Multiple endocrine neoplasia: Pathology review

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Case Study0:00–0:41

Two individuals came in for genetic testing based on recommendations from their primary care physicians. The first one is 24 year old Kurt, who was previously diagnosed with Zollinger-Ellison syndrome and also has an adenoma in one of his parathyroid glands.
On the clinical examination, doctors observed that he has gynecomastia. His mother also has parathyroid adenomas.
The other one is 19 year old Courtney, who was previously diagnosed with parathyroid hyperplasia and pheochromocytoma. Her father has recently been diagnosed with thyroid medullary cancer.Although their presentation and family history differ, both people have multiple endocrine neoplasias, or MEN for short.

MEN0:41–5:46

These are a group of inherited diseases which cause tumors to grow in the endocrine glands of the body. The endocrine glands affected in multiple endocrine neoplasia are the pituitary gland, thyroid gland, parathyroid glands, adrenal glands, and the pancreas.
So in multiple endocrine neoplasias, there are tumors that form in these glands that lead to overproduction of hormones.
Multiple endocrine neoplasias are caused by genetic mutations in one of two genes: either MEN1 or RET, which codes for receptor tyrosine kinase.
For your exams, remember that both of these genes have a dominant inheritance pattern, so only one copy of the mutated gene is needed to get the disease.
Okay, let’s start with the MEN1 gene that is found on chromosome 11 and codes for a tumor suppressor protein called menin, which - under normal circumstances - stops a cell from dividing uncontrollably.
MEN1 mutations cause MEN type 1. For your tests, you absolutely have to know that there are three types of tumors associated with MEN type 1: parathyroid, pancreatic, and pituitary.
The most common tumor is a parathyroid adenoma. Increased parathyroid hormone production causes increased bone breakdown, which leads to hypercalcemia.
The clinical manifestations of hypercalcemia can be recalled by the mnemonic: “Stones, bones, groans, and moans”. Stones refers to the calcium kidney stones.
Bones refers to bone pain that results from the increased resorption of bone in hyperparathyroidism. Groans refers to the abdominal complications in hypercalcemia:including peptic ulcer disease, pancreatitis, and constipation.
Lastly, moans refers to the psychiatric symptoms of hypercalcemia, such as altered mental status and psychosis.Pancreatic tumors cause problems based on the type of hormone they produce.
The first one is Zollinger-Ellison syndrome, where there’s one or more tiny tumors in the pancreas or the upper part of the small intestine.
These tumors, called gastrinomas, produce gastrin which increases the amount of hydrochloric acid in the stomach and can cause peptic ulcers, abdominal pain, and vomiting.
Insulinomas cause hypoglycemia, which is suggested by the Whipple’s triad. This includes symptoms of hypoglycemia such as hunger or dizziness, low glucose levels at the time of the symptoms, and finally, relief of symptoms when glucose is given.
On the other hand, glucagonomas cause hyperglycemia, but glucagonomas are pretty rare. Sometimes, the tumor is a vipomas which secretes vasointestinal active peptide and leads to watery diarrhea which can lead to dehydration, metabolic acidosis, and hypokalemia.
The pituitary gland develops benign tumors called adenomas which usually make an excess amount of at least one of the many hormones produced there.
Most commonly, there’s excess prolactin, which causes galactorrhea, or milk production in women who are not breast-feeding; and gynecomastia in men, which is excessive breast tissue growth.
The next most common hormone being overproduced is growth hormone, which has different effects depending on the age. In children, growth hormone causes gigantism , meaning they’ll get really tall.
In adults, growth hormone causes acromegaly where they have enlarged hands and feet, a large forehead, and a prominent jaw.
Sometimes, with MEN type 1, there can also be facial angiofibromas, which are benign tumors that consist of blood vessels and connective tissue.
They appear as small, reddish papules that don’t regress. Next, there can also be collagenomas, which are caused by the proliferation of normal collagen fibers.
They are also benign and appear like multiple, skin-colored or hypopigmented nodules on the face, neck, trunk and upper limbs.
Finally, meningiomas can also appear. These are benign tumors that arise from the meninges, which are the membranes that surround the brain and spinal cord.
In most cases, meningiomas are asymptomatic. Okay moving on to MEN type 2.

