Multiple endocrine neoplasia

Multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), along with Von Hippel-Lindau disease, are hereditary conditions that increase the risk of specific endocrine diseases. The genetic mutations responsible for these conditions are known, but the exact mechanisms leading to tumor development are still under active research.

Multiple Endocrine Neoplasia Type 1 (MEN1)

Individuals with MEN1 are susceptible to primary hyperparathyroidism, pituitary tumors, and pancreatic hormone-secreting neoplasia. This condition should be suspected in anyone who exhibits two or more endocrine tumors or has a family history of MEN1 along with features of an endocrine disorder. Additionally, some MEN1 patients may develop adrenocortical tumors (which can be non-functioning), carcinoid tumors, facial angiofibromas, collagenomas, or lipomatous tumors.

Parathyroid tumors

Primary hyperparathyroidism is the most common manifestation in MEN1, presenting at a younger age than in sporadic cases. These patients are at risk of the classic symptoms of hypercalcemia, often referred to as “bones, stones, moans, and groans.” Notably, the gender ratio for primary hyperparathyroidism in MEN1 is equal (1:1), which differs from the female predominance observed in sporadic cases (3:1 female-to-male ratio).

Patients with MEN1 typically exhibit mild hypercalcemia. In those with a family history, the condition may initially present as asymptomatic biochemical hypercalcemia with normal or elevated parathyroid hormone (PTH) levels. Unlike sporadic cases, histology in MEN1 often reveals parathyroid hyperplasia instead of a single adenoma. The surgical management of these patients is complex, as they may require multiple neck surgeries.

Treating a recurrence of primary hyperparathyroidism is notably more challenging than initial surgeries, particularly due to the difficulty in locating a small parathyroid adenoma in a previously operated neck. This complexity necessitates careful planning for potential future surgeries in these patients.

Some medical centers advocate for the removal of all four parathyroid glands in such cases. However, this approach leads to hypoparathyroidism, making patients reliant on calcium and one-alpha calcidol for life. It’s important to note that non-one-alpha-hydroxylated forms of calciferol (vitamin D) are ineffective without parathyroid hormone (PTH).

Alternatively, other centers prefer to remove each adenoma as it develops. While this might seem less invasive initially, it carries the risk of requiring multiple surgeries throughout the patient’s life, with each subsequent operation becoming increasingly difficult.

A crucial aspect of treatment is having a thorough discussion with the patient about these options. This includes considering the removal of all but half of a parathyroid gland. In such a procedure, the enlarged glands are removed, and part of one normal gland is also taken out. The rationale is that the remaining half-gland should produce sufficient PTH to prevent hypocalcaemia, while also reducing the risk of recurrent primary hyperparathyroidism. This approach aims to balance the need for effective treatment with the long-term management of the condition and the patient’s quality of life.

Pancreatic Tumors

The occurrence of pancreatic tumors in patients with Multiple Endocrine Neoplasia type 1 (MEN1) varies widely, with incidence rates reported between 30% and 80%, depending on patient age and the medical center’s expertise. These tumors often produce excessive amounts of hormones such as gastrin, insulin, glucagon, or vasoactive intestinal polypeptide (VIP), each associated with specific clinical syndromes. Diagnosis typically involves measuring fasting gut hormones in a blood sample.

In MEN1, gastrin-secreting tumors (gastrinomas) account for over half of all pancreatic islet cell tumors. Conversely, about 20% of gastrinoma patients have MEN1. Gastrinomas are a significant cause of morbidity and mortality in MEN1 patients, often leading to multiple ulcers with a risk of perforation. These tumors also have metastatic potential. This combination of recurrent peptic ulceration, high gastric acid production, and non-islet β cell pancreatic tumors is known as Zollinger-Ellison syndrome, characterized clinically by diarrhea and steatorrhea. Diagnosis is confirmed by elevated fasting serum gastrin levels and increased basal gastric acid secretion.

Treatment for MEN1 patients with Zollinger-Ellison syndrome primarily involves reducing basal acid output, usually achieved with parietal cell proton pump inhibitors. The ideal approach for non-metastatic gastrinomas is surgical excision. However, in MEN1 patients, gastrinomas are often multiple or extra-pancreatic, making the role of surgery controversial. Some centers advocate for aggressive, repeated surgeries, while others prefer long-term management with proton pump inhibitors. For example, in one study, only a small percentage of MEN1 patients remained disease-free immediately after surgery, and this number decreased further over five years, contrasting with better outcomes in non-MEN1 patients.

Treating disseminated gastrinomas is challenging. Options include hormonal therapy with octreotide (a human somatostatin analogue), chemotherapy with streptozotocin and 5-fluorouracil, hepatic artery embolization, and removing all resectable tumors. These methods have had occasional success, highlighting the complexity of managing this aspect of MEN1.

