functional pancreatic neuroendocrine tumors...jama oncol . 2017. using data from the seer program,...

Functional pancreatic neuroendocrine tumors

Presenter: John M. Creasy, MD (Duke University)Moderator: Toms Augustin, MD (Cleveland Clinic)

Introduction • Patients with pancreatic neuroendocrine tumors (PNETs) are diagnosed

younger and at earlier stage than those with pancreatic adenocarcinoma • Incidence of PNETs is currently 1 per 100,000 • Prior autopsy projects revealed incidence of PNETs in up to 10% of patients

with sections through the entire pancreas• Time trends reveal that the incidence of PNETs is increasing

Halfdanarson et al, Ann Oncol 2008Yadav et al, Am J Clin Oncol 2018

Kimura et al, Dig Dis Sci 1991Dasari et al, JAMA Oncol 2017

Dasari et al, JAMA Oncol 2017

PresenterPresentation NotesUsing data from the SEER program, pancreatic neuroendocrine tumors are on the rise given increased utilization and sensitivity of cross-sectional imaging, suggestive of increased detection in asymptomatic, non-functional tumors

Functional PNETs• Functional PNETs account for only 10% of all pancreatic neuroendocrine tumors• Presentation of functional tumors is usually due to symptoms • 9 well-described clinical syndromes directly attributable to the hormones they

secrete (Insulinoma, Gastrinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma (growth hormone releasing factor), ACTHomas, PTHrPomas, serotonin secreting PNET)

Dasari et al, JAMA Oncol 2017Halfdanarson et al, Ann Oncol 2008

Oberg, Gland Surg 2018

Functional PNETs

Chen et al in Current Surgical Therapy: 12th Edition 2019.

Functional PNET Annual Incidence Most common symptoms

Insulinoma 1-3 per million Hypoglycemia

Gastrinoma 1-3 per million Peptic ulceration

VIPoma 0.1 per million Watery diarrheaHypokalemiaAchlorhydria

Glucagonoma 0.01-0.1 Necrolytic migratory erythemaGlucose intoleranceThromboembolism

PresenterPresentation NotesPause: “poll the audience, how many are seeing these patients in their institution? Are they being referred to HPB or Endocrine?”

Difficult to study functional PNETs due to their incidence and the fact that most are grouped with gastrointestinal neuroendocrine tumors such as carcinoids being the most predominant

Case 1- Insulinoma• 66 yo male, with episodic symptoms of dizziness, confusion, and

seizures for the last 3 years, started on Keppra by PCP• Witnessed seizure in March 2018- glucose 30s upon arrival by EMS• Endorsed frequent snacking; 18lb weight gain over last 3 months• No history of diabetes or access to diabetic medications • Endocrinology referral obtained at VA

Labs• Glucose 37• C-peptide 5.69 ng/mL (ref 0.8-3.85)• Insulin 53.7 uIU/mL (ref 2-19.6)• Proinsulin 55.1 pmol/L (ref

CT A/P

PresenterPresentation NotesCT: 1.3cm lesion in the pancreatic tail, compatible with neuroendocrine tumor. No metastatic disease within the abdomen or pelvis.

CT A/P

PresenterPresentation NotesMRI: Enhancing lesion along the pancreatic tail which may represent a neuroendocrine tumor given clinical signs of insulinoma. High signal intensity on T2 weighted images and hyperintense on post contrast

Pause: “What sites would do any further imaging or workup for an insulinoma?” Would any centers obtain a DOTATATE PET/CT?”

Preoperative Preparation• Control hormone excess state

-Frequent snacking to minimize hypoglycemia-Diazoxide which inhibits insulin release

Surgery• Robotic vessel-preserving distal pancreatectomy with IOUS

Pathology: • Distal pancreas, resection:

1.7cm Well-differentiated neuroendocrine tumor in pancreatic tail (G1)Mitotic rate

Followup• One year s/p resection with no evidence of recurrence, normoglycemic

PresenterPresentation NotesPause: “What is the preference at different centers regarding enucleation versus resection? Are there situations where you would want to ensure lymph node sampling in an insulinoma?”

