This article is the second in a two-part series on thyroid cancer. Part one focused on thyroid cancer's rapidly increasing incidence. Part two discusses the treatment of small thyroid tumors.

Phrases such as "controversial issue" or "a matter of great debate" litter the published literature about the initial treatment of patients with small tumors of the most common type of thyroid cancer, papillary thyroid cancer (PTC). Of particular interest is the most appropriate treatment for tumors 1 centimeter or smaller in size.

The primary disagreement is whether just the wing, or lobe, of the thyroid in which the tumor resides should be removed, known as a lobectomy, or whether all or most of the thyroid gland should be removed, a total or near-total thyroidectomy. And the debate doesn't stop there. Experts disagree about whether patients who undergo the more aggressive procedure also require a treatment known as radioactive iodine (RAI) ablation.

These are important questions, because as the incidence of thyroid cancer continues to rise steadily, it's these small, malignant thyroid nodules that are driving it. By one estimate, small tumors may soon account for 90 percent of all PTCs treated in the United States, many of which will be smaller than 1 centimeter.

The Mortality Remains the Same
If clinical practice is any indication, much of the debate has largely been settled in favor of total or near-total thyroidectomy. One recent study, in fact, found that 90 percent of all PTC patients underwent the procedure, compared to approximately 70 percent two decades earlier.

Typically, cancer treatment patterns change when a given treatment generates notable improvements in survival or fewer side effects. But the mortality rate from PTC has remained flat, and extremely low, for the last four decades.

In any discussion about treatment, one thing seems abundantly clear: Observing the smallest tumors - what in prostate cancer is often called "watchful waiting" - isn't an acceptable option from the perspective of most patients.

"If they have cancer, my patients want it out," says Dr. Carmen Solorzano, chief of the Division of Endocrine Surgery at the University of Miami Miller School of Medicine.

And that's where the disagreements begin.

In patients with the smallest tumors confined to one lobe, argues Dr. Ashok R. Shaha, a professor of surgery at Memorial Sloan-Kettering Cancer Center, "there is no rationale for taking out the whole thyroid. You are punishing the patient, more or less, for their whole life."

The punishment, Dr. Shaha says, is that patients who undergo total thyroidectomy have to take thyroid hormone replacement for the remainder of their lives and require regular doctor visits to ensure the dosage is appropriate.

However, some endocrinologists also put patients treated with lobectomy on thyroid hormone medication, at least for a period of time.

Total thyroidectomy also is associated with other side effects, Dr. Shaha says, including hypoparathyroidism, in which the parathyroid gland can't produce enough calcium and phosphorous, and permanent damage to the laryngeal nerve.

In the hands of a good endocrine surgeon, counters Dr. Keith Heller, chief of endocrine surgery at New York University Medical Center, these risks are minimal.

In addition, Dr. Heller says, sometimes after a lobectomy, the final pathology report shows multifocal cancer, vascular invasion, or extension beyond the thyroid. If a lobectomy is done instead of removing the entire thyroid, a second operation might be recommended anyway, he says. Although he acknowledges that, in patients considered low risk, total thyroidectomy offers no survival advantage, Dr. Heller believes more aggressive treatment of tumors 1 centimeter or smaller is preferable, for just these situations. He's not alone.

"The problem is that these very small cancers, most of them have a good outcome, but not all of them," says Dr. Ernest Mazzaferri, chair of medicine at The Ohio State University, a long-standing proponent of more aggressive treatment.

It's not always as simple as just a single, small malignant nodule, he continues. The tumor may be invading outside of the thyroid "capsule." Or perhaps there is a family history of thyroid cancer or exposure to radiation. All suggest a tumor with the potential, albeit limited, to become aggressive.

These patients "don't always do so well," Dr. Mazzaferri says. "They can die from pulmonary or brain metastases. A small number, 1 percent, will die. None of us want to miss those."

To Irradiate or Not to Irradiate
Many patients who undergo a total or near-total thyroidectomy for small tumors also receive RAI. This long-used treatment, typically taking place 1 to 2 months after thyroidectomy, was an early precursor to targeted therapies: Thyroid cells excel at concentrating iodine, so the radioactive iodine migrates to any thyroid cancer cells that evaded the surgeon's scalpel and destroys them.

But the use of RAI in patients with smaller tumors is not without its critics.

Dr. Ian Hay, a heralded endocrinologist at the Mayo Clinic, and others have performed retrospective studies showing no significant difference in recurrence rate or cancer-specific mortality in low-risk patients who received RAI and those who did not.

Using RAI in these patients, Dr. Shaha believes, "is just unnecessary extra treatment."

Dr. Mazzaferri, however, has been outspoken in his support for RAI, even in patients whom some endocrinologists would consider low-risk.

"There are 11 different staging systems, and that, in and of itself, tells you part of the problem," he says. "We miss a lot of patients who have recurrent disease or who are in trouble by assigning some number to them that says you're low risk and we're not going to treat you any further."

In most cases, he argues, RAI is now a one-time treatment, and treatments have been modified so that smaller and smaller doses of radiation are used.

Because most patients with thyroid cancer live for decades after diagnosis, any sort of prospective clinical trial to compare treatment regimens is unlikely to happen. It would be extremely expensive, requiring thousands of patients and decades to complete.

There is, however, optimism that molecular markers can be found to identify patients with small tumors who should receive more aggressive therapy.

Many in the endocrinology community are hanging their hopes on a specific marker, a mutation in the BRAF gene. Several studies have shown an association between this mutation and outcomes such as treatment failure and recurrence.

The research into this mutation, Dr. Mazzaferri admits, is still in the developmental stage. But, he says, "I think down the road it will be a big player in helping us sort things out."

—Carmen Phillips