Pathology of Renal Neoplasms: Recent Advances

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

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

KIDNEY CANCER - CURRENT STATUS UNITED STATES, 2012 Including renal pelvis 64,770 (40,250, males; 24,520, females) New cases in 2012 13,570 (8,650, males;4,920, females)

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 1977 1984 to 1986 1996 to 2003 Kidney 51 56 66 Bladder 74 78 81 Prostate 69 76 99 Testis 83 94 97 Jemal A. et al. CA Cancer J Clin 2009;59:225-49

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

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 )

Increasing of Cancers of Kidney /Renal Pelvis USA (1995-2010) 70000 60000 Data obtained from Cancer Statistics by American Cancer Society 58240 50000 40000 30000 31200 20000 10000 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012: 64,77 0

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

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 2007. Hudes et al. NEJM 2007

Histology and Classification

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

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

Kidney Histology

RCC marker Kidney specific cadherin

Kidney specific cadherin

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

CRCC4 A B C D a b c d a b c d a b c d a b c d 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 PRCC5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 CHRCC4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 OC5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

RCC Histology and Incidence (Selective large series and TMH data) Histologic Type Incidence (5 studies)* TMH (n=1147) Clear cell 68% - 83.2% 77.2% Papillary 11% - 19.8% 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)

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

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

5 Malignant

Clear Cell RCC

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

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

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

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

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

Type 1 papillary RCC

Type 2 papillary

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

Foamy Macrophages

Type 2 PRCC macrophages

Mucin

Solid type

Type 1 papillary, solid

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?

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

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)?

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

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)

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

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

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

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

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

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

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?

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

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

Xp11 Translocation Carcinomas TFE3 TFE3 Shen SS, Truong LD, Ayala AG, and Ro JY. Arch Pathol Lab Med 2007 131:1234-43.

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?

Mucinous Tubular and Spindle Cell Carcinoma P504 RCCm CD15 Shen SS, Ro JY et al. Annals of Diag Pathol 2007 11:13-21.

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

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

CA9 CK7 CD10 HMCK

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

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

Tubulocystic RCC Also known as low grade CDC < 60 cases reported Strong male preponderance 7:1 34-90 (mean 60yo) Closely related to papillary RCC type 1 +CK7, AMACR, CD10, CK19

CK7 AMACR H&E RCC, low grade papillary RCC, tubulocystic RCC, high grade papillary Yang XJ, Zhou M, Hes O, Shen SS et al. 2008 AJSP 32:177;2009, 33:1840

Thyroid Follicular Carcinoma-like Tumor of Kidney Jung SJ, Chung JI, Park SH, Ayala AG, and Ro JY. Am J Surg Pathol. 2006 20 30:411-415 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 9q21-33. These findings are dissimilar to previously classified renal neoplasm

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;33:393-400 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

CK PAX2

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 +)

AMACR CK7 focal +

AMACR CK7-

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

CK7 + in both papillary and tubular areas

No VHL mutation No HMB45

---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?

3 Benign

Metanephric Adenoma

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. 2008 CAP Poster

Papillary RCC Metanephric Adenoma

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. 2008 CAP Poster

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

Papillary Adenoma

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

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

2 Entities no longer exist

Granular RCC

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

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

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

Issues of Granular RCC Chromophobe RCC Oncocytoma Angiomyolipoma Clear cell RCC

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

Sarcomatoid RCC

Sarcomatoid Changes Occur in All Types of RCC # Cases # Sarcomatoid (%) Clear cell 818 44 (5.4) Papillary 149 7 (4.5) Chromophobe 60 1 (1.7) Collecting duct 6 4 (66.7) Unclassified 15 6 (40) Total 1048 62 (6) (TMH Unpublished Data)

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

Sampling is important

Is this sarcomatoid?

Is this sarcomatoid??

