So in this lecture I'm going to be talking about the different methods of biopsy in patients with suspected lung cancer. And I have to say that probably one of the more common questions I get asked, whether somebody pages me, pulls me aside in a hallway, or by email, or through our electronic medical record, one of the most common questions I get asked is, can you get this? And by that people usually mean I got something that I'm worried about, it looks like lung cancer, how do we get a biopsy? And as a guy who does biopsies for a living I spend a lot of time looking at CAT scans trying to decide if I can get it, or if someone else can get it, or how we can get it. And so I think it's useful to have in your mind a sense of what tools are right for what patient when they need a biopsy. In my previous lectures, I've talked about lung cancer screening. I've talked about how we recognize the probability of cancer in a lung nodule, and I've talked a little bit about when we decide a biopsy is necessary. And hopefully from this lecture you can walk away with a sense of what are the right tools to use for any given patient who we think needs a biopsy. So, we'll start with a question, which of the following are true of lung biopsy? Is it A, lung biopsy carries a risk of pneumothroax of about 50%? Is it B, serious bleeding occurs in less than 1% of lung biopsies? C, in a patient with a peripheral lung mass and bulky mediastinal lymph nodes, a CT guided biopsy of the mass is indicted next. Is it D, lung biopsy requires the patient to be under general anesthesia to prevent lung motion? So which of those is correct? So by the end of this lecture, hopefully, it'll be easy for you to pick out the correct answer. The objectives of this lecture are to understand the different tools that we have, the different methods that we have available to us in patients in need of lung biopsy. How we choose between them, and of course to do that we need to know their limitations and their advantages. But importantly, I want you to know that what you biopsy and where you do that biopsy is more important than how. So the tools are important, but knowing what to biopsy is at least as important. So this is a picture that I took from a book chapter that I wrote a while ago. And when I talk about a biopsy, I'm generally excluding surgery. On one hand of this graph, on the left side, you've got people who are good surgical candidates with what looks like early stage lung cancer, stage one or two. Really high probability of lung cancer from reviewing the images, from the patient characteristics, and their exposure history, good pulmonary function, minimal co-morbid illness. The biopsy, in this case, is sending the patient to surgery to get that removed. Now on the other side of that coin, and again, where this line is divided, can be somewhat arbitrary, you've got people who are either poor risk candidates or very high risk, and they need a biopsy. And then you've got two choices of how to biopsy. Generally, when we're talking about the lung you've got a bronchoscope, a fiber optic scope, that allows you to go down through the throat, into the windpipe, and biopsy the lung. And you can see that there's a dividing line between that and CT guided biopsy. And so these are complimentary tools. They don't generally compete with one another, because they're tools to be used in different scenarios. So, when is bronchoscopic biopsy more appropriate that CT guided biopsy and vice versa? Those are questions that we hope to answer through this lecture. So, general characteristics of when we choose to do a CT guided biopsy, it's when the clinical stage is I, that is, all we see is lung cancer in the lung, no evidence of nodal involvement. Generally more peripheral location, so out near the chest wall, as opposed to located centrally near where all the large blood vessels are. No suspicious lymph nodes either on CAT scan or PET scan and we don't have available to us navigational bronchoscopy expertise and I'll show you what that is in a while. So if you lack that and you have these other characteristics, CT guided biopsy is clearly the way to go. On the other hand, when do we use a bronchoscope? Well, when we see that it's early stage disease I, II or III, but it's centrally located, more towards the center of the chest. Or when you've got big, bulky, or PET positive mediastinal lymph nodes. Why do we use a bronchoscope? It's simple, it's easier, and it's safer. If you have access to what we call navigational bronchoscopy, that is the ability to biopsy lung nodules using advanced computerized navigation techniques, and the nodule has what we call an airway sign, that is an airway that leads directly into the nodule, a bronchoscopic biopsy might be more appropriate because it's a little less likely to give you a pneumothorax. And if you have multiple nodules that need to be biopsied, it's probably safer to do that with a bronchoscope than it is with a CT guided biopsy. Again, because of the risk involved. So, we'll spend the rest of this lecture kind