MEN 25:46–6:12

It’s caused by a mutation in the RET gene, which is a proto oncogene that promotes normal cell division. When it mutates, it becomes an oncogene, which promotes constant cell division.
Mutated RET causes multiple endocrine neoplasia type 2A and 2B. In MEN type 2A, the most common problem is thyroid medullary cancer, which develops in virtually everyone with the disease.

MEN 2A6:12–7:26

This type of cancer develops from parafollicular cells or C-cells in the thyroid that produce calcitonin and can metastasize to other organs through the blood.
In this case, since thyroid medullary cancer is so frequent, a prophylactic thyroidectomy is needed. Next, the adrenal medulla form tumors called pheochromocytoma, which make too much epinephrine and norepinephrine.
This results in episodes of high blood pressure, headaches, palpitations, anxiety, and sweating. In addition, pheochromocytomas may secrete erythropoietin, resulting in polycythemia.
People with multiple endocrine neoplasia type 2A can also develop parathyroid hyperplasia, where all four parathyroids are enlarged and produce too much parathyroid hormone.
Similar to parathyroid adenomas, this results in hypercalcemia and its symptoms.In MEN type 2B, the type of tumors are the same as 2A except there is no parathyroid adenoma; this is something you absolutely have to know for your exams.

MEN 2B7:26–8:29

Instead of parathyroid adenoma, 2B have multiple mucosal neuromas, which are tumors that come from nerve tissue. With MEN type 2B, these affect the nerve fibers in the ganglia, which is called ganglioneuromatosis.
Ganglioneuromatosis usually occurs in the mouth, but can also happen in the intestine. Also, another high yield fact is that people with MEN type 2B tend to have a “marfanoid” habitus.
This means that their physical appearance is similar to those individuals with Marfan syndrome. This includes long limbs, sometimes with an arm span that exceed the height of the individual, as well as long fingers and a high arched palate.All right, as a quick recap!

Review8:29–9:52

MEN type 1 is caused by mutations in MEN1 gene and you have to remember the 3 P’s: parathyroid adenomas; pancreatic tumors like insulinomas, vipomas, and glucagonomas as well as gastrinomas that cause Zollinger-Ellison syndrome; and finally pituitary tumors which often release prolactin or growth hormones.
In some cases, there can also be angiofibromas, collagenomas, and meningiomas. Then there’s MEN type 2, which is caused by mutations in the RET gene.
With MEN type 2A, there are only two P’s: pheochromocytoma and parathyroid hyperplasia. Apart from this, individuals with MEN type 2A usually have medullary thyroid cancer.
Finally, there’s MEN type 2B, which is also caused by mutations in the RET gene. With MEN type 2B, there’s also one P: pheochromocytoma.
Apart from this, as with MEN type 2A, there’s also medullary thyroid cancer. However MEN type 2B is uniquely associated with mucosal neuromas that affect the mouth and intestine.
Now, back to our cases. The first one is 24 year old Kurt, previously diagnosed with Zollinger-Ellison syndrome, most likely due to a pancreatic gastrinoma, and parathyroid adenoma with a family history of parathyroid adenomas.

Summary9:52–10:48

Another clue is the gynecomastia, so we should get a prolactin level and a head MRI to check for a pituitary adenoma. Unsurprisingly the results of his genetic testing showed a mutation in the MEN 1 gene, so he has MEN type 1.
The other one is 19 year old Courtney, previously diagnosed with parathyroid hyperplasia and pheochromocytoma, with a family history of medullary thyroid cancer.
The results of genetic testing showed a mutation in the RET gene, so she is diagnosed with MEN type 2A. Courtney was advised to get a prophylactic thyroidectomy to prevent