In this episode of PodMD, Specialist Endocrine Surgeon and Surgical Oncologist Associate Professor Anthony Glover will be discussing the topic of Molecular Testing for Atypical Thyroid Nodules. We discuss how molecular testing compares to ultrasound and FNA cytology, the Bethesda categories it is most applicable to, common misconceptions around molecular testing, and more.
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Today I’d like to welcome back to the PodMD studio Associate Professor Anthony Glover.
Anthony is a Specialist Endocrine Surgeon and Surgical Oncologist who specialises in the work-up and treatment of diseases and tumours of the thyroid, parathyroid and adrenal glands.
You can read more about Anthony on his profile page on our PodMD website.
*Please listen to our disclosure at the end of this podcast
Today we’ll be discussing the topic of molecular testing for atypical thyroid nodules. Anthony, thanks very much for talking with us again on PodMD today.
Anthony: Thank you for having me.
To start us off, for GPs who may not be across this area yet, what exactly are atypical thyroid nodules, and how often do we see these indeterminate results in routine practice?
Anthony: Yeah, no, thank you. An atypical thyroid nodule is when a thyroid nodule is biopsied, and the FNA report will say that the result is atypical or sometimes suspicious or indeterminate. And what this means is that the cells that the pathologist has reviewed, they can’t confidently say that they think they are benign or they are malignant and so for a typical biopsy that has about a 10% risk of being thyroid cancer, and for a suspicious or indeterminate biopsy is about a 30% risk of being a thyroid cancer. They are quite common and because there is this risk that some people are often confused by what the results mean.
When we say molecular testing in this context, what are we actually talking about? Is this something done on the same biopsy sample GPs are already ordering?
Anthony: Yeah, so molecular testing is further testing that can be done on the biopsies that are previously done for the diagnosis of the atypical or suspicious thyroid nodule. And how it’s done is the cells on those biopsy slides are processed so their DNA or RNA is extracted. And then further testing is done on those cells to see if they have different mutations or different changes in their gene expression, in those cells, so using molecular testing or next generation sequencing. And so this testing is a newer form of assessing thyroid biopsies and it gives a greater certainty whether a biopsy could be a thyroid cancer or if it could be benign. It can be ordered on the prior biopsy samples and GPs are able to do that, but often it’s organised by a specialist.
Perfect. And where does molecular testing fit into the current thyroid nodule workup alongside ultrasound and FNA cytology?
Anthony: So it fits in as an additional test that can come after cytology. So with the initial cytology, for molecular testing to be performed, the pathologists need to see that there’s a sufficient number of cells. And it’s generally done for biopsies where you have atypical or indeterminate or suspicious results. So they’re usually within the Bethesda classifications of thyroid biopsies, usually for Bethesda 3 or Bethesda 4 results. It fits in as an adjunct because you don’t want to be doing this additional testing if the biopsy result is inadequate for a diagnosis, and it has a more limited role for people who have a thyroid nodule that’s diagnostic for a thyroid cancer on the biopsy.
Why is this such a challenging space and what makes atypical or indeterminate nodules difficult to manage based on cytology alone?
Anthony: Yeah, so the reason molecular testing is being invented is to add to what we already know about thyroid cytology and also to add in the knowledge we have now of the molecular biology of thyroid nodules and thyroid cancers. It’s difficult for pathologists to make a definitive diagnosis because they only have a small number of cells to look at when they’re doing an FNA biopsy and to make a diagnosis. And some types of thyroid cancers, you need the actual architecture of the nodule of the cancer to make the diagnosis. So just looking at the cells on cytology alone is not sufficient. The molecular testing with its additional information about any gene mutations helps make that diagnosis more accurate. And it means that many patients may need to be able to avoid having surgery for a diagnostic reason to find out if a nodule is a cancer or not. So that’s kind of why and what this molecular testing adds to patient care.
From a GP perspective, what’s the main clinical problem molecular testing is trying to solve?
