Adult epithelial renal tumors and update of WHO classification of renal tumors 2016

Renal cell carcinoma updates in pathology

1. ADULT EPITHELIAL RENAL TUMOURS & UPDATE OF WHO CLASSIFICATION OF RENAL TUMORS 2016 1 st PRESENTOR- Dr. Seema Rahar MODERATOR- Dr. Arvind Ahuja SUBJECT SEMINAR

2. 2004

3. WHO Classification of kidney tumours 2016 By International Society of Urological Pathlogy (ISUP)

4. CHANGES IN 2016

5. 2004 CLASSIFICATION

6. 2016 CLASSIFICATION

7. Changes from existing renal tumour types Subtypes named on basis of Cytoplasmic features – clear cell and chromophobe RCC Architectural features – papillary RCC Anatomic location of tumours- collecting duct and renal medullary carcinoma

8. Correlation with specific renal disease background - acquired cystic disease associated RCC Molecular alterations – MiT family translocation and SDH defecient RCC Familial forms of RCC are now discussed with corresponding sporadic tumour types .

9. ‘Multilocular cystic renal neoplasm of low malignant potential’ is now the WHO recommended term as no recurrence or no metastasis noted.

10. 3. WHO 2016 – Papillary adenomas are defined as - uncapsulated tumours with papillary or tubular architecture and diameter ≤1.5 cm . ( unlike 2015 size ≤ 0.5 cm)

11. 4. MEST – Mixed epithelial and stromal tumours include predominantly cystic or solid tumours Adult cystic nephroma was previously classified along with paediatric cystic nephroma . Now adult cystic nephroma is classified within spectrum of MEST .

12. 5. Renal carcinoids are now- designated as well differentiated neuroendocrine tumours placed within the group of endocrine tumours. The term carcinoid of kidney obsolete .

13. WHO GRADING (for CCRCC & PRCC)

14. FUHRMAN NUCLEAR GRADING GRADE FEATURE GRADE 1 Small, round and uniform nuclei. No evident nucleoli (100x magnification) GRADE 2 Nuclei with irregular outlines. Inconspicuous nucleoli (100x magnification) GRADE 3 Irregular nuclei with identifiable nucleoli at 100x magnification GRADE 4 Large, hyperchromatic , pleomorphic nuclei. Single or multiple nucleoli

15. New renal tumour entities Tubulocystic carcinoma Acquired cystic disease associated RCC Clear cell papillary RCC MiT family translocation RCC HLRCC syndrome- associated RCC Succinate dehydrogenase B deficiency RCC

16. TUBULOCYSTIC CARCINOMA

17. TUBULOCYSTIC CARCINOMA Consist of mixture of tubules and cysts with low grade nuclear features. Derived from PCT and distal nephron Mean age- 54 years M >F Excellent prognosis

18. TUBULOCYSTIC CARCINOMA Originally it was thought to be subtype of collecting duct carcinoma. Earlier designated as- Bellinian epithelioma or Carcinoma of collecting duct

19. GROSS - Tumor is small in size Well circumscribed tumour have a bubble wrap, swiss cheese or spongy appearance showing multiple small to medium sized cysts

20. TUBULOCYSTIC CARCINOMA MICROSCOPY - tubules and cystic structures of variable size, separated by delicate septa . Tubules are lined by single layer of cuboidal epithelial cells With abundant eosinophilic cytoplasm , round nuclei and prominent nucleoli and variable hobnail appearance

21. Tumor composed of variably sized tubules and cystic spaces

22. Variable sized cystically dilated tubules lined by eosinophilic cells with prominent nucleoli. Fibrotic stroma in between.

23. Tubules are lined by single layer of cuboidal , with abundant eosinophilic cytoplasm round nuclei and prominent nucleoli and variable hobnail appearance

24. Cells with abundant eosinophilic cytoplasm and high nuclear grade, prominent nucleoli. Occasional cells showing hobnailing

25. TUBULOCYSTIC CARCINOMA IHC CD 10, P504S/ Racemase + (proteins of PCT) CK 8, CK 7 , CK 18, CK 19 + (distal tubule) , Parvalbumin + (intercalated collecting duct cells) AMACR, P53, Vimentin +

26. Strong Racemase nuclear positivity

27. TUBULOCYSTIC CARCINOMA ULTRASTRUCTURE: display abundant microvilli with brush border organization as PCT cells MOLECULAR GENETICS – gains on chromosome 7, 17 and loss of Y ( like papillary RCC)

28. TUBULOCYSTIC CARCINOMA Differentials - Collecting duct carcinoma- Solid nature, high grade nuclear features, desmoplastic stroma, IHC -(AMACR, vimentin p53- less positive in CDC) Low grade multilocular cystic renal carcinoma Middle age females, large cysts lined by clear cells

29. TUBULOCYSTIC CARCINOMA Term Tubulocystic carcinoma restricted to tumours that display a typical macroscopic and microscopic appearance ( not used in situations where there is tubulocystic pattern admixed with usual elements of papillary RCC)

30. ACQUIRED CYSTIC DISEASE ASSOCIATED RCC

31. ACQUIRED CYSTIC DISEASE ASSOCIATED RCC ESRD is associated with increased risk of RCC especially in patients with acquired cystic kidney disease secondary to long term hemodialysis.

