and thank you everyone for joining the final session of the 2023 conference here in Hawaii. My name is Meena Peerzadeh, and I am an assistant professor at the University of Michigan. And I'm joined here with Professor David Smith from Louisiana State, and Associate Professor Christine Kanaka, also from the University of Michigan. So today's objectives, we will be doing a clinical pathological correlation format where we have several cases for you. We'll present the clinical, radiologic, and then pathologic tissue to review. So upon completion of this session, we will have had identified benign morphologic mimics of adenocarcinoma that are frequently misdiagnosed, describe the clinical implications of the pathologic diagnoses of ciliated muconodular papillary tumor and sclerosing pneumatocytoma, and discuss unusual radiographic presentations of granulomatous diseases and their clinical correlates. So case number one. We have an 80-year-old female, former smoker, 20-pack year history who quit over 30 years ago with a history of obstructive sleep apnea, acid reflux, and she's been followed in pulmonary clinic now for eight years for a predominantly ground glass nodule in the right lower lobe. It was first detected on a CT coronary, but now over the last one and a half years, it has noted some increase in growth with a solid component. She is asymptomatic with normal pulmonary function testing. And as you can see, I listed a few of the CTs and the sizes, and the two that we will review are the ones that are bolded. So it started off as a six millimeter ground glass nodule. By four years, five years later, it was over a centimeter, but the PET was negative. And in October of 2022, which we will look at, it had grown with a solid component. Given the growth, the patient opted for a VATS biopsy over surveillance, given that it has been surveilled for now over eight years. Yeah, so on the left, you have a CT from May of 2014, long time ago, and then we have a follow-up eight years later, and you see this nodule, this ground glass nodule in the right lower lobe. It looks sort of nondescript, right? It's very small in 2014, it's ground glass, which means that we don't really see any solid portion, but it is denser than normal lung. A few years later, obviously bigger. It has grown out, and you sort of see this... Oh, I gotta go over this way, sorry. You sort of see how it's contacting the pleura and almost pulling the visceral pleura and the parietal pleura in a little bit there. A lot of things can look like ground glass nodules, but a slowly growing ground glass nodule, we're obviously gonna be worried about cancer, and in particular, we'd be thinking adenocarcinoma. And, you know, that's a common disease, and so pretty much everybody is just gonna say this is highly concerning for an adenocarcinoma. The question of the PET, of course, you know, you think cancer is often hypermetabolic, but adenocarcinoma is one of those classic malignancies that because it's not so solid and so dense, we often don't get the high SUV readouts that you might for another malignancy. So a negative PET doesn't dissuade me from suggesting that this is probably adenocarcinoma. So this is the lung wedge was sent for frozen section, and me as the second reader on this, I read the final pathology. Just looking at these slides, I can tell you that the pathologist was measuring cancer. So what you have is kind of this sharply demarcated proliferation here that she's measuring this as kind of I'm imagining the invasive component. She was trying to assess whether or not this was minimally invasive or just an invasive adenocarcinoma. So reading into her thought process, that's what this looks like at low power to me. Certainly there's intraalveolar mucin, so clues that would say, all right, I'm already thinking cancer, adenocarcinoma, that would just kind of make me feel more confident in that assessment. Going to higher power, there are some kind of more angular looking glands here and kind of this proliferation of polygonal cells. So the frozen section diagnosis was read as adenocarcinoma with lipidic and acinar growth pattern at least minimally invasive. So this is the permanent H and E section, which again shows this proliferation of cells that is very much doing what I think adenocarcinomas tend to do is that they're kind of marching down the alveolar septa here and sharply demarcated from the surrounding normal appearing alveolated lung tissue. There is accumulation of mucin pools within distal alveolar air spaces. But moving to higher power, the proliferation of cells is ciliated cells here admixed with mucinous cells. So that speaks against a diagnosis of adenocarcinoma. These are benign bronchial epithelial elements. Additionally, there are these cytologically bland squamoid cells here kind of underneath much of that ciliated population. So this is ciliated muconodular papillary tumor final diagnosis. So a brief review of CMPT. This is also referred to as bronchial adenoma. I think that's getting a little bit more traction now, but if you were to do a literature search, both would come