Active Surveillance for Papillary Thyroid Cancer

This transcript has been edited for clarity.

Allen S. Ho, MD: Welcome, everyone. I'm delighted to be here. My name is Allen Ho. I'm a professor of surgery at Cedars-Sinai Medical Center and a head and neck surgeon. I am also the co-director of the Thyroid Cancer Program here at Cedars-Sinai.

We're very excited to be presenting to you this conversation on active surveillance for early-stage papillary thyroid carcinoma. I'm very lucky to be joined by my illustrious colleague, Wendy Sacks. Wendy, would you introduce yourself, please?

Wendy L. Sacks, MD: My name is Wendy Sacks. I'm an endocrinologist at Cedars-Sinai Medical Center, an associate professor of medicine, and the other co-director of our Thyroid Cancer Program.

Ho: It's a very interesting time to be managing thyroid cancer. There are many established principles, some evolving principles, and emerging ones as well. Would you mind giving me a brief overview of papillary thyroid carcinoma in terms of its incidence and how we're increasingly looking at it differently compared with the way we did in previous years?

Sacks: As you said, thyroid cancer is prevalent in the population. Papillary thyroid cancer is the most common type of thyroid cancer, with an estimated [44,000] cases just in [2022]. It is the most common cancer among adolescents and young adults and the seventh most common among women overall. In general, papillary thyroid cancer, which is considered a well-differentiated thyroid cancer and comprises approximately 80% of all thyroid cancers, has excellent prognosis. In general, localized differentiated thyroid cancer, especially papillary, has a favorable prognosis with a near 100% 5-year survival rate.

Ho: Many people sometimes wonder if this is a product of overdiagnosis, and some people wonder if there is a true increase in diagnosis. Can you comment a little bit more about what these concepts mean for papillary thyroid carcinoma?

Sacks: As you mentioned, there did seem to be an increase in the incidence of thyroid cancer worldwide. The incidence tripled from the 1970s through the early 2000s. There are studies that showed an increase in expected, over-observed thyroid cancers, and this seemed to be due to increase in screening and detection of small thyroid cancers. From about 2014 through present, it seems to have subsided in the sense that the incidence has leveled off.

Ho: What do you make of this leveling off of incidence?

Sacks: Several things have been implemented to reduce the overall incidence of detection of thyroid cancer. One is that the American Thyroid Association Management Guidelines recommended not to biopsy nodules ≤ 1 cm in size, even with suspicious ultrasound features. Another is that the American Thyroid Association endorsed active surveillance of small thyroid cancer, so that includes patients with nodules ≤ 10 mm, for those patients who had a high morbidity from surgery, or for those who would not do well with having had a thyroidectomy.

The United States Preventive Services Task Force recommendation statement to primary care doctors indicates that you don't need to screen for thyroid cancer. Therefore, there have been all these recommendations that have been implemented to reduce the actual diagnosis of thyroid cancer.

Ho: One thing that really gave me pause was not only all of the guidelines and task force recommendations you suggested, but also cadaver studies, which have really shown that a high percentage of patients who die of other causes, such as heart attack, stroke, or diabetes, if you dissect out their thyroids finely enough, you'll find an incidence of small thyroid cancers that is quite remarkable.

In that sense, many people are living with this disease and dying with this disease but dying of something else without it even being detected. It has really given us, as surgeons, pause in regard to what we should be doing.

I think that has brought us to what we are discussing today, which is that not only are patients eligible for surgical approaches, but also this concept of active surveillance.

Wendy, would you give us some of the reasons that active surveillance exists and why it may be useful for early thyroid cancer patients?

Sacks: That lends well, Allen, to discuss the group in Japan who started an active surveillance program back in the early 1990s, where they detected through screening a very high incidence, particularly in young women who had thyroid ultrasound done at the time of mammogram, they detected many small thyroid nodules. Because of the higher number of thyroid nodules detected, thyroid cancer was detected by follow-up biopsy. The group offered active surveillance to these patients, and over time, they were able to follow approximately 1000-1500 cases of ≤ 10 mm thyroid cancers.

They found that there was very slow growth, if any. By growth, they determined a ≤ 3 mm increase in size of the tumor or if there was a novel or new lymph node metastasis. They published their results every 5-10 years, showing that there are very low rates of actual growth of these small tumors and very low rates of new lymph node metastasis, from about 3% of lymph node metastasis and up to approximately 10% of increase in size of ≥ 3 mm.

