Table 1.

Clinical characteristics of 14 patients with metastatic insulinoma.

SubjectGenderAge of diagnosisWHO grading/Ki67 indexPrimary tumor and metastases at diagnosis. Subsequent progression to other sitesSynchronous or metachronous liver metastasesGermline testingHypoglycemia at presentation? yes or no. If no, when did hypoglycemia occur?
Glucose mg/dL/insulin mU/L/proinsulin pmol/L levels at diagnosis.
Treatments provided during follow-upOrder and timing of treatment in relation to original diagnosis of insulinoma. Treatments that led to control of hypoglycemia.Follow up duration
1M542; Ki67 11.6%CT abdomen 3.1 × 1.9 × 2.1 cm lesion in pancreas. > 20 liver metastases. No skeletal metastasesSynchronousInvitae cancer genetics panel (130 genes tested, 2018). Pathogenic variant in NBN: c.657_661delACAAA (p.Lys219Asnfs*16).Yes, at diagnosis. 45/51.2/700.Surgeries X 2
TACE x 3
Everolimus
Distal pancreatectomy; enucleation large liver lesion at 2 months.
TACE at 3 months, 7 months; 12 months.
Everolimus at 8 months for a total of 7 months.
Hepatectomy at 34 months.
Hypoglycemia resolved after 4 months following surgery and TACE x 2.
4.9; alive
2M65 2; Ki67 15%;CT abdomen: 2 cm lesion in pancreas. Liver metastases noted 9 years later. No skeletal metastasesMetachronousNAYes, at diagnosis. 47/34.2/93Surgery
TAE
Lanreotide
Surgery at diagnosis.
TAE 9 years later.
Hypoglycemia controlled by lanreotide.
10.9; alive
3F552; Ki67 5%MR abdomen up to 10 cm in pancreas, liver metastases. Octreoscan noted lesions in liver, pancreas, porta hepatis and spleen near hilum; lung nodules; L2 vertebral body. Subsequently development of more metastatic disease in skeleton & lungsSynchronous(Athena diagnostics MEN 1 mutation analysis, 2013). Negative MEN1 screenYes, at diagnosis. 40/35/297
.
Octreotide
Everolimus
PRRT x3
Lanreotide
Capecitabine/
temozolomide
cabozantinib
Nivolumab/
ipilimumab
SIRT
SBRT
No surgery.
Octreotide at diagnosis.
Everolimus at 2 months after diagnosis.
PRRT 7 months,10 months 12 months after diagnosis.
Switched to lanreotide at 1.6 years.
SIRT and SBRT (liver) at 2 yrs. Capecitabine/temozolomide at 2.6 years. Cabozantinib at 3.8 years.
Briefly participated in a nivolumab/ipilimumab clinical trial before death (at 4.5 years after diagnosis).

Hypoglycemia resolved after PRRT treatment.
4.7; died
4F652; Ki-67 7.3%CT abdomen: pancreatic mass 3.6 cm; 4 liver metastases. 8 years later developed periportal and retroperitoneal nodes; cervical spine body lesionSynchronousInvitae cancer genetics panel 71 genes tested, 2016. VUS FLCN gene(c.748C > A, p.Leu250Met)Yes, at diagnosis. 47/181/657octreotide
TAE x 4
Surgery
TACE x 1
microwave ablation
SBRT
FOLFOX
First treated with octreotide.
TAE x 2 at 5 yrs.
Distal pancreatectomy and left hepatectomy at 5 yrs.
TAE 5 yrs.
TACE 5.5 yrs.
TAE, 5.6 yrs.,
Microwave ablation 5.7 yrs.
Briefly given sunitinib but stopped because of intratumoral bleed.
SBRT to hepatic mets at 6.9 yrs.
FOLFOX at 7 yrs.
Octreotide controlled hypoglycemia. TAE temporarily reduced need for octreotide to control hypoglycemia.
8.2; died
5M48NACT abdomen and PET/CT scan: pancreatic and subcentimeter liver lesions. 4.2 years later, mass right iliac bone multiple foci retroperitoneal nodes and widespread metastases in skeletonSynchronousNAYes, at diagnosis. 36/37/160Diazoxide
Octreotide
TACE
Capecitabine/
temozolomide
Everolimus
Sunitinib
SBRT
Initially treated with diazoxide but had persistent hypoglycemia. Unclear if patient took drug consistently.
Octreotide 6 months after diagnosis.
TACE at 3 yrs. - octreotide held for one year before restarting.
Capecitabine/temozolomide at 4.5 yrs. for progression.
SBRT to right iliac bone at 4.6 yrs.
Everolimus at 4.9 yrs.
Hypoglycemia better after TACE. Then had mild hypoglycemia which resolved with octreotide therapy.
5.4; died
6F58 1; Ki 67 < 2% (1.3%)DOTATE PET CT scan—pancreatic tail lesion and liver metastases.. One year later widespread skeletal metastases..Synchronous(Ambry genetics 49 panel 2015). Negative MEN1 screenYes, at diagnosis.
38/79.6/700
Surgery
TACE x 2
Octreotide
Everolimus
Carboplatin/
etoposide
PRRT x 4
SBRT x3
Diazoxide and octreotide at diagnosis. TACE at 2 weeks and 2 months. Hypoglycemia resolved and diazoxide discontinued. Distal pancreatectomy, hepatectomy at 1.9 yrs. External radiation spine for metastatic disease at 2.3 yrs. Everolimus initiated. External radiation left hip and femur 3. 8 years. Everolimus discontinued. PRRT 4 cycles at 4 years. External radiation the sacrum, spine, rib. Restart everolimus 4.5 years. Recurrent hypoglycemia and started on carboplatin/etoposide at 4.8 years. Died 5 yrs. after diagnosis.
Hypoglycemia controlled after TACE, octreotide and surgery. Recurrent hypoglycemia with progression and controlled with carboplatin/etoposide.
5.1; died
7F672; Ki 67 16%;CT abdomen 2.8 cm pancreatic body lesion & hepatic masses.
10 years later lung nodules measuring up to 2.6 cm.
synchronousNANo, hypoglycemia occurred 8 months after diagnosis.