• All patients with surgery for insulinoma from 1983-2007 at MGH• Divided the series at 1994, based on the introduction of EUS

Nikfarjam et al, Ann Surg 2008

PresenterPresentation NotesThe two largest recent series come out of MGH and Verona, Italy


Demographic/Presentation N (%)Male/Female 26/35 (43/57)Age 53 (range 11-82)MEN-1 7 (11)Duration of symptoms (months) 18 (1-240)Symptoms

Confusion 41 (67)Visual disturbance 26 (42)Diaphoresis 18 (30)Fatigue 17 (28)

Weight gain 27 (44)

Results• Enucleation 21/61 (34%) and Distal pancreatectomy 24/61 (40%)

were most common procedures • 7/8 patients with positive margin were treated by enucleation, but no

patients with positive margin had recurrence • Symptom resolution seen in 55/61 cases (90%)• 5 year DFS was 90% and 5 year OS was 97%


PresenterPresentation NotesIn this dataset, MEN1 and lymph node metastases were not associated with DFS, LVI was the only significant independent factor on multivariate analysis

Insulinomas• Most common functional PNET• Similar to our case, most are:

• Single lesion, evenly-distributed throughout gland• Sporadic • Long interval between presentation of symptoms and diagnosis• Well-differentiated with low mitotic index • Excellent prognosis and survival

• Enucleate or resect based on location

Case 2- Gastrinoma• 40yo female with PMH of ALL s/p BMT 1991, ITP s/p splenectomy,

cholecystectomy, GERD, and erosive esophagitis • EGD showed esophagitis and peptic stricture at D1/D2 junction,

normal appearing mucosa with no evidence of atrophic gastritis• Fasting serum gastrin 883 pg/mL

Diagnosis• Gastric pH: 2.0 • Secretin stimulation test

-Administration of 0.4 mcg/kg by rapid infusion -Serum gastrin measured at baseline, 2min, 5min, and 10min intervals-Positive test is increase greater than 120pg/mL over basal fasting level

Gastrin (ref

CT scan • No CT findings to explain abnormal gastrin secretion

In-111 OctreoScan • No scintigraphic evidence of OctreoScan-avid tumor

EGD/EUS• Stricture in D1/D2, able to be traversed • Hypoechoic area with an irregular border identified in pancreatic head measuring

15mmx9mm, FNA performed. Normal PD and CBD. 15mm lymph node in the porta hepatis region and an 11mm hypoechoic peri-pancreatic lymph node identified.

• Pathology: • Duodenum- reactive epithelial and chronic inflammatory changes, negative for dysplasia or

malignancy, most suggestive of peptic duodenitis• Pancreas- benign pancreatic parenchyma and fibrotic tissue• Lymph Nodes- lymphoid tissue, no evidence of malignancy

History• Started on PPI (80mg q12), referred to surgeon but lost to followup• Presented 7 years later with nausea, vomiting • EGD demonstrated LA Grade D esophagitis, peptic-appearing stricture

in duodenal bulb with retained food in stomach; dilated duodenal stricture, stent placement

• Gastrin level on PPI: 224 pg/mL

PresenterPresentation NotesPause (Dotatate PET on next slide): If this patient presented to your center, what other imaging would you obtain? Would anyone have explored this patient based on the information alone 7 years ago?”

CT A/P

PresenterPresentation NotesGallium-68 Dotatate PET/CT: 1. Abnormal focal Ga-68 Dotatate uptake in the 3rd portion of the duodenum, likely representing gastrinoma2. No definitive Ga-68 Dotatate-avid metastatic disease3. Ga-68 Dotatate-avid soft tissue in the region of the splenectomy bed, stable since 2011, compatible with splenule.

Pause: “If this Dotatate PET was negative, how would we have managed this case?””

Surgery • Robotic resection of periduodenal mass, mass was not invading

duodenum or pancreas• Intraoperative US confirmed no additional lesions

Pathology • Periduodenal mass, excision:

Metastatic Well-differentiated neuroendocrine tumor (G2) in 2/2 lymph nodesMitotic rate

Followup • Held PPI x2 weeks• Gastrin- 16 pg/mL• Symptom free

PresenterPresentation NotesPause: “How long do you perform surveillance for gastrinoma patients? How is your surveillance performed? Who is seeing these patients in followup, an endocrinologist or an HPB surgeon?”

