Imaging and Management of Pancreatic Endocrine Tumors...

Imaging and Management of Pancreatic Endocrine Tumors in MEN 1

Marie Elaine StevensGeorgetown University School of Medicine, Year IV

Dr. Gillian Lieberman, MD

Marie Elaine Stevens, IVGillian Lieberman, MD

October 20, 2008

Agenda• Discuss Our Patient’s Presentation• Review MEN Syndromes• Present Our Patient’s Imaging Studies• Discuss Pancreatic Endocrine Tumors

– Pathophysiology– Imaging– Treatment

• Present Conclusions


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Our Patient: History

• Mr. T is a 32 yo male with a strong family history of MEN 1 presenting with severe abdominal pain

• He has a known history of Zollinger-Ellison syndrome from presumed gastrinoma (although prior imaging studies were negative)

• His disease is currently fairly well controlled with Omeprazole 40mg BID


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Our Patient: Laboratory Findings

• In addition to elevated serum gastrin, laboratory work-up revealed hyperprolactinemia and hypercalcemia– These findings are suggestive of a prolactinoma

and parathyroid adenoma, compatible with Mr. T’s presumed diagnosis of MEN 1

• At this time, Mr. T elected to undergo a full imaging work-up


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Multiple Endocrine Neoplasia: Epidemiology

• MEN syndromes are part of a group of autosomal dominant endocrine disorders first recognized in the early part of the 20th century

• The population prevalence of MEN 1 is about 1 in 30,000

• M EN 2 affects about 1 in 40,000 individuals– MEN 2-A accounts for most cases of MEN 2– MEN 2-B represents about 5% of all cases of MEN 2


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Spectrum of Disease: MEN 1 (Wermer Syndrome)

• Parathyroid Adenoma - 95%• Pituitary Adenoma - 50%

– Prolactinoma 25%– Nonfunctioning 10%– Growth Hormone 5%, ACTH 2%, Thyrotropin 5%

• Pancreatic Endocrine Tumors - 80%– Gastrinoma 40%– Insulinoma 10%– Nonfunctioning 20%– Glucagonoma 2%, VIPoma 2%, Somatostatinoma 2%

• Other Features– Forgut Carcinoid 15%, Adrenal Neoplasms 30%– Facial Angiofibroma 85%, Collagenoma 70%, Lipoma 30%,

Leiomyoma 5%, Meningioma 5%


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Spectrum of Disease: MEN 2MEN 2-A

(Sipple Syndrome)• Medullary Thyroid

Carcinoma - 100%• Pheochromocytoma -

50%• Parathyroid Adenoma -

10-35%

MEN 2-B• Medullary Thyroid

Carcinoma - 100%• Pheochromocytoma -

50%• Marfanoid Habitus - >95%• Intestinal

Ganglioneuromatosis and Mucosal Neuromas - >98%


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• Patients with MEN 1 possess a germline mutation in the MENIN gene– The MENIN gene is located on chromosome 11 and

produces a tumor suppressor protein called menin

• The gene responsible for MEN 2 is proto- oncogene RET– RET is expressed in neural crest-derived cells and encodes

for RET protein (the tyrosine kinase subunit of a cell surface receptor)

– Activation of RET leads to hyperplasia of target cells in vivo

Multiple Endocrine Neoplasia: Pathophysiology


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MEN Syndromes: ComparisonMEN 1 MEN 2-A MEN 2-B

Pituitary Adenoma >50%Pancreatic Endocrine Tumor

>80%

Parathyroid Adenoma 95% 10-35%Pheochromocytoma 50% 50%Medullary Thyroid Carcinoma

100% 100%

Intestinal Neuromas >98%Marfanoid Habitus >95%


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Our Patient: Imaging Work- Up for Hyperprolactinemia


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MRI of the Brain

• Findings: a 1.4 x 1.4 x 1.5 cm enhancing lesion likely representing a macroadenoma invading the left sphenoid sinus

PACS, BIDMCPACS, BIDMC


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Axial post-gadolinium T1WI Sagittal post-gadolinium T1WI

