Richard Zubarik, MD Professor of Medicine Director of Endoscopy Pancreas Cancer Richard Zubarik, MD Professor of Medicine Director of Endoscopy

Pancreas Anatomy

Physiology Ductal cell Islets of Langerhans Bicarbonate, water , digestive enzyme secretion Islets of Langerhans Hormones secreted directly into blood flow Alpha cell-glucagon Beta cell- insulin and amylin Delta cells- somatostatin gamma cells- pancreatic polypeptide Epsion cells- ghrelin Acinar cell synthesize, store, secrete digestive enzymes most active protein synthesizing cell in body

Pancreas Cancer

Pancreas Adenocarcinoma

The Numbers 4th 5% 1.4% 1 of 76 33,370

Pathophysiology Location: Local Invasion (most common) Distant Spread 80% head 70% biliary obstruction Local Invasion (most common) Stomach, Duodenum, Colon, Portal or Superior Mesenteric Veins, Superior Mesenteric Artery Distant Spread Liver, Peritoneum, Lung Desmoplastic lesions

Pathophysiology

Risk Factors Family History Smoking Alcohol Obesity Diabetes mellitus Chronic pancreatitis Familial cancer syndromes

Clinical Manifestations

Serum CA 19-9 Monosialoganglioside/glycolipid Advantages: Accessible Relatively sensitive/ specific for pancreatic cancer Levels correlate with: tumor size stage Present uses: Prognosis Monitor disease progression

Imaging Modalities

Pancreas Adenocarcinoma Staging

Therapy-Surgery Pancreaticoduodenectomy (Whipple procedure) Distal Pancreatectomy

Sener et al, J Am Coll Surg 1999;189(1):1-7. Surgery and Survival Sener et al, J Am Coll Surg 1999;189(1):1-7.

Therapy General Principles MDC Management of resectable disease Surgery Neoadjuvant Controversial, may downstage disease Adjuvant Chemotherapy beneficial Radiotherapy is controversial Management of Locally advanced disease Chemoradiotherapy downstages 30% to resectable Management of metastatic disease Gemcitabine –based combination treatments

Palliation-Pain Celiac plexus neurolysis: Anterior transgastric approach CT or fluroscopy- percutaneous Traverse bowel, further for needle to traverse, not real-time EUS- through stomach Stomach adjacent to celiac trunk, real-time Posterior approach Risk of paralysis (spinal arteries) Benefit Duration Narcotic use EUS guided 78-90% 8 weeks  Or 

Palliation-Biliary Obstruction

Palliation- Gastric Outlet Obstruction Improved dietary performance (86%) Comparison with surgery (2 studies) Shorter time to oral intake Shorter hospital stay Complication rates Endoscopic (0%) Open (37.5%) Laparoscopic (42.9%)

Pancreatic Neuroendocrine Tumors

Introduction Incidence 4/ 1 million population Classification A (PNET) Functional- clinical syndrome caused by hormone release Non-functional Classification B (NET) Well-differentiated endocrine tumor Benign behavior Uncertain behavior Poorly-differentiated endocrine tumor Mixed exocrine-endocrine tumors

Introduction Pathophysiology Symptoms PET tumors also produce inappropriate biologically active peptide release Tumor mass effect PET tumors also produce Chromogranins (chromogranin A) Alpha or Beta subunit of HCG Peptides often released even in “non-functional” tumors that do not cause a clinical syndrome Often multiple hormones released, but multiple tumor syndromes not common Symptoms from hormones predate tumor symptoms

PNET hormonal syndromes

MEN-1 Hyperparathyroidism 78-97% Pancreatic endocrine tumor 81-82% Gastrinoma 54% Insulinoma 21% Glucagonoma 3% VIPoma 1% Pituitary tumors 21-65%

Tumor localization Goals Help localize for surgery Detect multifocal tumors i.e. gastrinomas Detect metastatic disease Avoidance of surgery

Tumor localization 30 35 44 31 42 70 10 27 80 54 93 81 NA Insulinoma Other NET Tumor detection (%) Metastasis detection (%) Ultrasound 30 35 44 CT 31 42 70 MRI 10 27 80 Octreoscan 54 93 EUS 81 NA Selective venous sampling

Somatostatin Receptor Scan

Prognosis Overall Incomplete resection Liver metastasis 5- year survival 70% 43% 20% 10- year survival 50% 25%

Case 1 44 YO white male weighing 325 pounds who became agitated, confused after awakening. He had accompanying palpitations, headache and sweating. He had elevated insulin and proinsulin levels while fasting and a fasting glucose <35. Computed tomography and Octreoscan were negative.