up. This was initially described in 2002, but only added to the WHO of thoracic tumors in 2021. This is a benign lung tumor with no risk of recurrence or metastasis following resection. I think there's about one case report reporting that there was malignant transformation. And I would tell you, looking at that case, I would look at it with skepticism. I'm not sure that the diagnosis of CMPT was what it was to begin with. Slight female predominance, average age of 65 years. There's no correlation with smoker status. And these are often incidentally discovered as solitary peripheral lung nodules, including in patients that undergo resections for other reasons. The size is variable with an average size of 0.5 centimeters. So as our case illustrates, it's comprised of bronchiolar type, that ciliated respiratory epithelium. On the right-hand side, I've put for you, this is non-neoplastic. This is just an image that I took of bronchiolar type epithelium lining a bronchus, which shows the combination of the ciliated cells and the mucous-secreting cells. Here's CMPT, in which those ciliated cells are on the surface and the mucous cells are down below here in this example. But any one cell type can predominate. And in that last case, there were certainly quite a few squamoid cells. And I think that pointing out that those are cytologically bland is important, because you can have a pagetoid spread of squamous cell carcinomas. So this is a benign proliferation. This isn't malignant. There are pools of extracellular mucin. It can have this papillary and glandular architecture, which on frozen section can be so misleading. You know, as you saw, the pathologist was marking out areas in which she thought that there were acinar infiltrative growth, and that's just the tumor's growth pattern. So these are true neoplasms, not malformations. They have gene mutations, most frequently BRAF. For those of you in the audience that may be trainees and preparing for boards, these are frequently misdiagnosed during frozen section with a rate of discrepancy of greater than 80%. And certainly at our institution, I would say that's right on point. Virtually all of these are misdiagnosed as adenocarcinomas. So I want to bring that to your awareness so that when this comes back as a benign tumor, they're kind of illustrating that, where that pitfall can occur. Was the PURR resected too? In that case, you know what, I don't recall. It was, it was a wedge, so yes. On to case number two. So here we have a 51-year-old female never smoker with a past medical history of chronic myeloid leukemia who underwent an unrelated matched donor bone marrow transplant, but has been off immunosuppression for greater than five years. She was found to have a growing right upper load part solid nodule detected during surveillance of a type B thoracic dissection and aneurysm. She was asymptomatic from a pulmonary standpoint with normal pulmonary function tests. The nodule was first seen in 2013 as a four millimeter solid nodule. Over the years under surveillance, it grew and started to develop a mixed solid ground glass component. She underwent repair of her aneurysm and a few months later, it was decided that they, you know, with the continued growth and the solid component now being at nine millimeters, that she would opt for a VATS. And so here on the left, you have the 2013 study and four years later, we see that this nodule is getting bigger. These things are hard to pick out, especially near the hilo where the vessels are decently big. You know, if you got a big nodule out here, it's obviously different than a vessel, but in tight around the hilo, these things are very difficult to find. Anyway, this is clearly growing and clearly scary looking, a little bit of ground glass around the anterior left aspect of it, but a big solid component, pretty sizable lesion. And again, this time course of four years, like the last one, that is a doubling time that is in the realm of what we think of neoplasm. Infections double very fast. Inflammation tends to go away, but if you have this sort of inexorable slow growth, that's very scary from our point of view. So we would definitely worry about this being malignant. All right, here's the lung wedge for frozen section. I'm showing you this because this is a frozen section I read, and had I paid more attention to the gross, I probably wouldn't have blown the frozen section. I looked at this and I thought, that looks funny, and I kept it moving. This is what I saw. It was a proliferation of atypical kind of, where's my arrow here? Sorry. Sorry. These atypical columnar looking cells that kind of in this part of the tumor look very papillary in their growth pattern, going to higher power. Certainly there appears to be on frozen section a degree of cytologic atypia. These cells appear piled up. And I diagnosed adenocarcinoma without thinking much of it. All right, this is the permanent H&E section. You have here kind of the, these arrows are highlighting kind of the compressive growth as that, if you look, think back to that gross image of how sharply circumscribed it is. Same