**

• Findings: expansion, scalloping and erosion of the floor of the sella, with scalloping of the anterior and posterior aspects of the sella

CT of the Sella and Sinuses

PACS, BIDMC


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Axial C- CT

Mr. T: Follow-up of Hyperprolactinemia

Our Patient Underwent Transsphenoidal Resection of the

Prolactinoma

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Our Patient: Imaging Work-Up for Hypercalcemia

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• Findings: no focal tracer uptake to indicate a parathyroid adenoma

Nuclear Medicine Scan



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* ** ***

Parotid Glands

Submandibular Glands

Thyroid

Technetium-99m Sestamibi Scan Technetium-99m Sestamibi Scan

Thyroid Ultrasound

• Findings: a probable enlarged left parathyroid gland, which could represent adenoma

• Can this be visualized retrospectively seen on the patient’s Sestamibi scan?

PACS, BIDMC


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PACS, BIDMC

* *Submandibular Glands

Thyroid

Probable Parathyroid Adenoma

Technetium-99m Sestamibi ScanThyroid Ultrasound

*

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Mr. T: Follow-up of Hypercalcemia

Our Patient Underwent Resection of a Left Inferior Parathyroid

Adenoma


Our Patient: Follow-Up Imaging for Known History of Zollinger-Ellison Syndrome

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CT of the Abdomen

• Findings: new nodular hyperenhancing area within the pancreatic head, relative to the remainder of the pancreas and several smaller foci of relative hyperattenuation seen within the pancreatic tail, suggestive of multiple gastrinomas



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Axial C+ CT Axial C+ CT

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Follow-Up of Zollinger-Ellison Syndrome: Newly Discovered

Multiple Pancreatic GastrinomasMr. T Elected to Undergo Further Imaging Work-Up for Staging and Surgical Planning to Resect the

Gastrinomas






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Pancreatic Endocrine Tumors: Pathophysiology

• Pancreatic endocrine tumors occur in 80% of patients with MEN 1 – Tumors are often multicentric and may undergo malignant

transformation

• Patients with MEN 1 have a decreased life expectancy, with a 50% probability of death by age 50 years– Half of the deaths result from a malignant process or a

sequela of the endocrine disease– ZES is the major cause of morbidity and mortality in patients

with MEN 1


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• Nonfunctioning pancreatic endocrine tumors are the most common pancreatic tumors, occurring in 80- 100% of cases

• The name is a misnomer because most of them produce pancreatic polypeptide

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Types of Pancreatic Endocrine Tumors: Nonfunctioning Tumors


• Gastrinomas are the most common cause of symptomatic disease and are found in approximately 60% of patients with MEN 1

• Compared to the sporadic form in Zollinger-Ellison syndrome, gastrinomas in MEN 1 are more often duodenal, small, and multicentric

Types of Pancreatic Endocrine Tumors: Gastrinomas


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• Insulinomas account for approximately 20- 35% of pancreatic endocrine tumors– Similar to gastrinomas, they can be multicentric

(10-20%), where 25% metastasize either to regional lymph nodes or to the liver

• Glucagonomas occur in 3% of patients with MEN 1 and are silent or present with hyperglycemia– Typical skin lesions (necrolytic migratory

erythema) are rare in patients with MEN 1

Types of Pancreatic Endocrine Tumors: Insulinomas and Glucagonomas


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Pancreatic Endocrine Tumors: Imaging Modalities

• Contrast- Enhanced CT• MRI• Somatostatin Receptor Scintigraphy• Endoscopic Ultrasound• Intraoperative Ultrasound


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Our Patient: CT of the Pancreas

• High-resolution contrast- enhanced CT is the initial imaging technique used to localize and stage most pancreatic endocrine tumors

• However, it fails to help identify as many as 70% of lesions

PACS, BIDMC

PACS, BIDMC


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Axial C+ CT of the Abdomen

Axial C+ CT of the Abdomen

• Nodular hyperenhancing lesion in the pancreatic head• Several smaller hyperattenuating lesions in the pancreatic tail

