Emerging and Newly Recognized Subtypes of Renal Tumors: Keys to Recognition Session 1006

Transcription

1 Emerging and Newly Recognized Subtypes of Renal Tumors: Keys to Recognition Session 1006 Sean R. Williamson, MD Senior Staff Pathologist, Henry Ford Health System Clinical Assistant Professor of Pathology, Wayne State University School of Medicine

2 Speaker Disclosure In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my presentation.

3 Renal tumors general incidence Clear cell (60-70%) Papillary ~15% Chromophobe 5% Oncocytoma 5% Others <5%

4 Example -469 renal cell carcinomas Williamson SR, Eble JN, Cheng L, et al. Mod Pathol. 2013;26:

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6 Updates to classification Srigley JR, et al. Am J Surg Pathol. 2013;37: New WHO Classification upcoming 2016

7 Case: Recent diagnosis of pancreas cancer, also multiple bilateral renal masses

8 Clear cell papillary renal cell carcinoma Recently recognized as a distinct tumor type Usually most closely resembles clear cell RCC Immunohistochemistry and genetics different No known aggressive behavior to date Sometimes multifocal / bilateral

9 First recognized 2006 Clear Cell Papillary Renal Cell Carcinoma of the End-Stage Kidneys Tickoo et al Am J Surg Pathol. 2006;30: kidneys with ESRD 15 dominant tumors

10 Nomenclature Clear Cell Papillary Renal Cell Carcinoma of the End-Stage Kidneys GobboS, et al. Am J SurgPathol. 2008;32: tumors from 5 patients with (1) and without (4) ESRD

11 Nomenclature Clear Cell Tubulopapillary Renal Cell Carcinoma AydinH, et al. Am J SurgPathol. 2010;34: tumors from 33 patients

12 469 renal cell carcinomas Williamson SR, Eble JN, Cheng L, et al. Mod Pathol. 2013;26:

13 469 renal cell carcinomas Williamson SR, Eble JN, Cheng L, et al. Mod Pathol. 2013;26:

14 4 th most common subtype of RCC Zhou H, et al. Hum Pathol. 2014;45:59-64.

15 4 th most common subtype of RCC from Zhou et al Hum Pathol(n=290) Clear cell 70% Papillary 16.6% Chromophobe 5.9% Clear cell papillary 4.1% Higher % in partial nephrectomy population? Approximately 4.7% in Henry Ford Health System (active robotic partial nephrectomy practice) from 980 kidney tumor specimens (Swamy et al 2014 USCAP abstract) 7% of low-grade (1-2), low-stage (pt1a) CCRCC reclassified (Gill et al 2013 USCAP abstract, Roswell Park Cancer Institute) Unclassified 1.7% Others (tubulocystic, MTSCC, Xp11, ESRD-associated) 1.7% Zhou H Hum Pathol2014; 45:59-64.

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17 Solid areas essentially indistinguishable from clear cell RCC

18 Branched tubular / glandular configuration

19 Minute blunt papillae (35%) Focal branching papillae (51%) Majority/large areas of papillae (14%)

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22 Small papillae within small cystic spaces

23 Secretory cells

24 Secretory cells

25 Secretory cells

26 CK7 HMWK CD10 AMACR

27 Overlap with clear cell and papillary renal cell carcinoma CK7 AMACR HMWK CD10 CA-IX Clear cell + + Papillary +* + / + Clear cell papillary *Particularly type 1, less so in type 2

28 Cup-shaped staining

29 Genetic Characteristics Clear cell RCC 3p deletion and VHL abnormality frequent Clear cell papillary RCC Abnormalities of chromosome 3p absent VHL gene abnormalities absent Including promoter hypermethylaton CGH no chromosomal imbalances 1. Gobbo S, et al. Am J Surg Pathol. 2008;32: Aydin H, et al. Am J Surg Pathol. 2010;34: Adam J, et al. Histopathology. 2011;58:

30 Genetic Characteristics However, increased CA-IX, HIF-1α, and GLUT-1 detected by IHC Up-regulation of the HIF pathway by a non-vhl-dependent mechanism? Some mrna levels increased with similar pattern to clear cell RCC mirnapatterns overlapping between clear cell and papillary but lacking mirnasassociated with aggressive behavior CA-IX 1. Rohan SM, et al. Mod Pathol. 2011;24: Munari E, et al. Hum Pathol. 2014;45: Fisher KE, et al. Mod Pathol. 2014;27:

