accme/disclosures how molecular pathology has … · • originally reported in esrd but most...
TRANSCRIPT
4/5/2016
1
How Molecular Pathology Has Changed My Practice in Renal
NeoplasiaPedram Argani, MDThe Johns Hopkins Medical Institutions
Baltimore, MD, [email protected]
USCAP 2016
ACCME/DisclosuresThe USCAP requires that anyone in a position
to influence or control the content of CME disclose any relevant financial relationship
WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the
content of this educational activity and creates a conflict of interest.
Dr. Pedram Argani declares he has no conflict(s) of interest to disclose.
Renal Cell Carcinoma (RCC)-1997
• Clear cell• Papillary• Chromophobe• Collecting Duct
– Medullary
Renal Cell Carcinoma (RCC)-WHO 2016• Clear cell RCC
– Multilocular cystic renal neoplasm of low malignant potential
• Papillary RCC• Hereditary leiomyomatosis RCC (HLRCC)-associated RCC• Chromophobe RCC• Collecting duct carcinoma• Renal medullary carcinoma• Mucinous tubular and spindle cell carcinoma• MiT family translocation RCC• Succinate dehydrogenase (SDH) deficient RCC• Tubulocystic RCC• Acquired cystic disease (ACD) associated RCC• Clear cell papillary RCC
4/5/2016
2
Two Common Problems in Renal Tumor Classification
• RCC with Papillary Architecture and Clear Cells• Eosinophilic Renal Neoplasms
Case 1: 24 year old female with 3cm renal mass
Renal Cell Carcinomas Which Often Have Papillary Architecture and Clear Cells
• Clear cell RCC• Papillary RCC• Clear Cell Papillary RCC• Xp11 translocation RCC
4/5/2016
4
PAPILLARY RCC: CK7 CLEAR CELL RCC PAPILLARY RCC
Clear Cell Papillary RCC
• 1-4% of RCC• Originally reported in ESRD but most sporadic• All typical cases have had benign outcome• Histology
– Architecture: papillary, tubular– Cytology: clear subnuclear cytoplasmlinear
suprabasal low grade nuclei
CLEAR CELL PAPILLARY RCC
4/5/2016
5
CLEAR CELL PAPILLARY RCC
CLEAR CELL PAPILLARY RCCCA-IX CK7
MiT family Translocation RCC
• Xp11 translocation RCC• t(6;11) RCC
WHO 2016 Classification
Xp11 translocation Renal Cell Carcinoma (RCC)• Definition
– RCC with translocations involving Xp11– Gene fusions involving TFE3 transcription factor
• Diagnosis confirmed by– Nuclear labeling for TFE3 protein by IHC– TFE3 gene rearrangement by FISH
• Often young patients– Comprise majority of pediatric RCC– Comprise 1-2% of adult RCC
• Outcome overall similar to clear cell RCC– Children do better than adults
4/5/2016
6
Martignoni G et al. Mod Pathol 2009;22: 1016-1022
Cathepsin-K Immunoreactivity distinguishesTranslocation RCC from other RCC
RCC with Papillary Architecture and Clear Cells
CA-IX CK7 Cathepsin KClear Cell RCC +++ - -Papillary RCC - +++ -Clear Cell Papillary RCC ++ +++ -Xp11 translocation RCC - -/+ +/-
Back to Our CaseCK7-CA-IX-CATHEPSIN K-
4/5/2016
7
SFPQ BREAK-APART FISH
Red, centromeric; green, telomeric
Cristina Antonescu, MDMSKCC
TFE3 BREAK-APART FISH
Johns Hopkins Cytogenetics
Diagnosis: Xp11 Translocation RCC with SFPQ-TFE3 Gene Fusion
Fusion Age TranslocationASPL-TFE3 1-75 t(X;17)(p11.2;q25)PRCC-TFE3 2-69 t(X;1)(p11.2;q21)SFPQ-TFE3* 5-68 t(X;1)(p11.2;p34)NonO-TFE3* 29-51 inv(X)(p11.2;q12)CLTC-TFE3 14 t(X;17)(p11.2;q23)PARP14-TFE3 32 t(X;3)(p11.2;q23)DVL2-TFE3 73 t(X;17)(p11;p13)
Xp11 translocation RCC
*typically show subnuclear vacuoles mimicking clear cell papillary RCC*typically Cathepsin K negative Am J Surg Pathol 2016, in press
Hard to Classify Eosinophilic Renal Neoplasms
Case 2: 54 year old female with 5cm renal mass
4/5/2016
8
EPITHELIOID ANGIOMYOLIPOMA
Features Acceptable in Oncocytoma
• Capsular invasion• Vascular invasion (rare)• Degenerative atypia
Features that Exclude Oncocytoma
• Well-Formed Papillae• Clear cells (non-focal)• Wrinkly nuclei with well-preserved chromatin• Diffuse Cytokeratin 7 immunoreactivity
CK7
4/5/2016
9
Renal Cell Carcinomas with Eosinophilic Cytoplasm
• High Grade Clear Cell RCC• “Type 2” Papillary RCC• Eosinophilic Variant of Chromophobe RCC• Collecting Duct Carcinoma• Tubulocystic RCC• Acquired Cystic Disease-Associated RCC (ACD-RCC)• Renal Medullary Carcinoma• VCL-ALK RCC• Collecting Duct Carcinoma• SHDB RCC• HLRCC-associated RCC• MiT family translocation RCC
CLEAR CELL RCC
CLEAR CELL RCC “type II Papillary RCC”“Type II Papillary RCC”
4/5/2016
10
“Type II Papillary RCC”• TCGA Study (N Engl J Med 2016;374:135-45)
– At least 3 different entities genetically– 5% are actually MiT family Translocation RCC!
