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  • Enterprise | Interest

    Nothing to declare

  • IMMUNOHISTOCHEMICAL EVALUATION OF THE PHOSPHORYLATED AKT-1 EXPRESSION IN WELL-DIFFERENTIATED PANCREATIC NEUROENDOCRINE TUMORS

    Vera Delektorskaya, Olesya Solovieva, Galina Chemeris, Yuriy Patyutko

    N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian FederationMoscow, Russia

  • AKT

    The PI3K / AKT / mTOR Signaling Pathway

    3

    SSTR 1-5

    PI3K

    S6K1

    FOXO 1,3

    Cell cycle progressioneIF4E S6Protein synthesisP

    FOXO 1,3

    AKT

    a serine/threonine protein kinase (protein kinase B):

    a multifunctional kinase ;

    an important regulator of cellproliferation and survival.

    GrowthFactors

    Thr 308

    P

    P

    Ser 473

    Motility

    INTRODUCTION

    mTORC2 mTORC1

    p21cip1

    p27kip1

    PDK1PIP3 PIP2 PTEN

    AKT1

    S Falletta et al. mTOR inhibitors response andmTOR pathway in pancreatic neuroendocrinetumors . Endocr Relat Cancer. 2016; 23(11):883-91.

    one of the most frequentlyactivated protein kinases;

    promotes tumor growth,progression and spreading;

    an attractive target for therapy;

    a promising predictive markerof response to mTOR inhibitors.

    In PNET

    HL Robbins, A Hague. The PI3K/Akt Pathway in Tumors of endocrine Tissues. Front. Endocrinol. 2016.6:188

    TSC2

    RaptorRictor

    4EBP

  • 4

    The aim of the study was to investigate

    phosphorylated from of AKT1 kinase (p-AKT1)

    immunoexpression and clinical significance

    in well-differentiated pancreatic neuroendocrine tumors (PNETs)

    OBJECTIVEOBJECTIVE

  • 5

    Invasion/Recurrence :

    Adjacent tissue/capsule 23 (44.2%)Lymphovascular/perineural 25 (48.1%) Recurrence 3 (5.8%)

    Tumor size:

    Mean 5.2 cm (0.5 - 18 cm)

    Metastasis:

    Lymph node 15 (28.8%) Distant during follow-up 19 (36.5%)

    p=0.09

    p=0.001

    Staging of studied NETsStaging of studied NETs at initial diagnosis

    0%

    10%

    20%

    30%

    40%

    50%

    60%

    70%

    80%

    90%

    100%

    Grading of studied primary PNETs

    G2

    G3

    I

    II

    III

    IV

    G1

    Ove

    rall

    Surv

    ivin

    gD

    ise

    ase

    fre

    e S

    urv

    ivin

    g

    Age distribution:

    Range 24 77 yearsMedian age 53.41.4

    Gender distribution:

    Male 23 (44.2%) Female 29 (55.8%) (M:F 0.8)

    Functional status:

    Functional 7 (13.5%) Nonfunctional 45 (86.5%)

    CLINICAL & PATHOLOGICAL CHARACTERISTICS

  • 6

    RESULTS

    Pathology & Imunohistochemistry of PNETs. WHO 2017

    CgAH&E

    SynSSTR-2A

    RESULTS

    Ki-67 - 1%

    NET Grade 1Primary 14 (26.9%)Liver mts 3 (21.4%)

    NET Grade 2Primary 30 (57.7%)Liver mts 15 (50.0%)

    NET Grade 3Primary 8 (15.4%)Liver mts 4 (50.0%)

    Ki-67 - 8%

    Ki-67 - 30%

    n 4

    n 1

    n 5

    Primary PNETs G1-G3 52Liver metastases synchronous 22Liver metastases metachronous 5

    Ki-67 Index and Grade progression in liver metastases

  • RESULTS: p-AKT1

    The Patterns of phoshpo-AKT1 immunostaining in PNETs: Rabbit monoclonal [EP2109Y] to AKT1 (phospho Ser473)

    RESULTS: p-AKT1

    p-AKT1- Low expression p-AKT1 High expression

    Primary PNETs - 46.2 (24/52)Primary PNETs - 53.8 (28/52)

    pAKT-1 (0, 0%) pAKT-1 (1+, 1-10%)

