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Multiple Endocrine Neoplasia Type 1
Introduction
Multiple endocrine neoplasia type 1 (MEN1) is a rare endocrine tumor syndrome with high penetrance. This syndrome is also known as Wermer syndrome.[1] It primarily causes neoplasia of the parathyroid glands, the anterior pituitary gland, and the neuroendocrine tissue of gastro-entero-pancreatic organ systems. Hyperparathyroidism is the most common manifestation and occurs in 90% of cases. Similarly, pancreatic neuroendocrine tumors occur in 60% of cases, while pituitary adenomas occur in 40% of cases. The affected patient, however, may also develop less common endocrine and non-endocrine tumors such as carcinoid tumors of the thymus, bronchus, or stomach, adrenocortical tumors, cutaneous tumors, central nervous system (CNS) tumors, leiomyomas, lipomas, collagenomas, and angiofibromas.
MEN1 gene testing in an index case can confirm the diagnosis and allow early detection of asymptomatic mutation carriers years before a MEN1-associated tumor can be detected. However, approximately 20% of MEN1 kindred have no mutation in the MEN1 gene. Unfortunately, there is no genotypic-phenotypic correlation in MEN1, leading to different manifestations even among family members. Studies have demonstrated that nonsense and splicing mutations are associated with more aggressive neuroendocrine tumors.[2]
Etiology
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Etiology
Germline inactivating mutations of the MEN1 or menin gene on chromosome 11 results in MEN1 Syndrome. MEN1 syndrome is inherited in an autosomal dominant pattern. In approximately 90% of cases, mutations are inherited from an affected parent, while in the remaining 10% of cases, the syndrome occurs secondary to a de novo mutation. Given this latter figure, clinical diagnostic criteria remain of utmost importance in diagnosing this syndrome.
Marini et al. published an analysis of germline MEN1 mutations in 410 patients and found 99 different mutations, 41 frameshift, 26 missense, 13 nonsense, 11 splicing site mutations, 4 in-frame small deletions, and 4 large intragenic deletions spanning over 1 exon. The study also demonstrated that gastro-entero-pancreatic tumors were more common in patients with nonsense mutations, while thoracic neuroendocrine tumors were more common in individuals bearing a splice mutation.[3] Germline mutations of CDKN1B have also been associated with pituitary adenomas, parathyroid adenomas, and pancreatic neuroendocrine tumors. Therefore, it is possible that mutations in this gene could potentially account for MEN1 syndromes without MEN1 gene mutation.
Epidemiology
Diagnosis of MEN1 is established if the index case has at least two of the primary manifestations of MEN1 Syndrome (tumor of parathyroid glands, anterior pituitary gland, and a neuroendocrine component of gastro-entero-pancreatic tissue) or at least one MEN1-related tumor and a first-degree relative with confirmed MEN1 (positive MEN1 gene mutation), or finally, the index case has the pathologic mutation in the MEN1 gene.
MEN1 Syndrome is rare, with an incidence of 0.25% and an estimated prevalence between 0.02 to 0.2 per thousand. MEN1 has been shown to affect both males and females equally, which was demonstrated in the study by Gaudet et al., in which of the total 734 MEN1 patients, there was a slight female preponderance (57.8%). The prevalence of pancreatic tumors was higher in men, with the most common manifestation being gastrinoma. The prevalence of pituitary tumors was slightly higher in women, and thymic tumors were exclusively found in men.[4]
Clinical and biochemical manifestations develop in greater than 94% of the patients by the fifth decade of life. Regardless, the disorder affects all age groups and has even been reported in children as young as five years of age. Cushing disease may be the first presentation in children with MEN1, as reported by Makri et al. in their retrospective chart review of 238 patients admitted to the National Institute of Health (NIH) for evaluation of hypercortisolemia. Of the cohort, six patients were diagnosed with MEN1, in which 5 cases were familial and one case was sporadic.[5]
History and Physical
A comprehensive history should be obtained during an initial visit due to the multiple organ systems affected by MEN1 Syndrome. Likewise, comprehensive family history can lead to early diagnosis as MEN1 may affect members of the same family. Patients in the same family may have different manifestations due to heterogeneous phenotypic expression.