thing under the microscope, of course. In this background of hemocyturin, that's what's filling distal air spaces here. Here's your sharply demarcated tumor, so a pushing growth pattern that's hemorrhagic and angiomatoid patterns here, really these bloody lakes. There is focal papillary growth that I think that was better illustrated on the frozen section than perhaps on the permanent section. Going to higher power, you have these areas of sclerosis, these variable growth patterns, again, the hemorrhage. And here on this side, you have these lining cells, these cytologically bland surface cells, and interstitial polygonal cells, these round cells within the interstitium. They stain differentially. Here's the immunos from kind of the same regions of the tumor in which the surface cells are highlighted as positive for pancytokeratin and TTF1, whereas the interstitial cells are only TTF1 positive. And I'll tell you, I've seen cases misdiagnosed even on permanent section by not doing the pancytokeratin, but just doing that TTF1 stain or maybe misinterpreting that pancytokeratin and thinking that that means invasive. So these immunos can be misleading for the pathologist as well, and a potential area of pitfall in which I've seen diagnostic error occur. Final diagnosis, sclerosing pneumocytoma. So sclerosing pneumocytoma is an adenoma. It's derived from incompletely differentiated respiratory epithelium. There is a female predominance in the fifth decade as the case that we had today, and typically patients are asymptomatic with a solitary, on average, two to three centimeter tumor. It is well circumcised, subplural, and usually round to avoid an enhancement. There can be associated calcifications within the lesion in about a third of patients. And of course, about 50-50 PET avidity, so really not too helpful there. So on to case number three. We have a 58-year-old male, never smoker, with a history of diabetes, acid reflux, recently diagnosed prostate cancer, not having undergone treatment, and a recently diagnosed esophageal carcinoma of signet cell, status post neoadjuvant chemoradiation, who prior to surgery was found to have a 1.9 centimeter right lower lobe nodule prior to surgical resection of his esophageal tumor. So his CT in November of 22, and PET one month later, really only had the gastric abnormalities with no lesions within the lung. He completed neoadjuvant treatment within the next three months, and then the PET detected the new nodule in the right lower lobe with an SUV of 4.1, which was new compared to imaging and PET from five months prior. So this case was discussed in Tumor Board, and ultimately there was concern for metastatic disease, and they recommended BATS resection prior to esophageal surgery. So we're talking about this lesion back here in the as-ago esophageal recess. You know, it's got a solid component. It also has sort of a ground glass component around it. It's kind of big, measured at 1.9. That would be a fairly rapid doubling time for neoplasm, given that just a few months earlier, there was seemingly nothing there. But, you know, aggressive tumors also have aggressive METs that can grow quickly. The fact that the SUV is around four, certainly that's hypermetabolic, inflammatory, and infectious things can be hypermetabolic along with malignancy. But, you know, the solid part, which is really the part that's going to be showing up on the PET, is not that big. And so for there to be a small, solid portion and still an elevated SUV to the tune of four, you know, there's definitely some real metabolic activity going on in there. So from the radiologic point of view, inflammation, infection, maybe neoplasm, and it sounds like they opted to go for it. All right, so this is the lung wedge for frozen section. You can see here kind of confluent fibroblastic proliferation that looks like desmoplasia perhaps for an invasive tumor. Certainly cells are huge. I haven't even gone to higher power, and you can see them here. Higher power, very atypical-looking cells in a fibroblastic background. The pathologist diagnosed adenocarcinoma, deferred a permanent for classification of primary lung adenocarcinoma versus metastatic esophageal adenocarcinoma. This is what the permanent section looked like. So this is patchy. And this is patchy in a way that cancer isn't patchy. So the patchy fibrosis here, even at this power, makes you think this isn't cancer, and spoiler alert, we're at kind of keeping with the theme here, but kind of these fibroblastic and serpentine plugs. Going to higher power, here are those atypical cells, but they're almost too atypical. And what do I mean by that? They have lots of cytoplasm. They don't have the increased NC ratio that we would anticipate in an adenocarcinoma. And there's a spectrum of atypia. So really bad-looking cancers, they do still have kind of a clonality to them when you look at them. These are kind of all over the place. And you look at some areas, there's really large nucleus here, that one's kind of smaller, that one almost looks dying with a more dense cytoplasm. And there's no nuclear overlapping. That's