Lori Wirth, MD: Case No. 2 is a 60-year-old man who presents with a solitary nodule in the neck, occasional shortness of breath, and some fatigue. He has a past medical history notable for BPH [benign prostatic hyperplasia], hypercholesterolemia, has no family history of thyroid cancer, no family history of pheochromocytoma or hyperparathyroidism. On physical examination, and he has a palpable, hard, fixed, solitary mass in the central neck. TSH [thyrotropin] is normal, other laboratory tests are normal, and the ultrasound of the neck showed a 2.4-cm mass arising of the isthmus of the thyroid. There were several suspicious cervical nodes, ranging in size from 0.3 to 2.2 cm. An ultrasound-guided fine needle aspiration was done, showing medullary thyroid cancer [MTC]. Calcitonin and CEA [carcinoembryonic antigen] levels were checked; the calcitonin was 870 [pg/mL] and CEA was 229 [ng/mL]. Andrew, the patients refer to you as the endocrinologist; is there any additional work-up that the patient needs before going off the OR [operating room]?

Andrew Gianoukakis, MD: With regard to the actual tumor itself: it’s a large tumor, it’s palpable. The patient is likely to have, and we already know they have positive nodal disease in the neck. This patient also has calcitonin over 500 [pg/mL]. The combination of size of the primary lesion, neck nodal disease, and the calcitonin of over 500 [pg/mL] makes it highly likely that the patient will have distant disease. In terms of the actual disease and knowing the extent of the medullary at presentation and how aggressive one should be in the neck, one needs to exclude metastatic disease with the combination of size, neck disease, and level of initial calcitonin. Now after a full evaluation is performed to diagnose and understand the extent of the disease and decide on the surgical approach, if surgery will be warranted and the extent of the surgery, one needs to exclude a hereditary disorder, such as MEN2A [multiple endocrine neoplasia type 2A] or 2B [type 2B]. And most importantly before someone goes to surgery, we need to exclude the possibility of a pheochromocytoma, which would increase the risk of a surgery and complicate matters intrathyroidally. The pheochromocytoma would need to be diagnosed and addressed prior to the neck surgery.

Lori Wirth, MD: You mentioned MEN2A and 2B; do patients need to have the germline syndromes ruled out before they have surgery?

Andrew Gianoukakis, MD: Most importantly, you’d want to rule out a pheochromocytoma by doing a combination either/or plasma metanephrines, or urinary metanephrines and catecholamines. The molecular component, if there is a syndromic component, would be important in terms of family counseling. But of immediate importance, even if you came up with a negative germline mutation, you’d want to exclude a pheo [pheochromocytoma] prior to taking a patient to surgery.

Lori Wirth, MD: We send most of these patients to genetics counseling for the germline testing, which can take a little while to get an appointment with a genetics counselor, and then the send-out lab for the germline testing can take a little while as well. From a practical point of view, in our hands it’s not practical to rule MEN2A or 2B prior to surgery. But I agree with you: it’s critical to rule out pheochromocytoma when you’re taking any patient with MTC to the OR before they collapse on the table. We’ve talked about molecular testing for the patient, and Andrew you talked a little bit about germline testing and if it is necessary. Can we talk briefly about why we care whether there is MEN2A or 2B in any patient diagnosed with MTC?

Andrew Gianoukakis, MD: As noted, it’s a syndromic disease with multiple different components that characterize MEN2A and 2B. Importantly, the consideration of pheo, hyperparathyroidism, other abnormalities including ganglioneuromatosis, would be important to know for the individual, but also from a family counseling standpoint. In addition, whether in the germline state as part of a syndrome or whether somatic testing is done in the cases that are germline negative, looking for a somatic RET rearrangement will be important in terms of deciding on therapeutic options moving forward. This is whether you use an as needed systemic therapy that’s RET based versus multikinase inhibition.

Lori Wirth, MD: We’re basically talking about patients with MEN2A or 2B germline RET mutations; 25% of people with MTC will have familial syndromic medullary thyroid cancer in the setting of MEN2A or 2B. But in the patients who don’t have MEN2A or 2B, there still is a possibility of those tumors harboring RET mutations because the sporadic MTCs can develop somatic RET mutations in the same gene that we see in MEN2A and 2B; it’s just not germline. Marcia, assuming that this patient will eventually have their genetics counselor appointment and germline RET mutations will be ruled out, does the patient need other testing? If you’re going to do somatic testing, how do you do it?

Marcia Brose, MD: Again, I think the easiest thing is to do the somatic testing on the tissue that you get at the time of surgery. I usually do a full germline screen; we look for mostly RET and we’ll look for all the different RET point mutations, but there can be some other ones. However, they are extremely rare. In fact, I just heard that there was a TRK fusion in one of the first medullary [thyroid cancer cases], so it’s not that we’re expecting really anything else for actionable mutations in this group. If we see a RAS [mutation] however, that tends to be a poor prognostic sign, not actionable, but it might let us know that this patient is going to have a more aggressive outcome. There are some slight differences possibly in which mutation they have as far as how aggressive the actual course of disease is. I think those are details that go beyond where we are today. We are mostly just looking for somatic RET because those are, again, usually the reason for the cancer developing and because of that, these are very good targets for therapy.

Lori Wirth, MD: Marcia, I’m just curious, do you have a testing strategy where you do sequential testing of the tumor, doing a deep dive, looking for RET mutations. And then if the tumor is RET wild-type…?

Marcia Brose, MD: That’s a good question and that probably applies across all these different ones. Historically that would maybe make sense because it used to be very expensive to do these panels. But in the last few years, the panels that detect all of the RET mutations and also would tell us if they had RAS or anything else, are about down to the level of cost that by the time you do a sequential testing strategy, you actually pay more than if you do these panels up front. We have a solid tumor panel; we would run this through it the same way we would run a differentiated [tumor] as well. You can if you needed to, but I think that it’s sort of going away because we’re able to get these genomic-wide panels done in the same amount of time, with the same amount of effort. In addition, they can save tissue, at the same cost. Historically yes, I think we did much more of that. Going back to differentiated thyroid cancer, if you had a BRAF mutation, you don’t have to run looking for other things and you may know about that from a fine needle aspirate biopsy before they come. Really, we do look for other things, and we won’t know until we do a lot of these whether there are other mutations that might be targetable down the line. Over 65% of our patients will have a RET [mutation], either somatic or germline.

Lori Wirth, MD: Exactly. We do the same thing; we have a panel testing, and it ends up being more efficient and actually more cost efficient for us as well just to go straight to the panel. One critical point I want to loop back very briefly on, in terms of the germline testing, say you identify a RET C634 codon mutation by your somatic test, it is always important to go back and make sure that is not a germline mutation. It matters for the patient, but it also matters for the first degree family members, especially the young people, because you want to identify all of the first degree family members who may harbor the germline mutation, and evaluate them for the presence of medullary thyroid cancer because there’s a near 100% penetrance of the phenotype. You can do a prophylactic thyroidectomy in carriers of the germline gene and prevent them from getting a cancer that might otherwise kill them.

Andrew Gianoukakis, MD: As well as the other features of the MEN2A or 2B.

This transcript has been edited for clarity.