is to have you leave more confident than when you entered. When looking at these images, reviewing pathology reports, talking with colleagues at Tumor Board, other conferences, and then certainly when you sit for your certification, even if it's at home, doing longitudinal maintenance of certification. Next slide. And again, the method's intentional. We're gonna get through nine cases and then a rapid fire quiz at the end, time permitting. We're gonna activate you with a quick audience response question, really quick, single slice of an image, one-liner clinical history, show you some pathology, make you commit, and then our expert's gonna go through the pathological differential diagnosis, compare and contrast. These are all real patient cases submitted over the years by our Training and Transitions Committee here at CHESS. Then for reinforcement, everyone who showed up early this morning gets to leave with a digital goodie bag, some CHESS PDF radiology, pathology references, and just the most beautiful images ever that Dr. Butt collected for your personal use and so you can quiz yourself later. Sound okay? All right. Next slide. Here, if you haven't seen it, is the ABIM Blueprint, and it's the same for certification or maintenance of certification, longitudinal testing. And when you take the diffuse and obstructive lung disease, cancer, and infection, I think next, that's about 40% of the test, and each of these topics lend themselves to pathology, and we're gonna cover all of these entities today. So, you know, it won't be fully 80 questions, but it has the potential for that. Test writers like pathology, because it's hard to argue with. And actually, as you may know, the test is 240 questions, but 40 are those annoying practice questions that you worry about but they don't account for you. Next. And when you take the exam, you know, if you've done it recently, you have up-to-date, you have these other resources available. Doesn't help you with the images, although Google's working on a better pathology image search. You just have to know the keywords, the image context, and Dr. Butt is gonna provide all of that to you. All right, shall we begin? Great. So, case one. Your colleague asks your advice. 64-year-old patient, chronic dyspnea, some interstitial abnormalities, undergoes a transbronchial biopsy. Clearly some subplural, peripheral abnormalities. Next. And you're looking over the shoulder, kind of going through these images. First, low power. A little higher power. Okay. And then what do you recommend? Kind of a second-order question. Anticoagulation, diuretics, no therapy, a repeat biopsy, or systemic steroids. There's the QR code again if you need it. A lot of votes. I think we can advance. All right. We'll go to the next one. 48 people. All right. All right. So we have. So thank you for getting us started. I just want to say this is going to be indeed quite rapid fire. My goal here is to show you as many pictures of distinctive entities as possible that you might be tested on. So if you ever want to interrupt me to ask a question, please feel free to just raise your hand. I'm happy for that. So it looks like we have a lot of people want to give steroids. A small percentage want to do a repeat biopsy. Some want to do no therapy. No one went for diuretics. And one person wanted to anticoagulate this patient. All right. So the answer here is repeat biopsy. And the reason for that is, if we go back and look at the images. So on low power, this is actually a really generous biopsy. So whoever did this did a great job, right? They got a lot of tissue. So kudos. Unfortunately, there aren't any findings here. So if you look around, so this is some nice, let's see if this works here. So you have your alveolar septum, nice and thin and delicate, okay. You don't see acute lung injury. I don't see anything filling the spaces. There's maybe a very rare pigmented macrophages, so perhaps the patient's a smoker. But other than that, I don't see giant cells. I don't see granulomas. I don't see tumor. I don't see anything that could explain an abnormal imaging. You know, here's a piece of cartilage with some calcification, which you can see in older patients. But again, no findings. Again, here's a little bit of crush artifact from the forceps, but there's no actual findings. And so when you have non-diagnostic biopsies, best bet is to go and do a repeat biopsy so you actually have, to help better guide your treatment. So this is normal lung? Normal lung. And it's our last trick question of the day? Yes. Okay. I promise. No more normal biopsies. So that leads me into the first couple slides in this talk, which is basically, yes? Can you show us the crush artifact from the forceps? Yeah, for sure. So it's right here. So you see where it gets a little pink? So this can be misdiagnosed as fibrosis if you're not, if you're not used to looking at it. But this is basically where the forceps crushed the tissue right here and pulled it out. Alright. So I wanted to start off with a couple of slides talking about things that are not pathologic diagnoses, but are often questions, because people like to question you on them. Emphysema, of course, you don't need to take tissue for emphysema, but here's an example of central lobular emphysema. So here's a pulmonary artery. So this is our bronchovascular bundle, and you can see these emphysematous spaces pointed out by the arrows. So of course, radiology would be sufficient to diagnose this. There's also a little bit of fibrosis here, that smokers-related fibrosis that you can see, and a little bit of anthracotic pigment, a little bit of black material there. So this is central lobular emphysema. Should not be taking tissue for this diagnosis, and if you get this as a top-line diagnosis for tissue you take, I would consider that to be non-diagnostic, because you're not going to be doing a biopsy for that. All right? Another example is chronic bronchitis. So here's high power showing you a normal airway right here. So you can see your nice little cilia on the top, little buzz cut right there, and then interspersed goblet cells, okay? And then in chronic bronchitis, you get goblet cell hyperplasia. So basically, more blue. So you see a lot more goblet cells. So this kind of bluish look is what a mucin looks like in the goblet cells, all right? So I wanted to show you another picture. So this is also chronic bronchitis. And so this, in chronic bronchitis, you have hypertrophy and hyperplasia of your submucosal glands, all right? So these are your seromucinous glands that are in your more proximal airways. Incidentally, this is where all your salivary gland neoplasms come from. We're not going to talk about that today. That is not high yield, but I always like to throw that in there. And because of that, you get, you have something called a reed index. Now, I would like to emphasize that we do not do this in pathology, but it is unfortunately something that you could be tested on. So the reed index is the ratio between the thickness of the submucosal mucus-secreting glands and the thickness between the epithelium and the cartilage that covers the bronchi. Normally, it should be less than .4, but if you have thickening of those