the clue that is really helpful in the diagnosis of adenocarcinoma. There's intraalveolar fibrin deposition as well in the background. And again, a spectrum, even between these two images side-by-side here of these atypical cells. I want to contrast that for you. This is what invasive metastatic adenocarcinoma looks like, certainly whereas before I was highlighting that it had a patchy look to that fibroblastic proliferation. In invasive adenocarcinomas or metastatic, it's more of a confluent fibrosis. And certainly, OK, you can argue, well, what about multifocal minimally invasive? OK, but it doesn't look like our example. That was intraluminal fibrosis. This is confluent scarring. And certainly, it has a fibroblastic look, but desmoplasia has that. There's nuclear crowding and overlapping. Here's a pretty cytologically malignant-looking adenocarcinoma here. But hopefully, perhaps, you can appreciate that these cells, they're overlapping. They have a higher NC ratio, and they look like they're related, even though one doesn't look the same as the other. Also, I illustrated in the last one, or hopefully, I mentioned it, that there's a spectrum of atypia, and it blends seamlessly into the background. Cancer has this clonal march along the alveolar septi. I showed you in the first example of ciliated muconodular papillary tumor that sharp demarcation from the surrounding lung. And again, you're seeing that here in adenocarcinomas, where they drop off. I think things that also spread seamlessly into the background would be atypical alveolar hyperplasia, that sort of thing. That's when they're seamlessly blending versus you can draw. There's a tumor cell, and there isn't one. Those are clues I use as a pathologist when trying to make this diagnosis or differentiate cancer from less than cancer. So which one was that guy? Not cancer. Oh, neither of those are him. This is the patient. This is localized organizing pneumonia with radiation atypia. Yep. Yep, I just wanted to show you this as a contrast to try and put this is what cancer looks like, and if you don't have that burned into your brain, versus what reactive looks like. So certainly the pathologist was misled on frozen, but nothing bad here for this patient, just localized OP. Case number 4. We have a 73-year-old female former smoker of 100 PAC years who quit five years ago. She has a history of a right upper lobe adenocarcinoma status post lobectomy, then a left lower lobe adenose status post segmentectomy, and she was found to have a right middle lobe nodule of 11 by 11 detected during surveillance screening. Despite her two resections, she had normal pulmonary function testing, and she was asymptomatic from a pulmonary perspective. So her CT in August of 22 had no nodule. Three months later, it was first detected, and two months after that, given its persistent and speculated character, after discussion, she ultimately underwent a red resection after she failed a CT-guided biopsy due to patient factors. So I'm going to sound like a broken record here. You get the point that the radiologists are going to be pretty much worried about these and be wrong, you know, it's what happens. But here we, you know, this is another scary looking lesion, right? It's solid, and you see the speculations, all these little lines, the sort of, the contour that is all jagged and ragged. This is, this is either a lesion that's growing out into the parenchyma or there's some sort of a fibrotic reaction around it to try to wall it off, or both. But yeah, pretty big lesion. The speculation is very scary for us. So we would certainly be worried about this being a malignancy. All right. So here is, I'm just showing you the permanent. There was no discrepancy on frozen in this one. But here you have kind of this confluent area of very pink necrosis. So here's necrosis. Even at the periphery here, you can hopefully appreciate this palisading of cells that included this power, these multinucleated giant cells. Here we have contrasted a necrotizing granuloma versus non-necrotizing sometimes. So trainees ask me, how do I differentiate the two of them? The necrosis has this, well, in this type of necrosis, it's a very pink quality to it. And you're missing the cellularity. When you have a non-necrotizing granuloma, the cellularity is present throughout. So you have necrosis here. You have the multinucleated giant cells, the combination of non-necrotizing and necrotizing granulomas. And it includes sarcoid-like granulomatous inflammation. That's typical for this infectious entity. I've had cases in which these sarcoid-like granulomas predominate. But you still need to do the bug stain, because here's the GMS stain loaded with microorganisms. Does anyone know what this organism is? They're uniform and ovoid. Did I hear it? Histo. It's histo. This is histo. So these are ovoid and uniform here. I always think everyone likes to point out the budding for narrow-based versus broad-based budding and differentiating them. I think budding is really hard to sometimes see, especially with the Z-plane. So this is histo. Histoplasmosis granuloma. Where