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From OncoLog, April-May 2011, Vol. 56, No. 4-5

Understanding and Managing Multiple Endocrine Neoplasia Syndromes

By Zach Bohannan

Endocrine tumors caused by multiple endocrine neoplasia syndromes (MEN) pose a dual threat—both from the tumors’ potential for growth or metastasis and from their hormonal secretions.

Although endocrine tumors make up only about 3% of newly reported cancer cases, some individuals develop many of these tumors over the course of their lives because of rare genetic conditions such as MEN.

A number of genetic syndromes can cause the development of multiple endocrine tumors. The ones seen most often are broadly classified as MEN type 1 (MEN1) and MEN type 2 (MEN2). Each is characterized by mutation of a specific gene and a specific distribution of tumors.

MEN2

MEN2 is actually a set of syndromes caused by mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase. These mutations activate the receptor and cause cellular hyperplasia, tumor formation, and medullary thyroid cancer. Because of the nature of the mutations and RET’s location on a non-sex chromosome, MEN2 is inherited in an autosomal dominant fashion.

Although the mutant gene is present in every cell in the patient’s body, only a subset of the tissues in which the gene is expressed develop tumors or grow abnormally. “MEN2 mostly causes neoplasia in a few tissues, such as the thyroid, parathyroid, and adrenal glands, but why these tissues alone are affected remains unclear,” said Gilbert Cote, Ph.D., a professor in the Department of Endocrine Neoplasia and Hormonal Disorders at The University of Texas MD Anderson Cancer Center.

Because MEN2 is a genetic disorder, researchers have been able to develop a variety of tools to study the disease. The best source of information is harvested tumor samples. Dr. Cote said, “Most of our research is derived from the use of patient tumor tissues or primary cell lines.” A few MEN2 mouse models have been developed, but the associated traits in mice may differ from those in humans. One reason may be differences in the organisms’ life spans: MEN2 patients first develop thyroid tumors and then parathyroid and adrenal tumors; mice may not live long enough to develop tumors in all these sites.

MEN2 is divided into three clinical subtypes: MEN2a, MEN2b, and familial medullary thyroid carcinoma. The graph on page 1 shows the tumors associated with each subtype.

Thyroid tumors

The development of medullary thyroid cancer is often the first sign that a patient may have MEN2. Furthermore, nearly all MEN2 patients experience thyroid C-cell hyperplasia, even if they lack identifiable tumors, and most will develop thyroid cancer if their thyroid gland is not surgically removed at a relatively young age. Unlike most sporadic, nonhereditary thyroid cancers— which have a papillary or follicular histology—MEN2-associated thyroid tumors are derived from parafollicular C cells and almost always overproduce the hormone calcitonin. When produced in large amounts, calcitonin can cause flushing episodes and diarrhea.

A more detailed article about the treatment of thyroid tumors can be found in the July 2010 issue of OncoLog.

Pheochromocytoma

In the general population, most adrenal tumors are nonsecretory and are detected only incidentally. These tumors may require follow-up imaging studies and hormonal assessment, but many are benign neoplasia. However, MEN2 patients have about a 50% risk of developing pheochromocytomas, adrenal tumors that are usually benign but secrete epinephrine or norepinephrine.

The excess epinephrine and norepinephrine produced by pheochromocytomas can cause weight loss, anxiety, headaches, palpitations, sweating, and dangerously high blood pressure.

Treatment for MEN2

Surgery is currently the most common treatment for MEN2-related tumors. Several pharmacological agents are available to treat the various hormonal secretions produced by MEN2 tumors, but these agents generally do not affect the size or growth of the tumors themselves.

Since thyroid tumors are often the first malignancies to develop with MEN2, children identified as having the genetic disorder may undergo prophylactic thyroidectomies to prevent the development and spread of medullary thyroid cancer.

Prophylactic thyroidectomies may be recommended as early as within the first year of life for children with MEN2b and by 5 years of age for those with a less aggressive form of MEN2a. Prophylactic thyroidectomies may be deferred for children with lower-risk RET mutations until there is clinical evidence of C-cell hyperplasia or medullary thyroid cancer based on annual ultrasonography and measurement of serum calcitonin levels.

Lifelong thyroid hormone replacement is required after thyroidectomy, but the long-term effects of hypothyroidism, particularly if uncontrolled, remain largely unknown, as do oncological outcomes after prophylactic thyroidectomy.