Insulinoma Whipples triad (not specific) Hypoglycemic symptoms Blood sugar <50 Symptom relief with glucose ingestion Symptoms (fasting, exercise, missed meal) Neurologic neuroglycopenia Headache, confusion, lightheadedness, visual disturbance, irrational behavior, drowsiness, coma Catecholemine release Palpitations, tremor, sweating, irritability

Insulinoma Characteristics Most confined to pancreas Solitary Equal distribution in pancreas Usually not malignant (10%) Diagnosis 72 hour fasting glucose and insulin test Surgical cure rate 70-95%

Patient 2 41 YO male presented to clinic for a second opinion with watery bowel movements 5 times per day. He had mild diffuse abdominal discomfort, and had lost 20 pounds over the last year. He saw another gastroenterologist for this problem 3 years prior who did stool samples and a colonoscopy that was normal. He also had seen a naturopath.

Data Gastrin: 470 Chromogranin A: 2480 Basal acid output 16.93 Diarrhea resolved completely with PPI

Gastrinoma Zollinger Ellison Syndrome- gastric acid hypersecretion due to release of gastrin from and endocrine neoplasm Gastrin (gastric antrum): Primary stimulant of post-prandial acid secretion Trophic effect on gastric tissue (parietal cells) Adult pancreas does not secrete gastrin

Gastrinoma Symptoms: Peptic ulcer disease Diarrhea Duodenum 75% Uncommon sites in small bowel Diarrhea Volume Duodenal pH/ malabsorption Gastroesophageal reflux 66%

Gastrinoma When to think of gastrinoma: Duodenal ulcerations in unusual places Diarrhea in a patients with idiopathic peptic ulcer disease/GERD Patient with idiopathic peptic ulcer disease/GERD with history of hyperparathyroidism Prominent gastric folds on UGI or endoscopy with idiopathic peptic ulcer disease/GERD or idiopathic diarrhea

Gastrinoma Association 50% malignant Sporadic (75%) MEN-1 (25%) 50% malignant Duodenum most common extrapancreatic site

Gastrinoma Fasting serum gastrin Gastric acid testing 98% have elevated levels 60% of ZES patients have mild to moderate elevation Common differential: atrophic gastritis, PPI intake (look at gastric folds) Gastric acid testing Gastric pH <2 BAO >10 meq/hour (94% of ZES patients) Secretin injection test Sensitivity 87-93%; specificity > 90% Secretin promotes gastrin release in ZES 2 μg/KG prompts rise >200 pg/ml

Patient 3 SB is a 32 Y.O. female with abdominal distention and pain. She had an UGI that was mildly irregular at the duodenal sweep. CT showed a small hypervascular lesion in the neck of the pancreas c/w a NET. ACTH,calcitonin,gastrin, somatostatin,insulin and glucagon levels were normal. Calcium and CBC normal. Pancreatic polypeptide was 353 (normal <249). An EUS was performed.

Nonfunctioning Pancreatic Endocrine Tumors (PET) Definition PET with no clinical symptoms caused by hormone overproduction May have elevated: Pancreatic polypeptide HCG Chromogranin Neurotensin Usually: Large (72%>5cm) Malignant (64-92%) Head

Nonfunctioning PET Presentation Therapy Survival Most common Abdominal pain (36%) Jaundice (28%) Incidental at surgery (16%) Therapy Rare diagnosis established prior to surgery Survival 44% at 5 years

Therapy Localized Disease Surgery Enucleation, distal pancreatectomy, pancreaticoduodenectomy (Whipple procedure) Tumor type influences surgery Observation Non-functioning tumors <2cm Hepatic Metastasis resection transplantation Hepatic artery embolization Radiofrequency ablation/ cryoablation Chemotherapy (rapidly growing or poorly differentiated)

Summary Pancreatic cancer can be exocrine or endocrine in nature. Pancreatic adenocarcinoma (exocrine) is most common. The 5-year survival for pancreatic adenocarcinoma (5%) is much worse than for PNET’s. Pancreatic neuroendocrine tumors (endocrine) can cause symptoms from secreted biologically active peptides or from tumor effect Surgery is the only curative therapy for pancreatic cancer, but may not be needed in small non-functional pancreatic neuroendocrine tumors