In this blog I will share with you what’s new in papillary thyroid cancer therapy this year: 2016 update on risk stratification for treatment and defining a spectrum with three broad levels of cancer recurrence risk (low, intermediate, high risk) and role of molecular markers.
Let’s start with small thyroid cancers with low risk of recurrent disease. The idea here is that less or no treatment is more when it comes to tiny (less than 1-1.5 cm) thyroid cancers. This is particularly true for tiny cancers found in patients over 65, in whom these rarely grow. For cancers 1- 4 cm, just removing 1/2 of the thyroid is enough if the tumor is well in the middle of that half of the gland, and there are no worrisome lymph nodes detected on preoperative ultrasounds. Molecular markers have been identified that show less surgery is needed in the following circumstances: 1) if you have had molecular testing that shows only a RAS mutation, or 2) if you have had an Affirma assay which shows your nodule’s biopsy is “suspicious” (in contrast to malignant) and 3) if molecular markers on different assays do not show a BRAF-V600 or TERT mutation ( see below for more detailed information on these mutations). If these 2 later mutations are present then a total thyroidectomy is recommended. Note, a patient could have 5 or less lymph nodes with tiny (3 mm or less) deposits of cancer, detected after surgery, and still be in the low risk category because these little metastasis are common and of little clinical relevance. These patients’ cancers will not affect their mortality in any negative way.
The following information is for patients with more extensive disease and/or moderate to high risk of recurrence.
Radioactive iodine is now limited to patients with higher risks of recurrence. In this category are patients who have tumors greater than 4 cm or smaller tumors that have largely expanded beyond the thyroid capsule or invaded into the blood vessels and/or other structures in neck, or have more than 5 lymph nodes filled with tumor, or have less lymph nodes involved but the lymph nodes are large and cancer cells extends outside beyond the lymph node capsule.
Lastly, for those with highly aggressive thyroid cancers and higher risk of recurrence and mortality. These patients usually have “driver” mutations of BRAF and TERT in their tumor. These mutations of the BRAF gene which normally functions as a tumor suppressor gene, and of the TERT gene, which normally regulates cell survival by managing telomere recovery, result in uncontrolled cancer cell replication and proliferation of the tumor and the capacity for migration of the tumors to other locations. When these mutations are present patients may present with big lymph nodes, extensive cancer spread in the neck, and may have distant metastases in lungs and bone. Having these mutations make the thyroid cancer less sensitive or unresponsive to therapy with radioactive iodine. As a result, these patients have a higher risk of dying of thyroid cancer. These patients benefit from participating in thyroid cancer trials at major cancer centers that specialize in the use of tyrosine kinase inhibitors singly or in combinations with angiogenesis blockers. These new therapies can control progression of the cancers by preventing proliferation of tumor cells and blood flow to the tumors, and may make the thyroid cancers sensitive again to treatment with radioactive iodine. You may be wondering what assays are available to characterize risk: ThyroSeq was designed by Yuri Nifirokof and his wife Marina at University of Pittsburgh and this test is widely available. Memorial Sloan Kettering also has their own molecular assay. At this point, I have to give a shout out to Dr. Mingzhao Xing from Johns Hokins University who discovered that BRAF and TERT mutations existed and whose work leads the path as to how cancer care is happening now and will happen in the future. Dr. Zing was given the highest award that the American Thyroid Association can bestow. His award was given to him by his Johns Hopkins career mentor, Paul Ladenson, another great in our thyroid field.
Moving on to the role of molecular markers. As mentioned above, this is impressively changing the landscape of thyroid cancer care and thyroid nodule care. The new data suggests that knowledge of these mutations can help predict the actual risk that a particular lesion has for a patient. If it is a cancer, it helps predict risk of recurrence and helps stratify the aggressiveness of the approach to treat the cancer. This will be increasingly necessary for personalized and precision therapy. For example if you have a RAS mutation in a follicular lesion, or if you get a suspicious fine needle aspiration biopsy report by using the Affirma assay, and the tumor is small < 4 cm, then a hemi-thyroidectomy is appropriate, because this nodule is likely a low risk lesion. However,if the molecular analysis of your thyroid nodule or cancer shows the following mutations genes: BRAF, TERT, RAS with BRAF, RAS with TERT, and worst of all BRAF and TERT together, then the whole thyroid needs to come out. In the case BRAF and TERT dual mutations, in addition to a total thyroidectomy, the experienced surgeon will consider also dissection of the central neck to remove lymph nodes that are likely affected by the thyroid cancer. All patients need to have a preoperative ultrasound before going to surgery.
Lastly, it is recommended that patients go to endocrine surgeons, with high volume experience (more that 100 cases per year), for their thyroid surgery to treat thyroid cancer, to avoid higher risk of vocal cord damage and of developing permanent hypoparathyroidsm.