• High-resolution contrast-enhanced CT can also be used to generate reconstructed images used in operative planning

Our Patient: Reconstructed Images



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C+ CTA Reconstruction of the Abdominal Aorta C+ CTA Reconstruction of the Portal Vein

***

Celiac Trunk

SMA

Portosplenic Confluence




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Companion Patient #1: MRI of the Pancreas

• Pancreatic endocrine tumors have high relaxation times result in greater enhancement on T1- and T2-weighted images of pancreatic endocrine tumors, compared to adenocarcinomas

• The images above show lesions of the pancreas with solid and cystic components

Owen NJ. British J Rad 2001; 74: 968-973.Owen NJ. British J Rad 2001; 74: 968-973.


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Axial Fat-Saturated T1WI Axial Fat-Saturated T2WI




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Companion Patient #2: Somatostatin Receptor Scintigraphy (SRS)

• Pancreatic endocrine tumors express large numbers of SST receptors on their cell surfaces (except SSTomas)

• Radiolabeled octreotide used in SRS preferentially binds to SST receptors

• SRS is helpful in diagnosing small extrapancreatic metastases

• The octreotide scan to the right shows a large pancreatic-tail neoplasm, several tracer- enhancing hepatic metastases, and excretion of tracer in the bladder http://www.emedicine.com/med/images/276262-276943-4313.JPG


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*

Octreotide Scan

Companion Patient #3: Somatostatin Receptor Scintigraphy

Norton JA. Annals of Surgery 2004; 240: 757-773.

Norton JA. Annals of Surgery 2004; 240: 757-773.

• Another example of SRS localization of a gastrinoma in the area of the duodenum/pancreatic head

• The same patient undersent endoscopic ultrasound (EUS), which revealed a lesion situated between the pancreatic duct and CBD


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Octreotide Scan Endoscopic Ultrasound

**




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• EUS can help localize pancreatic endocrine tumors assess lymph node metastases

• It cannot, however, be used to evaluate hepatic and distant spread

• The images above show of pancreatic endocrine tumors in the pancreatic tail and uncinate process

Companion Patient #4: Endoscopic Ultrasound

Gauger PG. British Journal of Surgery 2003; 90: 748-754.Gauger PG. British Journal of Surgery 2003; 90: 748-754.


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*

*

Endoscopic Ultrasound Endoscopic Ultrasound

• In this study, 43 pancreatic endocrine tumors were demonstrated on initial EUS in 15 asymptomatic patients with MEN 1

• 60% of tumors were found in tail of pancreas– 16% body– 24% head/uncinate

process

Distribution of Tumors by Endoscopic Ultrasound

Gauger PG. British Journal of Surgery 2003; 90: 748-754.


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Distribution of Pancreatic Endocrine Tumors by EUS




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Our Patient: Intraoperative Ultrasound

• The advantage of intraoperative ultrasound is that it provides real- time images and information about the location and number of pancreatic endocrine tumors (sensitivity 90%)

• The images above show multiple solid hypoechoic nodules in the tail of our patient’s pancreas



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**

Intraoperative Ultrasound Intraoperative Ultrasound





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Pancreatic Endocrine Tumors: Surgical Treatment Options

• Role of surgery in MEN 1 is controversial– Most tumors are multicentric and cure is achieved

only occasionally • Surgery may be indicated in patients with no

distant metastases– Removal of tumors > 2 cm in reduces the

frequency of liver metastasis– Local tumor excision is preferred, with larger

tumors of the pancreatic body or tail removed by distal pancreatectomy


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• The goals of surgical therapy for pancreatic endocrine neoplasms include:– Controlling the symptoms of hormone

excess– Safely resecting the maximal amount of

tumor mass possible– Preserving the maximal amount of

pancreatic parenchyma possible

Goals of Surgical Therapy


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Surgical Treatment Options: Total Pancreatectomy