of talking about the relative advantages and disadvantages of each of these tools for biopsying lung nodules. So when do we choose to use a bronchoscope? As a pulmonologist, I get asked this all the time, and if there's one misconception that I could disabuse everybody of, it's the idea that you can go down into the lung and see a lung nodule. I've been doing brocoscopy for nearly 20 years and I've seen very, very few lung nodules, though I've biopsied hundreds of them. You generally can't see lung nodules, you can see the airways, and if you're lucky, sometimes you can see the airway that leads to the nodule, but you rarely see what you're doing a biopsy of in a lung. So, the bronchoscopic tool is most useful when we're trying to biopsy mediastinal lymph nodes, that is lymph nodes that are located in the center of the chest, not within the lung. We call these N2, it's nodal stage 2 disease, mediastinal lymph nodes, far, far away from the periphery of the chest where the CT guided biopsy is accessible. But the bronchoscope has the advantage of being able to get right next to the lymph node, which is located just on the other side of the airway. And as you'll see in a minute, we have tools that allow us to look through the airway. So, when we have large mediastinal lymph nodes, the bronchoscope is clearly the way to go. If you have a large central lesion in patients who are not otherwise candidates for surgery, or who refuse to have surgery, the bronchoscope is generally the safer way to get at that nodule. And finally, in some centers with experience in using navigation bronchoscopy some peripheral lesions can be biopsied more safely, particularly when they have the airway sign. And I will show you an example of that here in just a moment. So let's start with an example of a patient with a 1.4 cm lobulated upper node nodule. The patient has a background of emphysema, which you can sort of appreciate on this scan, the holes in the lung, there is the nodule. And lo and behold, on the soft tissue windows with contrast, there is a lymph node in that CT scan which looks somewhat suspicious. Well, if you follow our directions from the previous test, you find that this patient should have a PET scan. And then in this PET scan there's intense FDG activity in this nodule, which moves the probability pendulum, if you will, more towards cancer. And more importantly, this subcarinal lymph node, this mediastinal lymph node, has intense FDG uptake, as does an adjacent hilar lymph node, which is incompletely imaged here. So you have a lesion that looks like lung cancer with mediastinal lymph node involvement. My question now is, what do you do for this person? Do you send her to surgery to have that nodule removed? You just assume that it's cancer based on the PET scan, irradiate the lung nodule because she can't have surgery. Do you biopsy the lung nodule? Or do you biopsy the mediastinal lymph node? Or because you think she has advanced stage disease, do you send her to oncology to get chemotherapy? What's the right answer here? Well one way to approach this is to understand that for every stage of disease in lung cancer. And this may make lung cancer more unique amongst all the solid tumors that are common, is that the answer to how do you treat it is very very different based on the stage. What that means is, if you're going to open up the right toolkit. To treat that patient, you better get the stage correct. I call this table treating lung cancer 101 because this is a very rudimentary representation of how we would treat these patients but people with early stage disease who are receptable should go straight to have surgery. What about people who are too sick to have surgery? We have a lot of other treatment options and this alphabet soup simply refers to a variety of different radiation treatments, external radiation bean therapy, stereotactic body radiotherapy. Which is becoming standard care in this box, early stage unreceptable lung cancer. If we were to prioritizes this, this would be the biggest answer to the question of how we will treat people. But what about people with locally advanced disease, nodule involvement within in the lung or nodule involvement in the media which gets you up to stage three? In this case we try to biopsy those patients but we want to make sure that we're biopsying them so that we have a definitive answer to what stage it is and finally, metastatic lung cancer. Cancer that has spread from the lung to some other organ outside the chest. Here, radiation is only used for palliative purposes, and most of these patients will be treated with chemotherapy. You notice surgery plays no role in this. But the point is that if we want to treat the patient with the right tools, you have to start by getting the stage, and what that means for me. For the person who does the biopsy, we always want to biopsy what we call the most stage informative lesion. That's where the road map of the PET scan comes in handy. So the correct answer for this patient is we biopsy the mediastinal lymph node. It'll