The Heirs of MEN 2A

Delicate surgeries and genetic discovery
can inhibit a deadly inheritance

BY CANDACE O’CONNOR

"In kids, the pressure is greater than when your patient is someone with an established tumor. It is especially important that the operation be done perfectly."

JEFFREY F. MOLEY, MD

In parathyroid transplantation, Moley and his colleagues' success rate approaches
100 percent.

ABBIE CAMERON HAS BIG BLUE EYES, a mischievous grin, and the non-stop energy of any healthy two-year-old. What is not so evident is that she also has an abnormal gene, inherited from her father, Andy, that produces a disorder called Multiple Endocrine Neoplasia Type 2A (MEN 2A). That means she faces a 100 percent chance of someday developing medullary thyroid carcinoma (MTC), a rare but aggressive disease that accounts for 10 percent of all thyroid cancers or 1,500 new cases in the United States each year.

At the opposite end of the disease spectrum from Abbie are MEN 2A patients with advanced MTC, which has spread to nearby lymph nodes and triggered elevated levels of calcitonin, a hormone secreted by thyroid tumors. Surgery is the only effective treatment for MTC, yet many of these advanced patients have undergone multiple surgeries and their calcitonin levels still have not decreased—which means the disease is not yet under control.

Abbie Cameron and her father, Andy, are both genetically predisposed to medullary thyroid carcinoma (background).

From across the United States and as far away as Saudi Arabia, patients at all stages of disease converge on the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital to consult its endocrine cancer program, which is well known for innovative surgery and research. The program is headed by Jeffrey F. Moley, MD, the acknowledged world expert in the surgical treatment of MEN-2 syndromes, particularly the hereditary form of the disease, and in the recurrent cases, which present the most difficult surgical challenges of all.

Among patients newly diagnosed with MTC, says Moley, the cure rate after surgery is between 50 and 60 percent. Even in advanced cases, he has achieved a remarkable 25 percent biochemical cure rate among patients who undergo re-operation before the cancer has spread to distant sites, such as the lungs or liver. There is a special thrill, he says, in performing preventative thyroid removal in children, known to be carrying the gene for MTC, before cancer can develop. Abbie Cameron, for example, will likely undergo a thyroidectomy when she is five years old.

“It is very satisfying to treat these young patients,” says Moley, professor of surgery, chief of endocrine and oncologic surgery and associate director of the Siteman Cancer Center. “Year after year, we watch them and test them, and they are still doing fine. You get to know them as people—and you get to see them grow up.”

Within her family, Abbie has lots of genetic company. Her great-grandfather developed MTC, but thought he had the non-hereditary, “sporadic” version of the disease—until his son also developed it. So the next generation, Andy and his brother, were prepared; physicians in their hometown of Cincinnati closely monitored their levels of calcitonin, and at ages 11 and 13, they underwent successful back-to-back surgeries to remove their newly diseased thyroid glands.

Still, it was a surprise to find that Abbie had the MEN 2A gene, says Andy Cameron. He and his wife, Jessica, knew that she had a 50 percent chance of inheriting it. “But she was the first female in our family to have it, so we had never thought she would get it,” he says.

The gene that Abbie inherited was identified in 1993 by a School of Medicine research group, headed by Samuel A. Wells, MD, former chairman of the Department of Surgery, who had been working toward this breakthrough for 25 years. Wells and his team, which included Moley and Paul J. Goodfellow, PhD, discovered that small but critical abnormalities in a gene called “RET” are associated with MEN 2 syndromes. In 1994, they developed a genetic test for MEN 2A and began performing preventative thyroid removals in young patients at risk for the disease—the first instance of a genetic test leading to surgery intended to prevent cancer.
In small children with MEN 2A—or even infants when the case involves MEN 2B, another syndrome in the MEN family—surgery requires meticulous technique. The adult thyroid gland, located in the lower part of the neck just above the windpipe, has two lobes the size of walnuts; its four neighboring parathyroid glands are no bigger than grains of rice. In children, all these glands are almost unimaginably small.