seromucinous glands, you're going to get a change in your reed index. And for those of you that like cartoons, here's the cartoon for that. All right, so these are findings, again, that are potentially testable, but not really true pathologic findings. If you're getting a diagnostic, top-line diagnostic line of chronic bronchitis, that's unlikely to be what you actually did the biopsy for. All right, so moving on to case two. Well, great. So 60-year-old male, AML, about three weeks into chemotherapy, cough, kind of a nasty brown sputum, some chest discomfort, gets a CT-guided biopsy. X-ray, you know, kind of hints at an air-filled edge there. Confirmed by CT, small ipsilateral effusion, and there's the mass. All right, so what's your diagnosis here? So I'll give you a chance to look at that photo. Not too long, though. Open the poll. And for the folks that just joined us, you can scan that QR code, and then you can answer the question. The other thing to mention, all the answers are in alphabetical order, and that's what test writers do, because in the old days, they would hide the answer in C, and people caught on. So that's why it's alphabetical. It might be C. It's not C. Good test-writing skills, 101. Little bonus there. All right. All right, we're up to 53. Okay. All right, so we have 75% going for aspergillus. Nice. Okay. So this is indeed an example of aspergillosis. Okay, so let's look at a wedge, or probably maybe even a lobectomy from that particular patient. So here is low power of a bronchus. You can tell it's a bronchus because of the cartilage. So you have that pale bluish look with the little interspersed chondrocytes in there, discontinuous plates of cartilage in the wall. And this is your airway. And even on this low power, you should be able to see, this airway doesn't look quite normal. You know, like I showed you that normal airway, and then the one with chronic bronchitis. It should be pretty thin. But it looks like there's something going on. So if we go higher power, so this is adjacent to a piece of that cartilage, you start to see these hyphal forms. And they're eating into the cartilage. They're eating into the surrounding tissue. It looks like there might even be some necrosis, some kind of granular pink material here. So clearly not normal. All right. And then there's that picture that we showed you for the quiz question. So you have hyphal forms right here. They're branched about 45 degrees. And then you can see some septa right there. And so I think those are the features that led everyone to think about aspergillus. If you look elsewhere in this slope, this is a large pulmonary artery. Okay. And you can see that the fungus is actually invading into the pulmonary artery as well. So this was angioinvasive aspergillosis in this particular example. Now everybody picked aspergillus, which is absolutely correct. However, with just these pictures that we've shown you, it might not actually be aspergillus. So there's a distinctive morphologic feature that tells you for sure something is aspergillus. All right. So if you're hedging your bets, it's going to be aspergillus. But you need to see fruiting heads in order to definitively call something on histology aspergillus. And so when you see these very distinctive fruiting heads, all right, with these little balls around the surface, you can say something is aspergillus for sure. All right. So keep in mind testable points. Aspergillus has that 45-degree angle branching. And you have those septated hyphae. All right. And then if you see fruiting heads, you're good. All right. So if you do get a path report back and they're descriptive and they don't see fruiting heads and they might say favor aspergillus or just top-line it aspergillus, it may not be. So you want to wait for cultures to know definitively. Okay. So that leads us into our next fungus that I want you to be able to identify. And I'm going to show you a bunch of pictures of this because this is not one you want to miss. So this is an example of mucormycosis. All right. So this is something you're going to see in an immunocompromised patient, of course. So this is a pulmonary artery. And it's essentially filling this small artery here. And you can see the hyphae. So this is just H and E. This isn't a special stain. So you can see fungus without special stains. Some of them you can. Not all. This is one that you can. So you see they're variably sized hyphae. So this one maybe is a little narrow, but this one's quite broad. Almost has a twisted ribbon-like look. So here's another example. All right. This was from a lobectomy in a patient that did survive. They actually had aplastic anemia. So you can see that broad hyphae right there. All right. And then here's another example. And again, these are all just H and E pictures. I'm not even showing you any special stains because you can see them on H and E. But when you see that empty space, that's one of your clues that you're looking at a mucor case. All right. And that sort of almost twisted ribbon look. Now, we call them, you often hear them as saying you shouldn't see a septa. But actually, mucor is a posseseptate fungus. So you do occasionally see a rare septa in them. So if someone shows you a picture and it looks exactly like mucor and you happen to find one septa, don't let that trip you up. It's still going to be mucor. Okay. All right. So let's talk about our next infectious disease here. So this is an example of candida. So this is an acute pneumonia. Again, immunocompromised patients are going to get candida pneumonia. It would be unusual to see it in a patient who's immunocompetent. It's going to be an immunocompromised patient. Here's a GMS stain in the upper left showing you the little meatballs of the spaghetti and meatballs. Here you couldn't tell that this is candida. So candida is something that would be a little difficult to see on H and E. You could. But I don't think anyone would expect you to identify it on H and E. And here's a high power, again, showing you this is an H and E example where it was quite exuberant and you can see it and you can see the little spaghetti and meatballs. That's your clue that you're looking at candida. They're going to be very, very small in contrast to what you were seeing with the mucor, for example, which is going to be very large. Okay. So moving right along. So here's an example of nocardia. So this nocardia will often give you a necrotizing pneumonia, which means when you're looking at this, it's very hard to tell where the septa are because they're partially destroyed. So these are your alveolar spaces. This thin material is edema fluid and you see lots and lots of neutrophils and the bright pink material is fibrin. So this is the necrotizing pneumonia. I couldn't tell you this is nocardia just from this. You would have to do special stains. So here's a silver stain. This is GMS. This is one of our stains that will stain both fungus and bacteria. This is a higher power image. Nocardia has this very thin filamentous look, almost like a tangled nest of small snakes. But again, in contrast to, say, aspergillus, they're going to be very, very small and delicate. All right. So for those of you that like tables, here's your table. We