1 RCC Staging

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

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

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

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

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

Size Matters Largest dimension (3 dimension?) Multiple tumors Cut-off criteria for staging T1a vs. T1b (4 cm T1 substage) T2 (>10 cm substage, 2010 7 th AJCC)

T2 Tumors Are Uncommon T Stage # Cases % T1 628 60% T2 107 10% T3 295 28% T4 18 2% Total 1048 100% Form TMH RCC database (1990-2006)

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

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

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

Extent of perirenal fat invasion (focal vs. extensive) Jung SJ, Ro JY, Truong LD, Ayala AG, and Shen SS. Human Pathol. 2008 39:1689-94

Extent of Perirenal Fat Invasion Jung SJ, Ro JY, Truong LD, Ayala AG, and Shen SS. Human Pathol. 2008 39:1689-94

Adrenal Invasion Direct adrenal invasion : pt3a (AJCC, 2002) T4 in 2009 7 th AJCC staging More aggressive behavior than fat invasion (Han et al. J Urol 2003)

Adrenal Invasion Group 2-year 5-year Log Rank 1 (n=118) 80% 63% Vs. 2 p<0.001 2 (n=66) 55% 32% Vs. 3 p=0.017 3 (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. 2008 39:1689

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

K-M Survival analysis of pt2/pt3 RCC T2 Fat Inv. Groups p value T2 vs Fat Inv. 0.003 Fat vs RV Inv. 0.002 Renal Vein Inv.

Grading

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)

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

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

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

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

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

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;1233-40)

Gr 1 Gr 2 Gr 3

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]

Ancillary Tests

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

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

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

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

Vim RCC Marker AMACR

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

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

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

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 - CD117 - + (diffuse, often peripheral membranous accentuation - No Data - AMACR - (rarely focal +) - + (usually) - - EMA/MUC1 + + - (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-45 - - + in TFEB carcinoma, rarely + in TFE3 MiTF - - + in TFEB carcinoma, rarely + in TFE3 - + - + - + Actin-sm - - - - +/- - -

Renal tumors with papillary or Tubulopapillary Architecture Antibody Papillary RCC Collecting Duct Carcinoma Metanephric Adenoma CK7 + + - (may be + in branching tubules or papillary structures) CD10 + (often luminal pattern) Mucinous Tubular and Spindle Cell Carcinoma + + - - -/+ (focal) - RCC + - - Variable -/+ AMACR + - -/+ + - EMA/MUC1 + + - (may be + in branching tubules or papillary structures) + + WT1 - - + - - HMCK(34 E12) - +/- - -/+ + Clear Cell Papillary RCC CD57 - No Data + - No Data INI1 + + (lost in renal medullary carcinoma) + + + Ulex-1 - + - - No Data CAIX - (+ perinecrotic areas and papillary tips) -/+ (perinecrotic area) No Data No Data +

Antibody Renal tumors with Granular/Eosinophilic Cytoplasm Clear Cell RCC, Eosinophilic Chromophobe RCC, Eosinophilic Oncocytoma MiTF/TFE Family Translocationassociated Carcinoma Vimentin +/- - (rarely +) - -/+ + CD117 - + + - - Pax-2 + - (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-45 - - - + in TFEB carcinoma, rarely + in TFE3 MiTF - - - + in TFEB carcinoma, rarely + in TFE3 + + + Actin-sm - - - - +/- HMCK(34 E12) - - (rarely focal +) - - (occasionally focal +) - EMA/MUC1 + + (occasionally only focal +) + (occasionally only focal +) - (occasionally focal +) - CAIX + - - - (+ in some cases) -

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 CD99 - - + in synovial sarcoma Variable S100 - - Variable Variable Melan-A(MART-1) - - - + HMB-45 - - - + MiTF - - - + HMCK(34 E12) -/(rarely focal +) -/+ - - CK7 -/(rarely focal +) + - - CAIX + (usually) - - (+ in perinecrotic areas) - Angiomyolipoma - - - + +

Poorly Differentiated Carcinomas Antibody RCC, Unclassified Collecting Duct Carcinoma CK7 -/+ + + CK20 - - (rarely focal +) +/- P63 - - + HMCK(34 E12) -/+ +/- + Thrombomodulin - - +/- RCC +/- - - Uroplakin-3 - - +/- Vimentin +/- + -/+ CD10 +/- - -/+ CK5/6 - - +/- CK17 - - +/- INI1 + + (loss in medullary) + Ulex-1 - + -/+ Urothelial Carcinoma

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 + + - +/- + + WT1 + - - - + - S100 - - - - Variable -/+ FLI-1 - + - - - - 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) - + -/+

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

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

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