Gladwyn Leiman, MCCCh, FIAC, FRCPath Scott Anderson, MD

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1 Cytology Works shop #5 Gladwyn Leiman, MCCCh, FIAC, FRCPath Scott Anderson, MD Disclosur re information The speakers have no relationship that represents a possible conflict of interest with respect to the content of this presentation.

2 Resurgent Renal FNA in the Age of Nephron- Sparing Management of Renal masses Gladwyn Leiman & Scott Anderson University of Vermont, Fletcher Allen Health Care, Burlington, VT No conflicts of interest for either speaker CONFLICT OF INTEREST 1

3 Overview Gladwyn Leiman Renal cancer current status USA Acknowledge pre eminence of Radiology Evolution of local treatment of renal masses Indicate the Vermont experience Outline normal renal cell structures Show benign renal tumors Scott Anderson Malignant renal tumors Immunochemistry, limited useful panel 4 US Renal Cancer Burden ,240 new cases; 13,040 deaths Prevalence: 296,074 alive with renal cancer Male: female ratio 2:1 Mean age diagnosis: 61, 75% > age 55 33% increase in incidence from 1997 Stage and 5 year survival: Localized 61% 91% FYS * Regional 17% 63% FYS Distant 18% 11% FYS Massive personal and national burden Based on NCI's SEER data 5 Classic Renal FNA Born in 1930s Memorial, NYC Resuscitated 1960s Scandinavia Heyday in 1970s and 1980s Trans lumbar percutaneous route, US/CT Immense Cytopathology literature Large chapters in all texts (old and current) Sensitivity % for renal tumors Specificity % (rare false positives) Particular value in pediatric neoplasms Very low complication rate Integral component of FNA practice 6 2

4 Cytopathology 1990;1:65-72 Audit of fine needle aspiration cytology of 120 renal lesions. Leiman G Department of Anatomical Pathology, School of Pathology, South African Institute for Medical Research, Johannesburg. Solid renal masses in 120 patients were assessed by percutaneous FNA, performed under radiographic guidance, 109 U/S and 9 CT. Results: Neoplasms, 83: sensitivity 91.6% specificity 93.8% 7 3

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10 Nephron sparing surgery Radical nephrectomy has been standard Laparoscopic or /robotic approach, less morbidity Enucleation 89% 5yr survival Partial nephrectomy 92% 5yr survival Similar to radical surgery figures Ideal for polar tumors <4cm Unsuitable for central tumors, drainage system Method of choice for low grade malignancies Avoids muscle splitting surgery, morbidity, scar (Zini et al, Montreal, Cancer 2009;115:1465) 25 Laparoscopic nephrectomy

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12 Radiofrequency thermal ablation Converts radiofrequency to heat Retroperitoneal approach to avoid bowel Destroys by coagulative necrosis Tumors up to 4cm treated. Follow up CT indicates need for re treatment 31 Cryo ablation of Renal Tumors Small, peripheral or exophytic tumors suitable Laparoscopic retroperitoneal approach Freeze to minus 40degrees C Double freeze thaw technique used. Small series reported Avoids bowel No complications reported CT scans 6 12 months show partial resolution 33 11

13 Fine needle core biopsies Gaining enthusiasts in last 10 years Use (16) 18 gauge core needles Co axial system to diminish needle track spread, 20 gauge needle Under CT guidance to avoid necrosis Multiple cores can be done Tumor typing and grading possible Immediate on site diagnosis not possible 36 12

14 Further advantage of core Change in management 48% 60% AVOIDANCE OF RADICAL NEPHRECTOMY 38 13

15 Hemorrhage with FN core Univ Michigan, Ann Arbor 152 renal cores with co axial 18 ga needles 2 post procedural hematomas, immediate, one requiring transfusion One delayed retroperitoneal hemorrhage delayed, arterial pseudo aneurysm, rupture No tumor seeding Maturen et al. AJR 2007;188:

16 FAHC Renal FNA LESION : CT 58%, US 30%, intraop 11% AVERAGE SIZE: 3.6cm ( ) Based on 180 masses imaging measurements 44 FNAs (22%) from masses 2cm or less 97 FNAs (48%) from masses 3cm or less 44 15

17 Normal entities in Renal FNA Glomeruli Proximal and distal renal tubules Urothelial cells Liesegang rings 16

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19 Benign renal tumors Angiomyolipoma Angiomyliopma Myofibroblastomas, fibromas 18