talked about aspergillus, mucor, and candida. So to keep in mind for aspergillus, you can see this in several different clinical scenarios. So we showed you an example of angioinvasive aspergillus. You're going to see that in an immunocompromised patient. You often get infarctions associated with that. However, you can also see aspergilloma, like a mysotoma. So if you have a preexisting cavity, a bad tumor that maybe underwent radiotherapy, or a patient that had a pneumonia that resolved with a large cavity, another infectious process. You can have an aspergilloma form in that cavity. That is not invasive fungus. That's just an opportunistic infection. And then you can also see APPA, or allergic bronchopulmonary aspergillosis. So again, this is not an invasive infection. This is an allergic reaction. So you'll see patients developing bronchiectasis. They're going to have eosinophilic mucin, lots of eos, and then only very rare distorted hyphae on imaging. So if someone shows you a picture in a patient that has bronchiectasis, you see a rare little hyphae, you're not sure what it is, but then tons of eos and allergic mucin, think about ABPA. And then, of course, mucor, we talked about those wide posse septate, twisted ribbon, vascular invasion, infarction, and then candidiasis with the yeast and pseudohyphae, your spaghetti and meatballs. All right. So I wanted to take a minute to talk about the stains, because oftentimes you'll see pictures of stains, and that can help clue you into what you're looking at. So GMS or silver stain, you mostly see that in the context of fungus. But remember that GMS will actually also stain bacteria. It will also stain a pneumocystis. Tissue gram stain, of course, is going to stain just bacteria. That'll help you differentiate between gram negative and gram positive. We'll show you an example later on in the lecture. PAS, or periodic acid shift, is also fungus, but not pneumocystis. GMS is going to give you that black-gray look on a background of green, versus PAS is essentially a dark pink on a lighter pink. And then for acid-fast bacteria, including nocardia, zeonilsin, that's going to be the most common. I'll show you an example later, where you have blue with the red. And then oramirodamine is going to give you bright orange, and then phytostain. All right. So those are for acid-fast bacilli. And we'll show you some photos of those later. All right. And just for this last case, on the imaging, it was kind of the start of an early fungus ball. And as you know, that's more of a later finding up front. You might just see an infiltrate. And effusions are a little less common with aspergillus. So the imaging was tricky. And the other thing, so aspergillus, 45-degree angle, and it's got a little septae, like the letter A itself. Thank you. Thank you. All right. It's awesome. All right. Next slide. Next slide. That's all I got. All right. Let's go to case three, 76. Now, this is more chronic dyspnea. Cough, this copious, clear, almost watery sputum, gets a surgical lung biopsy. Really markedly abnormal x-ray, a complication of the biopsy, or post-operative chest tube there. Diffuse alveolar infiltrate. Pulmonary alveolar microlithiasis, interesting, okay. All right, so this is an example of mucinous adenocarcinoma, all right. So let me show you a low power of what a wedge might look like from that patient. All right, so on low power, you can see your alveolar spaces, but they're filled with a kind of a thin material, right? It's not white, so here's a artery here, that's white, but here there's some material filling the spaces. And then you notice where the circled areas are, there's some more blue, it looks like maybe something a little blue lining the alveolar spaces. If you go on a high power, you can appreciate what's going on there. So you have these cells that are lining the spaces and they don't look particularly malignant, right? This is the key for mucinous adenocarcinoma, is it doesn't really look malignant. The cytologic features are very, very bland, but the keys that help you differentiate what you're looking at is all this mucin that's in the surface of the cells here. It's right in the apex of the cell. And they form these discontinuous tufts along the alveolar spaces, okay. Here's another example. This one is a little bit more exuberant. You have papillary structures here. But again, you have this clearing in the surface of the cells and that's mucin. So even though the nuclei maybe don't look as ugly or as hyperchromatic as you're used to thinking about tumor, that's actually quite diagnostic of mucinous adenocarcinoma. I will say this is a very, very common case that we see on our consult service is mucinous adenocarcinoma because it can be really challenging even for experienced pathologists who maybe don't have lung experience to diagnose these tumors because the cytology is so bland. Here's another example. So this looks a little bit more like what you might expect with tumor. But again, you can see that mucin packed into the surface. So these are examples of mucinous adenocarcinoma. And the tricky thing is, is they can often present as a pneumonia. They might be bilateral, multifocal. And so I have seen so many cases like this come in as refractory pneumonia. They finally decide to get a biopsy and then the outside pathologist says, is this mucinous metaplasia? What's going on? And it's like, no, this is mucinous adenocarcinoma, antibiotics are not gonna help here. So keep in mind, so if you see cells with lots of mucin, yeah, question. Yeah, absolutely. If you get the tumor, yeah, absolutely. You can do this on transbronch. And something that I think is often the challenge is you might get a transbronch and because of the discontinuous nature, you might only get a rare tuft or two. And in the right context, something like this, I will call that mucinous adenocarcinoma. Yeah. Yeah. I mean, I'll do it for you. Yes. You needed the surgical biopsy. Yeah. You need the biopsy. And that's why, oftentimes, these patients end up going through multiple rounds of treatments with antibiotics. They're not recovering. And they're like, OK, we need a biopsy to figure out what's going on. And sometimes they come as just localized consolidations. It's that ground glass. Because they grow, oftentimes, in this lipidic pattern, which you often think about in terms of low-grade adenocarcinomas. But for mucinous adenocarcinomas, they often behave in a very, very bad fashion, even though they have this, very commonly, this lipidic pattern of growth. So they look benign, but they are not benign. You'll just get an alveolar infiltrate. And then they'll give you a biopsy. be the history of what's called bronchorrhea, that milky kind of sputum. And that's all of that extracellular mucin. And that's another really helpful clue in biopsies for pathology, and if you're looking at it, is that extracellular mucin, because that is not normal to see that filling alveolar spaces. You know, if you have bronchiectasis or something, you can have some post-obstructive changes, but the mucin looks a little bit different. Yeah, you had a question? Yes, yeah, and it's also a combination of the mucin content. And so the only differential would