32. ACQUIRED CYSTIC DISEASE ASSOCIATED RCC Present at a younger age Multicentricity and bilaterality is common Overall- better prognosis

33. GROSS - Tumour is usually small, maybe found within cyst

34. End stage renal disease kidney showing tumor

35. ACQUIRED CYSTIC DISEASE ASSOCIATED RCC MICROSCOPY Shows different patterns- cribriform, microcystic , alveolar,solid , papillary, diffuse pattern . Composed of large cells with finely granular eosinophilic or clear cytoplasm with grade 3 nuclei and prominent nucleoli

36. Showing tubular, papillary, cribriform pattern with large eosinophilic cells with prominent nucleoli Intratumoral oxalate crystals under polarised light.

37. Low power view showing microcystic pattern, with part of compressed kidney at one end

38. High power view showing tumor cells lining the cysts and lying in the septa

39. Presence of intratumoral oxalate crystals seen in most.

40. ACQUIRED CYSTIC DISEASE ASSOCIATED RCC IHC AMACR + CD 10+ RCC marker and glutathione S transferase alpha + CK 7 – Relatively good prognosis

41. CLEAR CELL PAPILLARY RCC

42. CLEAR CELL PAPILLARY RCC Account 5% of all resected renal tumours Arise sporadically in ESRD Usually unifocal, unilateral and small No evidence of VHL gene mutation Previously referred to as renal angioedematous tumours

43. GROSS well circumscribed enveloped by a thin capsule Lesion can be cystic, partially cystic and partially solid Areas of apparent hyalinization are common

44. CLEAR CELL PAPILLARY RCC MICROSCOPY Tumor cells are arranged in- Mixed papillary, solid-acinar , tubular and microcystic pattern. Cells are cuboidal with uniform clear cytoplasm and low grade nuclei. Linear arrangement of nuclei away from basal aspect, toward the middle or the apex of the cells.

45. Papillary arrangement of cells

46. Cells with clear cytoplasm and low grade nuclei. Linear arrangement of nuclei away from basement membrane

47. CLEAR CELL PAPILLARY RCC Stromal hyalinization and myoid metaplasia may be evident Tumor necrosis and vascular invasion are rare Overall indolent tumors

48. CLEAR CELL PAPILLARY RCC IHC CK 7+ Carbonic anhydrase IX+ AMACR, RCC marker,CD10- 34 β E12- patchy +

49. MiT Family translocation associated RCC

50. Translocation RCC (t-RCC) is an uncommon subtype. Characterized by recurrent gene rearrangements involving TFE3 and TFEB loci TFE3 or TFEB are members of MiT (microphthalmia transcription factor) family Which regulates differentiation in melanocytes & osteoclasts

51. t(Xp11) TFE3 is located on short arm chromosome X- Xp11 , may fuse to a number of translocation partners, most commonly- PRCC on ch 1q21 ASPL on ch 17q25 Results in overexpression of a functional TFE3 gene product

52. t(Xp11) Xp11 accounts for 40% of paediatric RCC and <5 % of adult RCC Exposure to cytotoxic chemotherapy is a risk factor

53. t(Xp11) GROSS Tumor is solid, tan gray with necrosis, haemorrhage, occasional papillary formations

54. t(Xp11) MICROSCOPY- These tumors are composed of large epithelioid cells arranged in branching, papillary structures with delicate fibrovascular cores or nested architecture. Two types ASPL-TFE3 RCC PRCC-TFE3 RCC

55. t(Xp11) ASPL – TFE3 RCC – abundant clear to eosinophilic cytoplasm, discrete cell borders, High nuclear grade with prominent nucleoli, Psammoma bodies are present PRCC- TFE3 RCC- less abundant cytoplasm, fewer psammoma bodies and hyaline nodules and a nested compact architecture

56. large epithelioid cells arranged in branching, papillary structures with delicate fibrovascular cores

57. Cells showing abundant clear to eosinophilic cytoplasm, with high nuclear grade. Psammoma bodies also seen

58. Cells with less abundant cytoplasm, fewer psammoma bodies and a more nested compact architecture

59. t(6;11) RCC Are less common than Xp11 t(6;11) RCC are characterised by- t(6;11)(p21;q12) which results from gene fusion between TFEB on ch 6p21 and α gene on ch 11q12 Leading to over expression of full length TFEB protein

60. t(6;11) RCC GROSS No distinctive gross appearance have been described Ranges from cystic to solid and mahogany in colour

61. t(6;11) RCC MICROSCOPY Typically exhibit biphasic pattern- Majority are large epithelioid cells with clear to eosinophilic cytoplasm minor population of small , eosinophilic cells with hyperchromatic nuclei that form rosette like structure.