A complete physical examination is of utmost importance during initial and follow-up visits. Attention should be directed to any visual field changes or masses in the neck or abdominal region. Physicians may identify MEN1 in many patients after incidental, abnormal laboratory, or imaging studies. Symptoms may differ depending upon which organs are affected. The physical examination may be normal in many of these patients as the tumor size may be small.
Evaluation
Evaluation of Multiple Endocrine Neoplasia Type 1 (MEN1) involves a comprehensive laboratory and radiographic workup to help identify individual conditions. The following discussion will focus on the workup of the individual parathyroid, anterior pituitary, and neuroendocrine tissue systems involved.
Parathyroid Glands
Evaluation of hyperparathyroidism involves the measurement of serum calcium and parathyroid hormone intact (PTH) levels. The PTH level may be minimally elevated or within the upper limits of normal, which can lead to a delay in diagnosis. Imaging modalities such as parathyroid ultrasound and 99-Technetium Sestamibi scans are of limited value due to diffuse hyperplasia involving multiple glands that may be seen in MEN1 patients.
Neuroendocrine Tissue Systems
Evaluation of gastro-entero-pancreatic tumors involves measuring serum levels of gastrin, glucagon, insulin, proinsulin, C-peptide, chromogranin A, pancreatic polypeptide, and vasoactive intestinal peptide (VIP). Elevated levels of typically one and sometimes more of the aforementioned markers indicate a diagnosis of neoplasia within gastric, enteric, or pancreatic tissues. Different modalities such as transabdominal ultrasound, computed tomography (CT), magnetic resonance angiography (MRI), octreotide scan (Octreoscan), and 68Ga-DOTATOC PET imaging are used for localization of the tumors and possible metastases. Of the imaging modalities, endoscopic ultrasound (EUS) is the most sensitive single modality to detect pancreaticoduodenal tumors. Multiple studies have reported significant superiority of EUS as compared to CT scans and somatostatin-receptor scintigraphy.[6]
Anterior Pituitary Gland
Evaluation of pituitary gland tumors involves measurement of pituitary hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor 1 (IGF-1), follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), thyroxine (T4), and cortisol levels.[7] These tumors most commonly secrete prolactin, followed by growth hormone. Serial basal PRL levels greater than 200 ng/ml confirm a prolactinoma. Elevated IGF-1 levels with the failure of GH suppression during an oral glucose tolerance test confirm a GH-secreting adenoma. Non-secreting pituitary tumors can cause hypopituitarism by compression of the pituitary gland. MRI of the pituitary gland with contrast is the best diagnostic imaging. Thin cuts through the pituitary gland should be completed to avoid missing smaller-sized tumors. Pituitary MRI is also used to evaluate the effectiveness of treatment during follow-up of pituitary tumors.
Treatment / Management
Parathyroid
Primary hyperparathyroidism (PHPT) is the most common and the first clinical manifestation of MEN1. It affects approximately 90% of MEN1 patients and is commonly diagnosed during the second decade of life.
Multi-gland, nodular hyperplasia is typical in MEN1 hyperparathyroidism and presents as hypercalcemia or its corresponding complications.
MEN1-related PHPT is associated with more severe bone disease despite a milder biochemical presentation (PTH value in the normal range) when compared with sporadic PHPT.[8](B2)
Parathyroid cancer is sporadic in MEN1. Di Meo et al. reported 17 cases of parathyroid cancer, of which 59% were seen in men, and the median age of diagnosis was 50.[9](B3)
Treatment of PHPT in MEN1 involving subtotal parathyroidectomy versus total parathyroidectomy remains controversial. Total parathyroidectomy with forearm transplantation is associated with a lower chance of persistent hyperparathyroidism; however, there is a higher risk of hypoparathyroidism of 22% to 36% compared to 10% with subtotal parathyroidectomy.[2] Bone mineral density improves after parathyroidectomy, but bone antiresorptive medications are recommended to treat osteoporosis in resistant cases.[10]
Non-Functioning Gastro-Entero-Pancreatic Tumors
Non-functioning pancreatic NETs are the most common gastro-entero-pancreatic tumors.[11] These lesions cause no clinical syndrome and may secrete a small amount of pancreatic polypeptide and gastrin. These represent the most frequent cause of death in MEN1 patients. There can be a delay in diagnosing non-functioning pancreatic NET due to the lack of specific symptoms or clinical findings.
