Case 3: RET Wild-Type Metastatic MTC

Marcia Brose, MD, presents the case of a 64-year-old woman with RET wild-type metastatic medullary thyroid cancer.

Marcia Brose, MD: The last case that we’re going to be talking about is a patient who had metastatic medullary thyroid cancer who did not harbor a RET mutation. That brings us back a little to our pre-RET inhibitor days. This is a 64-year-old patient who had a solitary nodule in her neck and persistent hoarseness, dysphagia, and fatigue. She had major depression with medication and episodic migraines. She had no known family history of thyroid cancer, pheochromocytoma, or hypoparathyroidism and had palpable lymph nodes in addition to her original mass. Her TSH [thyroid stimulating hormone] was 1.5 mU/L; everything was normal. The ultrasound revealed a 3-cm mass near the midline of her thyroid and no suspicious lymph nodes, but a fine needle aspirate showed medullary thyroid cancer [MTC]. Her starting calcitonin was 930 pg/mL, and her CEA [carcinoembryonic antigen] was 240 mcg/L. Is there any additional work-up that you would order for this patient? Lori, give us a start with the work-up for this patient.

Lori Wirth, MD: Pheochromocytoma.

Marcia Brose, MD: Right. We want to look for the most likely biochemical markers in the urine or the blood, to rule that out before they go to surgery. Is there anything else that you would do? We’ve reviewed this before, but Andrew, what else you would do at this time?

Andrew Gianoukakis, MD: I would similarly be concerned for distant disease at presentation for this patient. They’d deserve a systemic evaluation to then consider how aggressive you’d be in the neck and how you would approach the patient surgically.

Marcia Brose, MD: It’s interesting. Maybe it’s because we have all these therapies that I’m finding patients come to me who’ve not had germline RET testing. I do the first testing, and I just go straight to somatic, because the somatic testing is what’s going to determinate therapy. Then if they have the RET in the somatic testing, I go back and do the germline second. That’s happening more in our clinics. In the case of this patient, her catecholamines and metanephrines were all negative. She had a total thyroidectomy, a central neck dissection. It was 3 cm, arising more from the left lobe. There were no central compartment lymph nodes and no extrathyroidal extensions. She was T2N0MX, but we didn’t know what was going on metastatically. Andrew pointed out she has a high likelihood of having disease. No actionable gene alterations were identified, so now we don’t even have to do the germline testing because there were no RET mutations identified. Her ECOG performance status was 0. Would you initiate therapy for this patient? What would you look for? Andrew, do you want to start us off?

Andrew Gianoukakis, MD: Can you go back for a second? She doesn’t have distant disease yet, right?

Marcia Brose, MD: We haven’t done that. That’s a good point. We need to work her up for that.

Andrew Gianoukakis, MD: All we know is she has disease limited to the neck and a calcitonin that likely signifies systemic disease, but we don’t know anything about progression. We don’t know anything about initial extent of disease. My answer would be no. I wouldn’t initiate therapy for the patient now.

Marcia Brose, MD: OK. Lori, what if I say that we did metastatic work-up and found that she had disease and lymph nodes in her chest as well as pulmonary nodules. What would be your trigger? When would you start therapy? What are the things you’re looking for?

Lori Wirth, MD: It’s reassuring that she is RET wild-type, because we know that for RET-mutant disease, particularly the most common 1, RET M918T, patients have more aggressive disease. She may very well end up being 1 of those patients who has very indolent disease. As long as she’s asymptomatic, I’d want to know what the pace of her disease is. I’d do a short interval imaging study. It sounds like a neck and chest CT scan might tell us everything we know. It’s worth saying that liver-specific imaging is crucial for these patients because they can have tiny little miliary metastases in the liver that can be hard to pick up on just a regular abdominal CT. Liver MRIs or liver CT scans are helpful to rule those out. Similarly we can also see tiny little lytic bone metastases in these patients that are difficult to pick up on a PET [positron emission tomography] scan; they may not be positive on a regular bone scan. MTCs are not always terribly FDG [flurodeoxyglucose] avid. A gallium Ga 68-DOTATATE PET/CT, on the other hand, can pick up very small lytic bone lesions that are otherwise missed. That can be a useful imaging study to use at some point. But I’d be content sitting back and getting to know her disease a little better first before pulling the trigger on any systemic therapy.

Marcia Brose, MD: The interesting point is that you can have a patient who has metastatic disease in the chest, and it could have been there for 10 years. You don’t know when you first discover it how long it’s been there. It’s rare that a disease would skip the lungs and get to the liver. If you happen to have gotten the neck and the chest first and there’s nothing there, you might at some point want to get your baseline liver imaging in. But it’s good to get so you can rule it out, or make sure you know if they have cysts so that you have that view beforehand.

This transcript has been edited for clarity.

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