Post on 29-Mar-2018
Tumours of kidney and urinary tract – update on WHO classification, IHC
and molecular morphology STEWART FLEMING
UNIVERSITY OF DUNDEE
• MAJOR PARADIGM SHIFT IN EARLY 1990S IN UNDERSTANDING RENAL CANCER
A CLASSIFICATION …BASED ON UNDERSTANDING THE GENETIC ABNORMALITIES INVOLVED WILL BE ROBUST IN TERMS OF BIOLOGY, CLINICAL BEHAVIOUR AND RESPONSE TO THERAPY
Molecular differential pathology of renal cell tumours G. KOVACS
TUMOUR HISTOLOGY MATTERS BECAUSE IT REVEALS THE UNDERLYING GENETICS
WHO v4 • Clear cell renal cell carcinoma VHL and 3p-
– Multilocular clear cell renal cell neoplasm of low malignant potential • Papillary renal cell carcinoma c-met and chr 7+; Fumarate hydratase • Chromophobe renal cell carcinoma Multiple chromosome loss
– Hybrid oncocytic chromophobe tumour Folliculin • Carcinoma of the collecting ducts of Bellini • Renal medullary carcinoma INI1 and sickle cell • MiT family translocation renal cell carcinoma
– Xp11 translocation renal cell carcinoma – t(6;11) renal cell carcinoma
• Carcinoma associated with neuroblastoma • Mucinous tubular and spindle cell carcinoma Multiple chromosomal losses • Tubulocystic renal cell carcinoma Fumarate hydratase • Acquired cystic disease associated renal cell carcinoma • Clear cell papillary (tubulopapillary) renal cell carcinoma • Hereditary leiomyomatosis associated renal cell carcinoma Fumarate hydratase • SDH deficient RCC SDHB • RCC with monosomy 8 Monosomy * TCEB1 • ALK associated RCC ALK translocation or amplification • Renal cell carcinoma, unclassified
HISTOPATHOLOGY 3p LOSS
VHL MUTATION
Y N Y N
CLEAR CELL 25 8 18 25
PAPILLARY 1 7 0 8
ONCOCYTOMA 2 3 0 5
CHROMOPHOBE 0 3 0 3
FOSTER ET AL 1994 Somatic mutations of the von Hippel - Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma
GENETIC ALTERATION IN RCC CORRELATES STRONGLY WITH MORPHOLOGY
3p FISH
TUMOUR HISTOLOGY MATTERS BECAUSE IT REVEALS THE UNDERLYING GENETICS
WHO v4 • Clear cell renal cell carcinoma VHL and 3p-
– Multilocular clear cell renal cell neoplasm of low malignant potential • Papillary renal cell carcinoma c-met and chr 7+; Fumarate hydratase • Chromophobe renal cell carcinoma Multiple chromosome loss
– Hybrid oncocytic chromophobe tumour Folliculin • Carcinoma of the collecting ducts of Bellini • Renal medullary carcinoma INI1 and sickle cell • MiT family translocation renal cell carcinoma
– Xp11 translocation renal cell carcinoma – t(6;11) renal cell carcinoma
