CHAPTER I INTRODUCTION Multiple endocrine neoplasia syndromes are rare, inherited conditions in which several endocrine glands develop

noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors. Multiple endocrine neoplasia syndromes are caused by gene mutations, so they tend to run in families. Symptoms vary depending on which glands are affected. Genetic screening tests can be done to detect disease in family members of people who have multiple endocrine neoplasia syndromes. No cure is available, but doctors treat the changes in each gland as they occur with surgery or with drugs to control excess hormone production.1 Type 1 MEN is defined by hyperfunctioning tumors in all 4 parathyroid glands, pancreatic islets (eg, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor [VIPoma], pancreatic polypeptideproducing tumor [PPoma]), and the anterior pituitary (eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors). Other associated tumors include lipomas, angiofibromas, or those located in the adrenal gland cortex (rarely, in the adrenal medulla).2 Type 2A MEN is defined by medullary thyroid carcinoma (MTC),

pheochromocytoma (about 50% of cases), and hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases). Familial MTC is also recognized. Familial MTC is hereditary MTC without other associated endocrinopathies, although adrenomedullary hyperplasia secondary to a germline RET mutation may still be present but undiagnosed. Type 2B MEN is defined by medullary thyroid cancer and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus.2

CHAPTER II MULTIPLE ENDOCRINE NEOPLASIA SYNDROME 2.1 Risk Factor Multiple Endrocinological Neoplasia syndrome Type 2 (MENs 2) is caused by mutations in the RET (Re-arranged Transfection) gene, which cause affected cells to divide uncontrollably, resulting in tumor formation. Genetic testing can identify RET mutations in approximately 95% of people with clinical symptoms of MENs 2A and MENs 2B, and in about 88% of families with FMTC (Famillial Medullary Thyroid Carcinoma). All children of a parent with MENs 2 have a 50% chance of getting the disease.1 Genetic testing of blood samples can both confirm a diagnosis of MENs 2 in individual patients and identify family members who may be at risk of developing the disease. Depending on the specific RET mutation, predicting the severity and progression of the disease to some degree is possible. This is helpful in determining screening recommendations, as well as the appropriate age for performing a prophylactic thyroidectomy (surgery to remove the thyroid before disease strikes). General recommendations are to remove the thyroid gland: Within the first six months of life for individuals with MENs 2B. By five to 10 years of age for individuals with MEN2A and FMTC.1

2.2

Etiology The gene for type 1 MEN has been localized to chromosome band 11q13. It is a tumor suppressor gene that encodes menin, a nuclear protein. The gene for type 2 MEN is RET, located on chromosome band 10q11.2. In type 2A MEN, 95% of RET mutations occur in exons 10, 11, and 14. Mechanisms of tumorigenesis in vivo recently elucidated show allelic imbalance between mutant and wild type RET alleles. In type 2B MEN, RET mutations in exon 16 are found in 5% of cases.2 So-called inactivating mutations due to deletions of RET are associated with congenital neurologic defects, such as aganglionic colon (ie, Hirschsprung

disease). Of interest, these mutations also occur on exons 10 and 11 (associated with type 2A MEN).2

2.3

Epidemiology The frequency of multiple endocrine neoplasia type 1 (MEN1) is estimated to be 1 case in 30,000 persons.No racial predilection is known for multiple endocrine neoplasia type 1 (MEN1).The incidence of multiple endocrine neoplasia type 1 (MEN1) is equal for men and women.The age of onset of endocrine tumors is usually in the teenaged years; however, symptoms from these tumors may not appear for several years, and the diagnosis is frequently delayed until the fourth decade of life.3 The overall frequency in United States is 1 case per 30,000-50,000 persons. In decreasing order of frequency, MEN occurs as follows: MEN 2A, FMTConly, and MEN 2B. Type 2A MEN accounts for most cases of type 2 MEN. In general, type 2 MEN affects about 1 in 40,000 individuals, and fewer than 1000 kindreds are known worldwide. In MEN 2A patients, 50% of those with RET gene mutations develop the disease by age 50 years, and 70% develop the disease by age 70 years. Medullary thyroid carcinoma has been detected shortly after birth.3