42/104/260
Octreotide
TACE x 1
PRRT x 5
carboplatin/
etoposide
capecitabine/
temozolomide
SBRT
Hypoglycemia 8 months after diagnosis. PRRT two cycles eight months later. Also, TACE. Hypoglycemia controlled on octreotide. PRRT two cycles at 3.5 yrs. Carboplatin etoposide at 4 years. Switched to capecitabine/temozolomide for 1.8 yrs. and discontinued for progression. Remained on octreotide. External radiation to liver mets at 8.6 yrs. One more dose PRRT at 9.5 yrs. Died 10.4 yrs. after diagnosis.
Hypoglycemia controlled after PRRT and octreotide.
10.4; died
8M,731; Ki67 1.3%CT abdomen showed 6.4 cm pancreatic lesion and lymph node involvement.
2.5 years, later liver metastases.
Subsequently developed retroperitoneal nodes; osseous metastatic disease; small degree of lung disease
MetachronousCancer susceptibility multigene panel, 2015. Ambry Cancer Next Panel 2017. Negative for MEN1 mutations. VUS MRE11A geneYes, at diagnosis. 39/NA/NASurgery x 3
TAE x4
Octreotide
Diazoxide
Everolimus
Capecitabine/
temozolomide
PRRT x 4
Distal pancreatectomy at diagnosis with resolution of hypoglycemia. Liver metastases 2.5 years after diagnosis. Started Octreotide at 2.6 years. TAE 2.6 years; 3.3 years. Diazoxide at 3.5 years with mild improvement hypoglycemia. Resection liver metastasis with LN dissection at 4 yrs. - significant improvement in hypoglycemia. Everolimus at 4.8 yrs. with immediate resolution of hypoglycemia. TAE at 5.3 yrs.; 5.5 yrs. Partial hepatectomy & LN dissection 5.8 yrs. Everolimus & octreotide discontinued. Interval progression of metastatic disease. Restarted octreotide at 6.3 yrs. PRRT 6.4, 6.5. 6.8. 7 yrs. Capecitabine/temozolomide at 11 yrs. for progression of disease. Also, on octreotide.
Hypoglycemia controlled with surgeries and everolimus.
12.3; alive
9F622; Ki 67 3.5 %Initially only pancreas.
Portocaval nodes; liver nodules noted 3.75 yrs. Later
MetachronousInvitae Genetics 79 gene panel 2016. Negative MEN1 screenYes, at diagnosis. 56/105.8/294Surgery
Octreotide
SBRT
Pancreatectomy at diagnosis. Recurrent hypoglycemia 3 years later. Liver metastases noted at 3.75 yrs. Octreotide therapy at 4 yrs. SBRT at 5 yrs. Died from cirrhosis related to NASH.
Hypoglycemia controlled once patient went on octreotide.
5.8;died
10F202, Ki 67 20%CT 3.9 cm lesion splenic hilum; hepatic lesions; breast, L1 lesion; osseous mets. Rt internal mammary nodeSynchronousUC500 germline panel negativeNo, hypoglycemia documented 1.5 years after diagnosis, 48/45.1/195.Capecitabine/
temozolomide
Pembrolizumab
PRRT
Lanreotide
capecitabine/Temozolomide at diagnosis for 1 year. TACE at 1.4 years; than pembrolizumab + PRRT clinical trial (2 cycles) at 1.6 years. Also started lanreotide at 1.6 years
Hypoglycemia controlled with combination of pembrolizumab, PRRT and lanreotide
1.9 alive
11M713, Ki 67 80% (high-grade neuroendocrine neoplasm)CT abdomen 4.9 cm mass pancreatic head; liver metastases; skeletonSynchronousInvitae 62 gene germline panel negativeYes, at diagnosis, 60/49/664.2Surgery
Octreotide, Lanreotide, pembrolizumab
PRRT
Octreotide soon after diagnosis; Whipple procedure + RFA 2 months later. carboplatin + etoposide 6 cycles started 4 months later. pembrolizumab + PRRT clinical trial (2 cycles) 10 months later. Lanreotide 10 months later
Hypoglycemia controlled after PRRT and lanreotide
1.2 alive
12M502, Ki67 8%MR abdomen 4 × 2.5 cm mass distal body/tail of pancreas; multiple metastases in liverSynchronous----No, hypoglycemia 5 years after diagnosis
53/34/96.5
Microwave ablation liver metastases.
Surgery
octreotide
PRRT
Microwave ablation liver metastases 2 months after diagnosis.; Y90 SIRT at 5 months; Resection pancreatic tumor and lymph node dissection at 9 months. Octreotide at 1.4 years. PRRT x 2 cycles at 7 years.
Hypoglycemia controlled after PRRT and octreotide
7.3 alive
13F642, Ki67 17.3%CT abdomen 4.5 × 3.5 × 3.3 cm mass pancreatic tail and multiple metastases in liverSynchronousUC500 germline panel negative.No, hypoglycemia 1.7 years after diagnosis.
36/18.1/320
Octreotide
Capecitabine/
temozolomide
PRRT
SBRT
Pembrolizumab
FOLFOX
Carboplatin/etoposide
Octreotide at 2 months after diagnosis. Capecitabine/Temozolomide at 6 months. PRRT x 4 cycles at 1 year. SBRT to acetabulum and L4 met at 1.4 years. Pembrolizumab one dose + Y90 radioembolization at 1.6 years clinical trial.; FOLFOX at 1.8 years; carboplatin/etoposide 3 cycles at 2 years.
Hypoglycemia controlled after treatment with FOLFOX
2.5 died
14M301, Ki67 < 1%5 cm tumor pancreatic head. Liver metastases first noted 3.4 years laterMetachronousGermline testing UC500 germline panel MSH2 pL556S (c. 1667T > C, pLeu556Ser)—missense variant in the MSG2 DNA mismatch (MMR) protein—likely pathogenic for hereditary colorectal cancerNo, hypoglycemia 3.5 years after diagnosis.
41/20/229.7
Surgeries x 2
Lanreotide
Sunitinib
Pembrolizumab
Diazoxide
Capecitabine/
temozolomide
Whipple procedure at diagnosis; Lanreotide at 1.8 years; sunitinib at 6 years
Liver resection and microwave ablation at 7.4 years. Pembrolizumab at 8. 3 years (for high tumor mutation burden). Diazoxide at 9 years. Capecitabine/temozolomide 9.1 years
Hypoglycemia controlled with food and diazoxide
9.1 alive
SubjectGenderAge of diagnosisWHO grading/Ki67 indexPrimary tumor and metastases at diagnosis. Subsequent progression to other sitesSynchronous or metachronous liver metastasesGermline testingHypoglycemia at presentation? yes or no. If no, when did hypoglycemia occur?
