Pancreatic Neuroendocrine Neoplasm (pNEN) case

Endocrinology UnitPathophysiology DepartmentLaikon General Hospital

Case Presentation:Dr. Chatzellis Eleftherios MD

Intern in Endocrinology

58 year old male patient 2001: abdominal pain CT scan: 5cm tumor pancreatic tail

Multiple focal lesions in the liver FNAB (liver lesion) Well Differentiated NEN

grade 2 (ki67 = 4%) CgA = 5,2 nmol/l (<4), other markers negative No secretory symptoms (non-functioning pNEN) SRS (Octreoscan): avid uptake (Krenning score = 3) in both

primary pNEN and liver metastases

Case History - 2001

Case History

Chromogranin A

ki67

H&E stain

Case History 2001-2005 Sweden (Uppsala) Suggested surgery to reduce tumor

burden and local complications Patient refused Chemotherapy (Streptozotocin + 5-FU)

+ Somatostatin analogues (SSA’s) 1 year later (2002): DISEASE PROGRESSION (PD) Addition of pegylated INF-a Chemotherapy was discontinued after 2,5 years (mild

renal impairment) 2002-2005 : STABLE DISEASE (SD) CgA = 10,5 nmol/l (<4)

Case History 2006-2008 2006: Hypercalcemia occurred for the first time

Ca = 11,8 mg/dl (8,5 - 10,1)P = 1,98 mg/dl (2,5 - 4,5)PTH = 2,54 pg/ml (10 - 65)PTHrP = 84 pmol/l (<2)CgA = 45 nmol/l (<4)

Imaging: DISEASE PROGRESSION (PD) Increased SSA’s dosage [+peg-INFa] Normalization Ca 2006-2008: STABLE DISEASE (SD) - Biochemical control

Humoral Malignancy-associated Hypercalcemia(PTHrP- related)

Case History 2008-2009 2008: peg-INFa discontinued (depression) 2008: Hypercalcemia (12,9 mg/dl)

+ DISEASE PROGRESSION (PD) 2008-2009: 177Lu-DOTATATE x5 cycles (25.6 GBq) Increased SSA’s dosage Addition of pasireotide 1200μg bid Ca = 10,7 mg/dl, CgA=115 nmol/l, PTHrP=140 pmol/l 2009: DISEASE PROGRESSION (PD)

+ biochemical relapse (Ca = 11,8 mg/dl)

Case History 2009-2010 + Temozolomide + Capecitabine (CAP-TEM) 2009-2010: STABLE DISEASE (SD) Biochemical control of Ca required additional

treatment:SOM230 and SSA’sForced DiuresisPrednisolone 40mg/dBiphosphonates (i.v. zolendronate 4mg monthly)Cinacalcet 90mg/d]

SIDE-EFFECTS: Proximal myopathy - muscle atrophy, patient immobilization (wheel chair), severe Diabetes Mellitus (~100 IU insulin/d)

Case History 2010 Tumor burden reduction (cytoreduction) necessary

Biochemical control (Ca)Reduce treatment side-effects

OPTIONS:Surgery Patient still deniedPRRT Already performed (GFR, marrow toxicity)RF Ablation Not applicable due to large liver

lesionsEmbolization (TAE/TACE)

Pre-embolization evaluation : Portal vein thrombosis

Selective approach (embolization of small branches of hepatic artery)

Case History - TAE

Pre-embolization Post-embolization

Post-embolization status TMZ + Capecitabine SSA’s Pasireotide 1200mcg/d Prednisolone 40 mg/d Zolendronate 4mg/m Insulin treatment

Ca = 10,2 mg/dlCgA = 50 nmol/l

PTHrP = 38 pmol/l

Case History - TAE

TMZ + Capecitabine SSA’s at ½ dosage X Prednisolone 8 mg/d X X

Case History 2010 6 months after TAE Ca = 13,2 mg/dl DISEASE PROGRESSION (PD) Painful lump on left thigh

T1 T2

Case History 2010

Bone scintigraphy Tc 99m

Case History 2010 BONE METASTASES vs BENIGN LESION Bone Biopsy Brown tumor (in the context of

prolonged PTHrP action on bone) New liver lesion biopsy ki67 = 4%, IHC (+) for PTHrP

PTHrP Immunohistochemistry H&E stain

Bone biopsyLiver metastases biopsy

Case History 2010-2012 Temozolomide (200mg/m2 Days 1-5 q4w) +

Bevacizumab (10 mg/kg q2w) + Everolimus (10mg/d) [+SSA’s] Ca = 8,8 mg/dl Temozolomide and Bevacizumab D/C after 6 months

due to thrombocytopenia 2010-2012: STABLE DISEASE (SD)

Case History 2012-2014 2012: DISEASE PROGRESSION (PD) Ca=9,34 mg/dl, PTHrP = 50 pmol/l Sunitinib 37,5 mg/d [+SSA’s] 6 months later: Ca = 6,5 mg/dl !!! 2012-2014: STABLE DISEASE (SD)

April 2014: Patient deceased †(hepatic encephalopathy - malnutrition)

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20052001 2006 2006 2008 2009 2009 2009 2010 2010 2010 2012 2012 2014

SSA’s

STZ+5FU

Pegylated INFa

PRRT

Pasireotide

Everolimus Sunitinib

Embolization

PDPD PD PD

CAP-TEM

PD PD

BEV-TEM

PTHrP

Ca

CgA

†

Case synopsis WD pNEN grade 2 Stage IV (liver metastases) Change of functional status during disease course Rare PTHrP secretion (paraneoplastic syndrome) Even more rare: brown tumor due to PTHrP Employment of several treatment agents/modalities to

achieve both tumoral and biochemical control Importance of cytoreductive interventions and novel

molecular targeted therapies in controlling secretory symptoms/syndrome

Long survival despite metastatic disease at presentation (application of different therapeutic modalities)

Improving Survival of NET patients

James Yao, ENETS 2014