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25 Conclusion: Part I Renal tumors are more frequent More often asymptomatic, small and low grade Imaging is stunning in its capability Management philosophy is revolutionary Tissue typing on smaller samples is needed FNA (and FNB) are ideally suited to this The patient must get optimal care Multidisciplinary approach is essential WE ARE ALL ON A LEARNING CURVE 70 Malignant Renal Tumors Renal cell carcinoma is by far the most common renal malignancy Includes conventional (clear cell), papillary, and chromophobe types Risk factors include smoking and obesity Inherited cancer syndrome VHL The mean age of manifestation of RCC in VHL is 37 years, as compared with 61 years for sporadic RCC Conventional (clear cell) RCC Comprises 75% to 80% of all RCCs Average size is 7 cm, but small tumors are being detected with increasing frequencies Necrosis, hemorrhage, cystic degeneration, and calcification are common Results in "heterogeneous" appearance on imaging studies Cytogenetics del 3p (site of VHL gene) 24

26 Conventional (clear cell) RCC Cytologic features Lots of hemorrhage Occasionally, this is the only finding on FNA specimens Large cohesive cell groups Smears can be highly cellular composed of groups and individual tumor cells Abundant wispy cytoplasm with ill defined edges Cytoplasmic vacuoles Often peripherally placed, while the more granular cytoplasm is central Conventional (clear cell) RCC Cytologic features continued Cells have large, round, eccentrically placed nuclei Cells often have a "plasmacytoid" appearance Nucleoli vary in sized, depending on Fuhrman grade But can be less variable than other renal tumors Pink, strand like fibrillary material is highly characteristic on Romanowsky stains Transgressing vessels can be seen in about 1/2 of the cases Conventional (clear cell) RCC 25

27 Conventional (clear cell) RCC Conventional (clear cell) RCC Conventional (clear cell) RCC 26

28 Conventional (clear cell) RCC Conventional (clear cell) RCC Conventional (clear cell) RCC 27

29 Conventional (clear cell) RCC Conventional (clear cell) RCC Conventional (clear cell) RCC Differential Diagnosis Normal distal tubular cells Adrenal cortical cells Hepatocytes Macrophages Papillary RCC 28

30 Conventional (clear cell) RCC Immunocytochemistry CAM5.2 AE1/AE3 EMA Vimentin CAIX CD10 PAX2 PAX8 Positive HMWCK CK7 CK20 CEA Negative HMWCK CK5/6, 34BE12 Papillary Renal Cell CA Represents between 7% and 15% of all renal cell carcinomas Can be multifocal Tumors as large at 23 cm are possible Large tumors tend to be cystic and necrotic Contrast CTs tend to be hypovascular, as compared to Conventional RCC which is hypervascular Papillary Renal Cell CA Low grade or low stage tumors have an excellent prognosis Often small and peripheral Tend to be amenable to partial nephrectomy RCC considered papillary if >50% papillae Papillae can be packed very close, mimicking a solid growth pattern Cytogenetics Trisomies 7, 16, & 17 29

31 Papillary Renal Cell CA Cytologic features Type 1 Papillae with true fibrovascular cores, spherules, and tubules Small sized to medium sized cuboidal cells Uniform nuclei Scant to moderate cytoplasm Abundant intracytoplasmic hemosiderin (characteristic) Foamy macrophages Fibrovascular cores can be distended by macrophages Papillary Renal Cell CA Cytologic features Type 2 Large cells Large nuclei with prominent (grade 3) nucleoli Abundant granular cytoplasm Papillary Renal Cell CA 30

32 Papillary Renal Cell CA Papillary Renal Cell CA Papillary Renal Cell CA 31

33 Papillary Renal Cell CA Papillary Renal Cell CA Papillary Renal Cell CA 32

34 Papillary Renal Cell CA Differential Diagnosis Distal tubular cells Glomeruli Metanephric adenoma Conventional clear cell RCC For type 2 papillary RCC Use of cytogenetics can be very helpful Papillary Renal Cell CA Immunocytochemistry Stain AE1/AE3 Positive CAM5.2 Positive CK7 Positive Vimentin Positive HMWCK Negative AMACR Positive CAIX +/ EMA Positive Result Sarcomatoid Renal Cell CA Sarcomatoid areas are present in 1% to 6% of RCCs Most found in association with clear cell RCC, but sarcomatous transformation of chromophobe, collecting duct, and papillary RCCs occur High grade tumor with poor prognosis (many unresectable at presentation) 33