Glucose mg/dL/insulin mU/L/proinsulin pmol/L levels at diagnosis.
Treatments provided during follow-upOrder and timing of treatment in relation to original diagnosis of insulinoma. Treatments that led to control of hypoglycemia.Follow up duration
1M542; Ki67 11.6%CT abdomen 3.1 × 1.9 × 2.1 cm lesion in pancreas. > 20 liver metastases. No skeletal metastasesSynchronousInvitae cancer genetics panel (130 genes tested, 2018). Pathogenic variant in NBN: c.657_661delACAAA (p.Lys219Asnfs*16).Yes, at diagnosis. 45/51.2/700.Surgeries X 2
TACE x 3
Everolimus
Distal pancreatectomy; enucleation large liver lesion at 2 months.
TACE at 3 months, 7 months; 12 months.
Everolimus at 8 months for a total of 7 months.
Hepatectomy at 34 months.
Hypoglycemia resolved after 4 months following surgery and TACE x 2.
4.9; alive
2M65 2; Ki67 15%;CT abdomen: 2 cm lesion in pancreas. Liver metastases noted 9 years later. No skeletal metastasesMetachronousNAYes, at diagnosis. 47/34.2/93Surgery
TAE
Lanreotide
Surgery at diagnosis.
TAE 9 years later.
Hypoglycemia controlled by lanreotide.
10.9; alive
3F552; Ki67 5%MR abdomen up to 10 cm in pancreas, liver metastases. Octreoscan noted lesions in liver, pancreas, porta hepatis and spleen near hilum; lung nodules; L2 vertebral body. Subsequently development of more metastatic disease in skeleton & lungsSynchronous(Athena diagnostics MEN 1 mutation analysis, 2013). Negative MEN1 screenYes, at diagnosis. 40/35/297
.
Octreotide
Everolimus
PRRT x3
Lanreotide
Capecitabine/
temozolomide
cabozantinib
Nivolumab/
ipilimumab
SIRT
SBRT
No surgery.
Octreotide at diagnosis.
Everolimus at 2 months after diagnosis.
PRRT 7 months,10 months 12 months after diagnosis.
Switched to lanreotide at 1.6 years.
SIRT and SBRT (liver) at 2 yrs. Capecitabine/temozolomide at 2.6 years. Cabozantinib at 3.8 years.
Briefly participated in a nivolumab/ipilimumab clinical trial before death (at 4.5 years after diagnosis).

Hypoglycemia resolved after PRRT treatment.
4.7; died
4F652; Ki-67 7.3%CT abdomen: pancreatic mass 3.6 cm; 4 liver metastases. 8 years later developed periportal and retroperitoneal nodes; cervical spine body lesionSynchronousInvitae cancer genetics panel 71 genes tested, 2016. VUS FLCN gene(c.748C > A, p.Leu250Met)Yes, at diagnosis. 47/181/657octreotide
TAE x 4
Surgery
TACE x 1
microwave ablation
SBRT
FOLFOX
First treated with octreotide.
TAE x 2 at 5 yrs.
Distal pancreatectomy and left hepatectomy at 5 yrs.
TAE 5 yrs.
TACE 5.5 yrs.
TAE, 5.6 yrs.,
Microwave ablation 5.7 yrs.
Briefly given sunitinib but stopped because of intratumoral bleed.
SBRT to hepatic mets at 6.9 yrs.
FOLFOX at 7 yrs.
Octreotide controlled hypoglycemia. TAE temporarily reduced need for octreotide to control hypoglycemia.
8.2; died
5M48NACT abdomen and PET/CT scan: pancreatic and subcentimeter liver lesions. 4.2 years later, mass right iliac bone multiple foci retroperitoneal nodes and widespread metastases in skeletonSynchronousNAYes, at diagnosis. 36/37/160Diazoxide
Octreotide
TACE
Capecitabine/
temozolomide
Everolimus
Sunitinib
SBRT
Initially treated with diazoxide but had persistent hypoglycemia. Unclear if patient took drug consistently.
Octreotide 6 months after diagnosis.
TACE at 3 yrs. - octreotide held for one year before restarting.
Capecitabine/temozolomide at 4.5 yrs. for progression.
SBRT to right iliac bone at 4.6 yrs.
Everolimus at 4.9 yrs.
Hypoglycemia better after TACE. Then had mild hypoglycemia which resolved with octreotide therapy.
5.4; died
6F58 1; Ki 67 < 2% (1.3%)DOTATE PET CT scan—pancreatic tail lesion and liver metastases.. One year later widespread skeletal metastases..Synchronous(Ambry genetics 49 panel 2015). Negative MEN1 screenYes, at diagnosis.
38/79.6/700
Surgery
TACE x 2
Octreotide
Everolimus
Carboplatin/
etoposide
PRRT x 4
SBRT x3
Diazoxide and octreotide at diagnosis. TACE at 2 weeks and 2 months. Hypoglycemia resolved and diazoxide discontinued. Distal pancreatectomy, hepatectomy at 1.9 yrs. External radiation spine for metastatic disease at 2.3 yrs. Everolimus initiated. External radiation left hip and femur 3. 8 years. Everolimus discontinued. PRRT 4 cycles at 4 years. External radiation the sacrum, spine, rib. Restart everolimus 4.5 years. Recurrent hypoglycemia and started on carboplatin/etoposide at 4.8 years. Died 5 yrs. after diagnosis.
Hypoglycemia controlled after TACE, octreotide and surgery. Recurrent hypoglycemia with progression and controlled with carboplatin/etoposide.
5.1; died
7F672; Ki 67 16%;CT abdomen 2.8 cm pancreatic body lesion & hepatic masses.
10 years later lung nodules measuring up to 2.6 cm.
synchronousNANo, hypoglycemia occurred 8 months after diagnosis.
42/104/260
Octreotide
TACE x 1
PRRT x 5
carboplatin/
etoposide
capecitabine/
temozolomide
SBRT
Hypoglycemia 8 months after diagnosis. PRRT two cycles eight months later. Also, TACE. Hypoglycemia controlled on octreotide. PRRT two cycles at 3.5 yrs. Carboplatin etoposide at 4 years. Switched to capecitabine/temozolomide for 1.8 yrs. and discontinued for progression. Remained on octreotide. External radiation to liver mets at 8.6 yrs. One more dose PRRT at 9.5 yrs. Died 10.4 yrs. after diagnosis.