Algorithm for suspected ZES• Fasting serum gastrin (FSG) and gastric pH assessment • If FSG is normal x2 than ZES is excluded• If FSG is abnormal, stop proton pump inhibitors and institute H2

blocker if needed (hold 24-48hrs prior to procedure)• If FSG is >1000 pg/mL and gastric pH is

• Followed 151 consecutive patients who underwent laparotomy 1986-1998

• 123 sporadic gastrinomas, 28 with MEN and imaged tumor >3cm

Norton et al, N Eng J Med 1999


Results

PresenterPresentation NotesPatients with MEN1 associated gastrinomas were younger and had a higher preoperative serum gastrin, otherwise were similar


Results Sporadic

Gastrinomas MEN-1 Total

PresenterPresentation NotesLocation of primary tumor was more commonly in duodenum for sporadic gastrinomas, and more commonly in the pancreas for MEN1 associated gastrinomas


PresenterPresentation NotesThere is a chance of being cured for patients with sporadic gastrinomas, unlike those with MEN1


PresenterPresentation NotesOnly 4 of the 151 patients died from a cause related to ZES. Overall, 21 patients died from any cause, and the rate did not differ significantly between the two groups.

Conclusion• All patients with the Zollinger-Ellison syndrome who do not have MEN

type 1 or metastatic disease should be offered surgical exploration for possible cure. Patients with MEN-1 rarely become free of disease, therefore surgical exploration for cure is not routinely recommended.

• Long-term followup of ZES patients who underwent surgery compared with patient that did not undergo an operation

• Followed protocol in place at NIH (1980), UCSF (1997), and Stanford (2004)

Norton et al, Ann Surg 2006

Methods• 160 patients underwent exploration for possible cure • 35 patients with ZES did not undergo exploration because they could:

1) not give informed consent (n=1)2) refused surgery (n=19)3) had comorbid condition deemed too high risk (n=5)4) had MEN1 with no lesions found on imaging >2.5cm (n=10)

Norton et al, Ann Surg 2006

ResultsParameter Surgery (n=160) No Surgery (n=35) PDeveloped liver metastases 0.002

Yes 8 (5) 10 (29)No 152 (95) 25 (71)

Cause of deathDisease-related 2 (1) 8 (23)

Conclusion• Routine surgical exploration increases survival by increasing disease-

related survival and decreasing development of advanced disease

Controversies • MEN1 • Unable to localize preoperatively • Importance of lymph nodes

Thompson et al, Ann Surg 1989

PresenterPresentation NotesProtocol for surgical exploration included palpation, IOUS after extended Kocher, endoscopic transillumination of the duodenum was performed since 1987 and finally a 3cm long longitudinal duodenotomy on the anterolateral surface of the second portion of the duodenum; resectable liver metastases were removed

• Surgical correction of hyperparathyroidism • MEN1 patients often have multiple small gastrinomas, most centers

still adhere to resection only if >2.5cm• Recommend resecting insulinomas• Recommend close surveillance

Thakker et al, J Clin Endocrinol Metab 2012

Gastrinomas• Gastric acid hypersecretion controlled with PPI• Surgery, if resectable, gives best chance of cure• Liver metastases in 25% at presentation, associated with size of primary• Liver metastases, not lymph node status, associated with survival• Surgery shown to decrease incidence of liver metastases• Gastrinomas represent more than 50% of PNET in patients with MEN1,

only recommend resection when >2.5cm

Falconi et al, Neuroendocrinology 2016Weber et al, Gastroenterology 1995

PresenterPresentation NotesTakeaway Point: this is what I boiled it down for a fellow to need to know about gastrinomas.

Case 3- ACTHoma• Rare and complex case, unlikely to be encountered during a career• Introduce discussion on treatment strategy and management of liver

metastases in functional PNETs

• 12yo male with abdominal pain and jaundice

CT A/P

PresenterPresentation NotesCT C/A/P 1. Large pancreatic head mass with obstruction of the adjacent common bile duct and biliary ductal dilatation and gallbladder distention, appears to be encasement of the hepatic artery and main portal vein2. Severely atrophic pancreatic tail

EUS• 40mm x 43mm homogenous pancreatic head mass, intact interface

between the mass and the celiac trunk, FNA performed

Pathology: neuroendocrine tumor, intermediate grade (G2), IHC positive cytokeratin, synaptophysin, chromogranin; Ki-67 of 13%

History • Received CAPTEM (Capecitabine/Temozolamide) for 4 cycles • Recently diagnosed with DM and difficult to control HTN

• AM Cortisol 33 (ref 4-23), PM Cortisol 40 (ref 2-14)• ACTH 118 (ref 7-63) • Aldosterone < 4 (ref

CT A/P

PresenterPresentation NotesPET/CT:Pancreatic head mass demonstrates somatostatin receptors. A small focus of uptake projected over segment 8 may represent liver metastasis or peritoneal spread (given lack of lesion in same area on MRI).