Radiological screening for diagnosis of pancreatic NET in MEN1 is recommended at the age of 10 years.
Treatment of a non-functioning pancreatic NET is challenging and controversial because of the lack of consensus on surgical indications. Triponez et al. reported that tumor size in non-functioning pancreatic NET correlates with the risk of metastasis and death[11], but other studies did not confirm similar findings. Clinical practice guidelines for MEN1 recommend surgery if the tumor size is greater than 1 cm, while other studies do not recommend surgery until the size is 20 mm or larger. Surgery can be considered for tumors less than 1 cm if there is rapid growth. So far, tumor size has remained the deciding factor; however, it must be noted that aggressive surgical management can cause significant complications like diabetes mellitus, steatorrhea, and early dumping syndrome.
Functioning Gastro-Entero-Pancreatic Tumors
The neuroendocrine tumor (NET) of gastro-entero-pancreatic tissues occurs in approximately 30% to 75% of cases, yet post-mortem studies have shown a prevalence of 80% to 100%.[12] A non-functioning NET is more common than a functioning tumor.
Pancreaticoduodenal NET in MEN1 presents early in life, it is almost always present in multiple, and it has an uncertain behavior with a risk of malignancy. Somatostatin analogs have been used with some success in any stage of the disease and can be a reasonable choice in treating any neuroendocrine tumor.[13] (A1)
Functioning NET-secreting gastrin can cause peptic ulcer disease because of increased gastric acid secretion, known as Zollinger-Ellison syndrome. Functioning NET can also cause hypoglycemia by secreting an excessive amount of insulin. However, tumors secreting pancreatic polypeptide may not cause any clinical manifestations.[14](A1)
Gastrinoma
The most frequent islet cell neoplasm is gastrinoma. Gastrinomas in MEN1 can be pancreatic or duodenal and are most often diagnosed in the third or fourth decade of life. A detailed history, physical examination, and biochemical evaluation should be performed in patients with gastrinoma, as one-third of patients with gastrinomas have MEN1. These patients have elevated gastrin levels or hypergastrinemia and increased gastric acid output.
Duodenal gastrinomas in MEN1 syndrome are usually small (less than 1 cm), multifocal, and occur primarily in the proximal duodenum. Lymph node metastasis occurs in 45% to 95% of pancreatic and duodenal gastrinoma, with liver metastases less common in duodenal NETs.[12]
Insulinoma
Insulinoma is the second most common functional pancreatic NET. It represents 10% to 30% of patients with pancreatic NET in MEN1. These tumors secrete a significant amount of insulin which can cause the clinical manifestation of hypoglycemia, including neuroglycopenic symptoms and sometimes seizures or loss of consciousness. Patients with insulinoma due to MEN1 are mostly younger than 40 years old when compared with insulinoma patients without MEN1 that are older than 40 years old.[14](A1)
Fasting hypoglycemia with a glucose level of less than 45 mg/dl and concomitant hyperinsulinemia, defined as an insulin level greater than 6 uU/mL, are diagnostic of insulinoma.[15] An elevated level of proinsulin and C-peptide can confirm the diagnosis of insulinoma.(B3)
Surgical treatment is necessary for insulinoma patients. Preoperative tumor localization with different modalities, including transhepatic portal venous sampling, can improve the success rate of surgery. Surgical treatment can vary from the enucleation of a single lesion to partial pancreatectomy. These patients can be managed medically with diazoxide or octreotide; frequent carbohydrate meals may also help lower the hypoglycemia risk.