be a goblet cell. And so the way the mucin looks is a little bit different. So goblet cells look a little bit more blue and tend to be a touch more granular in contrast to the mucin that you see from a mucin-side adenocarcinoma. But for people studying for boards, they will not ask you to differentiate between the two. And you're going to touch on microinvasive adenocarcinoma, things that are tougher to get off of TBBX. Yes, exactly. All right, so that leads us perfectly into talking about more garden-variety adenocarcinoma. All right, so as you're all aware, in the WHO that came out back in 2021, I guess it's not that recent anymore, we have a range of adenocarcinoma, minimally invasive adenocarcinoma, and then invasive adenocarcinoma. So adenocarcinoma, and there's also AAH, atypical adenoma, which is hyperplasia, and you may have heard that as well. So I don't have a photo of it here, but it would look very similar to a portion of adenocarcinoma in situ. One point I did want to make, if you do a biopsy for a ground-glass lesion, and you get a top-line diagnosis back of atypical adenomatous hyperplasia, please question that. That is not a biopsy diagnosis. AAH is an incidental finding, it's a pre-neoplastic incidental finding that you're going to see in patients who are smokers, getting lobectomies for lung cancer, or something else going on. So if you have a top-line AAH that comes back, I would question that diagnosis. Okay, so adenocarcinoma in situ. So this is going to be a lesion, it's going to be ground-glass on imaging, it's going to be three centimeters or less, and it can have no invasion, which essentially means it has to be a pure lipidic pattern, okay? So here's high power of what that would look like. So this is adenocarcinoma in situ, where you're going to see the tumor cells lining the septa. So for lipidic adenocarcinoma, you don't have destruction of the underlying architecture of the lung. It looks like someone took a picture of the lung and then just lined tumor cells along the alveolar septa. All right, so AIS can have no areas of invasion. This is something that is less common in real life than I think is attempted to diagnose. If you look at the original studies that came out of MSK by Bill Travis, it's actually an extremely small percentage of cases pre-selected for grade one tumors, stage one tumors that are actually true AIS or MIA. So again, areas of invasion are actually pretty easy to find if you know where to look. All right, so here's an example of minimally invasive adenocarcinoma. So this, again, three centimeters or less and has five millimeters or less of an invasive area. So remember, for lung cancer, invasive cancer is any pattern other than lipidic. So if you see acinar, if you see micropapillary, papillary, solid, that's all invasion. In this particular case, you can see there's an area of acinar architecture right in the center. So you see these angulated glands right here surrounded by fibrosis. So this is acinar. And then surrounding this, you have the lipidic pattern, where it looks like a little thickened alveolar septa, but tumor cells. Very small, very innocuous. This is an example of MIA. All right, so let's go into our patterns. So I already showed you this. This is lipidic subtype. These are, of course, going to have the best prognosis. So you want patients to have as much lipidic as possible if they have to have lung cancer. It's a little bit higher power, again, showing you those tumor cells. You know they're tumor cells because they are larger than normal pneumocytes. And they often show crowding with their neighbors and have pleomorphism, meaning one cell is going to be a different size than the cell next to it. You should see all those features minimally in lipidic adenocarcinoma. Here's an example of acinar adenocarcinoma. So this is, I think, your classic garden variety when you think about lung cancer. You think about acinar, a subtype of adenocarcinoma. So you're going to see angulated glands and a desmoplastic stroma, which basically just means the fibrosis around the glands. If I showed you this without the label and said, where did this come from, you couldn't tell me, right? Adenocarcinoma looks like adenocarcinoma. There are subtle features that help you distinguish organ, but you do not need to worry about those. But the cells are larger. They're dark blue or hyperchromatic. And there is pleomorphism. One cell doesn't necessarily look like the cell next door. This doesn't look like normal lung. Here's a higher power example showing you those glands, little circular glands right there. Next up is papillary subtype. So when we talk about papillary subtype of adenocarcinoma of the lung, it's going to be like a papillary pattern anywhere else. You'll see fronds of tissue lined by the neoplastic cells. And the key for a papillary subtype is the fibrovascular cores. So when you think about fibrovascular cores, look for the blood vessels. Look for the round red dots. Look for the blood vessels in the core lined by cells that do not look benign. So these are fibrovascular cores. It's a papillary subtype. This is invasive adenocarcinoma by nature of the pattern. Next up is micropapillary. And I want you to remember what this looks like. And that's why I put it as the picture in the front. Micropapillary subtypes are associated with the worst prognosis in disease-free survival. You get these florets of cells. They look like little flowers, as well as individual tumor cells. And they tend to have a higher cytologic grade, which means they look uglier. So they're going to have more hyperchromation. They're going to look darker. They might have more pleomorphism. So these are all the features you might think about with micropapillary. Micropapillary is often missed. And the key to micropapillary to remember is they also can present as ground glass. So if you have a micropapillary-predominant tumor, it can show as ground glass. So you might be thinking lipidic, but it's actually micropapillary. And they're going to do worse. More likely to show a pleural invasion, more likely to show lymph node mets. So if something comes back as, oh, this is adenocarcinoma in situ, it all looks lipidic, oh, but there's a positive lymph node, question that diagnosis. It's probably micropapillary that was missed. All right. So last up for our patterns is SOLID. As the name implies, it's just a solid sheet of tumor cells. All right. So this is a solid sheet right here in the center. All these little blue cells are lymphocytes around the tumor. These are ugly cells. Again, if I just showed you this without any context, you could say, well, it's malignant, but I don't know what it is. All right. So this is solid adenocarcinoma. And again, just like micropapillary, they'll have a worse prognosis and worse disease-free survival. And we report subtypes down to 5%. And that is because, not necessarily because 5% versus 10% has prognostic significance, is that as low as 5% of a micropapillary or solid subtype has been shown to be associated with worse prognosis. And so that's why we report down to such small percentages. All right. So here's a needle core, just as a quick example. This showed up on imaging as a part solid, part