2.4

Pathogenesis and Pathophysiology Type 1 Multiple Endocrine Neoplasia Patients with multiple endocrine neoplasia type 1 inherit a mutation in a tumor suppressor gene called MEN1 on band 11q13. This gene encodes a protein, menin, whose functions are still being elucidated. For a tumor to form, both alleles of the gene must be mutated, inactivating the normal gene product. In people without MEN1, 2 independent somatic mutations must occur within a single cell for tumor formation. In an individual with MEN1, the first mutation is already present in all of the patients cells, so that only a

single somatic mutations is required. This accounts for the multiple tumors and the tumors occuring in an earlier age.2 Type 2A multiple endocrine neoplasia (Sipple syndrome) MEN 2 is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. Inherited as an autosomal dominant disorder, MEN 2 has 3 distinct subtypes, including MEN 2A, MEN 2B, and familial medullary thyroid carcinoma only (FMTC-only). The subtypes are defined by the combination of tissues affected. Developmental abnormalities may also be present. By age 70 years, the penetrance rate is 70%. Genetic testing and clinical surveillance beginning in childhood provide the opportunity to treat the devastating and sometimes fatal complications of this disorder.3 Virtually all MEN 2A patients develop medullary thyroid carcinoma. This is often the first expressed abnormality and usually occurs in the second or third decade of life. The medullary thyroid carcinoma in MEN 2A patients is typically bilateral and multicentric, in contrast to sporadic medullary thyroid carcinoma, which is unilateral.3 Pheochromocytomas are present in approximately half of MEN 2A patients. They are bilateral in 60-80% of patients, compared with 10% of patients with sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as the medullary thyroid carcinoma or several years later (both primarily occurring in the second or third decade). The pheochromocytomas of MEN 2A patients are nearly all benign. Parathyroid hyperplasias are present in nearly half of patients but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, symptoms can often be elucidated following comprehensive questioning.3 Type 2B multiple endocrine neoplasia Type 2B MEN represents about 5% of all cases of type 2 MEN. Patients have some aspects of a distinctive marfanoid phenotype and mucosal neuromas. MTC is relatively aggressive and frequently occurs in childhood. Children as young as 12 months may develop MTC. Therefore, prophylactic

thyroidectomy with lymph node dissection is recommended in children younger than 5 years who have a RET germline mutation in exon 16. Pheochromocytomas also occur earlier than in patients with type 2A MEN, and patients have the same features arising in the context of adrenomedullary hyperplasia, multifocality, and often bilateral involvement. In contrast to MTC, which frequently metastasizes, metastatic pheochromocytomas rarely occur in patients with type 2 MEN (0-25%). An important parameter in this setting is the follow-up period and the time of first occurrence or diagnosis.4

2.5

Clinical Manifestation Clinical Manifestation of Multiple Endocrine Neoplasia Type 1 Cutaneous tumors are common in MEN1. Recognizing these benign tumors is important because they can serve as markers for this tumor syndrome. Cutaneous tumors in multiple endocrine neoplasia type 1 (MEN1) are of long duration and generally grow slowly or not at all. This permanence helps differentiate these lesions from inflammatory skin lesions. 5 Angiofibromas (detected 5%-88% of patients with MEN1) are telangiectatic, skin-colored, pink or light-brown papules that are 1-4 mm in diameter. They are mostly located on the central part of the face. The angiofibromas in patients MEN1 tend to be smaller in size and less numerous than angiofibromas in patients with tuberous sclerosis. MEN1, angiofibromas are common on the upper lip and vermillion border of the lip. The age at onset of angiofibromas is later in MEN1, mostly occurring at the second decade and later in life. 5 Collagenomas (1%-72% of patients with MEN1) are also found. It is a skincolored to slightly hypopigmented, firm, round to oval papules that are 0.2-2 cm in diameter, mostly located on the upper part of the trunk and on the neck.5

Lipomas (3%-34% of patients with MEN1) which are soft, compressible, subcutaneous nodules that are generally 0.5-5 cm in diameter that are solitary or multiple, and they occur on the trunk, the extremities, and the scalp. 5

Figure1. A) Multiple facial angiofibromas, this patient has a positive family history for multiple endocrine neoplasia type 1. B) A large collagenoma shows an endocrinologic features of multiple endocrine neoplasia type 1 in this patient with hyperparathyroidism and Zollinger-Ellison syndrome. C) Woman with multiple endocrine neoplasia type 1 has a soft nodule on the forehead that is consistent with lipomas.