Some patients opted for surgery down the road due to anxiety, typically. They found that, for the patients who either opted for surgery later or required surgery later due to progression, these patients did not have an adverse outcome or an increased risk for recurrence despite their delayed surgery.

Ho: That's very important to note. It more or less speaks to the idea that if you have delayed surgery or what they might call rescue surgery because of nodule growth, patient anxiety, or cancer progression, you do just as well compared to patients who had surgery right away without any active surveillance. I think that just speaks to the concept that the window of safety and the window for cure is fairly wide open. Just because it has progressed to, say, 3 mm, as you've described, it's not so much a major setback and in fact, progression may be expected in a small percentage of patients. That's what rescue surgery is for. These patients do fine either way. This, therefore, really creates a nice option for patients who don't immediately want an operation.

As we know, a surgery itself is not necessarily morbidity free, although it generally is a safe operation. It can be done as outpatient and patients are back to work within a week or 2 with minimal pain.

There is a small risk for complications that we can't really ignore. They include things such as vocal cord paralysis and hypoparathyroidism, and finally, the idea that you're actually sacrificing a perfectly functional organ that's producing thyroid hormone. We really can't forget that fact that thyroid cancer doesn’t affect function of the organ itself.

Something like active surveillance may be very useful. Can you tell us a little bit more about how active surveillance works?

Active Surveillance in Practice

Sacks: At our center, we have a protocol where we monitor nodules ≤ 2 cm. The majority of studies so far, however, have looked at and monitored in an active surveillance protocol for ≤ 1.5 cm. Our protocol does include some larger tumors.

I find the most challenging part of active surveillance is selection. Who are the patients that we really can be comfortable with advising that active surveillance would be okay for them? This doesn't always depend on size. Even someone with an 8-mm nodule in a posterior location in the lobe approaching the recurrent laryngeal nerve may not be a good patient to advise for active surveillance compared with a 1.5-cm nodule in the middle of the lobe that doesn't show any extension to the capsule of the thyroid or posterior location.

Ho: That's very interesting. You're saying that size is actually a crude estimate or measurement of whether a person is eligible for active surveillance? If it's a small cancer very close to a critical structure, you're more likely to recommend surgery. In contrast, if it's a larger cancer, in this case, ≤ 2 cm in our center, that is well away from anything dangerous, you're more likely to say "No problem." Let's watch it and observe it carefully. Is that what you're trying to say?

Sacks: Yes, that's exactly right. Another difficulty in the decision making for active surveillance is assessment of the involvement of lymph nodes. The ultrasound is extremely helpful, but not always adequate because the thyroid gland is still in place, and we can't adequately assess for lymph node involvement behind the thyroid.

As we discussed, women have a higher incidence of thyroid cancer. They also have a higher incidence of Hashimoto thyroiditis, and with Hashimoto comes lymph nodes in the neck. Sometimes, those lymph nodes can be difficult to differentiate from metastatic lymph nodes. While a patient might have a small tumor, a small thyroid cancer, and they also have Hashimoto, if there are perithyroidal lymph nodes, it may be difficult to assess for metastasis.

Ho: That is the perfect segue to another comment I wanted to make. In order to successfully achieve a good practice in active surveillance, one needs a good team. For instance, a clinician who is focused on doing thyroid ultrasounds is much better equipped to recognize lymph nodes that others may miss or recognize lymph nodes that are cancerous vs a Hashimoto-type lymph node that you're describing.

I think another part of the rubric is having an open-minded team. If you have a progressive, open-minded team willing to learn from each other, as I've learned from you, along with an excellent supportive base, as well as radiology expertise, whether it's from the physicians or from radiology itself, then I think you could really set the stage for an active program that can thrive with surveillance as another approach in order to treat this more indolent cancer.

Sacks: Exactly. As I do this more often now, it becomes even more clear to me that you have to have a multidisciplinary team with a surgeon, endocrinologist, and the radiologist who agree that a particular patient is an appropriate candidate for active surveillance.

Expanding the Parameters of Eligibility

Ho: I would love to jump off of that comment and highlight the idea that having a team that is multidisciplinary and progressive in nature has led to the trial that we have recently published, which has expanded the parameters for what is appropriate for active surveillance by building off of the pioneering studies in Japan and our other colleagues in the United States and elsewhere.

