New Concepts and Refinements to. Existing WHO (2004) Renal Cell. Tumor Categories In Adults

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1 New Concepts and Refinements to Existing WHO (2004) Renal Cell Tumor Categories In Adults Dr Varsha Manucha Assistant Professor Department of Pathology and Laboratory Medicine Temple University Hospital

2 Lack of agreement as to the diagnostic features of renal adenoma Earliest confirmed case. Miriel G Treatise of renal diseases Albarran & Imbert Melicow Mainz classifica tion 1986 WHO st classification Konig et al Focus on determining tissue of origin of the tumors Ewing Grawitz intrarenal adrenal rest theory Fite Ultrastructural studies proved renal tubular epithelium as the tissue of origin Oberling et al 1981 WHO Heidelberg- Rochester classification WHO 2004 Cytogenetics studies Delahunt B & Eble JN. History of the development of the classification of renal cell neoplasia. Clin Lab Med (2005),25; PRC, Oncocytoma, CRCC, Collecting duct, medullary RCC described

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4 Advances in our understanding of basic morphology, immunohistochemistry, cytogenetics and molecular pathology is reflected in this current proposed ISUP Vancouver Classification of Renal Neoplasia.

5 Srigley JR, Delahunt B, Eble J N et al. Am j Surg Pathol 2013;37: New concepts New entities Emerging entities 1. Multilocular cystic renal cell carcinoma 2. Papillary renal cell carcinoma 3. Hybrid Oncocytic chromophobe tumor 4. Collecting duct carcinoma and Medullary carcinoma. 5.Mucinous tubular spindle cell carcinoma, 1.Tubulocystic RCC 2.Acquired cystic disease associated RCC 3.Clear cell papillary RCC 4.MiT family translocation RCC 5.Hereditary Leiomyomatosis associated RCC 1.Thyroid like follicular RCC 2.Succinate dehydrogenase B deficiency associated RCC 3.ALK translocation RCC

6 New concepts and refinements to existing WHO (2004) Renal Cell Tumor Categories 1. Multilocular cystic renal cell carcinoma 2. Papillary renal cell carcinoma 3. Hybrid Oncocytic Chromophobe tumor 4. Collecting duct carcinoma and Medullary carcinoma 5. Mucinous tubular spindle cell carcinoma.

7 Multilocular Cystic Renal Cell Carcinoma (MCRCC) 2004 (WHO) classification recognized MCRCC as a rare variant of clear cell renal cell carcinoma. Chromosome 3p deletion identified in 74% of MCRCC and VHL mutations in 25% of cases. Neoplastic cells strong positive for PAX2 and CA-IX Accounts for 4% of all clear cell RCCs Mid age adults; male: female ratio of 1.2 to 2.1:1 Halat S, Eble JN, Grignon DJ et al. MCRCC and Clear cell RCC. Modern Pathology (2010), 23;

8 Suzigan S, Lopez-Beltran, Montironi R et al. MCRCC- a report of 45 cases of a kidney tumor of low malignnat potential.am J Clin Pathol (2006),125:

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11 Clear cell RCC with cystic change

12 Suzigan S, Lopez-Beltran, Montironi R et al. MCRCC- a report of 45 cases of a kidney tumor of low malignnat potential.am J Clin Pathol (2006),125:

13 Based on the extremely good prognosis after surgery and a 5- year disease-specific survival rate of 100%, the consensus is to redisignate these tumors as Multilocular Cystic Renal Cell Neoplasms of Low Malignant Potential.

14 Unresolved issues Should MCRCC be staged? Should it be submitted entirely before a diagnosis is rendered? Aggressive potential mimics of MCRCC Clear cell RCC with extensive cystic change/ RCC with extensive necrosis Mimics with still unresolved significance Xp11 translocation carcinoma presenting with MCRCC like features Tubulocystic RCC Cystic partially regressed clear cell RC

15 New concepts and refinements to existing WHO (2004) Renal Cell Tumor Categories 1. Multilocular cystic renal cell carcinoma 2. Papillary renal cell carcinoma 3. Hybrid Oncocytic Chromophobe tumor 4. Collecting duct carcinoma and Medullary carcinoma 5. Mucinous tubular spindle cell carcinoma.