Other findings in Multiple Endocrine Neoplasm type 1 (MEN1) includes parathyroid tumors that cause hyperparathyroidism and hypercalcemia which may be asymptomatic in some patient with MEN1. Other abnormal tumors findings in MEN1 include gastrinomas, insulinomas, prolactinomas, and tumors.5 Clinical Manifestation of Multiple Endocrine Neoplasia Type 2 Patients may present with symptoms related to medullary thyroid carcinoma, hyperparathyroidism, or pheochromocytoma. Clinical presentation of MEN2 is also related to the patient's age. A young patient with an identified RET proto-oncogene mutation will probably be asymptomatic. These patients generally have thyroid C-cell hyperplasia without progression to medullary carcinoma. 6 If a patient has thyroid medullary carcinoma, he or she may have a history of diarrhea from extensive disease which may be related to elevated prostaglandin or calcitonin levels. All patients may have medullary thyroid carcinoma at the time of diagnosis, although their clinical presentation may be consistent with pheochromocytoma or hyperparathyroidism.6 Symptoms in MEN2 can include: hypertension, episodic sweating, diarrhea, pruritic skin lesions, or compressive symptoms from a neck mass.

Hypertension:

If pheochromocytomas develop, an increase in blood

pressure and heart rate may be the only signs. These increases can be chronic or episodic. Some patients have episodes of sweating and headaches.

Chronic constipation: This constant finding in MEN 2B patients results from hyperplasia of the intrinsic autonomic ganglia in the intestinal wall. Infants may show sign of failure to thrive.

Pruritic skin lesions: Cutaneous lichen amyloidosis in MEN 2A patients manifests as multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back. They are associated with deposition of altered cytokeratins rather than of calcitoninlike peptides.

Patients with hypercalcemia may present with constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastroesophageal reflux, and fatigue, or they may have no symptoms. They may also lose bone density. While from physical examination, the physical signs of MEN 2 are extremely variable and often subtle. A neck mass or dominant thyroid nodule is discovered. Anterior neck lymph nodes are nontender, arise insidiously with progressive enlargement, and may signify regional metastasis. 6 Other physical findings of MEN2 are marfanoid habitus of high-arched palate, pectus excavatum, bilateral pes cavus, and scoliosis in MEN 2B patients. There are certain neuromas on the eyelids, conjunctiva, nasal and laryngeal mucosa, tongue, and lips are also frequent findings. Patients also have prominent hypertrophied lips leading to a characteristic facies. While there may be localized pruritus appearace over the upper back in MEN 2B patients.6 MEN-2B, unlike MEN-2A, is characterized by the absence of

hyperparathyroidism and the presence of mucosal neuromas. The MTC of MEN-2B develops earlier in life and is more aggressive. Hypercalcemia may indicate bone metastases. Mucosal neuromas are the most distinctive feature of MEN-2B and may occur on the tongue, eyelids, or lips and along the

gastrointestinal tract. Intestinal neuromas may cause intermittent obstruction or diarrhea.6

2.6

Diagnosis and Differential Diagnosis The occurrence of one endocrine condition does not immediately lead to a suspicion of MEN syndromes. Diagnosis is based on the occurrence of one or more endocrine conditions and a family history of MEN1 or MEN2. 10 Genetic testing using DNA technology has been available for both MEN1 and MEN2. The identification of the MEN1 gene has made genetic screening for this gene more accurate. 10 A blood sample is usually analyzed for DNA testing, although other tissue can be used. The sample is sent to a laboratory that specializes in DNA diagnosis. There a geneticist will perform several tests on the DNA collected from the cells in blood sample. The exact tests performed will depend on whether MEN1 or MEN2 is suspected. Because different regions of the RET gene are associated with different endocrine conditions in MEN2A, several regions of the gene are examined. A positive result means the defective gene is present, and a negative result means the defective gene is not present.10 The test results for the RET gene mutations are more reliable than for the MEN1 gene because detection techniques for identifying MEN1 are still being developed. A clinical diagnosis of MEN2 is confirmed with genetic testing 9095% of the time. Even when a genetic test is negative, family medical records will be carefully reviewed to confirm the presence of MEN2, and periodic screening of related conditions will likely continue until age 30 or 40. The time required to obtain the test results for MEN2 is about 24 weeks, but MEN1 results will likely take longer because there are fewer diagnostic labs set up for MEN1 analysis. 10 Those considered at risk for MEN1 or MEN2 based on genetic tests or family history are offered preventative surgery, regular screening for associated endocrine conditions, or a combination of these treatment options. Conditions