Tonelli et al. reported 12 MEN1 insulinoma patients who underwent surgery; distal pancreatic resection was performed in 8 patients, and the remaining four underwent pancreaticoduodenectomy. Enucleation of another macroadenoma in the remnant pancreas was performed in 9 out of 12 patients. There were no clinical recurrences at a mean follow-up of 85 months, but recurrence of non-functioning pancreatic macroadenoma occurred in 1 out of 12 patients.[16]
Chemotherapy can be used in patients with metastatic insulinoma.
Glucagonoma
Glucagonoma occurs in less than 3% of MEN1 patients. The typical manifestations include necrolytic migratory erythema, weight loss, anemia, and stomatitis. Glucagon levels are significantly elevated in these patients, usually greater than 500 pg/ml.[17] The most common site of occurrence is the tail of the pancreas, and surgical removal is the treatment of choice. Metastatic disease is present in 50% to 80% of patients at the time of diagnosis. Medical management includes somatostatin analogs or chemotherapy.
VIPoma
VIPomas are not common in MEN1—these patients present with watery diarrhea, hypokalemia, and achlorhydria, also known as Verner-Morrison syndrome. Stool volume of more than 0.5 to 1 L per day during a fast is typical. The use of laxatives and diuretics should be ruled out before confirming the diagnosis of VIPoma. Like glucagonoma, the most common site of involvement is the tail of the pancreas. Surgical resection can be curative in the absence of metastatic disease. Medical treatment includes somatostatin analogs, metoclopramide, or chemotherapy agents like 5-fluorouracil or streptozotocin.
Pituitary Tumors
The prevalence of anterior pituitary tumors in MEN1 syndrome is approximately 20% to 60%, and the anterior pituitary tumor can be an initial presentation in about 25% of MEN1 patients.
Anterior pituitary tumors in MEN1 are more common in women and are predominantly macroadenomas.[18](B2)
Medical management includes the use of cabergoline or bromocriptine in patients with prolactinoma. Octreotide or lanreotide are used in GH-producing tumors.
Studies have shown that anterior pituitary tumors in MEN1 patients are more aggressive and less likely to respond to medical management; thus, they may require surgical management more often. Radiation treatment is used for patients with residual unresectable tumors.
Surgical management is performed in patients with large pituitary tumors with compression of the optic nerve, tumors more than 1 cm, or tumors which do not improve with medical management.
Carcinoid
Carcinoid tumors affect 3% of MEN1 patients. Common sites of involvement are the gastrointestinal (GI) tract, bronchi, pancreas, and thymus. Somatostatin analogs such as octreotide or lanreotide have been shown to cause regression of gastric carcinoids.[19] (B3)
Bronchial carcinoid tumors are more common in women, but thymic carcinoid tumors in European patients occur predominantly in men. Thymic carcinoids are aggressive in MEN1 patients. Goudet et al. reported a survival rate of only 9.5 years after diagnosing a thymic tumor, with 70% mortality linked directly to the tumor.[4](B2)
Screening for these patients is performed with radiologic imaging such as a CT scan and MRI every 1 to 2 years. Biochemical evaluation is not done routinely due to a lack of any specific biochemical abnormality or hormone production.
Surgical removal is the treatment of choice. Thymic carcinoid has been recognized and identified even in patients who underwent prophylactic thymectomy. Therefore, surveillance with imaging is required. Radiotherapy and chemotherapy can be employed in patients with unresectable tumors or metastatic disease.
Adrenal Tumors
Asymptomatic adrenal tumors occur in approximately 20% to 73% of MEN1 patients. Compared to adrenal incidentalomas, there is more likelihood of hyperaldosteronism and adrenocortical cancer but less likelihood of pheochromocytoma in those patients.[20](B2)
The incidence of adrenocortical cancer is approximately 1% in MEN1 patients, but this value can increase up to 13% with an adrenal tumor larger than 1 cm.
Biochemical evaluation of adrenal tumors includes measurement of plasma-free metanephrines, 1-mg overnight dexamethasone suppression test, 24-hour urine collection for free cortisol, and late evening salivary cortisol. Additionally, plasma renin and aldosterone levels should be obtained. Increased aldosterone:renin ratio (greater than 20) and increased urinary aldosterone secretion are diagnostic for an aldosteronoma.