62. biphasic pattern-nests of large cells with abundant eosinophilic cytoplasm. Few areas consisting of small cells encircling hyaline droplets are noted.

63. papillary and compact growth patterns with presence of psammoma body

64. Translocation RCC IHC PAX8+ TFE3, TFEB + HMB 45 and melan A + (Melanocytic markers) Cathepsin K+ (osteoclastic protein) CK, EMA – CA IX -

65. showing strong nuclear positivity for transcription factor E3 (TFE3).

66. HEREDITARY LEIOMYOMATOSIS RCC SYNDROME ASSOCIATED RCC

67. HEREDITARY LEIOMYOMATOSIS RCC SYNDROME ASSOCIATED RCC Autosomal dominant Germline mutation in fumarate hydratase gene located at chromosome 1q42 FH gene encodes kreb cycle enzyme that catalyze conversion of fumarate to malate

68. FH gene deficiency inhibits conversion of fumarate to malate Results in increased levels of fumarate intra cellularly Fumarate acts as inhibitor of prolyl hydroxylases results in pseudo hypoxic activation of HIF pathway

69. HIF accumulates and activates VEGF, PDGF, TGF α and EPO leading to angiogenesis

70. HEREDITARY LEIOMYOMATOSIS RCC SYNDROME ASSOCIATED RCC Associated with multiple cutaneous and uterine leiomyomas. Solitary but highly aggressive

71. HEREDITARY LEIOMYOMATOSIS RCC SYNDROME ASSOCIATED RCC MICROSCOPY Papillary, cribriform and solid architecture Prominent eosinophilic nucleoli with clear halo

72. Tumor showing papillary architecture with large nuclei, prominent eosinophilic nucleoli surrounded by a clear halo

73. Prominent eosinophilic nucleoli with clear halo

74. HEREDITARY LEIOMYOMATOSIS RCC SYNDROME ASSOCIATED RCC IHC CA IX + CK 7 – CK 20 -

75. SUCCINATE DEHYDOGENASE-B (SDHB) DEFECIENCY ASSOCIATED RCC

76. SUCCINATE DEHYDOGENASE-B (SDHB) DEFECIENCY ASSOCIATED RCC Associated with phaeochromocytoma / paraganglioma type 4 Loss of expression of SDHB - marker of dysfunction of mitochondrial complex 2

77. SDH deficiency prevents conversion of succinate to fumarate in krebs cycle This increases intracellular levels of succinate Increased succinate causes competitive inhibition of prolyl hydroxylases Leading to overexpression of HIF

78. SUCCINATE DEHYDOGENASE -B (SDHB) DEFECIENCY ASSOCIATED RCC Gross – uncapsulated, cut surface solid , brown Microscopy - compact nests of eosinophilic polygonal cells with vaculated cytoplasm or inclusions

79. compact nests of eosinophilic polygonal cells

80. eosinophilic polygonal cells with vaculated cytoplasm

81. Provisional new tumour entities Three rare RCC – Thyroid like follicular RCC Renal cell carcinoma in neuroblastoma survivors Translocation of ALK gene

82. THYROID LIKE FOLLICULAR RCC Characterised by macro/micro follicular architecture with dense colloid like material (resembling follicular neoplasm of thyroid ) Express CK AE 1 / AE 3 and CD 10. Do not express TTF1 and thyroglobulin .

83. Tumor showing macro/micro follicular architecture with dense colloid like material

84. tightly packed follicles lined by cells showing features resembling thyroid cancer.

85. RENAL CELL CARCINOMA IN NEUROBLASTOMA SURVIVORS Occurs in patients surviving neuroblastoma diagnosed in early childhood The interval between diagnosis of neuroblastoma and the development of renal cell carcinoma ranged from 3 to 11.5 years (mean 9 years)

86. RENAL CELL CARCINOMA IN NEUROBLASTOMA SURVIVORS MICROSCOPY Has papillary and solid growth patterns with oncocytoid cells with abundant eosinophilic cytoplasm The nuclei are irregular and nucleoli are readily seen.

87. Tumor showing papillary pattern, cells with abundant eosinophilic cytoplasm( oncocytoid like)

88. Limited role of IHC: CK, EMA, Vimentin + CK7, S-100 protein and HMB45 -

89. TRANSLOCATION OF ALK GENE Rare t(2;10) results in fusion of gene VCL with ALK. Tumor cells are polygonal to spindle shaped with abundant eosinophilic cytoplasm and frequent cytoplasmic lumina. Other fusion genes- TPM 3, EML4.