The Role of the Gastroenterologist in the Diagnosis and Treatment of NETS

David C. Metz, MD Professor of Medicine Perelman School of Medicine at the University of Pennsylvania Neuroendocrine Tumors

• Second most prevalent of the GI tract behind colorectal cancer1

• Over 100,000 patients are living with NETs in the United States

• Principles of care are different/unique compared to other solid tumors

JC et al. One hundred years after "": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063–72.

Incidence of Neuroendocrine Tumors Over Time is Increasing Analysis of SEER database (1973–2004)1

Yao JC et al. One hundred years after "Carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26(18):3063–72. Classic vs NET Tumor Size Paradigm

Metastases

Lymph Nodes

Primary

Classic solid tumor NETs: Three Patterns of Presentation

1. Hormonal syndrome Need to put 2 and 2 together (requires expertise) 2. Tumor symptoms (from growth) Usually present late (with mets) 3. Asymptomatic (incidental finding) Locoregional (resectable) vs. Widespread

Early diagnosis has prognostic implications because is the ONLY curative treatment modality Obstacles in the Early Diagnosis of NETs • Rare Diseases – Zebras, needle in haystack • Other more common diseases – Wolf in sheep’s clothing • Presentation varies from case to case • Often asymptomatic initially • Awareness of problem is low

• Requires astute physician with a high index of suspicion Delay in Diagnosis of Neuroendocrine Tumors1 • Currently over 90% of NET patients are misdiagnosed and treated for the wrong disease

• Average time to correct diagnosis is 5-7 years

• IBS and Inflammatory Bowel Disease (IBD) are the two most common misdiagnosed conditions for patients with carcinoid

• Diagnosis is usually not made until metastases to and symptoms occur

1. Moertel CG An odyssey in the land of small tumors. J Clin Oncol 1987: 5:1502 Case Presentation #1 • 47 yr old postmenopausal Female with longstanding IBS-D presents to the ER with worsening cramping abdominal pain, and . Her last BM was 24 hours before presentation • Physical exam reveals a mildly obese F in significant distress. She appears flushed and VS reveal a BP of 150/100, HR 108, RR 16, T 37.7. The abdomen is distended and tympanic with hypoactive bowel sounds but no organomegly or masses. • AXR reveals multiple small bowel air-fluid levels, there is no air in the . • An NG tube is placed and 2.3 liters of dark fluid is retrieved leading to significant improvement in her pain PMH • Longstanding attributed to IBS with >6 watery, non-bloody Bms/day. • Initially responded to OTC imodium but not recently, often wakes her from sleep, has been incontinent x3 in the last 6 months • Abdominal pain has also been more severe in the last year or so and is no longer responsive to anticholinergics • Also on hormonal replacement therapy for early onset menopause Some Questions

• Why is this not IBS-D? • What are the clues indicating another diagnosis? • What is the correct diagnosis? Carcinoid Syndrome: Case #1

Creutzfeldt W. Carcinoid tumors: development of our knowledge. World J Surg 1996;20:126–31. Carcinoid Syndrome: Differential Diagnosis • Diarrhea – Functional (IBS) COMMON – IBD FREQUENT – Celiac disease FREQUENT – Lactose intolerance FREQUENT – Other NETs (ZES, VIPoma, MCT) RARE

• Diarrhea plus is suggestive but consider – Menopause (not dry) – Mastocytosis (not true flush) – C1 esterase deficiency (not true flush) Carcinoid Syndrome: Differential Dx

IBD Carcinoid Crohn’s Ulcerative IBS Syndrome Disease Colitis Description of stool Mostly watery May be watery, Commonly mixed May be watery, often mixed with with blood usual low volume, blood may have mucus Nocturnal diarrhea Occurs Common Common Uncommon Rectal Unusual Fairly common Very common Uncommon Constipation May occur Infrequent – may Common (may occur in 10% of alternate patients with diarrhea) Flushing Common Not associated Not associated Not associated Abdominal pain Intermittent, Cramping, Variable Recurrent, often crampy or obstructive with bloating colicky Pain relieved upon Variable May be worse Usually disappears Common defecation

Adapted from: The NET Alliance monograph on ‘clues to detect the carcinoid syndrome’ Case Presentation #2

• 46 year old Man presents with heartburn, abdominal pain and diarrhea that have developed in the last 6 months • He has been on maintenance omeprazole for 4 yrs ever since his last presentation with a bleeding DU • H. pylori infection was excluded 4 yrs ago and he avoids ASA and NSAIDs because they “caused my last ulcer” • There is no history of renal stones or FH of ulcer disease • Physical examination is unrevealing • EGD reveals a 1.5cm duodenal bulb ulcer and hypertrophic gastric folds, gastric pH is 1.3, biopsies for H. pylori are negative, fasting serum is 466 pg/ml Some More Questions

