Renal Tumors with Granular Cytoplasm: Clues to Accurate Diagnosis

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1 Renal Tumors with Granular Cytoplasm: Clues to Accurate Diagnosis Current Issues in Surgical Pathology May 25, 2012 Jeffry P. Simko, PhD, MD Associate Professor Departments of Urology, Radiation Oncology and Anatomic Pathology Granular Renal Cell carcinoma: A Diagnostic Entity? Granular Variants of other Recognized Diagnostic Entities (Clinical behavior, Cytogenetics, Morphology, etc.) Lesions that can have Granular Cytoplasm Renal Oncocytoma Chromophobe RCC Hybrid tumors of Birt-Hogg-Dube Syndrome Clear Cell RCC Angiomyolipoma (epithelioid type) Translocation RCC family (Alveolar Soft Part Sarcoma) Carcinoid / Neuroendocrine Tumors / Paraganglioma Papillary RCC (Hereditary Leiomyomatosis Syndrome) Acquired Cystic Disease RCC RCCs status post Neuroblastoma Juxtaglomerular cell tumor Urothelial cell carcinoma, Collecting Duct carcinoma Malakoplakia / Xanthogranulomatous Pyelonephritis Adrenal rests and Adrenal tumors Stromal Tumors, Melanoma Renal Tumor Incidence (General) Unclassified 4% Oncocytoma 6% chromophobe 5% papillary 15% collecting duct 1% Others 1% clear cell 68% clear cell papillary chromophobe Oncocytoma Unclassified collecting duct Others 1

2 Renal Tumor Incidence (T < 1cm) Motivation: Benign 45% clear cell 14% papillary 41% clear cell papillary Benign Smaller tumors more likely benign Incidence up with increased screening imaging Ablation therapies where diagnostic tissue is severely limited Some tumor types have characteristic cytogenetic profiles Can help with diagnosis (Molecular characterizations) Relationship to certain familial (genetic) syndromes Targeted therapy development (Anti-angiogenics) Frank I, Blute ML, Cheville JC, et al., J Urol 170(6 Pt 1): (2003). Renal Oncocytoma: Benign Gross (characteristic): Cortex, Mahogany brown, central scar (bigger tumors?), circumscribed, no necrosis Microscopic architecture: Nests, sheets of nests, syncytial growth in myxoid / hyaline stroma (maybe fine vascular meshwork at periphery), rarely encapsulated (~10%) Cytology: Oncocytic cells with small round central nuclei, small nucleolus Karyotype: inconsistent -Y, -1 IHC + : CD117, Vim, E-Cadherin, PAX-2,8, S-100A IHC - : CK7, RCC, CA IX, AMACR 2

3 3

4 Renal Oncocytoma: Features causing imagined concern: Infiltration / entrapment of adjacent kidney (no capsule!) Infiltrating adipose tissue ( ~ 15%). Vessel invasion (~ 2 3%) Hypercellularity (focal oncocytosis) Enlarged irregular nuclei (degenerative atypia) Wrinkled nuclei and binucleates (chromophobe) Cyst formation Hale s colloidal iron positive (common in stroma, not uniform) Perinuclear halos (rare) Features that are of definite concern (WORRY a lot; to the point of maybe changing your Dx!) Areas of Sacromatoid / high grade / or recognizable RCC types Prominent necrosis (scant necrosis can be OK) Atypical mitoses (? Frequent mitoses?) Macronucleoli (? How big is too big? ) 4

5 Chromophobe RCC: Malignant ( Low grade) Gross: Cortex, tan to mahogany, central scar (~10%), circumscribed, encapsulated Microscopic architecture: Broad sheets to nests in fine vascular meshwork (vascular), encapsulated Cytology: Variably granular cytoplasm (clear cells at periphery, more eosinophilic towards center), THICK cell membranes, wrinkled central nuclei with binucleates and perinuclear clearing, Hale s colloidal Fe diffusely + Karyotype: Inconsistent losses 1,2,6,10,12-15,17,Y EM: Microvesicles (gives perinuclear clearing) IHC + : CD117, CK7, PAX-8, EMA, E-Cadherin IHC - : Vimentin, RCC, Pax-2, CA IX, AMACR Amin MB, et al., Am J Surg Pathol. 26(3): (2002). 5