give us an answer if there's cancer in there to whether or not she has cancer or whether or not more importantly. That one biopsy answers the second question is, to what stage her disease is and that tells us how we're going to treat it. So, when you have advanced stage disease, evidence on the PET, you have the biopsy that which proves that advanced stage. How do we biopsy mediastinal lymph nodes? Well the tool you see here is what's called endobronchial ultrasound scope Now, on the left, you have a blown up picture of the end of the scope. All total, this is about eight millimeters in diameter and the tip of the scope has a little camera and a fiber-optic source of light. Which lights up the airway and allows us to see what the real utility of this scope is this, which is simply small ultrasound tool. And that ultrasound tool looks sideways through the airway and it's designed so that the needle that comes out of this channel, right here at the top, goes right where the ultrasound's looking. So, this is a what you see is what you hit tool. This middle panel shows a balloon, filled with water. Or saline that keeps the liquid interface between the tissue you're trying to image and the scope, so that you can actually see through the airway, see the lymph node. And here you see the needle coming out of the scope, in the plane of the ultrasound. So what you see is what you hit. This is the operator's end of the scope. You can steer it with this. The needle goes down through the working channel here. This is the needle apparatus and this is ultrasound, which is the single most useful tool in biopsying anything that's close to a large central airway. So here's an example and I'll show you more in a second of what this is but this is, but this is a side viewing ultrasound. You can picture the scope coming out here at the top of this picture. And here you can see the needle going into this enlarged lymph node. And more importantly, what the ultrasound does, it allows you to doppler so you can see the vessels in the area. So, this allows us to go all the way up to, but avoid poking that needle into, this blood vessel. And this is about 4 centimeters in depth of imaging. So this is a fairly large looking lymph node which is being biopsied through this endobronchial ultrasound scope. And again, you see the needle coming out, and here you see it penetrating that lymph node. And that little needle is going to get you enough tissue to diagnose cancer in that lymph node. Here's another way to look at it. Here's a side viewing scope, and the way to get oriented to this is if I draw the scope in here, you can now see the scope coming down the airway looking sideways through the airway. Here's the airway wall and here's the needle coming out of the scope into this little eight millimeter lymph node. Now that's a pretty tiny lymph node, next this big vessel right over here which happens to be the pulmonary artery. And what you can see is the balloon up and the ultrasound scoop looking sideways to the airway. You could actually see the needle going into and out of the lymph node as you do the biopsy. This ability to view the biopsy in real time greatly increases the safety of intra-bronchial ultrasound. The risk of this procedure really entails just the risk of sedating the patient. There's a tiny risk of bleeding, perhaps less than 1 in 1,000. It's a very, very small risk. And almost no risk whatsoever of pneumothorax from puncturing the lung because, truthfully, this needle is going nowhere near the lung. This is in the mediastinum, and the lung is several centimeters away, way out here. I couldn't give the patient a pneumothorax with this needle even if I wanted to. So, EBUS or endobronchial ultrasound guided biopsy is the procedure of choice for people with suspected lung cancer that involves mediastinal lymph nodes. And unfortunately In this day and age, that's about 75% of our patients. The advantage is that it is extraordinarily safe. The bleeding risk is low, the pneumothorax risk is almost nonexistent. It gives you both diagnosis and mediastinal staging in one procedure. It does not require general anesthesia. This is mostly done In many institutions with conscious sedation makes it that much safer. You directly visualise what your biopsying, that is what you see is what you hit and you can get multiple passes, enough to give you additional materials, for the modern molecular tests that we now do on tumors. To generate additional treatment options and you can reach nearly every station of lymph nodes in the chest. There are exceptions to that. The ones that are not next to the air way, of course you can not reach, because you are a slave to the air way when you are doing endobronchial ultrasound. You can only go where the scope goes. It is the procedure of choice, as I said, but it has some disadvantages. You can't reach lymph nodes in what we call the pre-vascular space, what we call station five. These are lymph nodes that are located anterior to the great vessels around the aorta, or generally lower