• Why is this not idiopathic peptic ulcer disease? • What are the clues indicating another diagnosis? • What is the diagnosis? /ZES: Case #2 • Non-beta islet cell tumor (secretes gastrin) • Gastric acid hypersecretion • Fulminant peptic ulcer disease

• 60-90% malignant • Two main types: – Sporadic (~2/3) – MEN-1 (~1/3)

Zollinger and Ellison (1955); Jensen et al (1983); Stabile et al (1994) ZES Presentation • Ulcer complications common (up to 7%) • GERD frequent (60%) • GUs NOT typical • Abdominal pain is NOT universal • Diarrhea occurs in isolation in up to 35% – Secretory (osmolar gap low) – Responds to NG aspiration • Diagnostic Hallmark is inappropriate hypergastrinemia ZES: Pathophysiology

Acid LUMEN MUCOSA

H+ K+ ATPase

cAMP Ca2+ Ca2+ * Parietal Cell ↓pH ACh Gastrin * Vagus Nerve Blood

ECL Cell G Gastrin Cell ACh Gastrin *

Gastrinoma Cells Feedback Inhibition x D Cell DUODENUM Hypergastrinemia • Appropriate – Drugs (H2RA’s and PPI’s) – with/without PA – H. pylori pangastritis – Chronic renal failure – Vagotomy • Inappropriate – ZES (sporadic or MEN-1) – Retained antrum syndrome – Antral predominant H. pylori infection (G-cell ) – Massive intestinal resection (temporary) – Gastric outlet obstruction (reversible)

Metz DC. GI Neuroendocrine tumors: Pancreatic Endocrine Tumors Gastroenterology 2008;135:1469-92. Consider ZES (<1/1000 DU’s)

• Severe peptic disease: – Multiple, recurrent,non-healing ulcers • Acid hypersecretion: – Diarrhea • Before anti-ulcer surgery: – Before it’s too late • MEN-1 syndrome: – Pituitary, parathyroids,pancreas (3p’s) • Non-NSAID, non-H. pylori ulcers Other Functional NET Syndromes • Carcinoid syndrome – Flushing, diarrhea, wheezing, , cardiac disease • Zollinger-Ellison syndrome (Gastrinoma) – Gastric acid hypersecretion (pain, ulcers, diarrhea) • Syndrome – Neuroglycopenia, sympathetic overdrive, obesity • – , rash (MNE), anemia, hypoaminoacidemia, weight loss, thromoboembolism, • VIPoma – watery diarrhea, , and others (hyperglycemia, hypercalcemia, flushing) • Others: – ACTHoma – Cushing’s syndrome – GRFoma - – – hyperglycemia, steatorrhea, gallstones – Rare syndromes (calcium, erythropoeitin, etc) Management Principles • Confirm the diagnosis • Control the hormonal syndrome (if present) • Determine extent of disease • Consider surgery – for cure (if possible) – for debulking (if not) • Control tumor growth • Management is multidisciplinary – Medicine (GI, endocrine, ) – Surgery – Radiology (XRT, IR)

Control of Functional Syndromes • Somatostatin Analogs (e.g., ) – For most tumor types • Gastric antisecretory therapy (e.g., PPIs) – For ZES () • are an aberration – If malignant (15%) often no good medical options – everolimus Somatostatin Analogs Inhibit Secretory Capacity

Human somatostatin

ala gly cys lys asn phe phe trp

lys cys ser thr phe thr

D D phe cys phe βnal cys tyr D D trp trp

lys lys

thr cys thr cys val

Octreotide SMS Analogs for (Functional) NETs • Drugs of choice for syndrome management – FDA-approved for carcinoid, VIPoma and acromegaly – Often used off label for other syndromes • Role in tumor stabilization also established – Octreotide: Promid (alimentary tract only) – Lanreotide: Clarinet (included PNETs) Staging of Disease

• Endoscopy – Optical (EGD/Colonoscopy) – Capsule Endoscopy – Deep Enteroscopy (Spiral/Single-/double Balloon) – Endosonography (EUS-PNETs) • Imaging – Cross sectional studies (CT/MRI) – Functional Imaging (Octeoscan/MIBG scan) The Role of Endoscopy in Diagnosing NETS • GEPNETS comprise the overwhelming majority of NET primary tumors • With modern techniques endoscopy can now visualize the ENTIRE GI tract and its appendages (liver, pancreas, spleen, etc) – Small bowel accessible by deep enteroscopy – Pancreas (and other organs) accessible by endosonography • Newer techniques also permit tissue sampling and tattoo/clip localization Gastrointestinal Endoscopy • Optical endoscopy -EGD, Colonoscopy, push enteroscopy • Capsule Endoscopy • Endosonography (EUS) • Deep enteroscopy – double or single balloon, spiral enteroscopy