6 Clear cell RCC 6

7 Chromophobe RCC: Features causing confusion: Heavily eosinophilic cytoplasm (~ 30% of cases) Smaller cells with rounded nuclei and perinuclear clearing not consistent Round nuclei with nucleoli Unimpressive cell borders (not completely gone) No capsule (~30%) Multi-lobular, multifocal (~ 10%,? Worse?) Hyaline / myxoid stroma (focal, ~10% (central scar)) Nuclei wrinkled,? How to grade? (Sarcomatoid areas vs. none) Features that are of definite concern Sarcomatoid areas (Grade 4 chromophobe vs. other) No perinuclear clearing or clear cells throughout CD 117 7

8 CK 7 8

9 Hybrid Oncocytic tumors: Oncocytoma, but some Chromophobe features Dx: Oncocytic Neoplasm of uncertain malignant potential Chromophobe, but some Oncocytoma features Dx: Chromophobe RCC 9

10 Hybrid Oncocytic tumors: Oncocytoma, but some Chromophobe features Dx: Oncocytic Neoplasm of uncertain malignant potential Chromophobe, but some Oncocytoma features Dx: Chromophobe RCC? Is there a diagnostic entity lurking? Poorly defined, small numbers, outcome lacking 10

11 Hybrid Oncocytic tumors: Oncocytoma, but some Chromophobe features Dx: Oncocytic Neoplasm of uncertain malignant potential Chromophobe, but some Oncocytoma features Dx: Chromophobe RCC? Is there a diagnostic entity lurking? Poorly defined, small numbers, outcome lacking BHD Syndrome: Autosomal Dominant: LOF Mutations in Folliculin Gene (tumor suppressor gene at 17p11.2) Skin fibrofolliculomas, Spontaneous Pneumothorax Kidney tumors in ~ 30% of affecteds 50% Hybrid tumors, 35% Chromophobe, 10% clear cell RCC, 5% oncocytoma Oncocytoma cells mixed with Chromophobe cells True Hybrid Tumor Birt-Hogg-Dube Syndrome Tumor (NO METS YET) Needle Cores: Oncocytic Neoplasm (comment on possibilities) Linehan, et al. J Urol. (6 Pt 1): (2003). Clear cell RCC (Conventional, hypernephroma) Malignant (very unpredictable) Gross: Variable, Irregular lobules, yellow, orange, white, BLOODY, soft, necrosis, cystic, Vascular invasion Architecture: Variable, nests, sheets, tubular, alveolar, multilobulated, variably encapsulated, pushing borders, with fine vascular meshwork. Cytology: Clear cytoplasm to variably granular, cell membranes, central nucleus, variable nuclear features Cytogenetics: -3p (VHL) Syndromes: VHL (retinal angiomas, cerebellar hemangioblastoma, pheochromocytoma), others IHC +: Vim, EMA, CD10, RCC, PAX-2,8, CA IX, S-100alpha IHC - : CD117, CK7, E-Cadherin 11

12 12

13 Clear cell RCC: Features causing confusion (sampling): Eosinophilic cytoplasm throughout Prognostic (yes, but not independent of grade) DDx is grade dependent Alveolar pattern throughout (translocation tumor ASPS-like) Thick cell membranes (chromophobe) Infiltrative growth (think urothelial, collecting duct, mets.) Extremely uniform cells (neuroendocrine tumors) Rhabdoid type cells (epithelioid AML) Features of great concern (think something else): Papillary architecture (translocation tumors, papillary RCC, clear cell and papillary RCC) No fine vascular meshwork (xanthogranuloma, malakoplakia) Eosinophilic tumor with prominent perivascular cellularity (AML). Spindled / sarcomatoid throughout (RCC unclassified). Characteristic Clear RCC Chromo RCC Oncocytoma Tumor contour variable Usu spherical Usu spherical Tumor color variable Tan to mahogany Mahogany brown Gross scarring variable Central scar ~ 10% Central scar common Hemorrhage Common Possible Uncommon Cystic change Not uncommon uncommon Uncommon (rare) cytoplasm Usually clear Can be granular Usually clear Can be granular Usually granular Rarely clear (focal) Cell membranes Variable Thick, Plant-like Usually inconspicuous Nuclei Variable Wrinkled, binucleates Nucleoli Varialbe (grading) Uncommon (grading) Uniform, round, mononucleate Prominent, single, small, central Perinuc. clearing Absent Prominent Rare (focal) Stroma Vasc., fibrous vascular Myxoid, few vessels Hale's colloidal Fe Negative Positive diffuse Peripheral, stromal Invasion Yes yes Uncommon Fibrous capsule Variable common Uncommon IHC Ab Clear RCC Chromo RCC Oncocytoma CKIT (CD117) Negative Positive Positive Mitochondrial Variable Variable Positive S-100A1 Variable Negative Positive Immunohistochemistry: CK7 Negative Positive negative Cadherins (E, KS) Variable Positive Positive RCC Positive Negative Negative PAX2, PAX8 Positive Variable Positive CA IX Positive Negative Negative Associated (possible) cytogenetic 3p- (VHL LOF) Losses (1,2,6,10,13, 17,Y) 1-, Y- Syndromes VHL, many others BHD (hybrid tumor) BHD (hybrid) Extremely Heterogeneous staining patterns Ischemic areas stain differently Cyst fluids and blood can affect reactions Heterogeneous or biphasic tumors? Significance? Studies performed on clear-cut examples Antibody may not be 100% specific Mitochondrial Ag likely positive in any granular tumor. 13