Hypoglycemia controlled after PRRT and octreotide.
10.4; died
8M,731; Ki67 1.3%CT abdomen showed 6.4 cm pancreatic lesion and lymph node involvement.
2.5 years, later liver metastases.
Subsequently developed retroperitoneal nodes; osseous metastatic disease; small degree of lung disease
MetachronousCancer susceptibility multigene panel, 2015. Ambry Cancer Next Panel 2017. Negative for MEN1 mutations. VUS MRE11A geneYes, at diagnosis. 39/NA/NASurgery x 3
TAE x4
Octreotide
Diazoxide
Everolimus
Capecitabine/
temozolomide
PRRT x 4
Distal pancreatectomy at diagnosis with resolution of hypoglycemia. Liver metastases 2.5 years after diagnosis. Started Octreotide at 2.6 years. TAE 2.6 years; 3.3 years. Diazoxide at 3.5 years with mild improvement hypoglycemia. Resection liver metastasis with LN dissection at 4 yrs. - significant improvement in hypoglycemia. Everolimus at 4.8 yrs. with immediate resolution of hypoglycemia. TAE at 5.3 yrs.; 5.5 yrs. Partial hepatectomy & LN dissection 5.8 yrs. Everolimus & octreotide discontinued. Interval progression of metastatic disease. Restarted octreotide at 6.3 yrs. PRRT 6.4, 6.5. 6.8. 7 yrs. Capecitabine/temozolomide at 11 yrs. for progression of disease. Also, on octreotide.
Hypoglycemia controlled with surgeries and everolimus.
12.3; alive
9F622; Ki 67 3.5 %Initially only pancreas.
Portocaval nodes; liver nodules noted 3.75 yrs. Later
MetachronousInvitae Genetics 79 gene panel 2016. Negative MEN1 screenYes, at diagnosis. 56/105.8/294Surgery
Octreotide
SBRT
Pancreatectomy at diagnosis. Recurrent hypoglycemia 3 years later. Liver metastases noted at 3.75 yrs. Octreotide therapy at 4 yrs. SBRT at 5 yrs. Died from cirrhosis related to NASH.
Hypoglycemia controlled once patient went on octreotide.
5.8;died
10F202, Ki 67 20%CT 3.9 cm lesion splenic hilum; hepatic lesions; breast, L1 lesion; osseous mets. Rt internal mammary nodeSynchronousUC500 germline panel negativeNo, hypoglycemia documented 1.5 years after diagnosis, 48/45.1/195.Capecitabine/
temozolomide
Pembrolizumab
PRRT
Lanreotide
capecitabine/Temozolomide at diagnosis for 1 year. TACE at 1.4 years; than pembrolizumab + PRRT clinical trial (2 cycles) at 1.6 years. Also started lanreotide at 1.6 years
Hypoglycemia controlled with combination of pembrolizumab, PRRT and lanreotide
1.9 alive
11M713, Ki 67 80% (high-grade neuroendocrine neoplasm)CT abdomen 4.9 cm mass pancreatic head; liver metastases; skeletonSynchronousInvitae 62 gene germline panel negativeYes, at diagnosis, 60/49/664.2Surgery
Octreotide, Lanreotide, pembrolizumab
PRRT
Octreotide soon after diagnosis; Whipple procedure + RFA 2 months later. carboplatin + etoposide 6 cycles started 4 months later. pembrolizumab + PRRT clinical trial (2 cycles) 10 months later. Lanreotide 10 months later
Hypoglycemia controlled after PRRT and lanreotide
1.2 alive
12M502, Ki67 8%MR abdomen 4 × 2.5 cm mass distal body/tail of pancreas; multiple metastases in liverSynchronous----No, hypoglycemia 5 years after diagnosis
53/34/96.5
Microwave ablation liver metastases.
Surgery
octreotide
PRRT
Microwave ablation liver metastases 2 months after diagnosis.; Y90 SIRT at 5 months; Resection pancreatic tumor and lymph node dissection at 9 months. Octreotide at 1.4 years. PRRT x 2 cycles at 7 years.
Hypoglycemia controlled after PRRT and octreotide
7.3 alive
13F642, Ki67 17.3%CT abdomen 4.5 × 3.5 × 3.3 cm mass pancreatic tail and multiple metastases in liverSynchronousUC500 germline panel negative.No, hypoglycemia 1.7 years after diagnosis.
36/18.1/320
Octreotide
Capecitabine/
temozolomide
PRRT
SBRT
Pembrolizumab
FOLFOX
Carboplatin/etoposide
Octreotide at 2 months after diagnosis. Capecitabine/Temozolomide at 6 months. PRRT x 4 cycles at 1 year. SBRT to acetabulum and L4 met at 1.4 years. Pembrolizumab one dose + Y90 radioembolization at 1.6 years clinical trial.; FOLFOX at 1.8 years; carboplatin/etoposide 3 cycles at 2 years.
Hypoglycemia controlled after treatment with FOLFOX
2.5 died
14M301, Ki67 < 1%5 cm tumor pancreatic head. Liver metastases first noted 3.4 years laterMetachronousGermline testing UC500 germline panel MSH2 pL556S (c. 1667T > C, pLeu556Ser)—missense variant in the MSG2 DNA mismatch (MMR) protein—likely pathogenic for hereditary colorectal cancerNo, hypoglycemia 3.5 years after diagnosis.
41/20/229.7
Surgeries x 2
Lanreotide
Sunitinib
Pembrolizumab
Diazoxide
Capecitabine/
temozolomide
Whipple procedure at diagnosis; Lanreotide at 1.8 years; sunitinib at 6 years
Liver resection and microwave ablation at 7.4 years. Pembrolizumab at 8. 3 years (for high tumor mutation burden). Diazoxide at 9 years. Capecitabine/temozolomide 9.1 years
Hypoglycemia controlled with food and diazoxide
9.1 alive

Abbreviations: PRRT, peptide receptor radionucleotide therapy with 177-Lutetium labelled somatostatin analogs; SBRT, stereotactic body radiation therapy; SIR, selective internal radiation therapy; TACE, transarterial chemoembolization; TAE, transarterial embolization.