• WHO 2016 Classification– “may not …constitute a single well defined entity”– “a useful morphologic descriptor ”
Type II Papillary RCC: DDX
• Collecting duct carcinoma• Xp11 translocation RCC• Acquired Cystic Disease-Associated RCC
(ACD-RCC)• Hereditary Leiomyomatosis Renal Cell
Carcinoma (HLRCC)-associated RCC
Acquired Cystic Disease-Associated RCC (ACD-RCC)
• Most common RCC in End Stage Renal Disease (36%), particularly in ACD (46%)
• 50% multifocal, 20% bilateral• Indolent (caught early)
Tickoo S et al. Am J Surg Pathol 2006;30: 141-153
ACD-RCC: 3 Key Features
• Cribriform/Sievelike Architecture– Intercellular and Intracellular Lumina– Can be papillary
• Eosinophilic Cytoplasm, Prominent Nucleolus• Intratumoral Oxalate Crystals
4/5/2016
11
ACD-RCC ACD-RCC
Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC)-
associated RCC
Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) Syndrome
• Germline mutations in Fumarate Hydratase gene (1q42)
• Multiple Cutaneous and Uterine Leiomyomas– 50% of women have hysterectomy before age 30
• RCC (1/3 of patients)– Solitary– Aggressive– Loss of fumarate hydratase by IHC
4/5/2016
12
HLRCC-associated RCC HLRCC-associated RCC
Succinate Dehydrogenase Deficient RCC (SDH RCC)
• Germline succinate dehydrogenase B mutations
• PGL4 Syndrome– Pheochromocytoma– Paraganglioma– Type II GIST
• Pediatric, Carney syndrome
– Renal Neoplasms (14% lifetime risk)Barletta JA, Hornick JL. Adv Anat Pathol. 2012;19:193-203
SDHB RCC• Less than 0.6% of RCC• Typically young adults, 26% bilateral• Indolent course in most cases
– Rare cases with aggressive histologic features metastasize
– Can metastasize late (16, 30 years after resection)Gill AJ Am J Surg Pathol 2014;38: 1588-1602Williamson SR Mod Pathol 2015;28: 80-94
4/5/2016
13
SDHB RCC
• Compact nests of eosinophilic cells• Vacuolated cytoplasm• Pale eosinophilic cytoplasmic inclusions
– Giant mitochondria• Loss of SDHB protein by IHC
SDHB RCC VACUOLES
SDHB RCC INCLUSIONSSDHB IHC
4/5/2016
14
Renal Cell Carcinomas Associated with Sickle Cell Trait
• Renal Medullary Carcinoma– Often rhabdoid morphology– Loss of INI1 expression– Poor prognosis
• VCL-ALK RCC– Vacuolated Cytoplasm– INI1 intact– Prognosis unclear
Renal Medullary Carcinoma
INI-1
VCL-ALK RCC
ALK
Back to Our CaseAdditional Sections
4/5/2016
15
FUMARATE HYDRATASE
Diagnosis: HLRCC-Associated RCC
Hard to Classify Eosinophilic Renal Neoplasms• r/o Epithelioid Angiomyolipoma, Oncocytoma• Consider high grade clear cell RCC• Beware of type II PRCC• Clues
– Young age: MiT family Translocation RCC– ESRD: ACD-RCC– Sickle Cell Trait: RMC, VCL-ALK RCC– Vacuoles, Inclusions: SDHB RCC– Prominent Nucleoli: HLRCC-associated RCC
4/5/2016
16
Conclusions• Molecular pathology has helped establish many
new entities in renal neoplasia• Molecular tests should be used judiciously• First step is always careful morphologic
examination and formulating a differential diagnosis
• Sometimes the simplest steps (i.e., reviewing more sections) are the most useful ones