was she from? What's that? Where was she from? All of these cases are Michigan. Michigan. Michigan. Yep. Michigan. This one on the frozen, I did tell them I bet this turns out to be histo. So we get them right sometimes. All right. Case number five. We have a 52-year-old female, former smoker, 30-pack year, quit 14 years ago, eligible for lung cancer screening, who has a history of heartburn, diabetes, and had a screen-detected right upper lobe nodule, again asymptomatic with normal pulmonary function testing. And it was first detected in October. She had a pet a month later and underwent a vast resection, given her quite excellent functional status. They move fast, huh? How many months was that to resection? So October 22, we have this lesion, which is not dissimilar from a lot of the other ones we've seen. Here's a pet. This is the same data, just you can pick whether you like looking at a dark background or a light background. But anyway, this thing, it's not a big lesion. And the solid component is not that big either. But it's hot. For a little lesion like that to stand out from background to such a degree, definitely hypermetabolic. So no one was reassured by this pet. And they moved on to see what it was. All right, here's the wedge, and very similar look to the last case we saw of a necrotizing granuloma. Again, you have this confluent pink acellular zone. That's the necrosis. Looking at the necrosis in higher power here. This is actually, for this organism, I actually find it kind of the easiest. You can pick it out really nicely on H&E. I'll circle some for you. And I think once you start seeing them here, you're going to be able to pick out some more in the background. They have a characteristic kind of this contraction around it, a little space in there. They're variable in size. Of course, we still do the GMS. Here just highlighting the organisms being varied in size, and your mucin stain is positive. So there's only one organism, if you're getting ready for your boards, perhaps, or training, there's only one organism we need to worry about in the lung that's going to be positive on your mucin stain, and that's crypto. So the pitfall for the pathologist would be capsule deficient cryptococcus. So that's something to think of. You're down to your morphology. I think in that case, I may not be able to call it with total confidence on the GMS. So while we're good, we're not perfect. And after the pathology was done, the diagnosis was made, the patient did have fungal serologies, urine, and blood antigen testing, all of which were negative. So case number six, I believe is our last case. We have a 66-year-old male active smoker with CAD, obstructive sleep apnea, a history of renal cell carcinoma status post-resection, who had a left upper lobe mass that was incidentally detected in 2016 when he had a chest X-ray in the workup for a URI symptoms. He was followed up with dedicated chest imaging, and he was asymptomatic with normal pulmonary function testing. So when it was first noted in 2016, it was a large left upper lobe mass with extension to the pleura. The patient had recently had a cardiac stent placed and therefore could not hold his anticoagulation to undergo a percutaneous biopsy. So the decision was to undergo a BAL to rule out infection and to get cytology, which both came back negative. We continued to surveil it in the subsequent years. It started to continue to grow, develop an area of central necrosis, and it was kind of bilobed in structure with one of the components growing. Ultimately, he had a preoperative scan giving the ongoing growth of this mass in 2020 and underwent a resection. So here we are, first of all, with the lung window, and we see a big lesion. We see some speculation, obviously contacting the pleura, not a nice-looking lesion. You know, most of the time when we see lesions incidentally, and then, of course, when we see them again, most of the time when we see lesions incidentally, and then, of course, with follow-up, a lot of it is unenhanced imaging, right? So you tend not to see much of the internal architecture or the internal features of the lesion because we don't have the contrast to help us to see different parts. But on this study, we have contrast, and you can see that there is a difference between the attenuation of the extreme periphery of the lesion, especially posteriorly and along the left side, as opposed to centrally, which is a little bit darker, so a little bit lighter gray around the periphery, a little bit darker centrally. That is going to lead us to believe that the darker part has some necrosis in there as opposed to the well-vascularized peripheral portion. CT is not very good, as you may have gathered during this presentation, at figuring out what is going on in a lesion. At least we can see them, guys. I mean, we got you there. But when it comes to even with contrast-enhanced imaging, there's not a lot that we can offer for telling what the histology is going to be. So we rely on some morphological features like we've discussed. Is it speculated? How fast is it growing? And then we just have