Insulinomas, tumors of the islet β cells that secrete insulin, account for about one-third of all pancreatic tumors in patients with Multiple Endocrine Neoplasia type 1 (MEN1). In 10% of MEN1 patients, insulinomas co-occur with gastrinomas, and these two types of tumors may develop at different times. Insulinomas are more commonly diagnosed in MEN1 patients under 40, with many cases in individuals younger than 20. This contrasts with non-MEN1 patients, where insulinomas typically appear after the age of 40. In some cases, an insulinoma may be the first indication of MEN1, and around 4% of patients presenting with an insulinoma have MEN1.

Patients with insulinomas usually experience hypoglycemic symptoms, particularly after fasting or physical exertion, and these symptoms improve with glucose intake. Diagnosing an insulinoma involves biochemical tests showing elevated plasma insulin levels alongside hypoglycemia. Additionally, increased circulating levels of C-peptide and proinsulin can aid in the diagnosis. An insulin (C-peptide) suppression test may also be useful. Surgical options for insulinomas vary, ranging from enucleation of a single tumor to more extensive procedures like distal pancreatectomy or partial pancreatectomy. Surgery can be curative in some patients.

For metastatic disease, chemotherapy options include streptozotocin or octreotide. Medical management often involves regular carbohydrate meals and the use of diazoxide to help control symptoms and manage the condition.

Glucagonomas, which are rare glucagon-secreting pancreatic tumors found in the islet α cells, occur in less than 3% of patients with Multiple Endocrine Neoplasia type 1 (MEN1). These tumors may not always present with typical symptoms like skin rash (necrolytic migratory erythema), weight loss, anemia, and stomatitis. Often, their presence is indicated by glucose intolerance and hyperglucagonemia. Glucagonomas are most commonly located in the tail of the pancreas, and surgical removal of this region is the preferred treatment. Treatment can be challenging, as about half of the patients have metastases at diagnosis. Medical treatments, including octreotide and streptozotocin, have been successful in some cases.

VIPomas are pancreatic tumors that secrete vasoactive intestinal peptide (VIP), leading to symptoms like watery diarrhea, hypokalemia, and achlorhydria, a condition known as WDHA syndrome or Verner-Morrison syndrome. VIPomas are relatively rare in MEN1 patients. Diagnosis involves detecting elevated plasma VIP levels. Acute hypokalemia and dehydration can be life-threatening, requiring immediate and aggressive rehydration. As VIP is cleared by the kidneys, dehydration can lead to renal failure, further exacerbating the condition. Rehydration helps reduce VIP levels and alleviate severe diarrhea. Surgical removal, typically of tumors located in the tail of the pancreas, can be curative. For unresectable tumors, treatments like streptozotocin, octreotide, and corticosteroids have been beneficial.

PPomas are tumors that secrete pancreatic polypeptide (PP) and are found in many MEN1 patients. Despite the high frequency of these tumors, no clear pathological effects of excess PP have been identified, and the clinical significance of PP remains unclear. However, serum PP measurements have been proposed as a tool for detecting pancreatic tumors in MEN1 patients.

Pituitary Tumors

The prevalence of pituitary tumors in individuals with Multiple Endocrine Neoplasia type 1 (MEN1) varies widely, ranging from 15% to as high as 90%, depending on the intensity of the screening program used.

The most common type of pituitary tumor in MEN1 is a prolactinoma, which makes up about 60% of these tumors. Around 20% of pituitary tumors in MEN1 patients lead to acromegaly, and 5% are associated with Cushing’s disease. The remaining tumors are typically non-functioning. It’s worth noting that less than 3% of individuals presenting with a functioning pituitary tumor have MEN1, meaning the vast majority of these tumors occur sporadically. Regular screening for pituitary tumors, including prolactin level checks, is recommended for MEN1 patients.

The management of pituitary tumors in MEN1 is similar to the treatment of sporadic cases. This typically involves a combination of surgery, radiotherapy, and medical treatment.

In addition to pituitary tumors, MEN1 patients may also develop other types of tumors. Carcinoid tumors are found in about 3% of MEN1 patients, facial angiomas in nearly 90%, and adrenal tumors (usually non-functioning) in up to 40%. A small percentage of MEN1 patients may have functioning adrenal tumors, which can lead to conditions like Cushing’s or Conn’s syndrome.

Genetics of MEN1

The gene responsible for Multiple Endocrine Neoplasia type 1 (MEN1) was identified on chromosome 11 through genetic mapping studies focusing on MEN1-associated tumors. These studies revealed loss of heterozygosity in tumor cells, a condition where one allele of a gene carries a mutation and the other does not. In MEN1, the somatic cells are heterozygous, but this heterozygosity is lost in the cells that transform into tumors. This finding, supported by segregation studies in families with MEN1, aligns with Knudson’s model for tumour development, suggesting that the MEN1 gene functions as a tumor suppressor gene.

