Case 2: Diagnosing PD-L1+ and EGFR+ Lung Adenocarcinoma


Benjamin P. Levy, MD:Speaking ofEGFRand PD-L1 [programmed death-ligand 1], Lonny, for the critical role you play to make sure we get the information we need, you are the start of all this. Can you talk a little bit about not just biopsy techniques but also the tissue journey and how you ensure enough tissue when you’re there? Where does it get sent off to? Then we’ll talk to Sam about what he does with it when he gets it.

Lonny Brett Yarmus, DO:Sure, Ben. I think this is a great discussion and opportunity for bringing in multiple different specialties. For example, this case, from a minimally invasive approach, I completely agree with Mickey about the endobronchial ultrasound, but the adrenal gland is easily accessible with the esophageal endoscopic ultrasound.

Benjamin P. Levy, MD:Yeah.

Lonny Brett Yarmus, DO:It seems like a great opportunity for a combined procedural approach of EUS [endoscopic ultrasound] with gastroenterology and then the endobronchial ultrasound. Then you can really make a confirmatory diagnosis of metastatic disease. You can appropriately, as Mickey addressed, stage the mediastinum, and then work toward tissue acquisition for ancillary testing.

Benjamin P. Levy, MD:Talk a little bit about ROSE and having an on-site pathologist in the room, as well as where it goes from there.

Lonny Brett Yarmus, DO:ROSE, or rapid on-site evaluation, has really become an integral part of our procedure interface. This is not so much from an evidence base of improving or increasing diagnostic yield but really in terms of reducing complications and improving adequate tissue acquisition.

Having the cytotechnologist, cytopathologist, or pathologist in the room providing feedback, as we move from procedure to procedure, allows us to confirm a diagnosis but also gives us a stop point of when to collect and when to stop. Also, what’s becoming a lot more meaningful in the literature is what medium or what perforation techniques should be utilized to ensure that Sam has the appropriate information that he needs—the appropriate tissue or the amount of tissues so that they can go on and do the testing.

Benjamin P. Levy, MD:Sam, talk to us a little bit about biomarker testing. The first case was a squamous cell carcinoma. Maybe we do PD-L1 testing; yes, we do it reflexively. But this is an adenocarcinoma. This is someone who has never been a smoker. There’s a high likelihood of finding a genetic aberration. Walk us through current guidelines from molecular testing for your garden variety of a patient with stage IV.

Samuel Caughron, MD:This is a stage IV, as you mentioned. In advanced stage IV disease, biomarker testing should be done in all these patients. I will say often in the pathology lab, we don’t know what the disease stage is when the specimen comes to us and would encourage optimal communication between the team members. When that specimen comes down to pathology, it helps us do the testing if we know it’s stage IV and if reflexive testing is not done. But certainly in a patient with stage IV disease, it should be done.

You’ve got really 2 buckets—well, 3 buckets, I guess, today. You have your oncogenic driver mutations, and greater than 99% of the time I’ll get them mutually exclusive. This is going to includeEGFRas well asKRAS,BRAF,HER2,ERBB2, or evenNTRK. These are all oncogenic drug mutations and mutually exclusive. You then also have your immuno-oncology markers. You’ve got PD-L1 being the immunohistochemistry, and then you also have your MSI [microsatellite instability] and some other markers. Ideally, I think they all should be done in a patient with advanced disease like this. Next-generation sequencing can be used and can get many of these results, although not all of them. It really requires the pathologist to be actively involved from the beginning. A pathologist being involved in the evaluation of the biopsy is going to make sure we’ve got adequate tissue. If you don’t have adequate tissue, even with ROSE, sometimes the procedure has to be stopped. There has to be a discussion about what can we get done, and sometimes you have to triage it.

The guidelines would say that in a patient like this—they were updated in 2018, the CAP [College of American Pathologists] guidelines are like AMP [Association for Molecular Pathology] guidelines—at a minimum, testing forEGFR,ALK, andROS1should be done. There is expert consensus in those guidelines that has since moved on to what should be standard of care forBRAF, and nowNTRKprobably should be part of it.NTRKis a very low-frequency abnormality, and so that almost pushes you and many of these patients into next-generation sequencing. But that requires more tissue than you can get with some of the hot spot tests.

It does require a multidisciplinary discussion, and the pathologist should be knowledgeable about what the testing requirements are and what they think they can realistically get off the sample they have. They can potentially have a discussion about going back, that maybe even though you can use an ultrasound-guided technique to get to the adrenal gland, maybe a laparoscopic procedure is better to get a generous amount of tissue.

One last comment. Primary versus metastatic site. For most of these abnormalities, you’re going to get the same information, whether you test 1 or the other. Especially with the oncogenic driver mutations, they’re the same. There are not a lot of data out there about heterogeneity for some of the other markers.

The metastatic site, from a biological perspective, is generally going to be your most advanced with mutation status. In some ways, it would be preferred. But that’s without solid evidence.

Benjamin P. Levy, MD:Lonny, I want to get back to you really quickly in terms of the tissue acquisition and using EBUS [endobronchial ultrasound]. There are people out there who say, “Well, EBUS can’t get enough tissue for molecular testing. And there are some data on for 4-pass FNAs [fine-needle aspiration]. You can use a core biopsy with an EBUS, I understand, at times, which is our larger needle. Talk to us about the success of getting enough tissue with your tools.

Lonny Brett Yarmus, DO:Sure. As Sam mentioned, I think the communication between all parties is pretty essential, starting with understanding what the procedure is for. Right? If we already have a diagnosis, we go in up front with communication with our pathology colleagues: “I’m going to do basically 1 smear, confirm that I have tumor, and then everything else is going in a separate block to be tested at a later date.” So tissue preservation is critical.

To that end, we think there’s a lot of promise in onset preparation. There’s a lot of controversy on needle size, on which medium to place different samples in. There are guidelines that are actively being done right now in the field. But whatever the technique is, it should be catered to the institution and what pathology is used to doing and comfortable doing, and then optimizing that to ensure that you have enough tissue for testing.

Transcript edited for clarity.

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