Case 9 11.9.2019

Tanja Čugura

Joint Session Molecular Pathologyand Trainees:

Next Generation Pathology

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

• Physical examination: abdominal mass

in LUQ

• Abdominal CT scan large

retroperitoneal tumour

• Intraoperative frozen section: part of

tumour infiltrating the colon

Clinical data

Frozen section

• High-grade soft tissue sarcoma (dedifferentiated liposarcoma - DDLS)

• Sarcomatoid carcinoma

• Melanoma, GIST

• Primary colorectal adenocarcinoma – unlikely

→ Immunohistochemistry MDM2 + FISH MDM2

Frozen section DDX

IHC,MDM2

FISH, MDM2

Chromosome 12

centromere

MDM2

MDM2 amplification

Polysomy Chr. 12

Normal

Multivisceral resection

Carcinomatous component

Transition area

Transition area

IHC, MDM2, x10

FISH, MDM2

Transition area

DDX

• Collision tumour: high-grade sarcoma (DDLS) + type 1 papillary renal cell

carcinoma

• Sarcomatoid renal cell carcinoma (RCC)

IHC Sarcomatoid component Carcinomatous component

MDM2 + -

CK AE1/AE3 + focal +

CK18 + +

CAM 5.2 + focal +

CK7 - +

EMA + focal +

p53 - -

RCC - +

PAX8 - +

CD10 + +

Racemase - +

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

Gene mutations, copy number change, fusion

None present

Final diagnosis:

Sarcomatoid renal cell carcinoma with MDM2amplification

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 ?

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

• CK18, EMA, CKAE1/AE3, CAM 5.2 epithelial origin

CKAE1/AE3, IHCCK18, IHC

CAM 5.2, IHC EMA, IHC

• 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

Clinical relevance

• MDM2 inhibitors

• PD-1 and PD-L1 inhibitors subset of pt. develop hyperprogressive

disease

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