The protein encoded by the MEN1 gene is known as MENIN, comprising 610 amino acids and expressed in various tissues. Research into MENIN’s protein-protein interactions indicates its involvement in several crucial cellular processes, including transcriptional regulation, maintaining genome stability, and influencing cell division and proliferation. These interactions underline the significant role of MENIN in cellular function and its importance in the context of MEN1 and tumor development.

Multiple Endocrine Neoplasia Type 2 (MEN2)

Patients with Multiple Endocrine Neoplasia type 2 (MEN2) face significant risks of developing Medullary Thyroid Cancer (MTC), parathyroid hyperplasia, and pheochromocytoma. The risk of developing MTC in MEN2 patients is nearly 100%, making this a critical area for genetic screening. Early identification of the MEN2 gene in family members can be life-changing. Children who inherit the MEN2 gene are often recommended to undergo total thyroidectomy, along with lifelong monitoring for parathyroid disease through regular calcium measurements and for pheochromocytomas with routine catecholamine tests.

Without genetic screening and proactive management, individuals with MEN2 face a high risk of mortality by the age of 50, primarily due to complications from MTC and the cardiovascular impacts of an undiagnosed pheochromocytoma.

MEN2 was first described by John Sipple in 1961. The condition has three major variants: MEN2A, MEN2B, and Familial Medullary Thyroid Carcinoma (FMTC). These variants are associated with different mutations in the RET proto-oncogene, each leading to different clinical presentations and requiring specific management approaches. The identification of these variants and their associated genetic mutations has been crucial in guiding the treatment and management of MEN2.

Multiple Endocrine Neoplasia Type 2A (MEN2A)

Patients with MEN2A are at risk for medullary thyroid carcinoma, pheochromocytomas, and parathyroid hyperplasia. A striking characteristic of MEN2A is that nearly all patients develop thyroid cancer by the age of 10, prompting recommendations for prophylactic thyroidectomy. The risk of developing pheochromocytomas in these patients is about 50%, while parathyroid disease occurs in roughly 20%. During thyroidectomy, efforts are typically made to preserve the parathyroids to avoid lifelong dependency on calcium and one alpha calcidol supplements, which are required to manage calcium levels if the parathyroids are removed.

Multiple Endocrine Neoplasia Type 2B (MEN2B)

MEN2B patients face risks similar to those with MEN2A regarding medullary thyroid cancer and pheochromocytoma, but they do not have an increased risk of parathyroid disease. Instead, they often present with bowel ganglioneuromata and mucosal neuromas, which are visible in the mouth. Additionally, they may exhibit skeletal abnormalities such as kyphoscoliosis and have a facial appearance resembling Marfan’s syndrome, known as ‘Marfanoid habitus’, although they do not have true Marfan’s syndrome.

Familial Medullary Thyroid Carcinoma (FMTC)

FMTC patients predominantly present with thyroid cancer, as indicated by the name. Vigilance for pheochromocytomas is essential to ensure accurate diagnosis, especially to differentiate between FMTC and MEN2A.

The MEN2 Gene and Its Mutations

The gene responsible for MEN2 is located on chromosome 10 and is known as the RET proto-oncogene. In MEN2, there are strong correlations between specific genetic mutations and the phenotypic manifestations of the disease. The majority of MEN2A cases are caused by mutations in the cysteine-rich extracellular domain of RET (specifically at codons 609, 611, 618, 620, 630, and 634). These mutations lead to abnormal dimerization and activation of the RET receptor complex. Mutations in the intracellular tyrosine kinase domain (codons 768, 790, and 804) are less common and are traditionally associated with FMTC. They are rarely linked to other MEN2A-related tumors. In MEN2B, about 95% of cases involve a mutation leading to the substitution of methionine for threonine at position 918, altering the catalytic core of the receptor, which significantly impacts its function.

References

Trump, D., Farren, B., Wooding, C., Pang, J.T., Besser, G.M., Buchanan, K.D., Edwards, C.R., Heath, D.A., Jackson, C.E., Jansen, S., Lips, K., Monson, J., O’Halloran, D., Sampson, J., Shalet, S.M., Wheeler, M.H., Zink, A. & Thakker, R.V. (1996) Clinical studies of multiple endocrine neoplasia type 1 (MEN1) in 220 patients. Quarterly Journal of Medicine, 89, 653–69

Brandi, M.L., Gagel, R.F., Angeli, A. et al. (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 86(12), 5658–71.