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Joint Session Molecular Pathology and Trainees: Next Generation Pathology Case...
Transcript of Joint Session Molecular Pathology and Trainees: Next Generation Pathology Case...
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Case 9 11.9.2019
Tanja Čugura
Joint Session Molecular Pathologyand Trainees:
Next Generation Pathology
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Clinical data
• 66-year old male
• Diabetes type II, arterial hypertension
• 2w history: fatigue, weakness, night sweats
• Lab: leukocytosis DDx: myeloproliferative disorder
• Bone marrow Bx: unremarkable
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• Physical examination: abdominal mass
in LUQ
• Abdominal CT scan large
retroperitoneal tumour
• Intraoperative frozen section: part of
tumour infiltrating the colon
Clinical data
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Frozen section
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• High-grade soft tissue sarcoma (dedifferentiated liposarcoma - DDLS)
• Sarcomatoid carcinoma
• Melanoma, GIST
• Primary colorectal adenocarcinoma – unlikely
→ Immunohistochemistry MDM2 + FISH MDM2
Frozen section DDX
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IHC,MDM2
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FISH, MDM2
Chromosome 12
centromere
MDM2
MDM2 amplification
Polysomy Chr. 12
Normal
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Multivisceral resection
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Carcinomatous component
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Transition area
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Transition area
IHC, MDM2, x10
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FISH, MDM2
Transition area
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DDX
• Collision tumour: high-grade sarcoma (DDLS) + type 1 papillary renal cell
carcinoma
• Sarcomatoid renal cell carcinoma (RCC)
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IHC Sarcomatoid component Carcinomatous component
MDM2 + -
CK AE1/AE3 + focal +
CK18 + +
CAM 5.2 + focal +
CK7 - +
EMA + focal +
p53 - -
RCC - +
PAX8 - +
CD10 + +
Racemase - +
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Chromosome copy number analysis - FISH
Sarcomatoidcomponent
Carcinomatouscomponent
MDM2 Amplified Normal
Chromosome 7 Gain: 35% Gain: 32%
Chromosome 17 Gain: 20 % Gain: 16%
Chromosome 3 Gain: 26% Gain: 26%
Chromosome 8 Gain: 5% Gain: 7%
Papillary renal cellcarcinoma type 1
Cell of origin
Sarcomatoidcomponent
+ MDM2 amplification
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Gene mutations, copy number change, fusion
None present
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Final diagnosis:
Sarcomatoid renal cell carcinoma with MDM2amplification
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Sarcomatoid RCC
• 5% of all RCC
• Any RCC subtype
• Carinomatous & sarcomatoid component, 1 cell of origin
• Resemble fibrosarcoma, malignant fibrous histiocytoma
• Highly aggressive, poor prognosis
• MDM2 status ?
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MDM2 – Murine Double Minute 2 gene
• Proto-oncogene on Chr. 12q15
• Negative regulator of tumour supressor TP53
• Over-expressed MDM2:
↓cell cycle regulation & DNA repair,
↑DNA damage, malignant transformation
• MDM2 amplification = hallmark of well differentiated and dedifferentiated liposarcoma
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• CK18, EMA, CKAE1/AE3, CAM 5.2 epithelial origin
CKAE1/AE3, IHCCK18, IHC
CAM 5.2, IHC EMA, IHC
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• DDLS ≤100%
• Well-differentiated liposarcoma
>90%
• Intimal sarcoma 70-100%
• Low-grade osteosarcoma >89%,
high-grade osteosarcoma 10%
• Cholangiocarcinoma 15%
• Urothelial carcinoma 10%
• Sarcomatoid RCC 10% (RCC <0.6%)
• Colorectal carcinoma 9%
Glioblastoma 7-12%
Soft tissue Carcinomas
Tumours with MDM2 amplification
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Clinical relevance
• MDM2 inhibitors
• PD-1 and PD-L1 inhibitors subset of pt. develop hyperprogressive
disease
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Conclusion – sarcomatoid RCC with MDM2amplification
• Carcinomatous component can be minimal
• Dx pitfall – sarcomatoid RCCs can harbour MDM2 amplification
• Extensive sampling, immunohistochemistry panel
• Caution – small samples