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![Pancreatic polypeptidomas (PPomas)
Pancreatic polypeptide levels are elevated.
Chromogranin A levels can be elevated in any pancreatic
neuroendocrine tumor.
Screening should begin by age 10 years.
Carcinoid tumors
Elevated levels of chromogranin A, calcitonin, corticotropin, or
urinary 5-hydroxyindoleacetic acid (5-HIAA) can occur.
screening is dependent on radiological imaging as no
biochemical abnormality has been consistently observed.
Pituitary tumors
Assess growth hormone levels (insulinlike growth factor-1 [IGF-
1]) and prolactin.
Screening should begin by age 5 years.
Hyperparathyroidism
Calcium is elevated with an inappropriately elevated parathyroid
hormone level.
Screening should start by age 8 years.](https://image.slidesharecdn.com/multipleendocrineneoplasiamensyndromes-180316184612/75/Multiple-endocrine-neoplasia-men-syndromes-19-2048.jpg)
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Multiple endocrine neoplasia (men) syndromes
- 1. BY /Marwa MahmoudKhalifa Hematology Resident
- 2. Background Multiple endocrine neoplasia(MEN) syndromes consist of 2 categories, MEN type 1 (MEN1) and MEN type 2 (MEN2). MEN2 has been subcategorized into MEN2- A, MEN2-B, and medullary thyroid cancer (MTC)– only.
- 4. MEN type 1 The combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors is characteristic of MEN1. usually inherited as an autosomal dominant disorder can also occur sporadically (without a family history) In 1954, Wermer was the first to describe the syndrome as a distinct clinical entity.
- 7. Etiology The responsiblegene for (MEN1) is located at 11q13 and codes for the menin protein. Menin is involved with regulation of transcription and genome stability. Loss of heterozygosity for this region is associated with MEN1, suggesting that the gene has tumor suppression function. MEN1 is an autosomal dominant disorder, but sporadic mutations also occur.
- 8. Pathophysiology and presentations Parathyroidtumors Primary hyperparathyroidism, caused by hyperplasia of parathyroid glands, is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1) and occurs in approximately 90% of all patients. Clinical manifestations can include hypercalcemia, nephrolithiasis, and bone abnormalities (osteitis fibrosa cystica). Common symptoms associated with hypercalcemia include polydipsia, polyuria, constipation, and generalized malaise.
- 9. Pancreatic isletcell tumors (neuroendocrine tumors) the second most common manifestation of MEN1 30-80% of patients. Islet cell tumors encompass gastrinomas, insulinomas, glucagonomas ,vasoactive intestinal polypeptidomas (VIPomas), and pancreatic polypeptidomas (PPomas). often multicentric and may undergo malignant transformation. These tumors can produce peptides and biogenic amines. However, nonfunctioning pancreatic endocrine tumors are the most common enteropancreatic neuroendocrine tumor. important to diagnose, as malignant pancreatic neuroendocrine tumors are the most frequent cause of death in people with MEN1.
- 10. Gastrinomas the mostcommon functional pancreatic neuroendocrine tumors. often small, multicentric, and located in the duodenum, thus diminishing the probability of surgical cure. The features predictive of poor prognosis include pancreatic location of lesions, metastases, ectopic Cushing syndrome, and high gastrin level. The development of gastrinomas is preceded by multifocal hyperplasia of the gastrin-producing cells.
- 11. Insulinomas can bemulticentric and can metastasize either to regional lymph nodes or to the liver. Unlike non-MEN1 insulinomas, usually occur in patients younger than 40 years and many are diagnosed in patients younger than 20 years. Patients often present with hypoglycemic symptoms after a fast, low blood glucose with symptoms improving after glucose intake hypoglycemic symptoms (Whipple’s triad).
- 12. Glucagonomas occur rarely(3%) in patients with MEN1 can present silently or with hyperglycemia. Few patients show the typical skin lesions, known as necrolytic migratory erythema. Other presenting symptoms can be anemia, stomatitis, and weight loss, but these are often absent.
