (occasionally focal +) - CAIX (+ in some cases) -

200 Renal tumors with Spindle Cell Morphology Antibody PAN- CK(AE1/AE3) Spindle Cells in Sarcomatoid RCC Mucinous Tubular and Spindle Cell Carcinoma Sarcoma + (may be focal/rare cells) + - (may be focal + in leiomyosarcoma) Cam5.2 + (may be focal/rare cells) + - (may be focal + in leiomyosarcoma) EMA/MUC1 + (may be focal/rare cells) + - (may be focal + in leiomyosarcoma) Desmin - (may occasionally be +) - + in myosarcomas, occasionally in others Actin-sm - (may occasionally be +) - + in myosarcomas, occasionally in others CD in synovial sarcoma Variable S Variable Variable Melan-A(MART-1) HMB MiTF HMCK(34 E12) -/(rarely focal +) -/+ - - CK7 -/(rarely focal +) CAIX + (usually) - - (+ in perinecrotic areas) - Angiomyolipoma

201 Poorly Differentiated Carcinomas Antibody RCC, Unclassified Collecting Duct Carcinoma CK7 -/+ + + CK (rarely focal +) +/- P HMCK(34 E12) -/+ +/- + Thrombomodulin - - +/- RCC +/- - - Uroplakin /- Vimentin +/- + -/+ CD10 +/- - -/+ CK5/ /- CK /- INI1 + + (loss in medullary) + Ulex /+ Urothelial Carcinoma

202 Small Blue Round Cell Tumors of Kidney Antibody Wilms Tumor Ewing Sarcoma/ PNET Small Cell Carcinoma Lymphoma Desmoplastic Small Round Cell Tumor Synovial Sarcoma, Poorly Differentiated Vimentin /- + + WT S Variable -/+ FLI CD99 +/- + -/+ +/- -/+ -/+ NSE - +/- -/+ - + No Data HMCK(34 E12) - -/+ + (often dot-like) - - -/+ EMA/MUC1 -/+ - -/ /+ CD45(LCA) Chromogranin - - +/- - -/+ - Desmin Pax-2 + No Data No Data No Data No Data No Data PAN- CK(AE1/AE3) + (in tubules) +/- (focal) + (often dot-like) - + -/+

203 Contents 5: 5 types of malignant tumors 4: 4 +4 newly defined entities 3: 3 benign tumors 2: 2 entities no longer exist 1: 1 (+1) most important prognostic factor

204 Take Home Messages Do your BeST! Basic (effort) Study Think Enjoy Pathology of Renal Neoplasms

205 Thank you for your attention!