are screened following the accepted procedure for each condition. Diagnosis is based on clinical features and on testing for elevated hormone levels.10 Men 1 Hyperparathyroidism is diagnosed when high levels of calcium and intact parathyroid hormone are measured in a blood sample. Normal values of calcium for adults is 4.45.3 mg/dl (milligrams per deciliter), and normal values of parathyroid hormone are 1055 pg/ml (picograms per milliliter). Prior to the parathyroid test, no food should be eaten for at least six hours. An x ray of bones may be taken and then examined by a radiologist for signs of low bone density. An x ray of the abdominal region can reveal kidney stones. Patients should be screened yearly. 11 Diagnosis of a gastrinoma follows established procedures and includes measuring the levels of gastrin in the blood and the level of stomach gastic acid production. Hypoglycemia associated with insulinomas is diagnosed by measuring blood glucose levels. This test may be administered while a patient is experiencing symptoms related to low insulin levels or during a supervised period of fasting. Depending on the type of test given, no food should be eaten from 612 hours prior to the test. Normal glucose levels range between 64128 mg/dl. Blood glucagon levels above the normal range of 50100 pg/ml can indicate hyperglycemia, which is associated with glucagonomas. Large pancreatic tumors are identified using computed tomography (CT scans) or radionuclide imaging, but ultrasonography conducted during surgery is the best method for detecting small tumors. There is no accepted system for staging the pancreatic tumors associated with MEN1. 11 Prolactinomas, the pituitary tumors most often associated with MEN1, are diagnosed when prolactin levels are greater than 20 ng/l (nanograms per liter). A tumor is identified using magnetic resonance imaging (MRI). Tumors secreting excess growth hormone are diagnosed when hormone levels are above the upper normal range of 3 ng/l and from observable changes in physical appearance. 11

Men 2 Medullary thyroid carcinoma is diagnosed by measuring calcitonin levels in blood and urine samples and from a biopsy of any thyroid nodules. Levels of calcitonin above 50 pg/ml can indicate the presence of MTC. Patients showing normal calcitonin levels may require a different test, in which calcitonin is measured at regular intervals after an injection of pentagastrin, a synthetic hormone. 12 Fine needle aspiration is the biopsy procedure used to diagnose MTC and other forms of thyroid cancer. A sample of cells is removed from a nodule, and the cells are then examined under a microscope by a pathologist to determine if cancer cells are present. MTC has four stages, based on the size of the tumor and where the cancer has spread. Tumor staging follows the system established for other forms of thyroid cancer. 12 A high level of epinephrine relative to norepinephrine indicates a pheochromocytoma on one or both adrenal glands. A CT scan, an MRI, or radionuclide imaging will be performed to locate the tumor. 12 Diagnosis of hyperparathyroidism in MEN2A patients is identical to its diagnosis for MEN1 patients, but with screening recommended every two to three years. 12 The differential diagnosis of MEN 1 includes sporadic or familial tumors of the pituitary, parathyroids, or pancreatic islets. Hypercalcemia (from any cause) may cause gastrointestinal symptoms and increased gastrin levels, simulating a gastrinoma. Routine suppression of gastric acid secretion with H2-blockers or proton pump inhibitors causes a physiologic increase in serum gastrin that can be mistaken for a gastrinoma. H2-blockers and metoclopramide prolactinoma.11 Hereditary pheochromocytomas in MEN syndrome type 2 may occur in other conditions, such as in von Hippel-Lindau syndrome and neurofibromatosis. The hyperparathyroidism specifically in MEN syndrome type 2A can be also cause hyperprolactinemia, simulating a pituitary

present in MEN syndrome type 1, familial hyperparathyroidism, and familial hypocalciuric hypercalcemia.12

2.7

Treatment Almost everyone who inherits a mutant MEN1 gene develops at least one clinical manifestation of the syndrome. Most develop hyperparathyroidism, 80% develop pancreatic islet cell tumors, and more than half develop pituitary tumors. For most of these tumors, initial surgery is not curative and patients frequently require multiple surgical procedures on two or more endocrine glands during a lifetime. For this reason, it is essential to establish clear goals for management of these patients rather than to recommend surgery casually each time a tumor is discovered. Ranges for acceptable management are discussed below.13 In patient with asymptomatic hyperparathyroidism, observation may be appropriate. When surgery is indicated in MEN 1, all parathyroid tissue should be identified and removed at the time of primary operation, and parathyroid tissue should be implanted in the nondominant forearm. Thymectomy should also be performed because of the potential for later development of malignant carcinoid tumors. If reoperation for hyperparathyroidism is necessary at a later date, transplanted parathyroid tissue can be resected from the forearm under local anesthesia with titration of tissue removal to lower the intact parathyroid hormone (PTH) to 50% of basal.13 In the treatment of pancreatic islet tumors, there 3 general concepts which appear to be valid. First, islet tumors should be resected because medical therapy for the hormonal effects of these tumors is generally ineffective. Second, resection of these gastrin-producing islet cell tumors improves the cure rate. Third, total pancreatectomy at an early age may be justified to prevent malignancy for families who have a high incidence of malignant cell tumors that cause death.13