- 13. A characteristic rashcalled necrolytic migratory erythema seen in the face, lower abdomen, perineum, and lower extremities.
- 14. VIPomas occur inless than 1% of MEN1 patients. Presenting symptoms can include watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome). Tumors secreting pancreatic polypeptide (PPomas) may not be associated with clinical manifestations and may be nonsecretory. Growth hormone–releasing hormone tumors (GHRHomas) have been reported in patients with MEN1 and most commonly arise in the lungs, followed by the pancreas and small intestine
- 15. Pituitary tumors MEN1-associatedpituitary tumors most commonly secrete prolactin (60%), followed by tumors that secrete growth hormone (25%). Less than 5% secrete corticotropin and others are nonfunctional. Compared with non-MEN1 pituitary tumors, they tend to be larger (macroadenomas) and more aggressive, with a higher rate of infiltration of tumor cells into normal pituitary tissue. MEN1-associated pituitary tumors are less responsive to therapy. However, there is no distinct histological difference between MEN1 and non-MEN1 pituitary tumors.
- 16. Other tumors associatedwith MEN1 Carcinoid tumors can occur in patients with MEN1 and are located in the bronchi, gastrointestinal tract, pancreas, and thymus..Carcinoids can actively secrete hormones such as serotonin, somatostatin, corticotropin, and growth hormone. Cutaneous expression of MEN1 is common. Subcutaneous lipomas are found in one third of MEN1 patients,can also be retroperitoneal, visceral, or pleural. The presence of facial angiofibromas and collagenomas may allow presymptomatic diagnosis of MEN1 in relatives of diagnosed patients. Adrenal tumors occur and usually are nonfunctional. They are most often benign 20-40% of patients. Adrenal cortical carcinomas are rare in MEN1 patients Thyroid adenomas occur in 5-30% of patients and have no specific MEN1-reported clinical significance. Meningiomas and other central nervous system tumors have been reported.
- 17. Laboratory Studies Gastrinomas Screeningshould start by age 20 years. The diagnosis of gastrinoma is confirmed by a basal serum gastrin level >1000 pg/ml off proton- pump inhibitors. A basal gastrin levels >250 pg/ml is suggestive and can be confirmed with a secretion stimulation test
- 18. Insulinomas A supervised72-hour fast is used most often to confirm this diagnosis. Screening should start by age 5 years. Glucagonomas Elevated serum glucagon levels and hyperglycemia are present Screening should start in children younger than 10 years. Vasoactive intestinal polypeptidomas (VIPomas) Elevated serum levels of vasoactive intestinal polypeptide are present. Screening should start in children younger than 10 years.
- 19. Pancreatic polypeptidomas (PPomas) Pancreatic polypeptide levels are elevated. Chromogranin A levels can be elevated in any pancreatic neuroendocrine tumor. Screening should begin by age 10 years. Carcinoid tumors Elevated levels of chromogranin A, calcitonin, corticotropin, or urinary 5-hydroxyindoleacetic acid (5-HIAA) can occur. screening is dependent on radiological imaging as no biochemical abnormality has been consistently observed. Pituitary tumors Assess growth hormone levels (insulinlike growth factor-1 [IGF- 1]) and prolactin. Screening should begin by age 5 years. Hyperparathyroidism Calcium is elevated with an inappropriately elevated parathyroid hormone level. Screening should start by age 8 years.
- 20. Imaging Studies Sagittal (leftimage) and coronal (right image), T1- weighted magnetic resonance images of the brain in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These images show a pituitary macroadenoma
- 21. octreotide scan ina patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These nuclear images demonstrate abnormal activity in the pituitary macroadenoma (curved arrow), parathyroid adenoma (straight arrow), and gastrinoma metastases throughout the abdomen (arrowheads).