Anthony: So it’s trying to give a greater certainty if a nodule can be a cancer or not. So yeah, the traditional treatment for patients with an atypical nodule or Bethesda 3 nodule is to either repeat the biopsy within a few weeks after the initial biopsy or to consider surgery for diagnostic hemithyroidectomy while the traditional treatment for Bethesda 4 or suspicious or indeterminate thyroid nodule is to perform a diagnostic hemithyroidectomy. But we know both of those groups of patients, if they do go on to have surgery, many of them would have had surgery for a benign nodule that may not have needed surgery. So with this molecular testing, around 1/2 to two-thirds of patients who choose to do the testing will get a result which will change their management. So most commonly that will mean that they don’t need to have surgery and they can have observation of the nodule because the molecular testing has suggested or shown it’s a benign nodule for some other patients. The molecular testing may show it’s a cancer, which may change the type of operation the patients choose to have. So the main advantage is it gives patients more information so they can make a better decision about how to manage these nodules.
Perfect. And which patients on nodules should prompt a GP to start thinking about molecular testing?
Anthony: The kind of the ideal patients are patients that have asymptomatic nodules that don’t have another reason for having surgery. So if a patient has a large atypical suspicious thyroid nodule that’s causing symptoms, they have another reason to have thyroid surgery. So they’re not going to be, the molecular testing is not going to add that much more to their management. The other issue with molecular testing is it is a self-funded test. So it has only been available in Australia for the last couple of years and the test is self-funded. There’s a few different companies that are offering molecular testing, but the one most widely used in Australia is performed in the United States and it costs over $2,000 to perform. So obviously only some patients who are able to fund that will be interested in performing it. So it’s ideal for patients who have asymptomatic nodules who want to get more information and before considering further biopsy or surgery.
Are there any particular Bethesda categories where molecular testing is most useful? Following on that, are there categories where it’s generally not helpful?
Anthony: Yeah, so the classic use for it is Bethesda 3, so atypical or Bethesda 4, which are nodules which are suspicious for follicular neoplasm or indeterminate. So that’s kind of the main areas where this molecular testing has been developed and where it has the most use. There is also some interest in using molecular testing for patients who have been diagnosed with a thyroid cancer to give more information about how high-risk or how aggressive the thyroid cancer may be. That’s a new area and at the moment it’s more being used in a research focus but in the future molecular testing also may be able to be used for patients with thyroid cancer to help them make decisions about what type of thyroid surgery they’re going to have and also potentially in the future about what other treatments they may need such as radioactive iodine, but that’s an area of current research.
And how reliable are these tests in real-world practice? What should GPs understand about their accuracy or limitations?
Anthony: The tests are accurate. So in the United States, molecular testing now is seen as the standard of care in many kind of tertiary institutions and many kind of university hospitals. The main issues with the test is that it relies on the quality of the biopsy materials. So before the molecular testing is performed, the pathologists will assess the RNA and DNA that’s extracted from the cells to make sure that they’re suitable for molecular testing. The other limitation is it does take time. So with the current testing, it does have to be sent to the United States. So depending on where the biopsy is being performed and how fast the slides can be reviewed, the usual kind of turnaround time is around four to six weeks. So for some patients, and especially if they have other reasons for needing treatment, that may not be suitable. But for patients with asymptomatic nodules that are wanting to get more information, it is a useful test.
How does a molecular test result actually change what happens next for the patient?
Anthony: Yeah, so the main reason it changes what happens is it gives a different diagnosis. So with ThyroSeq, which is the most commonly used molecular testing in Australia, it has kind of 6 categories that will give as a diagnosis for a thyroid nodule. So 2 of them are negative for cancer, and so usually those patients won’t need to have surgery. So a patient has gone from having an atypical or suspicious nodule and if they get a negative molecular testing test, then that means that they generally won’t need to go ahead with surgery or further biopsies and they will be able to have their nodule observed. Similarly, for a person that has a suspicious nodule that comes back as a thyroid cancer, they will have more information to make decisions about the next stage of their treatment, which usually will be thyroid surgery. And the molecular testing will give some information on how aggressive that thyroid cancer is. So it can also help people if they’re deciding between having a hemithyroidectomy or half their thyroid removed or a total thyroidectomy, having the whole thyroid removed.