to pass it along. All right, so the patient underwent a lung wedge resection, and grossly there was found to be a 5-centimeter partially cystic mass. So here is the cystic area, and here this isn't just a torn piece of tissue. This is actually the cyst. I think this is kind of at this power. This may be an airway here, or it used to be an airway, surrounded by fibrosis on this side, and then kind of this pink and blue at this power, lesional tissue over here. So in contrast to the eosinophilic necrosis, you're probably always thinking, why is she always telling me pink? Pink necrosis, the quality of the necrosis tells me different things, how it looks. Pink necrosis tends to be infectious necrosis. Blue necrosis, while blastomycosis can have blue necrosis, basophilic geographic necrosis makes me think GPA. So that's what I'm going to be thinking about. So you can get led one way or the other by the quality of the necrosis, and certainly we don't put that in our reports, but that's something if you're ever struggling on a patient, what does it look like? So this is very blue necrosis. What makes it blue? It's the presence of neutrophilic inflammation and nuclear debris. So those dying cells impart a blue quality. Geographic meaning it's very irregular. Blastomycosis, I wouldn't rely heavily on this, but blasto tends to be more rounded. These are irregular. Here's a muscular artery here. I'll go to higher power, obviously, to show you that in a moment. But I want to point out here's the adventitia, or that's where it used to be, and it's involved by this basophilic necrosis going to higher power. I didn't really emphasize them on the first slide, but another clue that's really helpful in the diagnosis of GPA are having bizarre multinucleated giant cells. Sometimes you're just seeing those multinucleated giant cells. They have a really blue kind of funny look to them, and that's sometimes just a clue for me on maybe a small limited biopsy that if the story were right, you tell me that this is a person in which you're concerned about GPA. Well, gosh, there's some funny-looking multinucleated giant cells. I wonder if they have it. Again, the basophilic necrosis. The vasculitis of GPA tends to start at the adventitia and work its way in. Here's the vascular elastica right here being chewed up by the neutrophils. The neutrophil is the cell. Sometimes you can have some eosinophils present, but it's the neutrophil that's the constant in this entity. So neutrophil-rich granulomatous inflammation with geographic necrosis and vasculitis, but importantly without non-necrotizing granulomas. I showed you before on the cases that were infectious, at least on that first one, the combination of necrotizing and non-necrotizing. If you have non-necrotizing granulomas and you're trying to make a diagnosis of GPA, I would really think long and hard about that. You should not have non-necrotizing granulomas in the setting of a vasculitis or in rheumatoid, for example. So if the pathologist is giving you that combination, pause for a second. Really, they should be thinking infectious-infectious. Certainly we have cases in which they don't read the books, but really if there are non-necrotizing granulomas in the background, I'd be very concerned that this isn't a true vasculitis. Negative tissue special stains, always do them anyways, and what I'm worried about in this case is blastomycosis. I'm not doing those stains thinking that this is going to be AFB or something like that. This quality is very typical for only one thing, and that's blastomycosis or GPA. The diagnosis, as I've already alluded to, is GPA in this case. So granulomatosis with polyangitis, it is a systemic disease. It typically presents with pulmonary, sinus, and renal involvement. The nodules of the lung are usually multiple, bilateral, without a zonal predilectation. However, they do range from the 2 to 4 centimeter in size. There is, however, solitary lung lesions, which is considered the limited systemic involvement, but this is still a progressive disease, and it is treated similarly to the systemic disease with the same pathologic features in the solitary and the multifocal disease. We do often get serologic testing with the C. ancha being highly specific, and it is detected 90% of the time when you have multisystem involvement, but with limited pulmonary involvement, this may only be positive in 60% to 70% of cases. It's truly unknown if you have a solitary nodule because there are not many cases of these reported. So this diagnosis, when it is solitary nodule in the lung, is very dependent on your pathologist to be able to appropriately diagnose this condition because once it is resected, it still requires significant immune suppression treatment because we know it does go on to affect multi-organ system. We did. We got through that very fast. So thank you for joining this session. Yes, and we're happy to take questions.

clinical pathological correlation

ground glass nodule

ciliated muconodular papillary tumor

sclerosing pneumocytoma

localized organizing pneumonia

histoplasmosis granuloma

cryptococcosis