ground glass lesion. You can see there's acinar on the left. You can see these glandular structures. And then micropapillary on the right, little florets and individual cells. Okay. And I show you this because to remember that lung tumors are quite heterogeneous and you often have multiple patterns. It's rare to get a pure pattern. You're often going to get a whole bunch of different patterns. And like I said before, the exact percentages doesn't matter. We actually disagree with each other. We don't have a very good, like if I call something 15% micropapillary, someone else might call it 10% or 20%. It really doesn't matter. The trick is not to miss the fact this is micropapillary or solid there. So this is a good opportunity to briefly talk about IHC and lung cancer, something you're going to see in your reports and something you might be tested on. So adenocarcinoma, CK7, TTF1, Napsin A. All right, CK7 is not specific. That is a marker in general for adenocarcinomas above the diaphragm, okay. So breast is also going to stain with CK7. Some upper GI are going to stain with CK7. TTF1 and Napsin A are more specific, okay. So think about TTF1 as your most specific and sensitive for lung adenocarcinoma, although keep in mind it can be positive in other tumors like thyroid. All right, squamous cell carcinoma, there's a couple of markers. I'm sure you've seen these in reports, P40, P63, and CK56. P40 is the best stain to look for squamous cell carcinoma in the lung. If at all possible, you want your pathologist to be using P40 and not P63. And the reason for that is up to a quarter of lung adenocarcinomas can be positive for P63, okay. So for example, if I have a tumor that comes to me on the consult service that's P63 positive and TTF1 positive, that's a lung adenocarcinoma, not a squamous cell carcinoma, okay. If you have a tumor that is P40 positive with some weak patchy TTF1, that's going to be a squamous cell carcinoma likely with a nonspecific staining depending on the clone of TTF1 you use. So remember, P40 is going to supersede weak TTF1, TTF1 is going to supersede P63, okay. And then small cell carcinoma, which we'll touch on a little bit later, TTF1 positive and then positive for neuroendocrine markers such as synaptophysin and chromogranin. Another pitfall I want to point out is that neuroendocrine markers in the absence of neuroendocrine morphologic features mean nothing clinically. So if your pathologist says, yeah, you know, it didn't really look like a neuroendocrine tumor but I threw some stains on it and it's a little patchy positive and you wonder, well, should I treat them with like a small cell protocol or something like, no. If it doesn't look neuroendocrine morphology, don't do it, which is why we do not, we should not be doing these stains unless you see neuroendocrine morphology. And we'll show some pictures of that later. All right, and then last up, I'm going to talk about staining for mucinous adenocarcinoma since that was our index case here. So I've got 720, TTF1, I've got some percentages here. Don't remember those percentages. This is not an IHC game. So mucinous adenocarcinoma, in addition to being quite challenging to diagnose on biopsy, has a lot of immunophenotypic overlap between mucinous adenocarcinomas from other sites, in particular from the pancreas, okay. So pancreatic adenocarcinoma metastasized to the lung can look just like lipidic adenocarcinoma of the lung, and all the markers can overlap. You can have lung markers, you can have GI markers, both, each, whatever. So it's not an IHC game. So my recommendation is you should not be doing giant staining panels on mucinous adenocarcinoma. Look at the imaging, look at the clinical history. Does the patient have a large pancreatic lesion and now some lesions in the lung? That's going to be metastatic pancreatic adenocarcinoma, all right. The only time in which I think it might be valuable is if, for whatever reason, clinically or radiographically, you think they actually do have both. You could do stains to see if they show the same profile or different profiles, and that may be helpful. So only in rare circumstances, all right. Save the tissue for molecular. Okay. Oh, great. And can you go back two slides real quick? Yeah, sure. So the, hear me out. The P and P40, the P is like a backwards Q for squamous. No? This is good. All right, that's all I got. That's all I got. All right, keep going. Oh, this is good. So bad, it's good. So bad, it's good. You'll remember. All right, case four. All right. So 33, young patient, chest pain, dyspnea, cough, referred for you for tBNA. This one might be familiar. We'll look at the imaging. Clearly, widened mediastinum. There's a mass there. You don't know where exactly it is because it's just a PA view, but there's your CT. Contrast study. Some vascular impingement there. All right. How are we going to manage this patient initially? For the folks who just walked in, you can scan the QR code. All right, so we have systemic steroids, PET scan and bone marrow biopsy are our top. And then people kind of going around. Okay, so systemic steroids is the answer here. So this is an example. So let's see, so your stains are negative, right? So we have granulomas here, okay? And you don't really see much in the background. And the granulomas are lymphangitic, okay? So this is a bronchovascular bundle here. This is the background alveolar septa. There's not much going on there. So no interstitial pneumonia. And our stains for an infectious etiology are negative, all right? So this is an example of sarcoidosis. So here's a wedge. This is from a different patient. But I just wanted to highlight that lymphangitic distribution. So this is the pleura on the surface, and then down along interlobular septa and around a bronchovascular bundle, okay? So granulomas for sarcoid have a couple of characteristic features. They are non-necrotizing, okay? So there's no necrosis in granulomas for sarcoid. They very commonly have giant cells. And they often hyalinize, all right? So you get this pink material, this dense pink material. So you get this hyalinization. And they like to become confluent with each other and form these large nodules and masses, okay? So those are your characteristic features of granulomas from sarcoid. And then in addition, in sarcoid, you don't have a background of interstitial pneumonia. You're not going to see a lot of stuff going on around the granulomas themselves, okay? I want to take a second to talk about nonspecific inclusion bodies, because they always test you about these in the context of sarcoid. Although you can see them in any kind of granuloma just process. The top ones to keep in mind are asteroid bodies. They form these little stars. And Schaumann bodies, they form these concentric little rings on this deep purple material, both non-polarizable. Less common, calcium oxalate, this polarizes. I often see these mistaken for foreign materials such as microcrystalline cellulose, which it is not. And then the rarest of all and the most confounding are Hamasaki-Wessenberg bodies. They look like little yeast, and in fact, they actually stain positively for GMS. But they are nonspecific inclusion bodies and commonly seen in granuloma