Pause: “Would anyone favor something different than surgery?”

Surgery • Pancreaticoduodenectomy • Nodal disease along common hepatic, but able to dissect free• Able to dissect tumor from Portal vein/SMV confluence• Wedge resection of segment 8 liver metastasis

Pathology Pancreaticoduodenectomy:

4.5 cm well-differentiated neuroendocrine tumor (G2)5 mitoses/ 2 mm2

Ki-67 Labeling Index 19% + LVI, + PNI Retroperitoneal margin +7/26 Lymph nodesLiver wedge resection positive for metastatic neuroendocrine tumor

Summary: yT3N1M1a (AJCC 8th Edition)

Followup• Seen in clinic, blood glucose 90s, returned to school

PresenterPresentation NotesPause: “Thankfully this patients disease was limited and resectable and we treated it like we would a gastrinoma, but it poses a question… what would we have done with multiple bilobar metastases or an unresectable primary?

“How would your center manage a patient with significant bilobar liver metastases (especially since a functional tumor)?” Systemic therapy only? Resect the primary and debulk majority of disease? Resect the primary and give somatostatin analogs?

Metastatic PNETs• Limited studies, options include systemic and liver-directed therapy • NETTER-1 results in midgut neuroendocrine tumors showed impressive

results with peptide-receptor radionuclide therapy (PRRT)

Kunz, J Clin Oncol 2015Bertani et al, Ann Surg Oncol 2016

Kwekkeboom et al, J Clin Oncol 2005Strosberg et al, NEJM 2017

PresenterPresentation NotesAlmost all we know is extrapolated from NETs, functional PNETs are too rare for any trials, first line treatment is somatostatin analog In my review, PRRT was consistently the recent hot topic in this field Results of the NETTER-1 trial in midgut NET are very promising, with survival curves rarely seen in Oncology We know that PRRT in metastatic PNETs works better with less disease, and at least one Italian series (Ann Surg Oncol 2016) proposed resecting primary prior to PRRT since it was associated with better PFS

• PRRT in metastatic functional PNETs• Series of 34 patients treated at Erasmus Medical Center in the

Netherlands

Zandee et al, J Clin Endocrinol Metab 2019

PresenterPresentation NotesPRRT has been looked at in metastatic functional PNETs, very limited numbers

PRRT Protocol • Treatment with 4 cycles of 177 Lu-DOTATATE to a cumulative intended

dose of 27.8-29.6 GBq• Imaging performed every 3 months • Tumor response measured by RECIST



PresenterPresentation Notes17 of 23 patients with uncontrolled symptoms at baseline (ie 71%)


PresenterPresentation NotesVery small numbers, but show decrease in plasma hormone levels at 6 months At the time of radiological progression, symptoms were still controlled in 78%

Conclusion• Treatment with 177 Lu-DOTATATE is safe and effective therapy resulting

in radiological, symptomatic, and biochemical response in a high percentage of patients with metastatic functioning PNETs.


PresenterPresentation NotesPause: Has your center started to incorporate PRRT in your treatment algorithm? Where do you see the role of PRRT evolving?

Hopefully, the 12yo in this case will do well although his risk of recurrence is relatively high.

Questions

Functional pancreatic neuroendocrine tumorsIntroduction Slide Number 3Functional PNETsFunctional PNETsCase 1- InsulinomaLabsCT A/P CT A/P Preoperative PreparationPathology: FollowupSlide Number 13Slide Number 14Slide Number 15Slide Number 16ResultsInsulinomasCase 2- GastrinomaDiagnosisCT scan EGD/EUSHistoryCT A/P Surgery Pathology Followup Algorithm for suspected ZESSlide Number 29Results Results Slide Number 32Slide Number 33ConclusionSlide Number 35MethodsSlide Number 37Slide Number 38ResultsConclusionControversies Slide Number 42GastrinomasCase 3- ACTHomaCT A/P EUSHistory CT A/P CT A/P Surgery Pathology FollowupMetastatic PNETsSlide Number 54PRRT Protocol Slide Number 56Slide Number 57Slide Number 58ConclusionQuestions

functional pancreatic neuroendocrine tumors...jama oncol . 2017. using data from the seer program,...

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