• Carcinoma associated with neuroblastoma • Mucinous tubular and spindle cell carcinoma Multiple chromosomal losses • Tubulocystic renal cell carcinoma Fumarate hydratase • Acquired cystic disease associated renal cell carcinoma • Clear cell papillary (tubulopapillary) renal cell carcinoma • Hereditary leiomyomatosis associated renal cell carcinoma Fumarate hydratase • SDH deficient RCC SDHB • RCC with monosomy 8 Monosomy * TCEB1 • ALK associated RCC ALK translocation or amplification • Renal cell carcinoma, unclassified
0
10
20
30
40
50
60
70
80
90
100
CUMULATIVE FREQUENCY BY DIAGNOSIS OF RCC TYPES
RARE TYPES <2% 200-300 CASES PER ANNUM UK
COLLECTING DUCT CARCINOMA
1. Medullary involvement 2. Predominant tubular morphology 3. Desmoplastic stromal reaction 4. Cytologically high grade 5. Infiltrative growth pattern 6. Absence of other renal cell carcinoma subtypes or urothelial carcinoma • OCT ¾ neg, p63 neg • High MW CK pos
DISEASE SPECIFIC MORTALITY CCRCC CDC
WRIGHT ET AL
*p < 0.001
• Lymph node metastases are common and early (42%)
• Blood borne metastases M1 at presentation 45%
• 40% of CDC have urinary collecting system invasion
TUBULOCYSTIC CARCINOMA
• FORMERLY LOW GRADE CDC
• STRONG MALE PREDOMINANCE
• >75% KIDNEY CONFINED
• 10-15% PROGRESS WITH METASTASES AND DEATH POSSIBLE
TUBULOCYSTIC CARCINOMA OF KIDNEY
WELL
CIRCUMSCRIBED
TUBULAR OR
MICROCYSTIC
SINGLE LAYERED
CUBOIDAL EPITHELIUM
MILD NUCLEAR
PLEOMORPHISM
CHROMOPHOBE V ONCOCYTOMA IMMUNOPHENOTYPE
ANTIBODY CHROMOPHOBE ONCOCYTOMA
DIFFUSE CK7 65% RARE
FOCAL CK7 35% 79%
CD117 MOST MOST
RCC 45% <5%
CD82 78% RARE
AMACR 36% >90%
PAX 2 6% >90%
CHROMOPHOBE V ONCOCYTOMA
FLOW CYTOMETRY
ONCOCYTOMA DIPLOID
CHROMOPHOBE HYPODIPLOID
CHROMOSOMAL LOSSES
FISH
MOLECULAR VIRTUAL KARYOTYPING
CHROMOPHOBE V ONCOCYTOMA
CHROMOPHOBE
MULTIPLE
CHROMOSOMAL
LOSSES
ONCOCYTOMA
DIPLOID WITH
OCCASIONAL 1-
CHROMOSOME 2 PROBE BRUNELLI ET AL 2006
CHROMOPHOBE V ONCOCYTOMA
MORPHOLOGY
IMMUNOCYTOCHEMISTRY
FISH
CENTROMERIC PROBES 2,6,7,9,10,13,17
COMPARED TO CONTROL (CH 9)
>33% SINGLE COPY – LOSS
>11% ADDITIONAL COPIES - GAIN
ESRD ASSOCIATED RCC
• 30 YEAR HISTORY OF RCC IN ESRD
• PREVIOUSLY CONSIDERED TO BE MOSTLY PAPILLARY
• NOW AT LEAST TWO NEW TYPES OF RCC RECOGNISED IN THIS CLINICOPATHOLOGICAL CONTEXT – ACKD ASSOCIATED RCC
– CLEAR CELL PAPILLARY RCC IN ESRD
• 60% OF RCC IN ESRD
OXALATE AND ACKD RCC
SULE et al 2005
•OFTEN ENCAPSULATED
•OFTEN ARISING FROM CYST
•SOLID TUBULO-ACINAR MORE
OFTEN THAN PAPILLARY
ARCHITECTURE
•FINE LUMINAL SPACES
•CALCIFICATION & PSAMMOMA
BODIES
•LARGE CELL WITH EOSINOPHILIC
CYTOPLASM
•ONLY OCCASIONALLY CLEAR
CELL
IHC AND ACKD RCC
• There are conflicting data on CD57 expression.