cyst disease in the lymph nodes. But what you should remember most importantly are asteroid bodies and Schaumann bodies. And even though they're not specific to sarcoid, they almost always ask you about them in conjunction with a sarcoid case. All right, so now that we're talking about granulomas, let's talk about necrotizing granulomas. So here's an example of a TB case with a necrotizing granuloma. So for necrotizing, look for grungy pink material in the center of the granuloma. That's your key you're looking at necrosis. And this is in contrast to that hyalinization that I showed you which are kind of like, almost look like collagen bundles, these like strips, dense material. This is grungy, light pink material. All right, here's our Zeal-Nielsen stain for that particular case, and you can see lots and lots of acid-fast bacilli. So they look like little red snappers, that's what they've been called at. And if you have a really high-resolution image, you can see little beads along them. But they don't, that doesn't project well. Okay, this other stain that I talked to you about earlier, oramine rhodamine, it's an immunofluorescent stain. They'll look bright orange on immunofluorescence. These are great stains to use. I will say from the pathology standpoint, AFB can be very hard to find. And if you are very suspicious that a patient does, in fact, have a mycobacterial infection, and your pathology report comes back with only one block stained and there's multiple blocks, especially in a lobectomy or a wedge, have them stain more blocks or ask them to stain more blocks because likely it's there and you just can't find it. Okay, so moving right along, so this is an example of hypersensitive pneumonitis. So this is a different kind of granuloma, non-necrotizing granuloma and loosely formed. HP granulomas are granulomas that you can hardly tell they're granulomas, all right? They're just little collections of epithelioid histiocytes. And you're going to see them in the background of an interstitial pneumonia, lots of blue dots, right? Lots of blue dots everywhere. So this is a chronic interstitial pneumonia with these loosely formed granulomas. Here's some examples as well. I've tried to circle some of the granulomas. You can see giant cells also. You don't have to see giant cells, all right? HP granulomas are the ones that if you're squinting and wondering, is that a granuloma? And the patient has a bird, tell them to get rid of the bird. All right, here's another example. This one I think is a little easier to appreciate, this little loose granuloma. These are going to be airway centered. You're going to see these in patients that have tree and bud upper lobe predominant, you know, inhalational type diseases and then, you know, question them. Find out about the parakeets they're hiding in their bathroom. Okay. All right, case five, 74, smoker, fatigue, aortic stenosis, chronic joint pains and has a pet avid lung nodule. So systemic issues, this kind of concerning nodule here. It does have some pedavidity, doesn't always have to and gets some tissue diagnosis. All right, so there's our tissue. All right, so we have a contrast between GPA and rheumatoid nodule. I think that's a reasonable differential to consider here. All right, nice job. Okay, so this is actually an example of a rheumatoid nodule. You know, when you have rheumatoid nodules, history is helpful. Clinical history is very useful. You have to rule out infection. With GPA, which we'll talk about in a minute here, you want to see more basophilic necrosis. And this has kind of a mixture of more eosinophilic-type necrosis. But I think it's very reasonable to consider evaluating for GPA in a case like this. All right, so I wanted to take a minute to sort of jump the train tracks here and talk about something that sounds similar, has granulomatosis in the name, lymphomatoid granulomatosis. This is a very rare disease. It's a lymphoproliferative disease that is EBV-associated. But again, it's something that, for whatever reason, people love to test you on. This is an angio-destructive, angiocentric process. So this is a vessel here that is destroyed by lymphocytes. All right? And it's EBV-positive. So it's an Epstein-Barr virus-mediated process. So if you're going to be tested on something like this, you're going to get EBV in there somewhere, okay? And now let's talk about GPA, which I think is a reasonable differential for that rheumatoid nodule. So this is an example, a wedge of a patient with GPA. You see how it's more blue on the outside? Certainly some similarities, but it's more blue. You often see what we call Wagner's giant cells. You know, GPA used to be called Wagner's. Where you get these very distinctive look where all the nuclei are pressed to the edge and form almost this little horseshoe. Again, not specific, but quite characteristic of what you see in GPA. Here's another example from a wedge showing you the very blue look to the necrosis. There's some giant cells. So of course, necrotizing granuloma, which is processed, you can see with GPA. And then distinct, a very, very, very distinctive. If I see this, I can essentially make a diagnosis and say it's either GPA or eGPA is segmental vasculitis. All right? So these are key words to remember. So this is a pulmonary artery right here. Here's your lumen in the center. This part of the artery is completely normal. But this part, you can see there's destruction right through the wall with inflammatory infiltrate. So this is segmental vasculitis. Very, very characteristic for GPA as well as eGPA. And I also wanted to point out, though, GPA can present in several different ways. So it can present with these cavitating or necrotizing type nodules with segmental vasculitis. It can also present as diffuse alveolar hemorrhage or DAH. So here's an example on biopsy of DAH. You see fresh blood. You see hemocytorin-laden macrophages. So these are cells filled with chunky brown material. And the material is of varying sizes. And then you also see something called mineralizing elastosis, which is probably the most difficult thing to pick out of this picture. But it's this gray. You see this kind of wiggly line here? This is actually iron deposition on the elastic fibers. Now here's another example of some iron deposition around this small arterial. And you also see acute lung injury. So this bright pink material is fibrin. So GPA and eGPA can present with DAH. And that DAH can be seen with or without capillaritis. I think this is another very testable thing to know. And capillaritis is neutrophils. So you see these little cells here with these multilobed nuclei here filling the capillaries? This is capillaritis. All right? So if you see this in association with blood and hemocytorin-laden macrophages, DAH with capillaritis, it's a systemic vasculitic syndrome involving the lung. You've got to think about GPA. If you see eosinophils, you'll think about eGPA. And then the other thing to be considered would be a drug induced vasculitis. All right? So granuloma pearls. So when I see granulomas, I go through this in my mind. Is it necrotizing or non-necrotizing? All right? If it's necrotizing, infection, infection, infection. And then you might think