New drugs are also available to manage thyroid cancer in patients for whom surgery is not an option. Steven Waguespack, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders, said, “There is a new drug, vandetanib, that specifically targets the RET gene and shows promise for treating MEN2 patients with advanced medullary thyroid cancer when surgery may not be feasible.” Vandetanib recently was approved by the U.S. Food and Drug Administration for the treatment of such patients.

Pheochromocytomas are managed less aggressively than thyroid tumors in MEN2 patients because the adrenal tumors are rarely malignant. Usually, when a patient with MEN2 develops a pheochromocytoma, only the affected adrenal gland is removed. Jeffrey Lee, M.D., the chair of and a professor in the Department of Surgical Oncology, said, “Thankfully, patients can have one adrenal gland removed and still live a normal life.”

Eventually, many MEN2 patients may need to have both adrenal glands removed and receive replacement hormones, but delaying this treatment as long as possible (or removing just the part of the adrenal gland that contains tumor) allows patients to maintain a normal lifestyle for as long as possible. Most pheochromocytomas can now be removed using a minimally invasive approach, such as a retroperitoneoscopic adrenalectomy, allowing for more rapid recovery.

Although surgery remains the gold standard for treating MEN2 tumors, for patients who present with metastatic cancer there is no cure. Research on the molecular mechanism of MEN2 has led to some promising treatment options that attempt to target the activated RET tyrosine kinase receptor. A new class of agents known as tyrosine kinase inhibitors is being studied in clinical trials for the treatment of thyroid cancers. Among these drugs is the recently approved vandetanib. Studies conducted at MD Anderson and other cancer centers suggest this class of drugs may be effective at combating the thyroid tumors caused by MEN2.

MEN1

Although the disorders share a name, MEN1 and MEN2 are very different. For instance, parathyroid tumors are almost always present in patients with MEN1 but are relatively uncommon in patients with MEN2. MEN1 also causes pituitary adenomas and pancreaticoduodenal neuroendocrine tumors (PDNETs).

MEN1 is caused by a loss of function in the MEN1 gene. This gene is thought to play a role in chromatin maintenance, but the gene is not yet well understood. MEN1 is inherited dominantly, like MEN2.

Interestingly, the mutant MEN1 gene is also expressed in a wide variety of tissues other than those affected by MEN1. The disorder may require other triggering events that are specific to the tissues it affects. Dr. Cote said, “It may be that the tissues affected by MEN1 are more likely to experience mutations or loss of the normal copy of the MEN1 gene, but this is an area of active investigation.”

Parathyroid tumors

Parathyroid hyperplasia causes hyperparathyroidism in patients with MEN. A more detailed article on the symptoms and treatment of parathyroid tumors can be found in the March 2010 issue of OncoLog.

Pituitary adenomas

Like other MEN-associated tumors, pituitary adenomas resulting from MEN1 are usually benign, but they can secrete a variety of hormones and be more locally aggressive. Adrenocorticotropic hormone–producing pituitary tumors can stimulate the adrenal glands to secrete excess adrenal hormones and, therefore, cause many of the same symptoms as secretory adrenal tumors. Similarly, tumors that produce thyroid-stimulating hormone can mimic the effects of hyperthyroidism. Pituitary adenomas can also secrete growth hormone, which can cause gigantism or acromegaly, or prolactin, which can cause reduced sex hormone levels.

Despite their often slow-growing nature, pituitary adenomas can also pose a threat because of their location. The pituitary gland is confined in a small space, and even a minimal level of tumor growth can cause drastic symptoms. Notably, the tumors can cause pressure on—and damage to—the optic nerve or the surrounding healthy pituitary tissue.

PDNETs

Like other endocrine tumors, PDNETs can secrete hormones associated with their tissue of origin: the pancreatic islet cells. In fact, PDNETs are often classified according to their secretions, which can produce a variety of symptoms. For example, gastrin-secreting tumors (gastrinomas) can cause ulcers, and insulinomas can cause drastic hypoglycemia.

“These tumors present two distinct difficulties for treatment,” said James Yao, M.D., an associate professor in the Department of Gastrointestinal Medical Oncology. “On the one hand, you must manage the general oncological symptoms; but on the other hand, you must also manage the severe symptoms associated with any hormones the tumor produces.”

Managing MEN1

Like patients with MEN2, patients with MEN1 are regularly monitored for tumor development. They typically undergo yearly biochemical screenings and interval abdominal computed tomography or magnetic resonance imaging to detect any developing pituitary or pancreatic tumors. As is the case for MEN2, surgery is often the best option for most MEN1-derived tumors. Unfortunately, some of the tissues commonly affected by MEN1 tumors are more difficult to operate on than those affected by MEN2 tumors.