By establishing trust in the practice, we have expanded our eligibility for patients to not just, as you say, 1.5-cm cancers but 2-cm cancers and also allowing it more room to grow. Instead of a 3-mm nodule diameter cutoff, we're using a 5-mm nodule diameter cutoff. This expands the eligibility for active surveillance to actually [more than 70%] of thyroid cancer because the majority of thyroid cancers in the United States are ≤ 2 cm.

I think in that sense, it's very exciting to be able to prove feasibility for active surveillance for a large number of thyroid cancer patients, whereas before, I believe that other physicians might have been more reluctant to consider it.

Sacks: We are at a tertiary care center, and we have access to excellent radiology, surgical assessment, and endocrine assessment. We can allow for these expanded parameters of active surveillance and especially as part of a clinical trial. We've shown that expanding these parameters is okay so far, but it does bring into question whether this can be broadened to the community as mainstream practice. I think we don't yet have the answer for that.

As you evaluate a nodule that approaches 2 cm, the assessment for capsular invasion, extrathyroidal extension, and lymph node involvement does need to be very carefully assessed. You and I have seen patients who have smaller tumors where they, let's say, end up going for surgery rather than opting for active surveillance and we see pathologically they have a more aggressive variant of thyroid cancer or lymph node involvement or micrometastases that we couldn't detect on ultrasound.

Ho: As a follow-up to that point, I think that brings us to the larger question of the limitations of active surveillance. I think what you're speaking to is one of our findings in that patients who were eligible for active surveillance and met our criteria to be observed underwent surgery anyway, and about [19%] of those patients on final pathology were identified to have aggressive or intermediate risk features that would have disqualified them from active surveillance if we had known upfront.

This speaks to the limitations of ultrasounds that you're describing and that we really don't have a fine-tuned instrument to determine who is eligible and who is not. Now, the fact that these patients had those intermediate-risk features doesn't mean that they would have necessarily progressed or had a lethal outcome, but it does tell us that we have to be a little more careful as to who we select.

Patient Assessment

Sacks: It's important for physicians to know how to properly assess whether a patient is appropriate for active surveillance, and then when it comes to the patient, the physician has a duty to discuss all the options for care, which includes surgery, active surveillance, and the extent of surgery. It really does take a large amount of time, actually, for the physician to discuss this with a patient.

Ho: I think these patients have to be prepared to be compliant. It'll take years to decades of doing ultrasounds on a 6-month or 12-month annual basis to determine whether they will continue on active surveillance. If a patient is noncompliant, if they come from far away, if we feel that they may not be someone who will listen to our instructions over time, then perhaps surgery might be what we might describe as a cleaner, more definitive approach.

The other thing that I wanted to echo that might be a detriment to active surveillance is that of patient preference. Patients who are anxious and may perhaps be losing sleep, being very worried or constantly calling about their ultrasound and their diagnosis, they may not be a good fit for surveillance. They may be a better fit for an operation that may give them some peace of mind. That's to be determined on a case-by-case basis, wouldn't you say?

Sacks: Absolutely. I think that oftentimes it's the patient's family who really decides for the patient that they should move toward surgery as the initial therapy, even though the patient is less anxious. I think your comment about continued surveillance is a very important one. We have found that having someone like a research coordinator to help us keep track of follow-up of our active surveillance patients has really been crucial.

It's very difficult for physicians in practice to have the resources to keep up with all of these active surveillance patients. Hopefully, in the future, there will be very clear guidelines for those patients who we can do active surveillance on and risk stratify those patients. Perhaps over time there will be even less monitoring so that patients don't fall into a poor outcome because of lack of follow-up.

Ho: I'm very curious about what you might think about the future prospects of active surveillance.

Sacks: I do think that there are patients for whom active surveillance is clearly a benefit and that they will continue to become more identifiable over time. I think that molecular testing can be a future modality for helping us determine who are the best candidates for active surveillance vs immediate surgery.

Ho: I also would add that, in the treatment rubric, as we think about not only molecular testing but also patient preferences, there are many interesting research opportunities down the pike in regard to decision aids and conversation aids in order to elicit patient preferences that will help us, as clinicians, better determine whether a patient is a good fit.

Any last comments before we wrap up this interesting conversation?

Sacks: I absolutely agree with you regarding decision aids. I want to thank you for moderating our session.

Ho: Thank you, Wendy, for joining me.

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