paraesophageal lymph nodes, or out of the reach. Now you can take the endobronchial ultrasound scope and go down the esophagus and find these parasophogal lymph nodes, but there are other scopes that are designed for the esophagus that also have ultrasound and can reach parasophogal lymph nodes. That's what we called endoscropic ultrasound and this was a procedure generally invented by and for gastroenterologists who have a role to play in staging our patients with paraesophageal lymph nodes. The final disadvantage is that if you suspect somebody has lymphoma, If you may recall, lymphomas require generally large pieces of tissue to make the diagnosis and because you are doing a biopsy with a needle this is not an excellent way to make a diagnosis of lymphoma. If you are suspicious of lymphoma you may start with this procedure. You may often find yourself needing a second procedure if you remain suspicious for lymphoma after diagnosing with endobronchial ultrasound the presence of atypical lymphocytes. You generally need to see the architecture of the lymph node, and it's very rare that you can reveal that architecture with a needle-based biopsy, whether it's a core or a cytologic specimen. So, this is a great test but it's not a perfect test for biopsying diseased mediastinal lymph nodes. So, let's move on now to a different patient. Now, this patient is 61 years old with COPD, has very bad shortness of breath and is a smoker. And what you see in these CT scans is that she had an incidental lung nodule initially found on a chest x-ray, later confirmed on a CT scan, and then a PET scan. And what you see is intense FTG uptake in this nodule, and if you look closely what you see is this beautiful airway that leads you right into the nodule and in fact it kind of bifurcates right before the nodule. She's a very poor operative candidate according to the surgeon who evaluated her due to a very low pulmonary reserve and her poor functional status. And so, this is somebody who looks like they have early-stage lung cancer based on this CAT scan and the PET scan. She's clearly at risk based on her smoking history, and now we want to be able to provide her with another treatment option and that requires a diagnosis. So, that brings us to navigation bronchoscopy, and there are a number of manufacturers that create tools that allow us to navigate without seeing our way through the peripheral lung. This is just one such example of what's called electromagnetic navigation. And in this case, in all cases of navigation bronchoscopy, what happens is a very detailed CT scan is imported into some software that creates a map of the airways very specific to that patient. In fact, that is this patient's airway. It creates a three dimensional tree of the airway, and the user can then identify the nodule. And the computer will find the airway that leads you specifically to that nodule, in this case, the airway is highlighted by this pink. The user is allowed to review and edit the pathway to make sure that it's something that can be reached. And then the system will create what are called planar views, axial, sagittal, coronal views of the CAT scan, and what that will look like as you do the procedure. So this is Electromagnetic Navigation Bronchoscopy, in this case it's called iLogic is the brand of software. So, this requires a little bit of extra training, this is not something most pulmonologists are trained to do, but increasingly large numbers of pulmonologists are doing this procedure in their practice. Thoracic surgeons use this as well, to localize nodules. During the procedure, the patient in on a biopsy table, in this case, a fluoroscopy table. And if you peel back the patient mattress, what you'll find is this thing about the size of a cooking sheet. It's essentially a small magnet that creates a magnetic field. And during the procedure, the patient lays on that magnetic field. And a probe is traced through the airways passed through each of these segmental airways until the computer generates enough location data on that probe to recreate that three dimensional model. So the patient's anatomy is converted into this 3D tree. That 3D tree is then recreated with an airway exam that includes that catheter passed through the bronchoscope. And once the airway anatomy is registered the computer is then signaling the operator that we are ready to navigate to the lesion. It essentially works much like a GPS system does in your car. It is virtual imaging, it's not real-time imaging. And so there is some conformation of the location of your biopsy tools that are required. But once you get to where you're going you remove the locatable guide, that's the steerable part, leave the catheter in place and all your biopsy tools can be passed through that catheter into the nodule and allow you to get a biopsy. So you reach the nodule after your navigation. And we can then use a second tool, which is a complementary tool, in this case you can use fluoroscopy. We use radial ultrasound. And the radial ultrasound is simply another catheter, a