about GPA or eGPA, especially if you see basophilic or blue necrosis. All right? If it's non-necrotizing, if they're tightly formed or loosely formed. If they're tightly formed, think about infection, sarcoidosis or drug reactions. Remember, drug can basically cause anything in the lung. If they're loosely formed, again, infection, HP or drug. All right? So always, anytime you have granulomas, you need to rule out infection with cultures, serologies, whatever is at your fingertips and also needs to be, special stains need to be done. But loosely formed, HP, tightly formed, sarcoid, necrotizing infection versus some kind of autoimmune process. All right? So here's an example of HP granuloma. So loosely formed. Okay? Sarcoid, tightly formed. All right? With some hyalinization. Okay? Here's an amiodarone toxicity. Kind of loosely formed. Lots of foamy macrophages in there. Here's TB, necrotizing. All right? This is a lower power picture. All right? And then GPA, blue necrosis with giant cells. Okay? Beautiful compare and contrast. Thank you. And I think that's going to be in the bundle. We get you at the end. K6, 59, HIV positive but also a smoker. Dyspnea and cough. Let's move on. So again, just by plain film, some peripheral interstitial infiltrates. Next. Confirmed by CT. Statistically, you'll pick the right answer. And if not, that's okay, too. That's what we're here for. All right. All right. So we have a combination of COP and DIP, and next up, UIP, and a little less than the other, LIP and SIP. All right. Excellent. Okay, so this is an example of UIP, all right, of IPF. Okay, so usual interstitial pneumonia has a couple of characteristic histologic features that are key. So this is a wedge biopsy. So on the left, you can see pink material. So this is fibrosis, all right. And on the right, you can actually make out that it's lung, right. So if I just showed you this, you probably couldn't tell me it's lung. You'd say, that's fibrotic tissue. I don't know what it is. Here, you can actually see the alveolar septa. And you can kind of draw a line right here, right between the two. So it's a very sharp juxtaposition between the two. Okay. And then if you look a little bit higher power at that interface in between those two, you see these. So these are examples of fibroblast foci. So they're fibroblasts arranged in parallel to the septa here. Okay. And you have sort of almost a bluish grayish look, all right. So that's new fibrosis. And then in the background, so in this area here, you have what we call honeycomb change, all right. And that was on the imaging as well, where you have these dilated structures. They're lined by respiratory epithelium and surrounded by fibrosis. And you often see mucus stuck inside of them. There's a little bit here, a little bit there. Okay. So when we talk about UIP, you have that spatial and temporal heterogeneity. The spatial heterogeneity refers to the areas of dense fibrosis juxtaposed to normal appearing lung. Temporal heterogeneity refers to the fibroblast foci, which is new fibrosis, in contrast to the collagen fibrosis, which is older fibrosis. Honeycomb change are those dilated structures. You're going to see those in the periphery as even stacked cysts, all right, in the lower lobes. And then UIP is a pattern that is typically associated with the clinical syndrome, idiopathic pulmonary fibrosis. But it can also be seen as a pattern in patients with chronic HP, adverse drug reactions, and underlying systemic connective tissue diseases. So I like to point this out because even if you have a nice UIP pattern on imaging and the patient's a 35-year-old with SLE, that patient doesn't really have IPF. Now, they may be acting with a progressive pulmonary phenotype and may need antifibrotics anyways. But what if the patient has not a typical UIP pattern on imaging and they do a wedge and, like, gosh, it looks like UIP, but they're a middle-aged person with birds? It's probably actually just chronic HP. So I do think underlying etiology is very, very important. However, if you get, you know, a 75-year-old man ex-smoker with a UIP pattern, yeah, that patient's going to have IPF. So keep in mind underlying etiology can be helpful, although if they behave with a progressive fibrosing phenotype, they're going to need antifibrotics. Okay, so that leads us into the common differential for UIP, which is NSIP, or nonspecific interstitial pneumonia. The names are terrible. I apologize for my forefathers. So this is where you get relatively homogenous thickening of the alveolar septa by fibrosis, inflammation, or a mixture of both. NSIP patients can be idiopathic, or more commonly you can have an underlying systemic connective tissue disease. So this is characteristic what an NSIP would look like, especially if they're testing you in real life. It tends to be a little more murky. But it looks the same from pleura to pleura, right? Relatively the same homogenous thickening. This is mostly fibrotic NSIP. So here's a table to help you out with features between the two. So for UIP, you're going to have collagen fibrosis, subpleural or paraceptal, all right? So remember, this UIP starts in the paraceptal area and then edges in around, all right, forming these little donuts of fibrosis, okay? If you have completely fibrotic NSIP, you'll get homogenous diffuse collagen fibrosis. If it's pure cellular, you're not going to see any collagen fibrosis. Fibroblast foci, this is, again, you always hear fibroblast foci when they talk about UIP. So for testing purposes, fibroblast foci, think UIP. In real life, you can have them in NSIP. All right, honeycomb change, again, think UIP. These are buzzwords for UIP. But in real life, you can also see them in NSIP, okay? Organizing pneumonia, you're not going to see this as a feature in UIP, although I want to point out in the real world, you can have acute exacerbation or superimposed processes in patients with UIP, which is actually really, really common and often why they go to wedge biopsy. Hyaline membranes, this is acute lung injury. You see when diffuse alveolar damage, you're not going to see that in UIP unless it's acute exacerbation. And then NSIP, it's more common to see organizing pneumonia, and you shouldn't see hyaline membranes. And this is in the purest form, but you often see these combined in the real world for acute exacerbation and superimposed processes. All right, so here's an example of LIP. So in contrast to the UIP, LIP should be very, very, very blue, right? It should be so blue, you're worried the patient has lymphoma. Okay, so this is the most classic case of LIP. The septa are just filled with lymphocytes, and you see lymphoid aggregates, okay? Here's higher power, again, just blue, blue, blue, filling the alveolar septa. Think about LIP, okay? So rule out lymphoma. Okay, so that leads me into talking about acute lung injury, all right? So the two types I want to talk about are organizing pneumonia and diffuse alveolar damage, and I've got to talk fast here. All right, so organizing pneumonia is a nonspecific form of lung injury and repair. You guys know all of this. It's mucopolysaccharide-rich plugs of proliferating fibroblasts and alveolar spaces and distal bronchioles. Looks