Table 1.

Clinical characteristics of 14 patients with metastatic insulinoma.

SubjectGenderAge of diagnosisWHO grading/Ki67 indexPrimary tumor and metastases at diagnosis. Subsequent progression to other sitesSynchronous or metachronous liver metastasesGermline testingHypoglycemia at presentation? yes or no. If no, when did hypoglycemia occur?
Glucose mg/dL/insulin mU/L/proinsulin pmol/L levels at diagnosis.
Treatments provided during follow-upOrder and timing of treatment in relation to original diagnosis of insulinoma. Treatments that led to control of hypoglycemia.Follow up duration
1M542; Ki67 11.6%CT abdomen 3.1 × 1.9 × 2.1 cm lesion in pancreas. > 20 liver metastases. No skeletal metastasesSynchronousInvitae cancer genetics panel (130 genes tested, 2018). Pathogenic variant in NBN: c.657_661delACAAA (p.Lys219Asnfs*16).Yes, at diagnosis. 45/51.2/700.Surgeries X 2
TACE x 3
Everolimus
Distal pancreatectomy; enucleation large liver lesion at 2 months.
TACE at 3 months, 7 months; 12 months.
Everolimus at 8 months for a total of 7 months.
Hepatectomy at 34 months.
Hypoglycemia resolved after 4 months following surgery and TACE x 2.
4.9; alive
2M65 2; Ki67 15%;CT abdomen: 2 cm lesion in pancreas. Liver metastases noted 9 years later. No skeletal metastasesMetachronousNAYes, at diagnosis. 47/34.2/93Surgery
TAE
Lanreotide
Surgery at diagnosis.
TAE 9 years later.
Hypoglycemia controlled by lanreotide.
10.9; alive
3F552; Ki67 5%MR abdomen up to 10 cm in pancreas, liver metastases. Octreoscan noted lesions in liver, pancreas, porta hepatis and spleen near hilum; lung nodules; L2 vertebral body. Subsequently development of more metastatic disease in skeleton & lungsSynchronous(Athena diagnostics MEN 1 mutation analysis, 2013). Negative MEN1 screenYes, at diagnosis. 40/35/297
.
Octreotide
Everolimus
PRRT x3
Lanreotide
Capecitabine/
temozolomide
cabozantinib
Nivolumab/
ipilimumab
SIRT
SBRT
No surgery.
Octreotide at diagnosis.
Everolimus at 2 months after diagnosis.
PRRT 7 months,10 months 12 months after diagnosis.
Switched to lanreotide at 1.6 years.
SIRT and SBRT (liver) at 2 yrs. Capecitabine/temozolomide at 2.6 years. Cabozantinib at 3.8 years.
Briefly participated in a nivolumab/ipilimumab clinical trial before death (at 4.5 years after diagnosis).

Hypoglycemia resolved after PRRT treatment.
4.7; died
4F652; Ki-67 7.3%CT abdomen: pancreatic mass 3.6 cm; 4 liver metastases. 8 years later developed periportal and retroperitoneal nodes; cervical spine body lesionSynchronousInvitae cancer genetics panel 71 genes tested, 2016. VUS FLCN gene(c.748C > A, p.Leu250Met)Yes, at diagnosis. 47/181/657octreotide
TAE x 4
Surgery
TACE x 1
microwave ablation
SBRT
FOLFOX
First treated with octreotide.
TAE x 2 at 5 yrs.
Distal pancreatectomy and left hepatectomy at 5 yrs.
TAE 5 yrs.
TACE 5.5 yrs.
TAE, 5.6 yrs.,
Microwave ablation 5.7 yrs.
Briefly given sunitinib but stopped because of intratumoral bleed.
SBRT to hepatic mets at 6.9 yrs.
FOLFOX at 7 yrs.
Octreotide controlled hypoglycemia. TAE temporarily reduced need for octreotide to control hypoglycemia.
8.2; died
5M48NACT abdomen and PET/CT scan: pancreatic and subcentimeter liver lesions. 4.2 years later, mass right iliac bone multiple foci retroperitoneal nodes and widespread metastases in skeletonSynchronousNAYes, at diagnosis. 36/37/160Diazoxide
Octreotide
TACE
Capecitabine/
temozolomide
Everolimus
Sunitinib
SBRT
Initially treated with diazoxide but had persistent hypoglycemia. Unclear if patient took drug consistently.
Octreotide 6 months after diagnosis.
TACE at 3 yrs. - octreotide held for one year before restarting.
Capecitabine/temozolomide at 4.5 yrs. for progression.
SBRT to right iliac bone at 4.6 yrs.
Everolimus at 4.9 yrs.
Hypoglycemia better after TACE. Then had mild hypoglycemia which resolved with octreotide therapy.
5.4; died
6F58 1; Ki 67 < 2% (1.3%)DOTATE PET CT scan—pancreatic tail lesion and liver metastases.. One year later widespread skeletal metastases..Synchronous(Ambry genetics 49 panel 2015). Negative MEN1 screenYes, at diagnosis.
38/79.6/700
Surgery
TACE x 2
Octreotide
Everolimus
Carboplatin/
etoposide
PRRT x 4
SBRT x3
Diazoxide and octreotide at diagnosis. TACE at 2 weeks and 2 months. Hypoglycemia resolved and diazoxide discontinued. Distal pancreatectomy, hepatectomy at 1.9 yrs. External radiation spine for metastatic disease at 2.3 yrs. Everolimus initiated. External radiation left hip and femur 3. 8 years. Everolimus discontinued. PRRT 4 cycles at 4 years. External radiation the sacrum, spine, rib. Restart everolimus 4.5 years. Recurrent hypoglycemia and started on carboplatin/etoposide at 4.8 years. Died 5 yrs. after diagnosis.
Hypoglycemia controlled after TACE, octreotide and surgery. Recurrent hypoglycemia with progression and controlled with carboplatin/etoposide.
5.1; died
7F672; Ki 67 16%;CT abdomen 2.8 cm pancreatic body lesion & hepatic masses.
10 years later lung nodules measuring up to 2.6 cm.
synchronousNANo, hypoglycemia occurred 8 months after diagnosis.