Although the parathyroid glands are important for calcium homeostasis, typically all glands in patients with MEN1 are affected by parathyroid hyperplasia. As Nancy Perrier, M.D., a professor in the Department of Surgical Oncology, explained, “MEN1-associated hyperparathyroidism occurs at an earlier age than its sporadic counterpart, usually affecting patients by the third or fourth decade of life. Because it is the result of a genetic mutation of all parathyroid tissue, the syndrome is characterized by multiple gland involvement. If not treated as such, recurrent or persistent disease is common. The surgical procedure should include resection of the majority of parathyroid glands—usually a three-and-a-half-gland resection. Concomitant cervical thymectomy is advised to remove supernumerary glands and to decrease the risk of malignant thymic carcinoids.”

Pituitary tumors usually are not treated until they become clinically evident. Pituitary tumors’ hormonal secretions can often be managed pharmacologically, but surgery typically is undertaken for pituitary tumors whose symptoms cannot be managed pharmacologically.

Recent advances have made hormonal secretion management easier. The MEN1-associated tumors most affected by new pharmaceutical products are PDNETs. Previously, PDNET patients often died because of the secondary symptoms associated with hormonal secretions. However, modern drugs, like proton pump inhibitors that can be used to treat severe diarrhea, have made these symptoms more manageable and allowed doctors to focus on the treatment of oncological symptoms. The only exception is hypoglycemia caused by insulin-producing tumors, which remains relatively difficult to treat medically.

The primary treatment for PDNETs is surgical resection. “Surgical resection for MEN1-associated gastrinomas is associated with a durable return to normal gastrin levels,” said Elizabeth Grubbs, M.D., an assistant professor in the Department of Surgical Oncology. Unfortunately, in PDNETs there is a high chance of tumor recurrence even after complete surgical resection. In addition, unlike most of the other tumors caused by the MEN disorders, pancreatic tumors can be difficult to treat surgically, and the pancreas has no “back-up” glands to compensate for its resection. However, new research is offering some promising chemotherapeutic options for patients with advanced pancreatic tumors from MEN1 or other causes.

A multicenter clinical trial recently compared the effectiveness of everolimus, a mammalian target of rapamycin inhibitor, to that of placebo in patients with unresectable or metastatic pancreatic neuroendocrine tumors. The researchers found that the 18- month progression-free survival rate was significantly higher in the everolimus group (34%) than in the placebo group (9%). Dr. Yao, the principal investigator for the trial at MD Anderson, said, “We found that everolimus is actually very good at controlling insulin secretion from these tumors as well.”

Genetic testing

Since the MEN syndromes are caused by mutations, there is a growing role for genetic testing in their treatment. Many MEN patients know of their family history, but others undergo genetic testing after they develop a characteristic disease. Thereasa Rich, a genetic counselor with MD Anderson’s MEN Specialty Clinic, said, “If we see early medullary thyroid carcinoma, for instance, we often recommend genetic testing, since this disease is very rare in younger patients without MEN mutations.”

This testing also helps inform treatment options, especially for MEN2. However, the field of MEN-specific treatment is still in its infancy. The MEN Specialty Clinic at MD Anderson is a new interdisciplinary venture that integrates the results of genetic testing and treatment. Dr. Grubbs and Ms. Rich have recently received a grant to characterize in more detail the various mutations that cause MEN2. Ms. Rich said, “Many RET mutations have different effects. For instance, the RET918 mutation causes very aggressive medullary thyroid tumors, whereas some other mutations may not cause such aggressive disease and could be treated later.” Using this knowledge, endocrinologists, surgeons, and genetic counselors may be able to personalize treatment for each patient’s specific mutation.

A way forward

Currently, management of the MEN disorders is often limited to treatments for each tumor that arises. And because of the rarity of the syndromes, individual institutions generally have not seen enough MEN patients to make clinical trials feasible. However, because of the rapid increase in national and interdisciplinary collaboration, clinical trials and integrated treatment strategies are starting to be available for these and other rare disorders.

“This increased collaboration is rapidly leading to new treatments for these cancers,” Dr. Yao said, “It’s a very productive time for the treatment of rare diseases.”

For more information, contact Dr. Gilbert Cote at 713-792-2840, Dr. Elizabeth Grubbs at 713-792-0665, Dr. Jeffrey Lee at 713-792-7218, Dr. Nancy Perrier at 713-794-1345, Thereasa Rich at 713-563-1908, Dr. Steven Waguespack at 713-792-2841, or Dr. James Yao at 713-792-2828.

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