peripheral catheter, that is passed through the bronchoscope and allows you to ultrasound out in the periphery of the lung. Now this one has a balloon on it, but you don't need the balloon for peripheral nodules because you're already in teeny tiny airways that are probably just no bigger then this catheter itself. What it allows you to do is confirm whether you are indeed where the virtual imaging thinks you are. Once you've confirmed that, you can biopsy through that catheter. Now here's our patient and here's our nodule, and what you can see is that the navigation bronchoscopy catheter's put out there and you, at this point in time, this is just a millimeter or two difference between these two forks of airway. Here, you can see the catheter actually poking itself right through this nodule which is nicely delineated by this ultrasound picture of a solid lesion within the lung. The beauty of the lung is because it's mostly air. You'll see nothing unless you're inside the nodule. This confirms that our biopsy catheter is located within the nodule. You can then remove the ultrasound catheter and pass any standard broncoscopic biopsy tool out into that nodule to get your sample. In this case, the biopsy revealed squamous cell cancer. She went on to have stereotactic radio therapy. Five treatments over the course of a week and a half, and she went off to have her cancer cured that way. So, this is electromagnetic navigation bronchoscopic biopsy. What do the numbers tell us about the utility of this tool? Well it's good, it's not perfect. The data published by people who use this show us that with peripheral lesions that you can't see, with some airway sign, you've got about 60 to 70% chance of being able to biopsy the lesion. The glass half empty way of looking at this means you got a 25 to 30% chance or even more of missing, and that's a problem. Now, when you add in the use of radial ultrasound to confirm your location after navigation, you can get up to 80% yield of peripheral nodules with a fairly low pneumothorax rate, less than 5%. This is far less than one would expect with a CT guided biopsy. And a very low rate of major bleeding, less than 1%. This tiny catheter can penetrate the pleural surface even without a biopsy. So you can get pneumothorax with this approach, even without doing a biopsy. The advantages of this particular approach is that if you need to biopsy more than one nodule, for any variety of reasons, you can do that. It does not require general anesthesia. Most people will do it without, some do it with, but that's up to the operator. And it has a lower risk of pneumothorax than the CT guided biopsy, which we'll talk about later. And it allows you to place fiducial markers in and around the tumor which some radiation oncologists like to use to deliver more accurate radiation, and that depends on the radiation oncology system being employed in any institution. So fiducial markers allow the tumor to be tracked during respiratory motion. That can be useful as well. But the key use of navigation bronchoscopy is to allow us to biopsy lesions with an airway sign, with a lower risk procedure than CT guided biopsy. The disadvantages is that you do still have a risk of pneumothorax. It's probably slightly higher than standard bronchoscopy which is done blindly. It has a lower diagnostic yield than CT-guided biopsy, so these are complimentary tools and they can be thought of in that way. A trade-off, if you will between risk and yield and it does require a lot of experience in the user. It's not something that you can do occasionally and be good at it. This is a procedure with a learning curve that requires a lot of volume to maintain your proficiency. So let's talk now about CT-guided biopsy. What is the role of this tool in a patient with a lung nodule? So, we use this for people who need a diagnosis, with a peripheral lesion, who can't have surgery. So we need a diagnosis, we think it's cancer. They're in the high risk range. And we need to get the answer. This is, in most places, the most common way to do it. Or, in people who might have surgery but their surgical risk is much higher, or higher than the surgeon's willing to undertake without a biopsy. In those people, we recommend getting a tissue diagnosis. In the case of people with suspected metastasis, to the lung from other organs, or a metastasis from the lung to say, the liver, or the adrenal, or the bone. Often the CT-guided biopsy is the best way to make that diagnosis in the metastatic lesion. And, importantly, I think it's worth mentioning this, that in 2015, bone metastasis, though they may be easier to get, often have to go through a process of what's called decalcification. That process can render unusable many of the important molecular tests that oncologists require to make treatment decisions. So before you biopsy a bone lesion, talk to your oncologist. If that's the only metastatic lesion there, it may then be acceptable to go back and biopsy something within the chest. Because those soft tissue lesions can more