42/104/260
Octreotide
TACE x 1
PRRT x 5
carboplatin/
etoposide
capecitabine/
temozolomide
SBRT
Hypoglycemia 8 months after diagnosis. PRRT two cycles eight months later. Also, TACE. Hypoglycemia controlled on octreotide. PRRT two cycles at 3.5 yrs. Carboplatin etoposide at 4 years. Switched to capecitabine/temozolomide for 1.8 yrs. and discontinued for progression. Remained on octreotide. External radiation to liver mets at 8.6 yrs. One more dose PRRT at 9.5 yrs. Died 10.4 yrs. after diagnosis.
Hypoglycemia controlled after PRRT and octreotide.
10.4; died
8M,731; Ki67 1.3%CT abdomen showed 6.4 cm pancreatic lesion and lymph node involvement.
2.5 years, later liver metastases.
Subsequently developed retroperitoneal nodes; osseous metastatic disease; small degree of lung disease
MetachronousCancer susceptibility multigene panel, 2015. Ambry Cancer Next Panel 2017. Negative for MEN1 mutations. VUS MRE11A geneYes, at diagnosis. 39/NA/NASurgery x 3
TAE x4
Octreotide
Diazoxide
Everolimus
Capecitabine/
temozolomide
PRRT x 4
Distal pancreatectomy at diagnosis with resolution of hypoglycemia. Liver metastases 2.5 years after diagnosis. Started Octreotide at 2.6 years. TAE 2.6 years; 3.3 years. Diazoxide at 3.5 years with mild improvement hypoglycemia. Resection liver metastasis with LN dissection at 4 yrs. - significant improvement in hypoglycemia. Everolimus at 4.8 yrs. with immediate resolution of hypoglycemia. TAE at 5.3 yrs.; 5.5 yrs. Partial hepatectomy & LN dissection 5.8 yrs. Everolimus & octreotide discontinued. Interval progression of metastatic disease. Restarted octreotide at 6.3 yrs. PRRT 6.4, 6.5. 6.8. 7 yrs. Capecitabine/temozolomide at 11 yrs. for progression of disease. Also, on octreotide.
Hypoglycemia controlled with surgeries and everolimus.
12.3; alive
9F622; Ki 67 3.5 %Initially only pancreas.
Portocaval nodes; liver nodules noted 3.75 yrs. Later
MetachronousInvitae Genetics 79 gene panel 2016. Negative MEN1 screenYes, at diagnosis. 56/105.8/294Surgery
Octreotide
SBRT
Pancreatectomy at diagnosis. Recurrent hypoglycemia 3 years later. Liver metastases noted at 3.75 yrs. Octreotide therapy at 4 yrs. SBRT at 5 yrs. Died from cirrhosis related to NASH.
Hypoglycemia controlled once patient went on octreotide.
5.8;died
10F202, Ki 67 20%CT 3.9 cm lesion splenic hilum; hepatic lesions; breast, L1 lesion; osseous mets. Rt internal mammary nodeSynchronousUC500 germline panel negativeNo, hypoglycemia documented 1.5 years after diagnosis, 48/45.1/195.Capecitabine/
temozolomide
Pembrolizumab
PRRT
Lanreotide
capecitabine/Temozolomide at diagnosis for 1 year. TACE at 1.4 years; than pembrolizumab + PRRT clinical trial (2 cycles) at 1.6 years. Also started lanreotide at 1.6 years
Hypoglycemia controlled with combination of pembrolizumab, PRRT and lanreotide
1.9 alive
11M713, Ki 67 80% (high-grade neuroendocrine neoplasm)CT abdomen 4.9 cm mass pancreatic head; liver metastases; skeletonSynchronousInvitae 62 gene germline panel negativeYes, at diagnosis, 60/49/664.2Surgery
Octreotide, Lanreotide, pembrolizumab
PRRT
Octreotide soon after diagnosis; Whipple procedure + RFA 2 months later. carboplatin + etoposide 6 cycles started 4 months later. pembrolizumab + PRRT clinical trial (2 cycles) 10 months later. Lanreotide 10 months later
Hypoglycemia controlled after PRRT and lanreotide
1.2 alive
12M502, Ki67 8%MR abdomen 4 × 2.5 cm mass distal body/tail of pancreas; multiple metastases in liverSynchronous----No, hypoglycemia 5 years after diagnosis
53/34/96.5
Microwave ablation liver metastases.
Surgery
octreotide
PRRT
Microwave ablation liver metastases 2 months after diagnosis.; Y90 SIRT at 5 months; Resection pancreatic tumor and lymph node dissection at 9 months. Octreotide at 1.4 years. PRRT x 2 cycles at 7 years.
Hypoglycemia controlled after PRRT and octreotide
7.3 alive
13F642, Ki67 17.3%CT abdomen 4.5 × 3.5 × 3.3 cm mass pancreatic tail and multiple metastases in liverSynchronousUC500 germline panel negative.No, hypoglycemia 1.7 years after diagnosis.
36/18.1/320
Octreotide
Capecitabine/
temozolomide
PRRT
SBRT
Pembrolizumab
FOLFOX
Carboplatin/etoposide
Octreotide at 2 months after diagnosis. Capecitabine/Temozolomide at 6 months. PRRT x 4 cycles at 1 year. SBRT to acetabulum and L4 met at 1.4 years. Pembrolizumab one dose + Y90 radioembolization at 1.6 years clinical trial.; FOLFOX at 1.8 years; carboplatin/etoposide 3 cycles at 2 years.
Hypoglycemia controlled after treatment with FOLFOX
2.5 died
14M301, Ki67 < 1%5 cm tumor pancreatic head. Liver metastases first noted 3.4 years laterMetachronousGermline testing UC500 germline panel MSH2 pL556S (c. 1667T > C, pLeu556Ser)—missense variant in the MSG2 DNA mismatch (MMR) protein—likely pathogenic for hereditary colorectal cancerNo, hypoglycemia 3.5 years after diagnosis.
41/20/229.7
Surgeries x 2
Lanreotide
Sunitinib
Pembrolizumab
Diazoxide
Capecitabine/
temozolomide
Whipple procedure at diagnosis; Lanreotide at 1.8 years; sunitinib at 6 years
Liver resection and microwave ablation at 7.4 years. Pembrolizumab at 8. 3 years (for high tumor mutation burden). Diazoxide at 9 years. Capecitabine/temozolomide 9.1 years
Hypoglycemia controlled with food and diazoxide
9.1 alive
SubjectGenderAge of diagnosisWHO grading/Ki67 indexPrimary tumor and metastases at diagnosis. Subsequent progression to other sitesSynchronous or metachronous liver metastasesGermline testingHypoglycemia at presentation? yes or no. If no, when did hypoglycemia occur?