- 22. (CT) scan ofthe pancreas in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and a gastrinoma. This image shows a pancreatic head mass (large, white arrow), as well as a low- attenuating lesion in the liver (small, black arrowhead) that indicates metastases
- 23. (CT) scan imagewith oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S)
- 24. Endoscopic ultrasonogram in a patientwith an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV).
- 25. •99mTc MIBI) ina patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These images demonstrate persistent abnormal activity of the inferior right parathyroid gland that is consistent with an adenoma.
- 26. Anteroposterior radiographic view ofthe right hand in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and primary hyperparathyroidism. This image shows subperiosteal bone resorption along the radial aspects of the middle phalanges (arrows).
- 27. Other Tests Genetictesting Histologic Findings
- 28. Approach Considerations Hyperparathyroidism Surgery is the definitive treatment. Subtotal (3.5 glands)or total parathyroidectomy with forearm autotransplantation is performed with an open bilateral neck exploration. The recommended timing of surgery in a patient is controversial. Recurrent hypercalcemia is common. Transcervical thymectomy may need to be performed at the same time, owing to the mortality associated with malignant carcinoid tumors of the thymus.
- 29. Gastrinoma Inhibitionof acid hypersecretion is achieved with proton pump inhibitors. Histamine receptor antagonists may be added. Nonmetastatic gastrinomas located in the pancreas are rare but can be surgically excised. Removal of tumors larger than 2 cm in diameter reduces the frequency of liver metastasis, which is an important prognostic factor.Surgical cure of multiple duodenal gastrinomas is difficult Other novel approaches, such as chemotherapeutic agents or hormonal therapy with somatostatin analogs, can be considered to treat disseminated gastrinomas.
- 30. Insulinoma Surgicalremoval of the tumor is the treatment of choice. Unresectable tumors can be treated with diazoxide or octreotide. Chemotherapeutic agents or hepatic artery embolization has been used to treat metastatic disease Some authors recommend subtotal pancreatectomy (80% or more of the pancreas) in patients with multiple tumors or when the tumor is not localized.
- 31. Glucagonomas Surgicalremoval of the tumor is the treatment of choice. Usually, this involves excision of the tail of the pancreas. However, often times, metastases have already occurred at the time of diagnosis. Somatostatin analogs (lanreotide or octreotide), chemotherapeutic agents, and hepatic artery embolization have also been used Vasoactive intestinal polypeptide tumor (VIPoma) Somatostatin analogs control symptoms in 80% of cases, although surgical cure should be attempted. Asymptomatic nonfunctioning pancreatic neuroendocrine tumors A consensus regarding surgical indications has not been established. The goal is to reduce mortality and morbidity associated with metastatic disease while preserving pancreatic tissue. Conflicting expert opinion suggests surgical removal of tumors greater than 1 cm versus 2 cm.
- 32. Pituitary tumors Treatment is similar to non-MEN1–associated pituitary tumors. Prolactinomas are treated with bromocriptine or cabergoline. Octreotide or lanreotide is used for somatotrophinomas. Transsphenoidal tumor removal with radiotherapy can be used if necessary. Carcinoid tumors If resectable, surgery is the treatment of choice. For unresectable tumors, treatment with radiotherapy or chemotherapeutic agents can be used. Somatostatin analogs can help with symptoms and may shrink some tumors. Cutaneous manifestations of MEN1 Management is conservative for lipomas, facial angiofibromas, and collagenomas. Local excision can be performed if desired.