“And in kids, the pressure is greater than when your patient is someone with an established tumor,” says Moley. “It is especially important that the operation be done perfectly, because the patient does not yet have cancer. For the surgery to be worthwhile, there can’t be any complications.”

Jeffrey F. Moley, MD, with MEN coordinator
Mary DeBenedetti, RN

But there are also special pressures when the patient needs a re-operation, he says. One challenge is preserving the blood supply to the parathyroids or, if necessary, transplanting them in pieces to muscle pockets of the neck or forearm. Another is the painstakingly delicate business of removing affected lymph nodes—an essential step in returning calcitonin levels to normal and ensuring the best hope of a cure.

A third is guarding against damage to the recurrent laryngeal nerve, which controls vocal cord function. Once injured, nerve repair has limited success; the patient is left with vocal cord paralysis and permanent hoarseness. Yet the nerve is only the size of a thread and, in patients who have already undergone surgery, may be encased in scar tissue and very hard to find.

Moley has perfected his own, “back-door” approach to solving this problem. He approaches the nerve from behind and at an angle, locating it far down in the neck and tracing its route upward while clearing away muscle and other surrounding tissue. By isolating it in this way, he can avoid it while he proceeds with the rest of the surgery.

Moley’s interest in hereditary cancers developed during his residency at Yale, when he found a large colon tumor in a young man who mentioned that others in his family had also experienced this form of cancer. “It turned out that they had an inherited colon cancer syndrome and didn’t know it. There was a 50 percent incidence in each generation,” says Moley, who was recruited by Wells to come to St. Louis in 1988.

Today, his endocrine group—which also includes
L. Michael Brunt, MD, Terry C. Lairmore, MD, and new member, Bruce L. Hall, PhD, MD—handles a variety of endocrine cases, along with general surgical oncology. Another key team member is Mary DeBenedetti, RN, MEN coordinator, who keeps in touch with some 5,000 MTC patients worldwide, many of whom have received treatment at Washington University Medical Center.
One of those patients is Andy Cameron, now 30, who
has been coming to the Medical Center since his move to St. Louis six years ago. Like half of those with MEN 2A, he needed to have one adrenal gland removed due to early-stage tumor growth; soon he will face removal of the other. Both surgeries, performed at Siteman, are being done laparoscopically—a far easier operation for the patient, but tricky for the surgeon.

Through their research, Moley and colleagues at the School of Medicine are working to better understand the MEN syndromes. Moley recently has embarked on a clinical protocol in which advanced MTC patients with distant metastases receive a new tyrosine kinase inhibitor. With a National Institutes of Health grant, he and his wife, Kelle H. Moley, MD, are trying to identify novel glucose transporters in cancer, especially MTC, with the goal of developing new therapies. And Moley’s endocrine group is collaborating with Jeffrey D. Milbrandt, MD, PhD, professor of pathology and immunology and of medicine, who wants to trace the downstream signal pathways of RET and other genes expressed in these thyroid cancers.

On the clinical side, the work of Moley and his colleagues has already been very successful. In parathyroid transplantation, their success rate is close to 100 percent; they have had no recurrent laryngeal nerve injuries in adults or children. And they have had no deaths during surgery, nor have they needed to give any patient a blood transfusion.

Pictures from grateful patients are bundled in Moley’s desk drawer. One shows a smiling young man, posing with his wife and four small children, the youngest of whom are twins. The father had surgery in 1993, including lymph node removal, but his calcitonin levels were still high; after a second operation, they decreased to normal and have remained there ever since. Today, says Moley, “he is doing just great.”

Early diagnosis is the key, Moley adds, combined with aggressive treatment and strong follow-up. Since one in four cases of MTC result from hereditary syndromes, it is crucial for families to undergo genetic testing, as the Cameron family did through Siteman’s Hereditary Cancer Core. Andy Cameron’s DNA sample will serve a dual purpose: It also will be used to test his brother’s son, now one year old, to determine whether he has inherited MEN 2A.

If a family is affected, they should “look on the bright side,” says Andy Cameron. “It could be much worse. You just get the tumor out, go back for checkups, and take a pill for the rest of your life. Other than that, no one can tell you have it.”