35 Sarcomatoid Renal Cell CA Histology/Cytology High grade spindle cell neoplasm with or without epithelioid features Unlikely to be definitive on cytologic specimens alone Differential diagnosis includes sarcoma and angiomyolipoma Need Keratin or EMA for RCC diagnosis Sarcomatoid Renal Cell CA Sarcomatoid Renal Cell CA 34

36 Sarcomatoid Renal Cell CA Sarcomatoid Renal Cell CA Chromophobe Renal Cell CA Comprises 3% to 5% of all RCCs Patients have an excellent prognosis unless tumor is large or multifocal Must be distinguished from oncocytoma Cytogenetics Loss of entire chromosomes Most commonly 1, 2, 6, 10, 13, 17, & 21 35

37 Chromophobe Renal Cell CA Cytologic features Trabecular arrangement Koilocytoid cells Abundant cytoplasm Well defined cell borders Bi nucleation common Variation in nuclear size Hyperchromatic nuclei without nucleoli Aspirates are highly cellular and the cells are less cohesive than conventional (clear cell) RCC Chromophobe Renal Cell CA Chromophobe Renal Cell CA 36

38 Chromophobe Renal Cell CA Chromophobe Renal Cell CA Chromophobe Renal Cell CA 37

39 Chromophobe Renal Cell CA Chromophobe Renal Cell CA Chromophobe Renal Cell CA Differential diagnosis Oncocytoma Chromophobe have more nuclear variation Oncocytomas are arranged in rounded nests (difficult to discern on cytology samples) May need to diagnose Oncocytic Neoplasm Conventional (clear cell) renal cell carcinoma Chromophobe RCCs have more variation in cell and nuclear size Darker chromatin, without nucleoli 38

40 Chromophobe Renal Cell CA Immunocytochemistry Stain AE1/AE3 CK7 CD10 EMA CD117 Vimetin RCC Hale s colloidal iron Positive Positive Negative Positive Positive Negative Negative Positive Result Translocation associated RCC Described in 1999 Reported mainly in children and young adults Cytogenetics Translocations of X involving the transcription factor E3 (TFE3) gene Need a strong clinical suspicion (young individual) and immunohistochemistry to confirm (or cytogenetics) Translocation associated RCC Histology Mixed nested and papillary architecture made of cells with abundant voluminous cytoplasm Can have frequent calcifications Cytologic features Cells with abundant clear and granular cytoplasm Can resemble typical RCC on cytology 39

41 Translocation associated RCC Translocation associated RCC Translocation associated RCC 40

42 Translocation associated RCC Immunochemistry TFE3 Cam5.2 EMA Vimentin Stain Positive Negative Negative Negative Result Collecting Duct Carcinoma (Bellini Tumor) Rare tumor Poorly defined Characterized by: Medullary location Tubulopapillary architecture (on histology) Significant desmoplasia (on histology) Nuclear pleomorphism can range from significant to minimal Differential includes papillary RCC Stains for high molecular weight keratins Collecting Duct Carcinoma (Bellini Tumor) 41

43 Collecting Duct Carcinoma (Bellini Tumor) Collecting Duct Carcinoma (Bellini Tumor) Urothelial Carcinoma Arising from the renal pelvis Accounts for 5% to 10% of all renal tumors Histologically and clinically similar to urothelial carcinoma from the urinary bladder Strong association with tobacco and use of analgesics (phenacetin) Distinction from RCC is important as resection for urothelial CA will include the ureter 42

44 Urothelial Carcinoma Cytologic features Large cells with dark nuclei and dense cytoplasm Elongated cells Cercariform cells Cytoplasmic tails that are narrow in the middle and wide and flat at the ends Low grade vs High grade Differential diagnosis RCC and metastasis Urothelial Carcinoma Urothelial Carcinoma 43

45 Urothelial Carcinoma Urothelial Carcinoma Urothelial Carcinoma 44

46 Urothelial Carcinoma Urothelial Carcinoma Urothelial Carcinoma 45

47 Urothelial Carcinoma Immunochemistry CK7 CK20 P63 HMWCK Vimentin Stain Positive Positive Positive Positive Negative Result Metastatic Carcinoma Present in 7% of all cancer patients at autopsy Many are clinically silent Unlikely to be presenting symptom of the underlying malignancy Lung is most common primary site Clinical history is essential to recognize the tumor as a metastasis Immunostain Summary AE1/AE3 CK7 CK20 CD117 Vimentin RCC CD10 p63 Clear cell RCC Papillary RCC + + +/ + + Chromophobe RCC Oncocytoma + + +/ Urothelial CA

48 BACTERIA IN URINE: Image, Dr David Kaminsky, Palm Springs, CA

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