Download Imaging and Management of Pancreatic Endocrine Tumors in MEN 1

Marie Elaine Stevens, IV
Gillian Lieberman, MD
October 20, 2008
Imaging and Management of Pancreatic
Endocrine Tumors in MEN 1
Marie Elaine Stevens
Georgetown University School of Medicine, Year IV
Dr. Gillian Lieberman, MD
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
2
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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
3
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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
4
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
5
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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
• MEN 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
6
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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%
7
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Spectrum of Disease: MEN 2
MEN 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%
8
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Multiple Endocrine Neoplasia:
Pathophysiology
• 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 protooncogene 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
9
Marie Elaine Stevens, IV
Gillian Lieberman, MD
MEN Syndromes: Comparison
MEN 1 MEN 2-A MEN 2-B
Pituitary Adenoma
>50%
Pancreatic Endocrine >80%
Tumor
Parathyroid Adenoma 95%
10-35%
Pheochromocytoma
50%
50%
Medullary Thyroid
100%
100%
Carcinoma
Intestinal Neuromas
>98%
Marfanoid Habitus
>95%
10
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
11
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Our Patient: Imaging WorkUp for Hyperprolactinemia
12
Marie Elaine Stevens, IV
Gillian Lieberman, MD
MRI of the Brain
Axial post-gadolinium T1WI
Sagittal post-gadolinium T1WI
*
*
PACS, BIDMC
•
PACS, BIDMC
Findings: a 1.4 x 1.4 x 1.5 cm enhancing lesion likely
representing a macroadenoma invading the left sphenoid sinus
13
Marie Elaine Stevens, IV
Gillian Lieberman, MD
CT of the Sella and Sinuses
Axial C- CT
PACS, BIDMC
• Findings: expansion, scalloping and erosion of the
floor of the sella, with scalloping of the anterior and
posterior aspects of the sella
14
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Mr. T: Follow-up of
Hyperprolactinemia
Our Patient Underwent
Transsphenoidal Resection of the
Prolactinoma
15
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Our Patient: Imaging Work-Up
for Hypercalcemia
16
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Nuclear Medicine Scan
Technetium-99m Sestamibi Scan
*
* *
Technetium-99m Sestamibi Scan
*
Parotid Glands
*
*
Submandibular
Glands
Thyroid
PACS, BIDMC
PACS, BIDMC
• Findings: no focal tracer uptake to indicate a
parathyroid adenoma
17
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Thyroid Ultrasound
Thyroid Ultrasound
Technetium-99m Sestamibi Scan
Submandibular
Glands
*
PACS, BIDMC
•
•
*
*
Thyroid
Probable
Parathyroid
Adenoma
PACS, BIDMC
Findings: a probable enlarged left parathyroid gland, which
could represent adenoma
Can this be visualized retrospectively seen on the patient’s
Sestamibi scan?
18
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Mr. T: Follow-up of
Hypercalcemia
Our Patient Underwent Resection
of a Left Inferior Parathyroid
Adenoma
19
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Our Patient: Follow-Up
Imaging for Known History of
Zollinger-Ellison Syndrome
20
Marie Elaine Stevens, IV
Gillian Lieberman, MD
CT of the Abdomen
Axial C+ CT
PACS, BIDMC
•
Axial C+ CT
PACS, BIDMC
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
21
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Follow-Up of Zollinger-Ellison
Syndrome: Newly Discovered
Multiple Pancreatic Gastrinomas
Mr. T Elected to Undergo Further
Imaging Work-Up for Staging and
Surgical Planning to Resect the
Gastrinomas
22
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
23
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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
24
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Types of Pancreatic Endocrine
Tumors: Nonfunctioning Tumors
• Nonfunctioning pancreatic endocrine
tumors are the most common
pancreatic tumors, occurring in 80100% of cases
• The name is a misnomer because most
of them produce pancreatic polypeptide
25
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Types of Pancreatic Endocrine
Tumors: Gastrinomas
• 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
26
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Types of Pancreatic Endocrine Tumors:
Insulinomas and Glucagonomas
• Insulinomas account for approximately 2035% 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
27
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
28
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Pancreatic Endocrine Tumors:
Imaging Modalities
•
•
•
•
•
Contrast- Enhanced CT
MRI
Somatostatin Receptor Scintigraphy
Endoscopic Ultrasound
Intraoperative Ultrasound
29
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Our Patient: CT of the Pancreas
Axial C+ CT of the Abdomen
• High-resolution contrastenhanced 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
•
•
Nodular hyperenhancing lesion in the pancreatic head
Several smaller hyperattenuating lesions in the pancreatic tail
PACS, BIDMC
Axial C+ CT of the Abdomen
PACS, BIDMC
30
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Our Patient: Reconstructed Images
C+ CTA Reconstruction of the Abdominal Aorta
C+ CTA Reconstruction of the Portal Vein
Celiac Trunk
*
*
PACS, BIDMC
SMA
Portosplenic
Confluence
*
PACS, BIDMC
• High-resolution contrast-enhanced CT can also be used
to generate reconstructed images used in operative
planning
31
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Pancreatic Endocrine Tumors:
Imaging Modalities
•
•
•
•
•
Contrast- Enhanced CT
MRI
Somatostatin Receptor Scintigraphy
Endoscopic Ultrasound
Intraoperative Ultrasound
32
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Companion Patient #1: MRI of the Pancreas
Axial Fat-Saturated T1WI
Owen NJ. British J Rad 2001; 74: 968-973.
