Renal Neoplasia: Diagnostic Problems and Recently Recognized Entities
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1 Renal Neoplasia: Diagnostic Problems and Recently Recognized Entities John N. Eble, M.D. Department Pathology Indiana University, Indianapolis, IN Holger Moch, M.D. Department Pathology University Hospital Zurich, Switzerland
2 Renal Cancer Unusual and new renal tumor entities Clear cell carcinoma Granular cell carcinoma Renal cancer unclassified Collecting duct carcinoma clear cell carcinoma chromophobe carcinoma oncocytoma Papillary carcinoma Type 1 Type 2 metanephric adenoma,adenofibroma
3 renal cysts Case 1 Case history 37 year old man with detection of left renal tumor by CT multiple smaller renal tumors in the same and contralateral kidney some tumors were cystic
4 Case 1 Macroscopic findings Tumor diameter 5 x 5 x 1.5 cm. cut-surface yellow some cysts in the tumor
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8 Case 1 Risk factors for VHL Syndrome younger than 50 years multifocal unilateral or bilateral tumors family history of renal cancer or other VHLassociated tumors Germline mutation analysis missense mutation of the VHL-gene on 3p25-26
9 Case 1 Diagnosis VHL-associated clear cell renal cell carcinoma as an example for hereditary renal cell carcinoma
10 VHL-associated RCC Incidence 1: :45000 Neumann HP et al.: Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma. J Urol 16, pp , 1998 Prevalence: 1.6 % in unselected RCC patients occur 25 years earlier better 10 years survival (p<0.001) metastases occur only in tumors larger than 7 cm
11 VHL subtypes HB RCC PCC Mutation type Type Deletion, truncation Type 2A Tyr98His*; Tyr112His Type 2B Missense Type 2C Leu188Val; Val84Leu; Ser80Leu * "Black forest" founder mutation HB: Hemangioblastoma RCC: Renal cell carcinoma PCC: Pheochromocytoma
12 Clear Cell Renal Cancer VHL Deletion (FISH): 69% (Cancer Res 1998)
13 pvhl in Tumor Initiation and Progression Elongin B Cul 2 Elongin C Rbx1 pvhl β α HIFα HIFα HIFα O 2 O 2 VEGF
14 Progression: pvhl and Survival 100 Nuclear expression (n=147) pvhl 19 in nucleus 80 Tumor-specific survival p<0.001 No nuclear expression (n=64) months loss of nuclear expression associated with worse prognosis Schraml et al.: Am J Pathol 2003
15 Clear Cell Renal Carcinoma Multilocular clear cell renal carcinoma Eble and Bonsib. Extensively cystic renal neoplasms. Semin.Diagn.Pathol. 15: 2-20, 1998
16 Multilocular cystic renal cell carcinoma
17 Multilocular cystic renal cell carcinoma
18 Hereditary Renal Cancer Syndromes Syndrome Gene Protein Chromo - some Kidney Skin Other Tissue von Hippel -Lindau Hereditary papil renal cancer Hereditary leiomyomatosis and RCC Birt -Hogg -Dubé lary Constitutional chromo - some 3 translocation Hyperparathyreoidism - jaw tumor (HP -JT) Familial papilary thyroid cancer (FPTC) VHL pvhl c-met HGF-R FH FH BHD Folliculin 3p25 Multiple, bilateral clear -cell renal cell carcinoma (CCRCC), renal cysts 7q31 Multiple, bilateral papillary renal cell carcinomas (PRCC), Type 1 1q42-43 Papillary renal ce l carcinoma (PRCC), non -Type 1 17p11.2 Multiple chromophobe RCC, conventional RCC, hybrid oncocytoma, papillary RCC, oncocytic tumors unk nown Multiple, bilateral clear -cell renal cell carcinomas (CCRCC) HRTP2 1q25-32 Mixed epithelial and stromal tumors, papillary RCC: cysts Unknown gene - Retinal and CNS haemangioblastomas, phaechromocytoma, pancreatic cysts - Nodules (leiomyomas) Uterine leiomyomas and leio myosarcomas Facial fibrofoliculomas Lung cysts, spontaneous pneumothorax Parathyroid tumors, fibro -osseous mandibular and maxilary tumors 1q21 Papillary RCC, oncocytoma - Papilary thyroid cancer, nodular thyroid disease
19 Birt Hogg Dubé syndrome Facial fibrofolliculoma and trichodiscoma: multiple, whitish (2-4 mm) smooth papules commonly present in great numbers over the face, neck, oral cavity, and upper trunk, sometimes pedunculated (acrochordons). Lung cysts with risk of spontaneous pneumothorax (34x) Colonic polyps Renal tumors (oncocytoma and chromophobe) Mutations in human folliculin (BHD) gene on
20 Birt Hogg Dubé syndrome
21 Hereditary Papillary RCC c-met Gene on 7q31
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23 Hereditary Leiomyomatosis and RCC Syndrome (HLRCC) Fumarate Hydratase (FH-) Gene on 1q42
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25 Case 2 Case history 62 year old man tumor was detected incidentally by ultrasound Renal angiography showed relative hypovascularity of the tumor
26 Case 2 Macroscopic findings 3.5 x 2 x 1.5 cm in diameter tumor hemorrhage and pseudoencapsulation