Glucose mg/dL/insulin mU/L/proinsulin pmol/L levels at diagnosis.
Treatments provided during follow-upOrder and timing of treatment in relation to original diagnosis of insulinoma. Treatments that led to control of hypoglycemia.Follow up duration
1M542; Ki67 11.6%CT abdomen 3.1 × 1.9 × 2.1 cm lesion in pancreas. > 20 liver metastases. No skeletal metastasesSynchronousInvitae cancer genetics panel (130 genes tested, 2018). Pathogenic variant in NBN: c.657_661delACAAA (p.Lys219Asnfs*16).Yes, at diagnosis. 45/51.2/700.Surgeries X 2
TACE x 3
Everolimus
Distal pancreatectomy; enucleation large liver lesion at 2 months.
TACE at 3 months, 7 months; 12 months.
Everolimus at 8 months for a total of 7 months.
Hepatectomy at 34 months.
Hypoglycemia resolved after 4 months following surgery and TACE x 2.
4.9; alive
2M65 2; Ki67 15%;CT abdomen: 2 cm lesion in pancreas. Liver metastases noted 9 years later. No skeletal metastasesMetachronousNAYes, at diagnosis. 47/34.2/93Surgery
TAE
Lanreotide
Surgery at diagnosis.
TAE 9 years later.
Hypoglycemia controlled by lanreotide.
10.9; alive
3F552; Ki67 5%MR abdomen up to 10 cm in pancreas, liver metastases. Octreoscan noted lesions in liver, pancreas, porta hepatis and spleen near hilum; lung nodules; L2 vertebral body. Subsequently development of more metastatic disease in skeleton & lungsSynchronous(Athena diagnostics MEN 1 mutation analysis, 2013). Negative MEN1 screenYes, at diagnosis. 40/35/297
.
Octreotide
Everolimus
PRRT x3
Lanreotide
Capecitabine/
temozolomide
cabozantinib
Nivolumab/
ipilimumab
SIRT
SBRT
No surgery.
Octreotide at diagnosis.
Everolimus at 2 months after diagnosis.
PRRT 7 months,10 months 12 months after diagnosis.
Switched to lanreotide at 1.6 years.
SIRT and SBRT (liver) at 2 yrs. Capecitabine/temozolomide at 2.6 years. Cabozantinib at 3.8 years.
Briefly participated in a nivolumab/ipilimumab clinical trial before death (at 4.5 years after diagnosis).

Hypoglycemia resolved after PRRT treatment.
4.7; died
4F652; Ki-67 7.3%CT abdomen: pancreatic mass 3.6 cm; 4 liver metastases. 8 years later developed periportal and retroperitoneal nodes; cervical spine body lesionSynchronousInvitae cancer genetics panel 71 genes tested, 2016. VUS FLCN gene(c.748C > A, p.Leu250Met)Yes, at diagnosis. 47/181/657octreotide
TAE x 4
Surgery
TACE x 1
microwave ablation
SBRT
FOLFOX
First treated with octreotide.
TAE x 2 at 5 yrs.
Distal pancreatectomy and left hepatectomy at 5 yrs.
TAE 5 yrs.
TACE 5.5 yrs.
TAE, 5.6 yrs.,
Microwave ablation 5.7 yrs.
Briefly given sunitinib but stopped because of intratumoral bleed.
SBRT to hepatic mets at 6.9 yrs.
FOLFOX at 7 yrs.
Octreotide controlled hypoglycemia. TAE temporarily reduced need for octreotide to control hypoglycemia.
8.2; died
5M48NACT abdomen and PET/CT scan: pancreatic and subcentimeter liver lesions. 4.2 years later, mass right iliac bone multiple foci retroperitoneal nodes and widespread metastases in skeletonSynchronousNAYes, at diagnosis. 36/37/160Diazoxide
Octreotide
TACE
Capecitabine/
temozolomide
Everolimus
Sunitinib
SBRT
Initially treated with diazoxide but had persistent hypoglycemia. Unclear if patient took drug consistently.
Octreotide 6 months after diagnosis.
TACE at 3 yrs. - octreotide held for one year before restarting.
Capecitabine/temozolomide at 4.5 yrs. for progression.
SBRT to right iliac bone at 4.6 yrs.
Everolimus at 4.9 yrs.
Hypoglycemia better after TACE. Then had mild hypoglycemia which resolved with octreotide therapy.
5.4; died
6F58 1; Ki 67 < 2% (1.3%)DOTATE PET CT scan—pancreatic tail lesion and liver metastases.. One year later widespread skeletal metastases..Synchronous(Ambry genetics 49 panel 2015). Negative MEN1 screenYes, at diagnosis.
38/79.6/700
Surgery
TACE x 2
Octreotide
Everolimus
Carboplatin/
etoposide
PRRT x 4
SBRT x3
Diazoxide and octreotide at diagnosis. TACE at 2 weeks and 2 months. Hypoglycemia resolved and diazoxide discontinued. Distal pancreatectomy, hepatectomy at 1.9 yrs. External radiation spine for metastatic disease at 2.3 yrs. Everolimus initiated. External radiation left hip and femur 3. 8 years. Everolimus discontinued. PRRT 4 cycles at 4 years. External radiation the sacrum, spine, rib. Restart everolimus 4.5 years. Recurrent hypoglycemia and started on carboplatin/etoposide at 4.8 years. Died 5 yrs. after diagnosis.
Hypoglycemia controlled after TACE, octreotide and surgery. Recurrent hypoglycemia with progression and controlled with carboplatin/etoposide.
5.1; died
7F672; Ki 67 16%;CT abdomen 2.8 cm pancreatic body lesion & hepatic masses.
10 years later lung nodules measuring up to 2.6 cm.
synchronousNANo, hypoglycemia occurred 8 months after diagnosis.
42/104/260
Octreotide
TACE x 1
PRRT x 5
carboplatin/
etoposide
capecitabine/
temozolomide
SBRT
Hypoglycemia 8 months after diagnosis. PRRT two cycles eight months later. Also, TACE. Hypoglycemia controlled on octreotide. PRRT two cycles at 3.5 yrs. Carboplatin etoposide at 4 years. Switched to capecitabine/temozolomide for 1.8 yrs. and discontinued for progression. Remained on octreotide. External radiation to liver mets at 8.6 yrs. One more dose PRRT at 9.5 yrs. Died 10.4 yrs. after diagnosis.
