David C. Metz, MD

Neuroendocrine Tumors: The GI PerspectiveGI Perspective

David C. Metz, MDProfessor of Medicine

Perelman School of Medicine at the University of Pennsylvania

Neuroendocrine Tumors

• Second most prevalent cancer of the GI tract b hi d l t l 1behind colorectal cancer1

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

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

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 ::3063–72.

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David C. Metz, MD

Neuroendocrine Terminology

• Neuroendocrine tumors include carcinoid tumors and pancreatic neuroendocrine tumors (PNETs)and pancreatic neuroendocrine tumors (PNETs)

• Carcinoid tumors are in the alimentary tract or elsewhere (lung, thymus, testis ovary, etc); PNETs are in the pancreas

• Carcinoid tumors may be functional (carcinoid syndrome) or non-functional

• PNETs may be functional (various types) or non-functional

• Functional syndromes require production of biologically active amines

Incidence of Neuroendocrine TumorsOver Time is IncreasingAnalysis 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.

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David C. Metz, MD

Classic vs NET Tumor Size Paradigm

Lymph Nodes

Metastases

Primary

Classic solid tumor Neuroendocrine tumor

Grade and Differentiation• GRADE refers to pathologic features of growth rate

– Mitoses or Ki 67 staining (biologic aggressiveness)• DIFFERENTIATION refers to pathologic features ofDIFFERENTIATION refers to pathologic features of

malignancy – Histologic appearance (degree of resemblance to normal)

• Grade and differentiation are related but not equal• Biological behavior of low or Intermediate grade• Biological behavior of low or Intermediate grade

well differentiated tumors can only be determined clinically during follow up

Kulke, MH. Pancreas 2010;39:735-52. Klimstra, DS. Pancreas 2010;39:707-12

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David C. Metz, MD

Pathologic Classification of NETs

Differentiation Grade Frequency Comments

Well Low Common <2 mitoses/10hpf Low Ki 67

Variable prognosis

Intermediate Less common Intermediate prognosis

Poor High Rare Poor prognosis

Klimstra, DS. Pancreas 2010;39:707-12

Hereditary vs. Sporadic

• Multiple Endocrine Neoplasia syndrome type 1

• Three of the five phacomatoses– Von Hippel-Lindau (VHL)

• PETs (non-functional >>insulinoma/vipoma) in 12-17%– Von Recklinghausen’s disease (NF-1)

• Occasional duodenal somatostatinomas (often non-functional) >>insulinoma/gastrinomas) g

– Tuberous sclerosis • Rare PETs (non-functional, insulinomas/gastrinomas)

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David C. Metz, MD

MEN-1 Syndrome

• Multiple Endocrine Neoplasia syndrome type 1A t l d i t (K d ’ t hit• Autosomal dominant (Knudsen’s two hit hypothesis; retinoblastoma)

• Gene cloned (11q13), product Menin• 3 P’s: Parathyroid hyperplasia (early)

Pituitary adenomas (Prolactinoma, Cushings)

Entero-Pancreatic tumorsOthers: Lipomas, adrenal hyperplasia, etc

Biochemical Products• Functional products

– Carcinoid syndrome• Serotonin, 5HIAA, 5HTP, substance P, kallikrein, etc

P ti d i t– Pancreatic endocrine tumors• Gastrin• Insulin• VIP• Others (glucagon, somatostatin, etc)

– Utility• Syndrome diagnosis and to monitor hormonal therapy

N d i k• Neuroendocrine markers– Chromogranin A– Others (pancreatic polypeptide, bHCG, etc)– Utility

• Tumor diagnosis and to monitor growth or anti-tumor therapy

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David C. Metz, MD

Functional NET Syndromes• Carcinoid syndrome

– Flushing, diarrhea, wheezing, pellagra, cardiac disease• Zollinger-Ellison syndrome (Gastrinoma)

– Gastric acid hypersecretion (pain ulcers diarrhea)Gastric acid hypersecretion (pain, ulcers, diarrhea)• Insulinoma Syndrome

– Neuroglycopenia, sympathetic overdrive, obesity• Glucagonoma

– hyperglycemia, rash (MNE), anemia, hypoaminoacidemia, weight loss, thromoboembolism, glossitis

• VIPoma – watery diarrhea hypokalemia achlorhydria and others (hyperglycemiawatery diarrhea, hypokalemia, achlorhydria and others (hyperglycemia,

hypercalcemia, flushing)• Others:

– ACTHoma – Cushing’s syndrome– GRFoma - acromegaly– Somatostatinoma – hyperglycemia, steatorrhea, gallstones– Rare syndromes (calcium, erythropoeitin, etc)

Octreotide for Functional NETs• Drug of choice for syndrome management

(FDA-approved for carcinoid, VIPoma and acromegaly)acromegaly)

• Role in tumor stabilization established for alimentary tract tumors (Promid)

• Correlate with hormonal measurements in nadir– Functional (24 hr urine)– Structural (CgA)

• Correlate with functional and structural imaging

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David C. Metz, MD

Anatomic Classification of NETs1,2

1. Vinik AI, Renar IP. Neuroendocrine Tumors of Carcinoid Variety. In: De Grool L, ed. Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 1995:2803–14.2. NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors.