readily be used to facilitate specific molecular diagnostic test, generally to look for targetable mutations in the tumor. That is a very, I think that's an advanced concept, but you do need to know about this if you're going to biopsy something that you suspect is a bone metastasis, talk to the person who may be treating the patient to make sure that that tissue will be useable for what they need. This what a CT-guided biopsy looks, you actually have the patient on the table. They are put into the scanner, the image itself is brought into the view and markers may be put on the chest to facilitate placement of the biopsy needle. And here of course, you see the needle going through the lung and that is the chief risk of the CT-guided biopsy, and that is about 15 perhaps 2-% of people will have a pneumothorax because of course, you're putting a needle through their lung. What's amazing to me is that that number isn't higher, and in skilled hands this is still the most accurate way to biopsy any lung nodule that requires a diagnosis to inform treatment decision. CT-guided biopsy, in most of the world is a standard procedure. There are many, many radiologists out there with a lot of volume experience in doing this far more radiologists, with good volume of experience in this than there are pulmonologists or surgeons in doing navigation bronchoscopy. But as time goes by, experience becomes more equally balanced and this is an option that I find to be complimentary to navigational bronchoscopy and vice versa. So more to the advantages of CT-guided transthoracic needle biopsy in a patient with a lung nodule. Again, a lot of people know how to do this and do it well. So it's generally something you can get done, even in hospitals where there aren't great experts in it, does not require general anesthesia, and is extremely accurate. That is, if you go to biopsy a nodule, jn most centers, upwards of 94, 95% of the time, you're going to come away with an answer and it can reach most of the lung. There are limitations though, which we should talk about. It is the highest risk of all the procedures we have to biopsy the lung for pneumothorax. In very experienced hands, pneumothorax will occur 15% of the time, in less experienced hands, it's likely that that number's going to be higher, but only about one out of three people with a pneumothorax, as a result of a biopsy will need to have that treated. That is, most people, it will resolve on its own. Or it's so asymptomatic, it requires no treatment. Serious bleeding, again is unlikely to occur. Again, less than 1% of the time. Now, there are some nodules where this procedure is quite difficult. Remember the lung is an organ that's always moving, particularly the lower part of the lung. So nodules located in this area of the lung, just above the diaphragm, can be extremely difficult. If you're not sure, you should ask your radiologist, the ones that do the procedure, they'll be the best ones to tell you whether they can safely get the nodule or not. And more importantly, the CT-guided is almost never useful as a staging tool. So when you biopsy a lung nodule, you better be darn sure there aren't any involved mediastinal lymph nodes. Why? Because they will give you the stage and there's almost no risk of a pneumothorax in biopsying mediastinal lymph nodes. So while you can get a diagnosis in most people with a CT-guided biopsy, it can only be considered definitive staging if there's no evidence of nodal involvement. So the take home points here is that both bronchoscopic and CT-guided biopsy techniques can get at most lung lesions. The choice of your approach depends somewhat on the nodule location, the patient preferences, particularly when the risks and benefits are balanced, the advantages and disadvantages of these two approaches for biopsy and lung nodules are complementary, and the most important thing I can say is that if and when you do biopsy of a lung nodule, please make sure that that biopsy answers both questions. Is this cancer, and what stage is it? And that's where a endobronchial ultrasound becomes such a useful tool, because such a large proportion of our patients already have nodal involvement. The safety of endobronchial ultrasound makes it procedure of choice for anybody with suspected nodal involvement in the lung nodule or lung mass. So let's get back to the first question. Which of the following are true of lung biopsy? And now you should be able to answer this question based on what we just talked about. The right answer is B. Serious bleeding occurs in less than 1% of lung biopsy. Lung biopsy does not carry a risk of pneumothorax of about 50%. It's 15% of CT guided-biopsy, much less than that from macroscopic biopsy, and even in high risk patients, 50% is probably a high number. Patients with peripheral lung mass and bulky mediastinal lymph nodes, I would not biopsy the lung mass, I would biopsy the lymph nodes. And finally, lung biopsy almost never requires general anesthesia, although for some patients it can facilitate safety in the biopsy.