Hypoglycemia controlled after PRRT and octreotide.
10.4; died
8M,731; Ki67 1.3%CT abdomen showed 6.4 cm pancreatic lesion and lymph node involvement.
2.5 years, later liver metastases.
Subsequently developed retroperitoneal nodes; osseous metastatic disease; small degree of lung disease
MetachronousCancer susceptibility multigene panel, 2015. Ambry Cancer Next Panel 2017. Negative for MEN1 mutations. VUS MRE11A geneYes, at diagnosis. 39/NA/NASurgery x 3
TAE x4
Octreotide
Diazoxide
Everolimus
Capecitabine/
temozolomide
PRRT x 4
Distal pancreatectomy at diagnosis with resolution of hypoglycemia. Liver metastases 2.5 years after diagnosis. Started Octreotide at 2.6 years. TAE 2.6 years; 3.3 years. Diazoxide at 3.5 years with mild improvement hypoglycemia. Resection liver metastasis with LN dissection at 4 yrs. - significant improvement in hypoglycemia. Everolimus at 4.8 yrs. with immediate resolution of hypoglycemia. TAE at 5.3 yrs.; 5.5 yrs. Partial hepatectomy & LN dissection 5.8 yrs. Everolimus & octreotide discontinued. Interval progression of metastatic disease. Restarted octreotide at 6.3 yrs. PRRT 6.4, 6.5. 6.8. 7 yrs. Capecitabine/temozolomide at 11 yrs. for progression of disease. Also, on octreotide.
Hypoglycemia controlled with surgeries and everolimus.
12.3; alive
9F622; Ki 67 3.5 %Initially only pancreas.
Portocaval nodes; liver nodules noted 3.75 yrs. Later
MetachronousInvitae Genetics 79 gene panel 2016. Negative MEN1 screenYes, at diagnosis. 56/105.8/294Surgery
Octreotide
SBRT
Pancreatectomy at diagnosis. Recurrent hypoglycemia 3 years later. Liver metastases noted at 3.75 yrs. Octreotide therapy at 4 yrs. SBRT at 5 yrs. Died from cirrhosis related to NASH.
Hypoglycemia controlled once patient went on octreotide.
5.8;died
10F202, Ki 67 20%CT 3.9 cm lesion splenic hilum; hepatic lesions; breast, L1 lesion; osseous mets. Rt internal mammary nodeSynchronousUC500 germline panel negativeNo, hypoglycemia documented 1.5 years after diagnosis, 48/45.1/195.Capecitabine/
temozolomide
Pembrolizumab
PRRT
Lanreotide
capecitabine/Temozolomide at diagnosis for 1 year. TACE at 1.4 years; than pembrolizumab + PRRT clinical trial (2 cycles) at 1.6 years. Also started lanreotide at 1.6 years
Hypoglycemia controlled with combination of pembrolizumab, PRRT and lanreotide
1.9 alive
11M713, Ki 67 80% (high-grade neuroendocrine neoplasm)CT abdomen 4.9 cm mass pancreatic head; liver metastases; skeletonSynchronousInvitae 62 gene germline panel negativeYes, at diagnosis, 60/49/664.2Surgery
Octreotide, Lanreotide, pembrolizumab
PRRT
Octreotide soon after diagnosis; Whipple procedure + RFA 2 months later. carboplatin + etoposide 6 cycles started 4 months later. pembrolizumab + PRRT clinical trial (2 cycles) 10 months later. Lanreotide 10 months later
Hypoglycemia controlled after PRRT and lanreotide
1.2 alive
12M502, Ki67 8%MR abdomen 4 × 2.5 cm mass distal body/tail of pancreas; multiple metastases in liverSynchronous----No, hypoglycemia 5 years after diagnosis
53/34/96.5
Microwave ablation liver metastases.
Surgery
octreotide
PRRT
Microwave ablation liver metastases 2 months after diagnosis.; Y90 SIRT at 5 months; Resection pancreatic tumor and lymph node dissection at 9 months. Octreotide at 1.4 years. PRRT x 2 cycles at 7 years.
Hypoglycemia controlled after PRRT and octreotide
7.3 alive
13F642, Ki67 17.3%CT abdomen 4.5 × 3.5 × 3.3 cm mass pancreatic tail and multiple metastases in liverSynchronousUC500 germline panel negative.No, hypoglycemia 1.7 years after diagnosis.
36/18.1/320
Octreotide
Capecitabine/
temozolomide
PRRT
SBRT
Pembrolizumab
FOLFOX
Carboplatin/etoposide
Octreotide at 2 months after diagnosis. Capecitabine/Temozolomide at 6 months. PRRT x 4 cycles at 1 year. SBRT to acetabulum and L4 met at 1.4 years. Pembrolizumab one dose + Y90 radioembolization at 1.6 years clinical trial.; FOLFOX at 1.8 years; carboplatin/etoposide 3 cycles at 2 years.
Hypoglycemia controlled after treatment with FOLFOX
2.5 died
14M301, Ki67 < 1%5 cm tumor pancreatic head. Liver metastases first noted 3.4 years laterMetachronousGermline testing UC500 germline panel MSH2 pL556S (c. 1667T > C, pLeu556Ser)—missense variant in the MSG2 DNA mismatch (MMR) protein—likely pathogenic for hereditary colorectal cancerNo, hypoglycemia 3.5 years after diagnosis.
41/20/229.7
Surgeries x 2
Lanreotide
Sunitinib
Pembrolizumab
Diazoxide
Capecitabine/
temozolomide
Whipple procedure at diagnosis; Lanreotide at 1.8 years; sunitinib at 6 years
Liver resection and microwave ablation at 7.4 years. Pembrolizumab at 8. 3 years (for high tumor mutation burden). Diazoxide at 9 years. Capecitabine/temozolomide 9.1 years
Hypoglycemia controlled with food and diazoxide
9.1 alive

Abbreviations: PRRT, peptide receptor radionucleotide therapy with 177-Lutetium labelled somatostatin analogs; SBRT, stereotactic body radiation therapy; SIR, selective internal radiation therapy; TACE, transarterial chemoembolization; TAE, transarterial embolization.

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