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32 Case 2 Diagnosis Papillary renal cell carcinoma (Type 1)
33 Papillary Carcinoma no 3p Deletions Polysomy 17: 60 % (J Path 2000)
34 Papillary Renal Cell Type 1 Type 2 Carcinoma Delahunt and Eble: Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod. Pathol. 10: , 1997 Jiang et al.: Chromosomal imbalances in papillary renal cell carcinoma. Am.J.Pathol. 153:
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36 Type 2
37 Type 2
38 Type 1
39 Papillary renal cell carcinoma Type 1 Type 2
40 Type and Prognosis of Papillary Renal Cancer Moch et al.: Cancer 89, 2000 Survival (%) type 1 (n=18) type 2 (n=47) p< months
41 Papillary Adenoma Grignon and Eble: Papillary and metanephric adenomas of the kidney. Semin.Diagn.Pathol. 15:41-53, 1998
42 Small Renal Tumors (<1.5 cm) with Early Events p Y- cl ear cel l (n=14) papi l l ary (n=23) J Urol 1998
43 Definition Adenoma Tumours with papillary or tubular architecture of low nuclear grade and 5 mm in diameter or smaller While grade 1 papillary tumours between 0.5 cm and 2 cm are strictly defined as carcinomas, many pathologists prefer to report them as papillary epithelial neoplasms of low malignant potential for practical reasons
44 Tumor Diameter and Metastasis at Autopsy (871 Patients) max.tumordiameter n M1 oder N1 1-3 cm (3.4%) cm (2.2%) cm (1.3%) 1.0 cm 396 0
45 Tumor Diameter and Risk of Metastasis (Logistic Regression Analysis) 100 Risk of Metastsis (%) Diameter (cm)
46 Differential Diagnosis Metanephric adenoma Metanephric stromal tumor Collecting duct carcinoma Mucinous tubular and spindle cell carcinoma Mixed epithelial and stromal tumor Juxtaglomerular cell tumor Complex Cysts
47 Renal Cyst in ADPKD Ki-67
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49 Metanephric Neoplasia Metanephric adenoma Muir et al.: Metanephric adenoma, nephrogenic rests, and Wilms tumor: a histologic and immunophenotypic comparison. Am.J.Surg.Pathol.25: , 2001
50 Metanephric Adenoma Metanephric Adenofibroma
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53 Case 5 Case history 14 year old boy who felt pain while playing soccer a CT revealed a mass in the right kidney a nephrectomy was performed
54 Case 5 Macroscopic findings tumor diameter 7 x 5 x 2 cm firm, grey-white appearance with irregular borders poorly circumscribed with central location
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56 Cytogenetics t(x;17)(p11;q25)
57 Case 5 Diagnosis Xp11-translocation carcinoma in children and young adults
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59 Xp11 Translocation Carcinomas Heimann et al.: Fusion of a novel gene, RCC17, to the TFE3 gene. Cancer Res 61: , 2001 Argani et al.: Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcomas. Am J Surg Pathol 159: , 2001 Argani et al.: PRCC-TFE3 renal carcinomas. Am J Surg Pathol 26: , 2002
60 Am J Surg Path 28, Carcinoma < 20 years clear cell 6 (15%) papillary 9 (22%) chromophobe 2 collecting duct 2 after neuroblastoma 1 Translocation carcinoma 8
61 Xp11 Translocation Carcinoma in Adults 14/28 pts: Stage 4 11/13 pts: pn1 5/6 pts developed hematogenous metastases Xp11 Translocation Carcinoma in Adults are Aggressive Cancers Argani, P et al.: Am J Surg Pathol 2007
62 PRCC-TFE3 Renal Carcinomas t(x;1)(p11.2;q21)
63 Am J Surg Path February 2005
64 t(6;11)(p21;q12) renal carcinoma 12 cases Ages 6-53 years (median 18 years) 1 metastasis in limited follow up All HMB45+, Melan A+ Usually Cytokeratin-
65 t(6;11) and Xp11 renal translocation carcinomas: Similarities Clinical Usually affect children and young adults Morphology Epithelioid cells, predominantly clear cytoplasm Immunohistochemistry Minimal cytokeratin labeling Nuclear labeling for aberrant transcription factor Melanocytic marker expression Genetics TFEB and TFE3 are related transcription factors Both activate similar genes in vitro Both overexpressed by promoter substitution
66 MiTF TFE3 TFEB TFEC MiT (MiTF/TFE) subfamily of transcription factors Homologous DNA binding and activation domains Recognize identical DNA sequences Heterodimerize in all combinations Activate transcription of similar genes in vitro
67 Translocation Carcinomas (MiTF/TFE Transcription Factor Family) Xp11.2: ASPL-TFE3 Renal Carcinomas t(x;17) PRCC-TFE3 Renal Carcinomas t(x;1) Other TFE3 Renal Carcinomas (PSF-, NonO-, CLTC) t(6;11): TFEB Renal Carcinomas
68 Diagnostic IHC Markers from the MiTF/TFE Transcription Factor Family Gene MiTF TFE3 TFEB TFEC IHC Assay Yes Yes Yes No Neoplasm Malignant Melanoma Alveolar Soft Part Sarcoma, Xp11 translocation carcinomas t(6;11)(p21;q12) renal carcinomas?