Treatment of prolactinomas with dopamine agonists (bromocriptine, cabergoline, or quinagolide) usually returns the serum prolactin level to normal and prevents further tumor growth. Surgical resection of a prolactinoma is rarely curative but may relieve mass effects.13 The first thing to be considered in treating MEN syndrome type 2 is its screening. Death from MTC can be prevented by early thyroidectomy. The identification of RET protooncogene mutations and the application of DNAbased molecular diagnostic techniques to identify these mutations has simplified the screening process, that should be performed on an individual with proven MEN 2A. Establishment of the specific germline mutation facilitates the subsequent analysis of other family member.13 The long term goal of treatment of pheochromocytoma is to prevent death and cardiovascular complications but the major question is whether to remove both adrenal glands or to remove only the affected adrenal at the time of primary surgery. Most clinicians recommend removing only the affected adrenal. If both adrenals are removed, glcocorticoid and mineralocorticoid replacement are mandatory. An alternative approach is to perform a corticalsparing adrenalectomy, removing the pheochromocytoma and adrenal medulla, leaving the adrenal cortex behind. This approach is usually successful and eliminates the necessity for steroid hormone replacement in most patient, although the pheochromocytoma recurs in small percentage.13

2.8

Prognosis As of yet there is no cure for this condition, but patients suffering from Multiple Endocrine Neoplasia Type 1 tend to live long and productive lives. Early diagnosis improves survival chances significantly. Periodic checkups are vital for those suffering from this condition, (recommended by the International Guidelines for Diagnosis and Therapy of MEN syndromes group). 12

This is because the condition has the ability to attack other glands and also even after being treated the chance that residual tissue may grow is present. Hence, it is important that patients be monitored and their treatment be catered specifically to their condition, as the disease varies from individual to individual (eg: depending on the glands involved). 12 In a survey carried out among 230 patients with MEN 2, 5.2 % died and medullary thyroid cancer and 0.047% of unknown causes. However, of 163 patients followed up to 50 percent experienced recurrences. In cases were thyroid removal is necessary, in such cases the patient will require hormonal therapy for the remaining years of their life. 12 According to surveys that have been conducted the mortality age of a person suffering from Multiple Endocrine Neoplasia does not differ significantly from that of the general population. 12 However, mortality rates at a younger age may occur; anywhere between the age of 10 to 50 years. The cause of early mortality are caused by two factors either; complications or evolution of the malignant process. In the former complications that rise due to hormonal secretion by the tumors for example malignant hypercalcaemia, hemorrhagic ulcers and carcinoid tumors. Whereas in the latter progressing may form pancreatic neuroendocrine tumors. 12

2.9

Complication The complications of type 1 MEN syndrome is the recurrence of the tumor. In type 2 MEN syndrome, the complications may include hypercalcemia, chronic constipation, hypertensive episode, and recurrence of medullary thyroid carcinoma.12

CHAPTER III SUMMARY

1. Multiple endocrine neoplasia syndromes are rare, inherited conditions in

which several endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors.
2. Patients with multiple endocrine neoplasia type 1 inherit a mutation in a

tumor suppressor gene called MEN1 on band 11q13. MEN 2 is a rare familial cancer syndrome caused by mutations in the RET protooncogene. 3. MEN-1 is a syndrome characterized by neoplasms of the parathyroid, endocrine pancreas, and anterior pituitary. MEN-2 is subdivided into MEN-2A (medullary carcinoma of the thyroid, pheochromocytoma, and primary hyperparathyroidism) and MEN-2B (medullary thyroid carcinoma, pheochromocytoma, and mucosal neuromas)
4. Diagnosis is based upon the occurrence of one or more endocrine

conditions and a family history of MEN 1 and MEN 2. 5. Treatment is given based on clinical manifestation exhibited by each type of this syndrome.
6. According to surveys that have been conducted the mortality age of a

person suffering from Multiple Endocrine Neoplasia does not differ significantly from that of the general population. 7. The complications of type 1 MEN syndrome is the recurrence of the tumor. In type 2 MEN syndrome, the complications may include hypercalcemia, chronic constipation, hypertensive episode, and recurrence of medullary thyroid carcinoma.

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