•
•
Axial Fat-Saturated T2WI
Owen NJ. British J Rad 2001; 74: 968-973.
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
33
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Pancreatic Endocrine Tumors:
Imaging Modalities
•
•
•
•
•
Contrast- Enhanced CT
MRI
Somatostatin Receptor Scintigraphy
Endoscopic Ultrasound
Intraoperative Ultrasound
34
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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 tracerenhancing hepatic metastases,
and excretion of tracer in the
bladder
Octreotide Scan
*
http://www.emedicine.com/med/images/276262-276943-4313.JPG
35
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Companion Patient #3: Somatostatin
Receptor Scintigraphy
Octreotide Scan
Endoscopic Ultrasound
*
*
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
36
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Pancreatic Endocrine Tumors:
Imaging Modalities
•
•
•
•
•
Contrast- Enhanced CT
MRI
Somatostatin Receptor Scintigraphy
Endoscopic Ultrasound
Intraoperative Ultrasound
37
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Companion Patient #4: Endoscopic Ultrasound
Endoscopic Ultrasound
Endoscopic Ultrasound
*
*
Gauger PG. British Journal of Surgery 2003; 90: 748-754.
•
•
•
Gauger PG. British Journal of Surgery 2003; 90: 748-754.
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
38
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Distribution of Tumors by 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 Pancreatic Endocrine Tumors by EUS
Gauger PG. British Journal of Surgery 2003; 90: 748-754.
39
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Pancreatic Endocrine Tumors:
Imaging Modalities
•
•
•
•
•
Contrast- Enhanced CT
MRI
Somatostatin Receptor Scintigraphy
Endoscopic Ultrasound
Intraoperative Ultrasound
40
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Our Patient: Intraoperative Ultrasound
Intraoperative Ultrasound
Intraoperative Ultrasound
*
*
PACS, BIDMC
•
•
PACS, BIDMC
The advantage of intraoperative ultrasound is that it provides realtime 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
41
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
42
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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
43
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Goals of Surgical Therapy
• 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
44
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Surgical Treatment Options:
Total Pancreatectomy
Total Pancreatectomy
http://www.aafp.org/afp/20071201/afp20071201p1679-f3.jpg
• Long-term benefit of total pancreatectomy is
unproven in pancreatic endocrine tumors and the
associated surgical morbidity seems unacceptable
45
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Surgical Treatment Options: Classic Whipple Procedure
Axial C+ CT
Classic Whipple Procedure
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
PACS, BIDMC
Intraoperative Ultrasound
Axial C+ CT
*
http://www.aafp.org/afp/20071201/afp20071201p1679-f3.jpg
PACS, BIDMC
PACS, BIDMC
• Lesions in the head or uncinate process of the pancreas
can be resected with pancreaticoduodenectomy
(Whipple Procedure)
46
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Surgical Treatment Options: Distal Pancreatectomy
Endoscopic Ultrasound
Distal Pancreatectomy
*
Gauger PG. British Journal of Surgery 2003; 90: 748-754.
Gauger PG. British Journal of Surgery 2003; 90: 748-754.
•
•
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
47
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Agenda
•
•
•
•
Discuss Our Patient’s Presentation
Review MEN Syndromes
Present Our Patient’s Imaging Studies
Discuss Pancreatic Endocrine Tumors
– Pathophysiology
– Imaging
– Treatment
• Present Conclusions
48
Marie Elaine Stevens, IV
Gillian Lieberman, MD
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
49
Marie Elaine Stevens, IV
Gillian Lieberman, MD
References
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•
•
•
•
•
•
•
•
•
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.
50
Marie Elaine Stevens, IV
Gillian Lieberman, MD
Acknowledgements
•
•
•
•
•
•
Dr. Robert Kane
Dr. Katie Krajewski
Dr. Andrew Hines-Peralta
Dr. Gillian Lieberman
Maria Levantakis
Larry Barbaras
51