- 33. SOMATOSTATIN ANALOGS Usedsince 1980’s Hormone blocking agents that are synthetic somatostatin derivatives (ex: octreotide and lanreotide) Octreotide acts primarily on somatostatin receptor subtypes II and V. It inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, vasoactive intestinal peptide, and GI peptides. Side effects: development of gallstones secondary to inhibition of cholecystokinin release, pain at site, hypo or hyperglycemia, rash, alopecia, fluid retention
- 35. Type 2 multipleendocrine neoplasia (MEN 2) Sipple first described an association between thyroid cancer and pheochromocytoma in 1961. The thyroid cancer found with pheochromocytoma was discovered in 1965 to be a medullary carcinoma characterized by stromal amyloid. In 1968, this familial constellation of pathology in conjunction with parathyroid hyperplasia was recognized as (MEN 2). the distinction between MEN 2A and MEN 2B was not made until 1975
- 36. Phenotype -MEN 2A patients do not have the phenotypic abnormalities of mucosal neuromas and marfanoid habitus found in MEN 2B patients Medullary thyroid carcinoma - MEN 2A patients have a less virulent than do MEN 2B patients Parathyroid hyperplasia - MEN 2A patients may have, which is exceedingly rare in MEN 2B patients A third subtype of MEN 2 is familial medullary thyroid carcinoma only (FMTC only).
- 37. Etiology MEN 2is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene localized to 10q11.2 . Inherited as an autosomal dominant disorder,
- 38. Pathophysiology and presentations Medullarythyroid carcinoma Virtually in all patients with MEN 2A. the first expressed abnormality and usually occurs in the second or third decade of life. typically bilateral and multicentric, in contrast to sporadic medullary thyroid carcinoma, which is unilateral. Pheochromocytoma Pheochromocytomas are present in 50% of MEN 2A patients. bilateral in 60-80% of patients, compared with 10% of patients with sporadic pheochromocytomas. diagnosed at the same time as medullary thyroid carcinoma or several years later (with both occurring primarily in the second or third decade). nearly all benign. Even so, these lesions can cause a life-threatening hypertensive episode or arrhythmia. Parathyroid hyperplasia in nearly half of patients with MEN 2A but are less common than pheochromocytomas. can be clinically silent. .
- 39. Hypertension Ifpheochromocytomas 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. Diarrhea If a patient has medullary thyroid carcinoma This may be related to elevated prostaglandin or calcitonin levels. Pruritic skin lesions Cutaneous lichen amyloidosis in MEN 2A patients manifests as multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back..
- 41. The marfanoidhabitus of high-arched palate, pectus excavatum, bilateral pes cavus, and scoliosis are observed in MEN 2B patients. Neuromas on the eyelids, conjunctiva, nasal and laryngeal mucosa, tongue, and lips are frequent findings. Patients also have prominent, hypertrophied lips leading to a characteristic facies. Localized pruritus appears over the upper back in MEN 2B patients.
- 43. Approach Considerations Performgenetic screening for RET mutations in all index patients. If a mutation is identified, also screen family members who are at risk. baseline calcitonin levels and of serum calcium and parathyroid hormone (PTH) levels, along with urine collection for catecholamines and metanephrine concentrations. Imaging Studies Perform computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the adrenals. A metaiodobenzylguanidine (MIBG) scan is useful for localizing pheochromocytomas
- 44. Fine-needle aspiration Avoid the removal of cells from thyroid masses for cytology in patients with type 2 multiple endocrine neoplasia (MEN 2) who have had their diagnosis previously confirmed by either genetic analysis or elevated calcitonin levels as biopsy increases the possibility of tumor spread
- 45. Management of comlications Pheochromocytoma Preoperatively, prepare patients by treating them with an alpha-blocker or a tyrosine hydroxylase inhibitor, such as metyrosine, for 1-2 weeks, after which administration of a beta-blocker can be considered Hypercalcemia Patients presenting with severe hypercalcemia should first be hydrated, after which they should be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, glucocorticoids, or bisphosphonates (such as pamidronate).
- 46. Treatment strategy Surgicaltreatment is the standard with replacement therapy after the surgey Patients require hormone replacement following total thyroidectomy and bilateral adrenalectomy or when they have postoperative hypoparathyroidism. In addition, patients who develop postoperative hypoparathyroidism need supplemental calcium and/or vitamin D. The corticosteroid cortisone and the mineralocorticoid fludrocortisone acetate can be used in combination in patients suffering from adrenocortical insufficiency.