14 Summarize: Classic features - > Easy to tell apart Rare hybrid tumors do exist Uncertain malignant potential or unclassified Always think Clear Cell RCC first Poorer outcome and survival Sampling, sampling, sampling Extra care on needle cores Clear cell & chromophobe can have oncocytes Syndromes associated with these tumors Molecular characterization AML (epithelioid): Malignant (? Subset?) Eosinophilic epithelioid and spindled cells Perivascular hypercellularity (benign?) Mimicker of Clear cell RCC and Melanoma Tuberous sclerosis association (TSC1), ~ 30% Recently reported Translocation tumor association (non-renal tumors only & without TSC; ~ 25%) Argani, et al., AJSP 34(10): (2010). Risky features: TSC association, multifocal, necrosis, T > 7cm, stage > pt2, carcinoma-like growth IHC + : HMB-45, melan-a, SM Actins IHC - : Keratins, EMA, S-100 (weak focal at best) Nese N, et al., Am J Surg Pathol 35(2): (2011). Nese N, et al., Am J Surg Pathol 35(2): (2011). Nese N, et al., Am J Surg Pathol 35(2): (2011). 14

15 Carcinoid / Neuroendocrine: RARE (21 cases is largest series) Seem locally aggressive & low grade malignant Typical neuroendocrine growth patterns: Nested/organoid with fine vascular meshwork (sometimes fibrohyaline stroma), uniform nuclei (either round or columnar), granular chromatin (salt and pepper) IHC + : Synaptophysin, Chromogranin, Cam 5.2, Vimentin IHC - : RCC, PAX2, PAX8, CA IX, CK7 (rare pos.), CK20 D Hansel, et al., AJSP 31(10): (2007). Translocation tumors (pediatric PRCC): ~ ½ of child RCCs (? 1-4% of adult tumors?) Gross: similar to clear cell RCC Microscopic: Mixed clear and Papillary areas t(x)(p11.2), TFE3 gene locus (TFE3 IHC +) t(x,1)(p11.2,q21) PRCC t(x,17) ASPL (alveolar soft part sarcoma) Other rare ones t(6;11) IHC +: RCC, CD10, Pax 2,8, TFE3 (TFEB), HMB45, melan-a, cathepsin-k IHC - : CKs, EMA, Vim (all weak) Ross H, Argani P, Pathology 42(4): (2010). 15