69 ASPL-TFE3 Renal Carcinomas: Standard IHC 50% are completely negative for cytokeratins and EMA - Remainder are usually only focally positive CD10, RCC are more consistently positive TFE3 (polyclonal, Santa Cruz); Sensitivity 97.5% Argani et al.: Am J Surg Path 27, 2003
70 Am J Surg Pathol 2005;29:
71 Case 6 Case history 53 year old woman Detection of a renal mass by CT nephrectomy patient free of disease 5 years after nephrectomy
72 Case 6 Macroscopic findings tumor wellcircumscribed solid uniform grey cut surface
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78 Case 6 Diagnosis Mucinous tubular and spindle cell carcinoma
79 Mucinous Tubular and Spindle Cell Carcinoma Parwani et al.: Low-grade myxoid renal epithelial neoplasms with distal nephron differentiation. Hum.Pathol.32: , Rakozy et al.: Low-grade tubular-mucinous renal neoplasms. Mod.Pathol.15: , 2002
80 CK19 Ulex europaeus Mucinous Tubular and Spindle Cell Carcinoma THP CD 10 und RCC distal Tubule Glom erulum Collecting duct proxim al Tubule Henle's loop CK 19
81 Mucinous Tubular and Spindle Cell Carcinoma Loopoma? mucinous low grade carcinoma Differential Diagnosis: Collecting duct carcinoma Sarcomatoid RCC Papillary Type 1 RCC Metanephric adenoma Juxtaglomerular cell tumor
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83 Immunohistochemistry AMACR RCC CD10 c-kit HMWK CK7 EMA MTSC (%) Papillary Type 1 (%)
84 Juxtaglomerular cell tumor Renin
85 Case7 Case history 47 year old woman CT: 12 cm measuring tumor
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87 Case 7 Macroscopic findings Solid tumor with areas of hemorrhage, necrosis
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91 SYT-SSX Fusion from translocation t(x;18) SYT-SSX
92 Case 7 Diagnosis Renal Synovial Sarcoma
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94 Primary Renal Synovial Sarcoma Immunophenotype: EMA + CD56 + CD99 +/- CD34- Desmin- Actin- Cytokeratin -
95 Differential Diagnosis Wilms-Tumor PNET Cellular Mesoblastic Nephroma Mixed epithelial and stroma tumor/cystic nephroma (cystic hamartoma of renal pelvis) Solitary fibrous tumor
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97 Molecular detection of a SYT-SSX Fusion from Translocation t(x;18) A M β-globin SYT-SSX 300 bp 100 bp B SYT: 18q11 SSX1/SSX2: Xp11
98 Mesoblastisches Nephrom t(12;15)
99 CD 34 Solitary Fibrous Tumor
100 Primary Renal Synovial Sarcoma Age distribution: years Literature: 22 cases 4 local recurrencies! Therapy Ifosfamide Cyclophosphamide, Etoposide
101 Case 8 Case history 30-year-old woman with persistent abdominal pain Large palpable mass in the right side of the abdomen CT showed an 8 x 7 x 6 cm right renal tumor with lymph node enlargement and multiple lung and skeletal metastases tumor debulking through nephrectomy no evidence of recurrent disease after 28 months of radiotherapy and high-dosed chemotherapy
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103 Case 8 Macroscopic findings 12 cm in diameter a gray to tan surface with areas of hemorrhage and necroses pseudocapsule
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106 CD 99 Ewing-Sarcoma/PNET
107 Case 8 Diagnosis Primitive neuroectodermal tumor of the kidney (Ewing sarcoma)
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111 Ewing-Sarcoma/PNET Immunophenotype: CD99+, HBA-71+ Cytokeratin (+) Vimentin+ Desmin - FLI-1 + WT-1 - Parham DM et al.: Am J Surg Pathol 25; 2001
Disclosure. Relevant Financial Relationship(s) None. Off Label Usage None MFMER slide-1
Disclosure Relevant Financial Relationship(s) None Off Label Usage None 2013 MFMER slide-1 Case Presentation A 43 year old male, with partial nephrectomy for a right kidney mass 2013 MFMER slide-2 2013
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