16 Papillary renal cell carcinoma Comprise 6-18% of renal tumors in reported series Mean age 61.8 years; range years Incidental, hematuria, abdominal pain and abdominal mass; more likely to be multifocal

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18 Drs Delahunt and Eble (1997) Subdivided 105 papillary renal cell carcinomas based on morphologic features Type 1 (n=67) small cells with small oval nuclei inconspicuous nucleoli, foamy macrophages psammoma bodies Type 2 (n=38) large cells with abundant eosinophilic cytoplasm varying degrees of pseudostratification large spherical nuclei with prominent nucleoli larger tumors Stages 3 or 4 Delahunt B & Eble JN. Papillary renal cell carcinoma: A clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol (1997),10;

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22 At the conference there was consensus (75%) that tumors should be classified as type 1 or type 2.

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25 Controversies Debate about prognostic relevance of subtyping remains cases that showed a mixed pattern ; papillary tumors with oncocytic change??? different studies quote different percentages of type 1 and type 2 tumors highlighting issues related to this sub classification many tumors may display prominent papillary architecture such as collecting duct carcinoma, MiTF-TFE/TFE family translocation-associated renal carcinomas, clear cell tubulopapillary RCC are subjected to misclassification as type 2 papillary RCC. Kunju LP, Wojno K, Wolf SJ et al. Papillary renal cell carcinoma with oncocytic cells and Non overlapping low grade nuclei : expanding the morphologic spectrum with emphasis on clinicopathologic, immunohistochemical and molecular features. Human pathol (2008), 39;96-101

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28 Papillary RCCs seem to constitute clinically, histologically, and even genetically a heterogenous group. Nucleolar grading has shown strong association with patient outcome and should be used as the sole grading criterion for grading PRCC. The future prognostic model of PRCC may need to be based primarily on the nuclear characteristics, irrespective of the cytoplasmic features Sika-Paotonu D, Bethwaite PB, McCredie MR et al. Nucleolar grade but not Fuhrman grade is applicable to Papillary renal cell carcinoma. Am J Surg Pathol (2006); 30:

29 New concepts and refinements to existing WHO (2004) Renal Cell Tumor Categories 1. Multilocular cystic renal cell carcinoma 2. Papillary renal cell carcinoma 3. Hybrid Oncocytic Chromophobe tumor 4. Collecting duct carcinoma and Medullary carcinoma 5. Mucinous tubular spindle cell carcinoma.

30 Hybrid Oncocytic/Chromophobe Tumors Characterized by the association of both oncocytes and chromophobe cells within the same tumor Adult patients; no sex predilection Delongchamps NB, Galmiche L, Eiss D et al. Hybrid tumor, oncocytoma-chromophobe renal cell carcinoma of the kidney : a report of seven sporadic cases. BJU International (2009),103;

31 HOCTs occur in 3 clinico-pathologic situations with similar morphologic features but distinct molecular genetic profile Unilateral and solitary Sporadic multiple numerical aberrations (both mono- and polysomies) Multiple and bilateral Oncocytosis losses involving chromosomes 1, 14, 21, and Y. Sporadic or associated with chronic renal failure/long-term hemodialysis Birt-Hogg-Dube syndrome germline mutations in the FLCN gene, which encodes folliculin autosomal dominant condition characterized clinically by skin fibrofolliculomas, spontaneous pneumothorax, and renal cancer. Peterson F, Gatalica Z, Grossman G et al. Sporadic hybrid oncocytic/chromophobe Tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural and molecule cytogenetic study of 14 cases.virchows Arch (2010),456 ;

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36 no evidence of malignant behavior documented in different series although the follow up was too short could have a low malignant potential but can be established only on a longer follow up. Consensus (73%) is to recognize HOCT as a subcategory of CHRCC

37 New concepts and refinements to existing WHO (2004) Renal Cell Tumor Categories 1. Multilocular cystic renal cell carcinoma 2. Papillary renal cell carcinoma 3. Hybrid Oncocytic Chromophobe tumor 4. Collecting duct carcinoma and Medullary carcinoma 5. Mucinous tubular spindle cell carcinoma.