• Advantages – Biopsy and pH determination – Localization – Therapy Gastric

• EGD permits categorization of gastric carcinoids (with pH and gastrin determination) which is essential for proper management (types 1, 2, or 3) • Endoscopic resection achievable by endoscopic mucosal resection (EMR) after EUS (if amenable) especially relevant for type 3 carcinoids (as well as type 1 and 2 lesions within guidelines) Gastric Carcinoids: My Management Algorithm Gastric Carcinoid

Gastric pH and Fasting Gastrin pH and FSG high pH low, FSG high pH and FSG normal

Type I (atrophy) Type II (MEN-1/ZES) Type III (sporadic)

Map stomach Octreoscan EUS

Gastric Ca. None Pit., PTH, enteropanc. Invasive Not invasive

O.R. Individualize Individualize O.R. ? EMR (<3cm) Gastric Carcinoids in PA Vary Type II Gastric Carcinoids in ZES/MEN-1 syndrome

3/03 3/04 Type III Gastric Carcinoid

Photo courtesy Gregory Ginsberg, MD Duodenal Carcinoids

• Multiple duodenal lesions pathognomonic of MEN-1 syndrome • Isolated lesions can be resected if amenable by EUS (no nodes and non- transmural) • Intraoperative transillumination may be helpful in selected cases with very small lesions • Need for preop EUS in all cases is controversial Multiple Duodenal Tumors in MEN-1 Duodenal Transillumination

Frucht, Gastro, 1990 EUS for PNETs

• Able to distinguish NETs (especially non- functional lesions) from (and other pancreatic lesions – , IPMNs, etc) • Allows for tissue diagnosis by FNA (and even core biopsy – provides Ki 67 %/mitotic count) • Especially useful for insulinomas (ALWAYS in pancreas, often octreoscan negative) • Helpful in assessing patients with suspected MEN-1 syndrome (multiple lesions) • Helpful to distinguish cysts from solid lesions in VHL • Use in all preop cases is controversial EUS of Cystic PNET

Circumferential Probe

Linear Probe

Photographs courtesy Gregory Ginsberg, MD EUS FNA of a PNET

Video courtesy Vinay Chandrasekhara, MD Small Bowel Carcinoids

• The “last frontier” in endoscopy – VCE is non-invasive but limited (no tissue, can impact) – Deep enteroscopy can visualize the ENTIRE GI tract and permit tissue sampling (may require 2 procedures) • Use for all preop cases is controversial Capsule Endoscopy

Two endoscopic images that may show the location of the patient’s primary tumor in the submucosa

Liang PS et al. Radiol Case Rep. 2007;2:90.

ＬＡＳＴ Fluoroscopic Results

Anterograde route Retrograde route Ileal Carcinoid on DBE

Video courtesy Vinay Chandrasekhara, MD DBE drawbacks

• Long procedure times

• Cost of capital investment

• Technical skills

Complications of DBE

• >9000 procedures

• Major Complications: <1% (mortality: 0.01%)

• Those seen were in patients with Crohn’s disease or with a h/o abdominal surgery

• Acute pancreatitis: 0.5%

Single Balloon Enteroscopy (SBE) • Simpler design • Potentially lower capital investment • Less preparation time (5 min vs 15 min for DBE) • No latex balloons

• Disadvantages – Depth of small bowel intubation falls short of DBE

• Kawamura et al., GIE 2008;68:6:1112-6. Single balloon Enteroscopy (SBE) Olympus Spiral (Overtube) Enteroscopy

DSB; Spirus Medical Inc, Stoughton, Mass Working length 118 cm Internal diameter 9.8 mm External diameter 14.5 mm Spirals 5.5 mm – distal 22 cm Colonic Carcinoids

• Often discovered at routine screening colonoscopy (usually small, TI intubation advisable if easily accomplished) • Lower EUS permits assessment of nodes and resectability of distal lesions • Carcinoids (submucosal) appear different from mucosally based polyps – index of suspicion needed (may bemore common in Asian population) Terminal Ileal Carcinoid Prolapsing into

Photographs courtesy David Jaffe, MD Rectal Carcinoid Removal by EMR

Carcinoid clues: central umbilication, yellowish discoloration, firm lesions, ? Asian

Photographs courtesy Michelle Beilstein, MD Rectal Carcinoid Completion Resection

Pictures courtesy Vinay Chandrasekhara, MD Managing the Effects of Therapy

• Pancreatic resections • Octreotide (Distal or Whipple’s) – Gallstones – Pancreatic insufficiency – Steatorrhea – Dumping syndrome – Diabetes • Others – Immunity (spleen) – Adhesions

• Terminal ileal resection – B12 deficiency – Bile Salt Diarrhea – Overgrowth

Multidisciplinary Care is Ideal • Many options and no standard algorithm exists (therapy should be individualized) • Tumor Board is ESSENTIAL component • Flexibility is KEY

Summary and Conclusions

• Endoscopy is useful in the diagnosis and management of GEPNETs • Now able to image and sample the entire luminal GI tract and related intra- abdominal viscera • Cost effective use of these interventions remains to be defined