Pancreas Cancer

Richard Zubarik, MD

Professor of Medicine

Director of Endoscopy

Pancreas Anatomy

Acinar cell

synthesize, store, secrete digestive enzymesmost active protein synthesizing cell in body

Ductal cell

Bicarbonate, water , digestive enzyme secretion

Islets of Langerhans

Hormones secreted directly into blood flowAlpha cell-glucagonBeta cell- insulin and amylinDelta cells- somatostatingamma cells- pancreatic polypeptideEpsion cells- ghrelin

Physiology

Pancreas Cancer

Pancreas Adenocarcinoma

The Numbers

4th

1.4%

1 of 76

5%

33,370

Pathophysiology

•Location:– 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

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• CT or fluroscopy- percutaneous

– Risk of paralysis (spinal arteries)

Benefit Duration Narcotic use

EUS guided

78-90% 8 weeks Or

Palliation-Biliary Obstruction

Palliation- Gastric Outlet Obstruction

• 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

• 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

Insulinoma Other NET Other NET

Tumor detection (%)

Tumor detection (%)

Metastasis detection (%)

Ultrasound 30 35 44

CT 31 42 70

MRI 10 27 80

Octreoscan 54 70 93

EUS 81 70 NA

Selective venous sampling

54 70 93

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

• Duodenum 75%• Uncommon sites in small bowel

– Diarrhea• Volume• Duodenal pH/ malabsorption

– Gastroesophageal reflux• 66%

Gastrinoma

• When to think of gastrinoma:1. Duodenal ulcerations in unusual places2. Diarrhea in a patients with idiopathic peptic

ulcer disease/GERD3. Patient with idiopathic peptic ulcer

disease/GERD with history of hyperparathyroidism

4. Prominent gastric folds on UGI or endoscopy with idiopathic peptic ulcer disease/GERD or idiopathic diarrhea

Gastrinoma

• Association– Sporadic (75%)– MEN-1 (25%)

• 50% malignant

• Duodenum most common extrapancreatic site

Gastrinoma

• Fasting serum gastrin– 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– 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

– Surgery

• 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