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Gastric Carcinoids and Hypergastrinemia

Carcinoid % total Assoc. Gastrin Acid Sec. Mets

Type I 75 PA/atrophy Inc. Low V. rare

Type II 5-10 ZES/MEN-1 Inc. High Rare

Type III 15 25 None Normal Normal CommonType III 15-25 None Normal Normal Common

Adapted from Metz and Jensen. Chap. 48. In: Gastrointestinal Cancers. 2nd edition. Rustgi AK and Crawford JM, editors. WB Saunders, Philadelphia, PA. 2001; pp681

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David C. Metz, MD

Midgut Carcinoids

Location Multiplicity Functional Surgically curable

Ileal Yes Yes (mets) Rarely (mets)

Appendiceal No Rarely Yes (esp <1-2 cm)pp y ( p )

Isac. Acta Oncol 2003;42:672. and Yantiss. Am J Surg Pathol 2003;27:811

Extent of Disease at Diagnosis Diagnosis is often delayed 5–7 years on average, and the

probability of metastatic disease at diagnosis is increased1

5%4% 28% 30%

92%

49%

23%

29%

41%

The median age of diagnosis for NETs of the rectum is 56 years, for NETs of the lung is 64 years, and for NETs of the jejunum/ileum is 66 years2

1. Modlin IM et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61–72.2. 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;26:3063–72.

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David C. Metz, MD

Staging of Disease

• Imaging– Cross sectional studies (CT/MRI)– Functional Imaging (Octeoscan/MIBG scan)

• Endoscopy– Optical (EGD/Colonoscopy)

Capsule Endoscopy– Capsule Endoscopy– Deep Enteroscopy (Spiral/Single-/double Balloon)– Endosonography (EUS-PNETs)

EGD

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David C. Metz, MD

Colonoscopy

Photographs courtesy David Jaffe, MD

Capsule Endoscopy

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

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

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David C. Metz, MD

Fluoroscopic Results

AnterogradeAnterograde routeroute Retrograde routeRetrograde routeImages courtesy David Jaffe, MD

Primary Tumor IdentificationMRI EUS Octreoscan

Metz DC. Gastroenterology 2008;135:1469-1492Kwekkeboom DJ. Neuroendocrinology 2009;90:184-189

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David C. Metz, MD

Liver MetastasesCT MRI Octreoscan

SensitivitySensitivity 80-90% 80-95% >90%

Sundin A. Neuroendocrinology 2009;90:167-183Schillaci O. J Nucl Med 2003;44:359-368

68 Ga Octreotide PET Imaging with CT fusion: Imaging of the future

Photographs Courtesy Kjell Oberg, MD

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David C. Metz, MD

Management Principles

• Confirm the diagnosisC t l th h l d (if t)• Control the hormonal syndrome (if present)

• Determine extent of disease• Consider surgery

– For cure (if possible) – For debulking (if not)

• Long term management– Hormonal syndrome (if present)– Growth

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David C. Metz, MD

Management Principles (Cont.)• Management is multidisciplinary

– Medicine (GI, endocrine, oncology)ed c e (G , e doc e, o co ogy)– Surgery– Radiology (XRT, IR)

• Non-surgical therapy should not be squandered– Wait for symptoms or evidence of rapid growth

Therapy for Metastatic Disease: Limited Options

• Watch (especially if asymptomatic)Octreotide (? retards growth)• Octreotide (? retards growth)

• Chemotherapy (temporizing, PNETs>> GI NETs)– Streptozotocin, capecitabine/temozolomide

• Small molecules– Everolimus, sunitinib

• PRRT (experimental)• PRRT (experimental)– Yttrium or lutetium octreotide/tate

• Regional therapy (XRT to bone, chemoembocryotherapy, yttrium beads, etc)

• Transplantation (difficult to qualify)

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David C. Metz, MD

PROMID: Time to Progression

Rinke A, et al. J Clin Oncol 2009;27:4656-63

Other Methods of Debulking

Interventional RadiologyCh /bl d b li i• Chemo/bland embolization

• Radioactive beads• Radiofrequency ablation

SurgerySurgery• Transplantation (controversial)

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David C. Metz, MD

Systemic Therapies• Radioactive

– MIBG– MIBG– PRRT

• Chemotherapy• Small molecules

(PNETs)Sunitinib– Sunitinib

– Everolimus– Many more to

come

Managing the Effects of Therapy

• Pancreatic resections (Distal or Whipple’s)

• OctreotideGallstones(Distal or Whipple s)

– Pancreatic insufficiency– Dumping syndrome– Diabetes– Immunity (spleen)

– Gallstones– Steatorrhea

• Others– Adhesions

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

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David C. Metz, MD

Multidisciplinary Care is Ideal• Many options and no standard algorithm

exists (therapy should be individualized)• Tumor Board is ESSENTIAL component• Tumor Board is ESSENTIAL component• Flexibility is KEY

Conclusions

• NETS come in many different flavors but h l t f f t ihave lots of features in common

• They differ in many important ways from other more typical solid malignancies

• Management requires consideration of both functionality and tumor growthboth functionality and tumor growth

• Multidisciplinary care is the norm

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