essentially identical to fibroblast foci, except of the location. It's in the alveolar spaces and the bronchioles, not in the interstitium, okay? Ideology is broad. Basically, anything that can damage the lung, okay? So here's an example of organizing pneumonia. You should be able to recognize this. This plug, plugs of fibroblasts. Remember that kind of myxoid, bluish-grayish look, filling the spaces, all right? Here's another example. You can see they can form these funny little branch patterns as they fill the alveolar spaces, all right? This patient was a smoker. They also had some pigmented macrophages. All right, so DAD, that's your histologic counterpart to acute respiratory distress syndrome. Again, nonspecific. Anything that can really damage the lung is going to give you DAD. So you may have seen this chart before. Basically, this shows you all the different patterns of DAD. It starts out as exudative, then it goes into the transition, proliferative, and fibrotic stage. So DAD can end in progressive fibrosis or stable fibrosis, or it can completely resolve. We've seen lots of patients end up with stable fibrosis and even potentially progressive fibrosis with COVID. Or they can completely resolve if they're lucky. And the reason I show this chart is not for you to remember the exact number of days where you see each thing, but to know that depending on where you take the biopsy, we can see a variety of histologic changes, and oftentimes all concurrently, especially if it's due to an underlying infectious etiology. It's not just one, you get damaged once, and then it goes through this beautiful phase, right? You get continual damage. You get lots of different histologic findings. So you start out on day one, just a little bit of fibrin, a little bit of maybe edema. Day two, you start to see more organization, hyaline membranes. Day seven, you start to see fibroblastic proliferations going on in the interstitium, but it's all the same disease. For your purposes, in terms of recognizing histology of DAD, no hyaline membranes. This is what you need to be able to recognize. And it's basically as if somebody drew a pink highlighter, a pink highlighter along the alveolar septum, all right? Those are hyaline membranes, okay? All right, so I'm going to briefly talk about some smoking-related diseases. Respiratory bronchiolitis interstitial lung disease is a clinical pathological diagnosis. We have to make this diagnosis together. You see fibrosis, and you see pigmented macrophages. So these are respiratory bronchiolitis. Again, terrible name because it's not really inflammation of the bronchiole, but you have inflammatory cells. So these are smoker's macrophages, different from hemocytin-laden macrophages because they're more powdery-looking, and they have these tiny little anthracotic flecks in them. All right? DAP, which somebody, I think a fair number of you picked for that previous case, the alveolar septum shouldn't necessarily be damaged, right? They may have some smoking-related fibrosis, but the alveolar septum shouldn't be damaged. You basically just see lots and lots of those pigmented macrophages filling alveolar spaces. Again, terrible name. They're not squamous cells. They're macrophages. It's not an interstitial pneumonia. They're in the alveolar spaces. All right, case 7. Okay, 23-year-old, stem cell transplant, cough, dyspnea, fever, gets the BAL. So again, diffused alveolar infiltrates. All right, there's your diff quick. What do we think this is? We're running up on our time here, so... We're going to make it. We're going to make it. Got to vote quick. All right. So let's see. All right, excellent. So we have a mix between pneumocystis and CMV. Nice. All right, so this is an example of pneumocystis. So these are cytology preparations where you see these tiny little circles with little dots in them. All right, so that's your key. Bunch of tiny little circles, little dots. They look almost foamy. All right, here's what they look like on a GMS stain. They have a crushed ping-pong ball shape. All right, here's what histology looks like. This is quite characteristic. On the height of the AIDS epidemic, they were diagnosing this multiple times every week. You get fluffy pink material in the alveolar spaces. That's what pneumocystis looks like. And then when you do a stain, you see those crushed ping-pong balls on GMS. All right, more fungus to memorize. This is histoplasma. So these are a GMS stain in the upper left. These are macrophages with little yeast forms. There's a narrow-based budding right there inside the macrophages. If you see histoplasma with cytoplasmic histoplasma in the macrophages, that is what you see in disseminated histo in contrast to maybe an old hyalinizing granuloma. Here's a pap stain. Very nicely, you can see all those tiny little yeast forms in there. All right, and here's another GMS showing you, highlighting that narrow-based budding for histo. All right, that's in contrast to blasto. So blasto is gonna have broad-based budding. These are much larger than histo. All right, here it is on DIFQUIC on the right side. All right, here's H&E, broad-based budding, necrotizing granuloma. Remember, think infection, infection, infection. There's our GMS, again, broad-based budding. All right, and these are much larger. Histo would be like, I don't know, a little closer to that compared to that. Very small. Here's an example of coccidioides. All right, so this is a large necrotic area in the lung. Coccidioides is extremely distinctive. You know, I live in Arizona, so I can't not show you coccidioides. Diagnosis every week. Thick-walled spherules with tiny little endospores inside. All right, here it is on GMS, although cocci is one of the fungi that you can see on H&E. You don't even need a GMS, but you can see these spilling out their spherules. Super, super distinctive. Pro tip from Arizona, when cocci is exposed to air, it will form hyphae. So if you get a PATH report that comes back as concurrent infection of aspergillus and coccidioides and they have a cavitating lesion, you might question that. It's probably all just coccidi. All right, here's cryptococcus. All right, this is a large nodule in the lung. You have this common halo artifact, okay? So, and then crypto has narrow-based budding, but it's going to be larger than histo. And key on mucocarmin, you have, it'll stain positive. The capsule is very mucin-rich, and it'll stain positive for mucocarmin. Here's a chart-based form. Histo, small, narrow-based budding. Pneumocystis, crushed ping-pong ball, no budding. Think about that foamy pink material. Blasto, large with broad-based budding. Cocci, thick-walled spherules with endospores and cryptococcus, clear halo, mucocarmin positive, narrow-based budding. All right, here's some viral pictures for you. There's CMV with our cytoplasmic and nuclear, and HSV with a kind of margination right there. You're never going to see measles without the worsened deficiency cell. And there's adenovirus with its smudgy look. It just... Hold on.

lung diseases

histologic findings

granulomas

sarcoidosis

tuberculosis

hypersensitivity pneumonitis

necrotizing granulomas

idiopathic pulmonary fibrosis

non-specific interstitial pneumonia