Does this testing reduce the need for diagnostic surgery or does it mainly help guide surgical decisions?
Anthony: It does both, but generally its most common use will be to reduce the need for diagnostic surgery. So yeah, around 1/2 of patients who do these tests who would have gone on to surgery in the past will be able to avoid surgery. And in a smaller number of patients, probably less than 5%, it may help as well with the surgical decisions and that’s more for people that have had a thyroid, been diagnosed with a thyroid cancer for the molecular testing and it may help them decide what type of surgery to have.
Excellent. And at what point should a GP refer to an endocrine surgeon or a specialist before or after considering molecular testing?
Anthony: Yeah, it’s definitely fine for a patient to be referred before doing the molecular testing. It is an involved discussion with a patient and talking about their treatment options, which often will come down to a repeat biopsy, diagnostic surgery, observation or molecular testing. And depending on the patient, depending on their thyroid nodule and depending on the diagnosis of their initial FNA biopsy, there is quite a lot of nuance and discussion and also understanding the patient’s values and preferences. So there’s definitely no reason why a GP can’t do that and can refer if they wish to. But generally, an endocrine surgeon or someone who regularly treats thyroid nodules will be able to explain this in detail with a patient and understand which is the best option for them.
Do you prefer GPs to organise molecular testing themselves or should that be done after specialist review?
Anthony: Either is fine, but yeah, with the cost of molecular testing, some patients may wish to be seen first by the specialists that will be reviewing those results, but it’s definitely fine for GPs to organise the testing themselves. Some GPs, you may have noticed that on some of the thyroid biopsy results now, that some pathology companies will offer to organise molecular testing. And that can be done directly with the pathology companies without a specialist involvement and just requires consent from the patient and that they’re willing to pay for the cost of the testing as it’s not currently covered by Medicare.
What are some common pitfalls or misconceptions you see among referrers when it comes to molecular testing? Any practical tips for avoiding inappropriate use?
Anthony: Yeah, like it’s still kind of a developing area in Australia. So the main issue would be the time it takes to get the testing and avoiding using it when there’s other reasons to have thyroid surgery, so people have big nodules or symptomatic nodules. The molecular testing is probably not going to be that useful. So, unless the patient has a particular reason they want to do it, it’s generally not going to be helpful. The other issue is just the time it takes. The usual kind of turnaround is 4 to 6 weeks. So depending on what the patient’s priorities and preferences are, this may or may not be suitable for them. So it’s just something to consider when organising the testing.
And looking ahead, how do you see molecular testing evolving in thyroid nodule management over the next few years?
Anthony: Yeah, so molecular testing being widely available in the United States the last 10 years, and it’s become more accurate. And so a lot of the kind of commercial testing platforms are now up to their third or fourth kind of versions, and they’ve kind of added more genetic or genomic tests that they do to try and make the testing more accurate. And in the future, it will also be able to be used for management of thyroid cancer and potentially deciding which patients can have active surveillance of small thyroid cancers or should have surgery. And then for patients having surgery, the type of operation they should have and the further treatment. This is currently happening in a research space and it definitely will happen in the future. And I hope in the next future years that the testing will become more widely available in Australia and hopefully be available under Medicare as it saves a lot of patients from surgery, which reduces costs to the overall health system.
To sum up first, could you please identify the three key take-home messages from today’s podcast?
Anthony: Yeah, so I think for patients that have Bethesda 3, Bethesda 4, so atypical or suspicious thyroid nodule biopsy, they do have another option, and that’s molecular testing. So secondly, molecular testing can be done on the prior biopsy, but the patient is required to self-fund it. And thirdly, the results take around four to six weeks. And so having the patient assessed and understanding what they can expect from the results is essential for anyone who’s considering doing this. But around half of the patients who do this test will be saved from having a thyroid operation.
Perfect. Well, thanks again for the time and insights you’ve provided today, Anthony.
Anthony: Thank you.