16 Characteristic Clear RCC Chromo RCC Oncocytoma Tumor contour variable Usu spherical Usu spherical Tumor color variable Tan to mahogany Mahogany brown Gross scarring variable Central scar ~ 10% Central scar common Hemorrhage Common Possible Uncommon Cystic change Not uncommon uncommon Uncommon (rare) cytoplasm Usually clear Can be granular Usually clear Can be granular Usually granular Rarely clear (focal) Cell membranes Variable Thick, Plant-like Usually inconspicuous Nuclei Variable Wrinkled, binucleates Nucleoli Varialbe (grading) Uncommon (grading) Uniform, round, mononucleate Prominent, single, small, central Perinuc. clearing Absent Prominent Rare (focal) Stroma Vasc., fibrous vascular Myxoid, few vessels Hale's colloidal Fe Negative Positive diffuse Peripheral, stromal Invasion Yes yes Uncommon Fibrous capsule Variable common Uncommon References: 1. Munichor M, Lichtig C, Tzin G, Weiss A., Prognostic significance of granular cell content in renal cell carcinoma, Eur Urol 22(3): (1992). 2. Veloso JD, Solis OG, Barada JH, Fisher HA, Ross JS, DNA ploidy of oncocytic-granular renal cell carcinomas and renal oncocytomas by image analysis, Arch Pathol Lab Med 116(2): (1992). 3. Crotty TB, Lawrence KM, Moertel CA, Bartelt DH Jr, Batts KP, Dewald GW, Farrow GM, Jenkins RB, Cytogenetic analysis of six renal oncocytomas and a chromophobe cell renal carcinoma. Evidence that -Y, -1 may be a characteristic anomaly in renal oncocytomas, Cancer Genet Cytogenet 61(1): 61-6 (1992). 4. Hartwick RW, el-naggar AK, Ro JY, Srigley JR, McLemore DD, Jones EC, Grignon DJ, Thomas MJ, Ayala AG, Renal oncocytoma and granular renal cell carcinoma. A comparative clinic pathologic and DNA flow cytometric study, Am J Clin Pathol 98(6): (1992). 5. Akhtar M, Kardar H, Linjawi T, McClintock J, Ali MA. Chromophobe cell carcinoma of the kidney. A clinic pathologic study of 21 cases, Am J Surg Pathol 19(11): (1995). 6. Amin MB, Crotty TB, Tickoo SK, Farrow GM, Renal oncocytoma: a reappraisal of morphologic features with clinic pathologic findings in 80 cases, Am J Surg Pathol 21(1): 1-12 (1997). 7. Amin MB, Paner GP, Alvarado-Cabrero I, Young AN, Stricker HJ, Lyles RH, Moch H, "Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases," Am J Surg Pathol 32(12): (2008). 8. Trpkov K, Yilmaz A, Uzer D, Dishongh KM, Quick CM, Bismar TA, Gokden N, "Renal oncocytoma revisited: a clinicopathological study of 109 cases with emphasis on problematic diagnostic features," Histopathol 57(6): (2010). 9. Humphrey PA, "Oncocytoma of the kidney," J Urol 187(5): (2012). 10. Li G, Barthelemy A, Feng G, Gentil-Perret A, Peoc'h M, Genin C, Tostain J, "S100A1: a powerful marker to differentiate chromophobe renal cell carcinoma from renal oncocytoma," Histopathol 50(5): (2007). 11. Shen SS, Truong LD, Scarpelli M, Lopez-Beltran A, "Role of immunohistochemistry in diagnosing renal neoplasms: when is it really useful?," Arch Pathol Lab Med 136(4): (2012). 12. Delahunt B, Sika-Paotonu D, Bethwaite PB, McCredie MR, Martignoni G, Eble JN, Jordan TW, Fuhrman grading is not appropriate for chromophobe renal cell carcinoma," Am J Surg Pathol 31(6): (2007). 13. Adamy A, Lowrance WT, Yee DS, Chong KT, Bernstein M, Tickoo SK, Coleman JA, Russo P, "Renal oncocytosis: management and clinical outcomes," J Urol 185(3): (2011). 16

17 References (cont): 14. Gobbo S, Eble JN, Delahunt B, Grignon DJ, Samaratunga H, Martignoni G, Zhang S, Wang M, Brunelli M, Cossu-Rocca P, Cheng L, "Renal cell neoplasms of oncocytosis have distinct morphologic, immunohistochemical, and cytogenetic profiles," Am J Surg Pathol 34(5): (2010). 15. Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ, Renal tumors in the Birt-Hogg-Dubé syndrome," Am J Surg Pathol 26(12): (2002). 16. Waldert M, Klatte T, Haitel A, Ozsoy M, Schmidbauer J, Marberger M, Remzi M, "Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes," Eur Urol 57(4): (2010). 17. Petersson F, Gatalica Z, Grossmann P, Perez Montiel MD, Alvarado Cabrero I, Bulimbasic S, Swatek A, Straka L, Tichy T, Hora M, Kuroda N, Legendre B, Michal M, Hes O, "Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases," Virchows Arch 456(4): (2010). 18. Aydin H, Magi-Galluzzi C, Lane BR, Sercia L, Lopez JI, Rini BI, Zhou M, "Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association," Am J Surg Pathol 33(2): (2009). 19. Argani P, Aulmann S, Illei PB, Netto GJ, Ro J, Cho HY, Dogan S, Ladanyi M, Martignoni G, Goldblum JR, Weiss SW, "A distinctive subset of PEComas harbors TFE3 gene fusions,"am J Surg Pathol 34(10): (2010). 20. Ross H, Argani P, "Xp11 translocation renal cell carcinoma," Pathology 42(4): (2010). 21. Grubb RL 3rd, Franks ME, Toro J, Middelton L, Choyke L, Fowler S, Torres-Cabala C, Glenn GM, Choyke P, Merino MJ, Zbar B, Pinto PA, Srinivasan R, Coleman JA, Linehan WM, "Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer," J Urol 177(6): ; discussion (2007). 22. Delahunt B, Eble JN, McCredie MR, Bethwaite PB, Stewart JH, Bilous AM, "Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases," Hum Pathol 32(6): (2001). 17

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