    No staining Weak staining Moderate staining Strong staining

    pAKT-1 (3+, 51-100%)pAKT-1 (2+, 11-50%)

    The pancreatic well-differentiated neuroendocrine tumors - PNETs 7The percentage & the intensity of nuclear and cytoplasmic staining for pAKT

    Liver metastases - 59.3 (16/27)Liver metastases - 40.7 (11/27)

  • Parameters G1-NETs G2-NETs

    n 14 30

    Ki-67 index

    < 3% 3-20%

    Angioinvasion

    4 15

    Liver mts 3 12

    SSTR-2A positive

    8 25

    p-AKT1High levels

    3; 21.4% 14; 46.7%

    p-AKT1Low levels

    11; 78.6% 15; 53.3%

    8

    RESULTS: p-AKT1

    Expression of p-AKT1 in WHO Grade 1/Grade 2 PNETs (primary & metastatic)

    21.4% (3/14)

    RESULTS: p-AKT1

    p-AKT1 (2+) in NET G1, Ki-67 2%

    PNETs Grade 1

    46.7% (14/30)

    p-AKT1 (3+) in NET G2, Ki-67 - 5%

    PNETs Grade 2

    Liver metastases Grade 1/2

    46.7% (7/15)

    p-AKT1 (3+) in NET G2, Ki-67 8% p-AKT1 (3+) in NET G2, Ki-67 15%

  • Parameters G3-NETs Pancreas

    G3-NETs Liver

    n 8 12

    Ki-67 index

    23% -35%

    25% - 45%

    SSTR-2A positive

    7 10

    p-AKT1High levels

    7; 87.5% 9; 75.0%

    p-AKT1Low levels

    1; 12.5% 3; 25.0%

    9

    RESULTS: p-AKT1

    Expression of p-AKT1 in WHO Grade 3 PNETs (primary & metastatic)

    RESULTS: p-AKT1

    pAKT-1 (3+) in NET G3, Ki-67 - 26%

    87.5% (7/8)

    pAKT-1 (3+) in NET G3, Ki-67 35%

    Primary PNETs Liver Metastases

    75.0% (9/12)

    pAKT-1 (3+) in NET G3, Ki-67 - 40%

  • RESULTS: p-AKT1

    Matched pair analysis: Expression of p-AKT1 in primary PNET and corresponding liver metastases

    RESULTS: p-AKT1

    10

    pAKT-1 (2+) pAKT-1 (2+) pAKT-1 (3+)

    Primary PNET G2 Ki-67 - 30%Liver metastasis (metachronous)

    Grade 3in 3 years

    Grade 2

    Liver metastasis (synchronous)Ki-67 - 4%

    Pancreatoduodenectomy (2012) Liver resection for metastases (2012) Liver resection for metastases (2015)

    Ki-67 - 9%

    p-AKT1 in metastases as compared to primary

    15 (55.6%) | 9 (33.3%) | 3 (11.1%)

  • 11

    RESULTS: pAKT-1

    Correlation of pAKT-1 expression in PNETs to clinicopathological parameters and survival

    p=0.05p=0.11

    Time, months

    RESULTS: p-AKT1

    Overall survival Disease free survival

    Correlation to

    Grade (0.004), Ki-67 Index (p=0.029), perineural invasion (0.031), and pTNM stage (p=0.0008)

    Disease free survival, % (Kaplan-Meier) according to p-AKT1 expression in 52 cases of PNETs

    No Correlation to

    Age, gender, angioinvasion, tumor size, lymph node & distant metastasis (p=0.09), and SSTR 2A status

    Overall survival, % (Kaplan-Meier) according to p-AKT1 expression in 52 cases of PNETs

    LowHigh

    LowHigh

    p-AKT1 expression

    p-AKT1 expression

  • 12

    CONCLUSION

    PHOSPHORYLATED AKT1 EXPRESSION IN PNETs

    P-AKT1 is observed in different groups of PNET patients with the highestnuclear expression levels in well-differentiated primary and metastaticG3-NETs;

    The association of p-AKT1 to enhanced aggressiveness and histologicalgrade suggests its potential value as prognostic and predictive biomarkerand target for therapy in PNETs.

    CONCLUSION

  • 13

    29th European Congress of pathology

    N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian [email protected]