38 Collecting duct carcinoma Rare (<1% of renal malignancies). Wide age range (13-83 years). Male to female ratio of 2:1 Patients present with abdominal pain, flank mass and hematuria; metastasis to bone at the time of presentation in 1/3 rd patients

39 Diagnostic criteria for CDC 1. at least some of the lesion involves the medullary region 2. predominant formation of tubules 3. a desmoplastic stromal reaction 4. high grade cytologic features 5. infiltrative growth pattern 6. absence of other typical RCC subtypes or urothelial carcinoma

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41 Collecting duct carcinoma vs Urothelial carcinoma The distinction of CDC from urothelial carcinoma can be difficult and is somewhat controversial, it does have significant implications. Albadine et al CDC PAX8+/ p63- sensitivity of 85.7% and specificity of 100%. UC PAX8- /p63+ sensitivity of 88.2% and a specificity of 100% Albadine R, Schultz L, Illei P et al. PAX8 (+)/p63(-) Immunostaining pattern of renal collecting duct carcinoma versus urothelial carcinoma of the upper tract. Am J SUrg Pathol (2010),34;

42 Controversial issues Tumors with >95% morphology of CDC, but with focal urothelial carcinoma Consensus (68%) that these cases should be diagnosed as urothelial carcinoma with prominent glandular differentiation Undifferentiated carcinoma If even a minor component that meets the criterion for CDC is present than the diagnosis should be Poorly differentiated CDC Differentiation from medullary carcinoma

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46 Medullary RCC is enlisted as a separate category in WHO classification of tumors, some consider it a variant of CDC occurring in patients with Hemoglobinopathy. Recently, multiple cases in non AA without Hemoglobinopathy have been described. No consistent pattern of chromosomal abnormalities found in Medullary renal cell carcinoma. Increased hypoxia-inducible factor 1α expression important in hypoxia-induced signaling pathways raising the possibility that it could then be high-grade clear cell renal cell carcinomas. Gatalica Z, Lilleberg SL, Monzon FA. Renal medullary carcinomas: histopathologic phenotype associated with diverse genotypes.human Pathol (2011),42;

47 the question weather renal medullary carcinoma is a distinctive clinicopathologic subtype or within the entity of collecting duct carcinoma is unanswered. however reported response to Topoisomerase therapy and specific combination chemotherapy argue for their accurate distinction from CDC and other renal cell carcinoma subtypes.

48 1. Multilocular cystic renal cell carcinoma 2. Papillary renal cell carcinoma 3. Hybrid Oncocytic Chromophobe tumor 4. Collecting duct carcinoma and Medullary carcinoma 5. Mucinous tubular spindle cell carcinoma.

49 Mucinous Tubular and Spindle Cell RCC Low grade tumor described in 1990s Adults over wide range affected Female predominance ( 3 to 4 :1) Majority discovered incidentally during abdominal imaging studies.

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52 Controversies Disputed molecular genetics Some demonstrated lack of typical gains of chromosomes 7, 17 and loss of Y while other investigators suggested gain of chromosomes 7 & 17 Fine SW et al. Am J Surg Pathol. (2006); Farghaly H. Ann Diagn Pathol. (2006); Guarded prognosis Reports of local recurrence in the renal bed and metastasis to regional lymph nodes. Case report of metastasis to liver and abdominal lymph nodes. Kuroda et al. Ann diagn Pathol. (2011);15: Pillay N et al. Hum Pathol. (2008); 39:

53 1. Multilocular cystic renal cell carcinoma is now Multilocular cystic renal cell neoplasm of low malignant potential. 2. Papillary renal cell carcinoma attempts should be made to classify type 1 or type 2 or not specified Oncocytic variant is not a distinct entity 3. Hybrid Oncocytic Chromophobe tumor at present best classified under Chromophobe RCC. 4. Collecting duct carcinoma and Medullary carcinoma accurate distinction must be attempted 5. Mucinous tubular spindle cell carcinoma. prognosis is guarded

54 The goal is to be able to devise a classification of tumors which is based on a sound understanding of the genetic abnormalities, is robust in terms of clinical behavior and response to therapy and yet be based on morphological criteria which can be readily recognized in routine histopathological specimens.

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