• Usually CK7, CD10 and RCC positive
CD57 IHC
CLEAR CELL PAPILLARY RCC
• ACKD OR NON-CYSTIC ESRD
• TUBULO-PAPILLARY ARCHITECTURE
• MAY BE CYSTIC
• CLEAR CELL CYTOLOGY
• SUBNUCLEAR CLEAR CYTOPLASM
– MIMICKING SECRETORY ENDOMETRIUM
CLEAR CELL PAPILLARY RCC
• NO VHL MUTATION NOR 3P LOSS
• NO TRISOMIES OF 7 AND 17
• POSITIVE CK7, HIF1a, CaIX
• NEGATIVE CD10, AMACR, TFE3
MiT FAMILY TRANSLOCATION RENAL CELL CARCINOMA
• YOUNGER PATIENTS
• MIXED CLEAR CELL
AND PAPILLARY
• VOLUMINOUS
CYTOPLASM
• PSAMMOMA BODIES
• TFE3, rarely B or C in
nucleus
• FISH
TFE 3 IHC
INHERITED RCC
• VHL
• FAMILIAL PAPILLARY RCC
• BIRT HOGG DUBE SYNDROME
• TUBEROUS SCLEROSIS
• HLRCC
• SDHB
• NON-SYNDROMIC FAMILIAL RCC
DIAGNOSIS – MUTATION – FAMILY MEMBERS - SCREENING
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA (HLRCC)-ASSOCIATED
RENAL CELL CARCINOMA AND FUMARATE HYDRATASE MUTATION
• FIRST REPORT TYPE 2 PAPILLARY
• SECOND REPORT LOW GRADE CDC (TUBULOCYSTIC)
• SUBSEQUENT REPORTS ARCHITECTURE MAY BE TUBULAR, PAPILLARY, TUBULOCYSTIC OR MIXED
• USUALLY SOLITARY TUMOUR
• NUCLEOLAR MORPHOLOGY
• AGGRESSIVE BEHAVIOUR
• MUTATION MUST BE DEMONSTRATED
TOMLINSON ET AL 2002 ALAM ET AL 2003
2010 FAMILY HISTORY SUMMARY
Malignant phaeochromocytoma aged 24
EC
Renal tumour histologyunknown
ADRENAL
PHAEOCHROMOCYTOMA
RCC RCC
?VHL NO VHL MUTATIONS
?
SUCCINATE DEHYDROGENASE DEFICIENT RCC 2010
MUTATION IN THE SDHB GENE ARE FOUND IN THE FAMILY MEMBERS WITH THE CANCERS BUT NOT THOSE WITHOUT
Isaacs J et al
2-OXOGLUTARATE AND FUMARATE/SUCCINATE COMPETE FOR THE BINDING SITE ON THE PROLINE HYDROXYLASE
HIF PROLINE HYDROXYLATION
UBIQUITIN DEPENDENT DEGRADATION
NORMOXIA NORMAL pVHL
VHL MUTATION
HIF PROLINE HYDROXYLATION
DEGRADATION FAILURE
MUTANT VHL
O2
O2
O2 FAILED HIF PROLINE HYDROXYLATION HIF
ACCUMULATION
NORMOXIA
O2 HIF PROLINE HYDROXYLATION
NORMOXIA
O2
NORMAL pVHL HIF PROLINE
HYDROXYLATION
NORMOXIA
O2
NORMAL pVHL HIF PROLINE
HYDROXYLATION
NORMOXIA
O2 UBIQUITIN DEPENDENT HIF DEGRADATION
NORMAL pVHL HIF PROLINE
HYDROXYLATION
NORMOXIA
O2
VHL MUTATION
O2 HIF PROLINE HYDROXYLATION
VHL MUTATION
O2 HIF PROLINE HYDROXYLATION
VHL MUTATION
O2 MUTANT VHL HIF PROLINE
HYDROXYLATION
VHL MUTATION
O2
VHL MUTATION
O2 HIF PROLINE HYDROXYLATION
VHL MUTATION
O2 HIF PROLINE HYDROXYLATION
VHL MUTATION
O2 O2
VHL MUTATION
O2 HIF PROLINE HYDROXYLATION
VHL MUTATION
O2 MUTANT VHL HIF PROLINE
HYDROXYLATION
VHL MUTATION
O2 MUTANT VHL HIF PROLINE
HYDROXYLATION
VHL MUTATION
O2 MUTANT VHL HIF PROLINE
HYDROXYLATION
VHL MUTATION
O2 DEGRADATION FAILURE
MUTANT VHL HIF PROLINE HYDROXYLATION
VHL MUTATION
O2
O2 O2 O2 FAILED HIF PROLINE HYDROXYLATION
O2 FAILED HIF PROLINE HYDROXYLATION
O2 HIF ACCUMULATION
‘PSEUDOHYPOXIA’
FUMARATE OR SUCCINATE ACCUMULATION
CONCLUSIONS
• MOLECULAR ALTERATIONS REMAIN AS THE BASIS FOR THE CLASSIFICATION OF RENAL CANCER
• ACCURATE AND COMPLETE CATEGORISATION OF INDIVIDUAL TUMOURS IS BASED ON SOUND MORPHOLOGY SUPPORTED BY IHC AND MOLECULAR GENETICS