• Long-term benefit of total pancreatectomy is unproven in pancreatic endocrine tumors and the associated surgical morbidity seems unacceptable

http://www.aafp.org/afp/20071201/afp20071201p1679-f3.jpg


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Total Pancreatectomy

Surgical Treatment Options: Classic Whipple Procedure

• Lesions in the head or uncinate process of the pancreas can be resected with pancreaticoduodenectomy (Whipple Procedure)

http://www.aafp.org/afp/20071201/afp20071201p1679-f3.jpg


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PACS, BIDMC

PACS, BIDMC PACS, BIDMC

*

In our patient, the lesion in the head of the

pancreas was excised with a classic Whipple

Procedure

Unfortunately, multiple lesions in the pancreatic

tail were left behind

Intraoperative Ultrasound Axial C+ CT

Axial C+ CT

Classic Whipple Procedure

Surgical Treatment Options: Distal Pancreatectomy

• The EUS above of companion patient #4 shows a tumor in the tail of the pancreas

• This patient underwent distal pancreatectomy and splenectomy, enucleation of a pancreatic head endocrine tumor, and duodenotomy with excision of duodenal gastrinoma

Gauger PG. British Journal of Surgery 2003; 90: 748-754.Gauger PG. British Journal of Surgery 2003; 90: 748-754.


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Endoscopic Ultrasound Distal Pancreatectomy

*





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Pancreatic Endocrine Tumors: Conclusions• The major cause of morbidity and mortality in patients

with MEN 1 is the sequela of endocrine disease (eg Zollinger-Ellison Syndrome)

• Contrast-enhanced CT, MRI, somatostatin receptor scintigraphy, EUS and intraoperative ultrasound all have important, complimentary roles in the diagnosis and treatment of pancreatic endocrine tumors

• The role of surgery in MEN 1 is controversial and efforts should be made to preserve the maximal amount of pancreatic parenchyma possible while resecting the tumor mass


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References• Kroneberg: Williams Textbook of Endocrinology, 11th Edition. Chapter 40 - Multiple

Endocrine Neoplasia. Robert F. Gagel, Stephen J. Marx. Saunders, 2008.• Squire’s Fundamentals of Radiology: 6th Edition. Robert A. Novelline, MD. Harvard

University Press, 2004.• eMedicine: Multiple Endocrine Neoplasia. Robert J Ferry Jr, MD. Article Last Updated: Jun

12, 2008• eMedicine: Wermer Syndrome (MEN Type 1). Irina Lendel, MD. Article Last Updated: Jan

8, 2007• eMedicine: Neoplasms of the Endocrine Pancreas. Eric J Hanly, MD. Article Last Updated:

Jun 29, 2006.• Hellman P, Hennings J, Akerstrom G, Skogseid B. Endoscopic ultrasonography for

evaluation of pancreatic tumours in multiple endocrine neoplasia type 1. British Journal of Surgery 2005; 92: 1508-1512.

• Owen NJ, Sohaib SAA, Peppercorn PD, Monson JP, Grossman AB, Besser GM, Reznek RH. MRI of pancreatic neuroendocrine tumours: Pictoral Review. The British Journal of Radiology 2001; 74: 968-973.

• Doherty GM. Multiple Endocrine Neoplasia Type 1. Journal of Surgical Oncology 2005; 89: 143-150.

• Norton JA, Jensen RT. Resolved and Unresolved Controversies in the Surgical Management of Patients With Zollinger-Ellison Syndrome. Annals of Surgery 2004; 240: 757-773.

• Gauger PG, Scheiman JM, Wamsteker EG, Richards MI, Doherty GM, Thompson NW. Role of endoscopic ultrasonography in screening and treatment of pancreatic endocrine tumours in asymptomatic patients with multiple endocrine neoplasia type 1. British Journal of Surgery 2003; 90: 748-754.


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Acknowledgements

• Dr. Robert Kane• Dr. Katie Krajewski• Dr. Andrew Hines-Peralta• Dr. Gillian Lieberman• Maria Levantakis• Larry Barbaras


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