There is no consensus about managing non-functioning adrenal tumors in MEN1 patients. Nevertheless, due to the increased risk of adrenocortical cancer, surgery is recommended if the tumor size is larger than 4 cm or if a tumor sized between 1 and 4 cm has significant, measurable growth over six months with suspicious radiological features.
LeBodic et al. reported an immunohistochemical study of 100 pancreatic tumors in 28 MEN1 patients. They found that out of 100 tumors, 83 produced a predominant hormone, 10 were pluri-hormonal, and multiple tumors had a different predominant hormonal secretion in the same patient in 23 out of 28 patients.[21](B3)
Breast
Breast cancer is more common in female MEN1 patients and occurs at an early age. Rachel et al. found that the median age of breast cancer in women with MEN1 was 45 compared to 57.5 years in female relatives without MEN1 and 61.2 in the Dutch reference population.[22] The importance of breast cancer screening cannot be overstated in these patients.
Differential Diagnosis
Differential diagnoses of MEN1 include Von Hippel-Lindau Syndrome, Neurofibromatosis Type 1, tuberous sclerosis complex, and Multiple Endocrine Neoplasia Type 4.
Prognosis
The prognosis of the MEN1 patient is variable. Tumors associated with MEN1 are more aggressive and challenging to treat. Average life expectancy is shorter in patients with non-functioning pancreatic NET than in patients without pancreatic NET tumors due to tumor expansion complications. Additionally, neuroendocrine tumors can metastasize quickly and can cause premature death. Studies have shown an increased risk of premature death and decreased average life expectancy in MEN1 patients.[23] These patients can also develop significant morbidity from surgical complications; early diagnosis and treatment are of utmost importance.
Complications
The complications in MEN1 can occur secondary to the pathophysiology or the surgical treatments.
Regarding pathophysiology, pituitary tumors can cause pituitary insufficiency and visual field defects. Parathyroid tumors can cause metabolic bone disease and kidney stones. Tumors of gastro-entero-pancreatic tissue can cause excessive secretion of gastrin, insulin, glucagon, or vasoactive intestinal peptide, damaging the gastrointestinal system. Similarly, full-body complications may occur as a result of metastases.
Deterrence and Patient Education
Patient education is vital. Once the physician diagnoses MEN1, the patient's family should see a genetic counselor to learn about the disease and how it may impact the patient and the patient's family. A genetic counselor should also encourage the rest of the family to get genetic testing done. Complete knowledge of the disease can help the patient to make an appropriate and informed decision.
Pearls and Other Issues
Because of the rarity of the MEN1 syndrome and the complexity of the disease, clinical management is difficult. Most recommendations regarding the management of MEN1 patients lack a high level of evidence suggesting the need for more research in this field. Al-Salameh et al. reported that only 11 out of the 47 recommendations for MEN1 are considered to have a high level of evidence.[1][24]
Enhancing Healthcare Team Outcomes
MEN1 is a complex syndrome that increases morbidity and mortality by causing multiple aggressive tumors. An interprofessional team should manage these patients in a tertiary care center, including an endocrinologist, endocrine surgeon, gastroenterologist, neurosurgeon, genetic counselor, nursing staff, pharmacist, and patient navigator or advocate for achieving better outcomes.[25]
Clinicians will determine the therapeutic path to be followed and consult with other specialists as the case dictates. Oncology specialized pharmacists can play a crucial role in chemotherapy regimens, checking for appropriate dosing, performing medication reconciliation, and being available for other team members to answer questions about the most effective agents. They can also counsel the patient regarding adverse effects and answer patient questions. Nurses will administer these agents and need to communicate with the ordering clinician and the pharmacist regarding appropriate dosing and administration. Nurses will also play a critical role in surgical management, prepping the patient, assisting during the procedure, and providing post-operative care while keeping clinicians updated on the patient's status.
Everyone on the interprofessional team must maintain meticulous records regarding all patient interventions and interactions so that everyone involved in care can access the same updated data. This interprofessional approach will yield the best patient outcomes with the fewest adverse events. [Level 5]
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