31 Molecular-Genetic Characteristics Papillary RCC Very frequent gains (trisomies) of chromosomes 7 and 17 Chromosome 7 ~75% Chromosome 17 ~80-90% by FISH Clear cell papillary renal cell carcinoma Rare low copy number gains of chromosome 7 and/or 17? Nonspecific, sometimes present in non-neoplastic appearing tubules of ESRD HesO, et al. VirchowsArch. 2008;453: Gobbo S, et al. Am J Surg Pathol. 2008;32:

32 Brannon AR, et al. Eur Urol. 2012;61: Brannon et al.

33 Brannon et al. Six large, public clear cell RCC gene expression databases 480 tumors Identified 2 dominant subtypes of clear cell RCC cca and ccb Third subtype Wild-type VHL Papillary architecture with clear cells May represent a new variant of clear cell RCC Brannon AR, et al. Eur Urol. 2012;61:

34 Brannon AR, et al. Eur Urol. 2012;61:

35 Prognosis Excellent No tumor with reported progression or metastasis thus far Almost all low-grade and low-stage Of at least 148 cases in the literature, only 3 pt2 (otherwise all pt1) Rarely Fuhrman 3 focally, usually 1-2 With additional follow-up studies low malignant potential tumor? Zhou H, et al. Hum Pathol. 2014;45:59-64.

36 Differential Diagnosis Clear cell RCC can have branched tubular appearance and secretory cells Williamson SR, et al. Am J Surg Pathol (in press)

37 Williamson SR, et al. Am J Surg Pathol (in press) Clear cell RCC can have branched tubular appearance and secretory cells

38 Williamson SR, et al. Am J Surg Pathol (in press) CK7

39 Williamson SR, et al. Am J Surg Pathol (in press) CD10

40 Williamson SR, et al. Am J Surg Pathol (in press) CA-IX

41 Williamson SR, et al. Am J Surg Pathol (in press) 3p FISH

42 Clear cell papillary-like morphology in VHL disease Williamson SR, et al. Am J Surg Pathol. 2013;37:

43 CK7

44 CD10

45 3p25 region FISH Therefore more similar to usual clear cell? Another study: Rao P, et al. Hum Pathol. 2014;45:

46 Differential Diagnosis -Clear Cell Change in Papillary Renal Cell Carcinoma Usually scant or eosinophilic cytoplasm Cytoplasmic clearing not rare if searched for Klatte et al.39% of cases (median 10% of cells) J Urol 2011

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51 AMACR typically strong positive in PRCC with clear cell changes Gobbo S, et al. Am J Surg Pathol. 2008;32:

52 Differential Diagnosis Multilocularcystic renal cell carcinoma

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54 Molecular-Genetics Examined 19 cases Chromosome 3p deletion analysis by dual-color interphase FISH 14 of 19 cases showed 3p deletion 17 of 19 control cases of clear cell RCC (F1-2) Supporting the hypothesis that MLCRCC is a subtype of CCRCC

55 Molecular-Genetics 15 cases VHLgene mutation by whole genome amplification and direct sequencing VHL mutation in 25% (3/12) tumors Perhaps artifactuallylowered by contamination with non-tumor cells (punches performed of tumor septa) IHC revealed strong nuclear p27 in 14/15, in contrast to only 30% of CCRCC

56 Clear cell papillary predominantly cystic

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59 Clear cell papillary Solid areas with branched tubules Papillary tufts into cysts Individual cells in septa not typical No 3p deletion or VHL abnormality CK7 positive No known malignant behavior to date Multilocularcystic No solid areas No papillary tufts Cells andclusters of cells in septa 3p deletion and VHL gene abnormalities CK7 often some positivity No known malignant behavior to date longer established 1. Williamson SR, et al. Am J Surg Pathol. 2012;36: von Teichman A, et al. Mod Pathol. 2011;24: Halat S, et al. Mod Pathol. 2010;23:

60 Renal cell carcinoma with angioleiomyoma-like stroma Epithelial elements dispersed in smooth muscle stroma Controversial whether related to clear cell papillary or a distinct entity CK7+ 1. Williamson SR, et al. Mod Pathol epub. 2. Peckova K, et al. Ann Diagn Pathol epub. 3. Kuhn E, et al. Am J Surg Pathol. 2006;30:

61 Several names used RCC with angioleiomyoma-like stroma 1,3 Some evidence for a distinct entity Renal angiomyoadenomatoustumor 4,5 My interpretation of the literature = clear cell papillary with predominance of tubules and stroma, not much cysts / papillae Others may argue for distinct entity Clear cell renal cell carcinoma with smooth muscle stroma 2 Unknown? A manifestation of clear cell or something else? 1. Williamson SR, et al. Mod Pathol : Shannon BA, et al. Hum Pathol. 2009;40: Peckova K, et al. Ann Diagn Pathol (5): Michal M, et al. Virchows Arch. 2009;454: Michal M, et al. Ann Diagn Pathol. 2000;4:

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65 CA-IX CK7 CD10 HMWK

66 Clear cell papillary vsrcc with angioleiomyoma-like stroma Clear cell papillary RCC with angioleiomyomalike stroma CA-IX+, CK7+, HMWK+ Yes Yes AMACR - Yes Yes CD10 + Focal or cysts only Yes Epithelium floating in sea of smooth muscle Smooth muscle entraps adjacent tissues 3p deletion Aggressive behavior No No No None reported Williamson SR, et al. Mod Pathol Feb;28(2): Yes Yes No but some very similar tumors with 3p deletion uncertain classification Nonereported, but few cases

67 Tuberous sclerosis? Two recent studies reported a subgroup of RCC in TSC resembles RCC with angioleiomyoma-like stroma Related to TSC? The stromais not AML Negative for HMB45, melan- A, and cathepsink 1. Yang P, et al. Am J Surg Pathol. 2014;38: Guo J, et al. Am J Surg Pathol

68 More clear cell tumors Translocation-associated renal cell carcinoma Xp11.2 (TFE3 gene) t(6;11) (TFEB gene) Together with t(6;11) recognized as MITF family in Vancouver classification Not a new entity, but the spectrum of findings in these tumors continues to grow

69 Xp11.2 translocation-associated RCC Large fraction of RCC in children / young patients ~50% Small fraction of RCC in adults 1-4% May be greater number overall in adults since RCC in children is rare SrigleyJR, et al. Am J SurgPathol. 2013;37:

70 Xp11.2 translocation-associated RCC Behavior / prognosis not entirely understood Favorable short-term prognosis in children if only regional LN+ Adults may be worse Poor survival when distant mets Late metastasis also described years after DX Targeted therapies may be considered Much less understood compared to clear cell 1. SrigleyJR, et al. Am J SurgPathol. 2013;37: Geller JI, et al. Cancer. 2008;112:

71 Xp11 RCC in adult prototypical features: mixed papillary and nested architecture

72 Mixed clear cell and eosinophilic cell pattern

73 Melan- A

74 TFE3 protein IHC

75 Clues: prominent hyaline stroma Another case: 41 year-old, clear cell-like

76 Calcifications / psammoma bodies This tumor was negative for: AE1/AE3, CAM 5.2, EMA Limited labeling for keratins / vimentin Sometimes melanocytic antigens

77 Xp11.2 translocation-associated RCC Broadening morphologic spectrum with increased awareness Multilocularcystic-like pattern Mimicking urothelial Eosinophilic tumors 1. RaoQ, WilliamsonSR, et al. Am J Surg Pathol. 2013;37: Green WM, et al. Am J SurgPathol. 2013;37:

78 1. Rao Q, Williamson SR, et al. Am J Surg Pathol. 2013;37: Green WM, et al. Am J Surg Pathol. 2013;37: Broadening morphologic spectrum multilocular cystic-like pattern cystic tumor in young woman

79 Xp11.2 translocation-associated RCC Suspicious features: Prominent hyalinized stroma Psammoma bodies in a clear celllike tumor Pigment Mixed clear cell and papillary features Young patient age IHC: Limited keratins / vimentin Sometimes melanocytic + Some renal tubular differentiation PAX8, CD10 1. Camparo P, et al. Am J SurgPathol. 2008;32: ArganiP, et al. Am J SurgPathol. 2010;34:

80 Xp11.2 translocation-associated RCC TFE3 IHC strong positive often correlates with TFE3 gene fusion Awareness of background / endogenous TFE3 protein FISH appears more sensitive / specific if in doubt Cathepsin K Diffuse positivity in a subgroup of translocation carcinomas Negative / focal in other RCC types 1. RaoQ, et al. Am J SurgPathol. 2013;37: Martignoni G, et al. Mod Pathol. 2009;22: Martignoni G, et al. Mod Pathol. 2011;24: Green WM, et al. Am J SurgPathol. 2013;37:

81 MelanoticXp11 Translocation Renal Cancers Very rare clear cell epithelial-like morphology but no IHC evidence of epithelial differentiation Negative PAX8, PAX2, keratins, CD10, EMA, RCC antigen Melanocytic antigens positive but not MITF or S100 Muscle antigens negative not PEComa Argani P, et al. Am J Surg Pathol. 2009;33:

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83 TFE3 FISH also revealed rearrangment in this tumor

84 Renal Cell Carcinoma Associated with Also occurs in younger patients TFEB and alpha / MALAT1 genes on chromosomes 6 and 11 May resemble clear cell, Xp11 translocation carcinoma Prototypical appearance: Second population of smaller, lymphocyte-like cells around hyaline basement-membrane material t(6;11)

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87 Renal Cell Carcinoma Associated with Melanocytic markers typically + (melan A > HMB45) Cathepsin K + Variable but some labeling for renal epithelial markers: Keratins, EMA, CD10, RCC, AMACR, PAX8, PAX2 t(6;11) -IHC 1. Argani P, et al. Am J Surg Pathol. 2012;36: Smith NE, et al. Am J Surg Pathol. 2014;38: Inamura K, et al. Am J Surg Pathol. 2012;36:35-42.

88 Renal Cell Carcinoma Associated with t(6;11) other patterns In addition to rosettelike pattern Multilocular cystic-like Clear cell-like Eosinophilic cells / pleomorphic 1. Argani P, et al. Am J Surg Pathol. 2012;36: Smith NE, et al. Am J Surg Pathol. 2014;38: Inamura K, et al. Am J Surg Pathol. 2012;36:35-42.

89 Tubulocystic renal cell carcinoma Uncommon tumor, classification evolved from low-grade collecting duct carcinoma Some collecting duct carcinomas have areas of morphologic similarity However, no compelling evidence currently for relationship Now included as a new entity in ISUP Vancouver Classification Srigley JR, et al. Am J Surg Pathol. 2013;37:

90 Tubulocystic renal cell carcinoma Predominantly men (> 7:1) Behavior: Mostly indolent, many presenting at pt1-2 stage, although few cases with recurrence, metastasis Dedifferentiation term proposed in a few cases with transition to a more poorly differentiated tumor Srigley JR, et al. Am J Surg Pathol. 2013;37:

91 Variable-sized tubules and cystic structures

92 Lined by cuboidal cells with eosinophilic cytoplasm, prominent nucleoli (usually grade 3) and at least focal hobnail-like pattern

93 Tumor with dedifferentiation? Al-Hussain TO, et al. Hum Pathol. 2013;44:

94 Tubulocystic RCC Relationship to papillary RCC debated Sometimes concurrent PRCC and tubulocystic Mixed results: gains of chromosomes 7, 17, loss of Y, others lacking Gene expression clustering with PRCC Others have found differences between PRCC and tubulocystic 1. Zhou M, et al. Am J Surg Pathol. 2009;33: Yang XJ, et al. Am J Surg Pathol. 2008;32: Tran T, et al. Histopathology (epub)

95 Acquired cystic kidney diseaseassociated renal cell carcinoma Unlike clear cell papillary RCC, appears to be restricted to the ESRD / ACKD setting Most common RCC subtype in end-stage kidneys Also recognized as new tumor type in Vancouver Classification

96 Acquired cystic kidney diseaseassociated renal cell carcinoma Cribriform architecture Intratumoral oxalate crystals Likely a good prognosis, diagnosed early in ESRD patients However, possibly rare cases with metastasis, particularly if high-grade rhabdoid or sarcomatoid features

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101 Cyst in ACKD with associated tumors atypical cyst or cyst with epithelial proliferation? Cytogenetic abnormalities in the cysts -Cheuk W, et al. Hum Pathol. 2002;33:

102 Atypical cyst in ACKD -Putative precursor to ACKD tumors

103 Hereditary Leiomyomatosisand Renal Cell Carcinoma -Associated Not a new entity, but previously labeled type II papillary RCC in 2004 WHO Classification Now regarded as unique tumor type Aggressive behavior Unlike hereditary papillary RCC syndrome, not multiple Fumaratehydratasegene (FH) chromosome 1q42

104 Prominent nucleolus with perinucleolar clearing resembling CMV inclusion Merino MJ, et al. Am J Surg Pathol. 2007;31:

105 Hereditary Leiomyomatosisand Renal Cell Carcinoma -Associated Often presents at advanced stage and death from disease Patients also have uterine leiomyomasand cutaneous leiomyomas Uterine leiomyomasmay also show these nuclear features Young age with uterine leiomyomas raises suspicion Under age 40 Even small renal masses likely require aggressive treatment 1. Merino MJ, et al. Am J Surg Pathol. 2007;31: Gardie B, et al. J Med Genet. 2011;48: Garg K, et al. Am J Surg Pathol. 2011;35:

106 Hereditary Leiomyomatosisand Renal Cell Carcinoma -Associated Solitary renal tumor may be the only presenting finding GardieB, et al. J MedGenet. 2011;48: IHC profilegenerallynot specific Twonewpromising IHC markers Chen YB, et al. Am J SurgPathol. 2014;38: succinocysteine Otero2014 USCAP abstract FH protein Trpkov2015 USCAP abstract FH and 2SC

107 Succinate dehydrogenase (SDH) Patients with germline mutation Hereditary pheochromocytomaparaganglioma syndromes Gastrointestinal stromal tumors (GIST) Renal tumors In provisional category of Vancouver Classification deficient RCC 1. Williamson SR, et al. Mod Pathol. 2015: 28: Gill AJ, et al. Am J Surg Pathol. 2011;35: Gill AJ, et al. Am J Surg Pathol : Doyle LA, Hornick JL. Histopathology. 2014;64: Paraganglioma

108 Grossly red-brown or tan-brown, variegated, hemorrhagic. Sometimes partly cystic

109 Microscopically predominantly solid or nested

110 Entrapped tubules

111 Intratumoral mast cells common

112 SDHB IHC

113 PAX8 Ksp-cadherin Keratin EMA

114 CK7 contrast to oncoctyoma CKIT neg, highlights mast cells Vimentin

115 High-grade SDH-deficient tumor with papillary morphology Courtesy Dr. Anthony Gill, Royal North Shore Hospital, NSW Australia

116 Courtesy Dr. Anthony Gill, Royal North Shore Hospital, NSW Australia

117 Thyroid follicular-like RCC Also provisional category in Vancouver Classification Few cases reported & overlap with other tumor types Resembles thyroid follicles Atrophic kidney-like renal tumors same entity? 1. Amin MB, et al. Am J Surg Pathol. 2009;33: Hes O, et al. Ann Diagn Pathol. 2014;18:82-88.

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119 Exclude metastatic thyroid cancer

120 Differential diagnosis: Solid papillary RCC Metanephric adenoma Neuroendocrine tumor

121 AMACR unusual for PRCC WT1 against metanephric CD56 against neuroendocrine Synapto against neuroendocrine

122 Thyroid follicular-like RCC IHC TTF / thyroglobulin negative PAX2 / PAX8 variable, often negative CK7, vimentinvariable, often negative Some keratins + AMACR Contrast to PRCC Genetics Limited data, different gene expression compared to clear cell and chromo Behavior Few metastases reported, including regional lymph node and lung 1. Amin MB, et al. Am J Surg Pathol. 2009;33: Hes O, et al. Ann Diagn Pathol. 2014;18:82-88.

123 RCC with ALK gene rearrangement 2 children with sickle trait, eosinophiliccells with intracytoplasmic vacuoles / spindle-shaped cells VCL- ALK rearrangement Debelenko LV, et al. Mod Pathol. 2011;24: adultrccsfrom355 screenedby IHC withtpm3-alk and EML4-ALK papillary morphology Sugawara E, et al. Cancer. 2012;118: adult RCCsfrom 534 screenedwithfish, Mayo Clinic clear cells, papillary architecture, psamomma bodies Sukov WR, et al. Mod Pathol. 2012;25: Provisional in Vancouver Classification due to few cases and uncertainty if distinctive morphology

124 Thank you questions, suggestions?