Chapters Transcript Cases That Have Changed my Mind/Mistakes I Have Made Course: Pulmonary Pathology Society Biennial Meeting Thank you very much and and thanks to the. Moderators, but I'm not quite sure whether I should thank the organizers, right? Cause there's only a couple of reasons you get asked to give a talk about mistakes I have made, right? One is your old check and, and 2 is you've made a lot of mistakes, so you know, check. And this one I've made a mistake on twice. You'll see why. But you've also heard about this lesion already today. All right. This is an 11 year old boy who presented with cough, fever, and vomiting, and was found to have left upper lobe collapse. At bronchoscopy, he had an obstructing polyploid fleshy mass, and the biopsy was called bronchial papilloma. Sound familiar? 13 months later, it recurred, and that was also called a bronchial papilloma. Then a year and a half later. During follow up again, he ended up finally having a left upper lobe sleeve resection. So, this is a really old case, and I'll show you another section in just a moment. To show you how it's surfaced. But this is from 1988. There's a papillary lesion here, as we can see. Here's A little bit later, very similar lesion here it is in higher power. You see these long sort of almost micropapillary like structures, there's areas of squamous metaplasia. There's no real invasion here. It looks like it's probably benign. And that, those are the lesions that were called bronchial papilloma. And then this was the resection. He needed a sleeve resection, so there's the bronchial cartilage, and there's this fairly large mass which was occluding the lumen. There it is on a little higher power. Papillary cystic. And there it is again. So a little higher power, yet to show you that there's really no cytologic atypia. There's some use in the cells, there's ciliated cells. The squamous epithelium is not in these particular sections, but as we saw there were areas where there was squamous metaplasia. So this is a free association Slido. I'd like everybody to put their diagnosis out there. It's gonna be a word cloud. I love word clouds. You like word clouds? Like, you know, the, the bigger the more, the more people who select the same diagnosis, the bigger the word will get. All right, well, you are way smarter than I am, but you just heard a talk on this entity. I have to say, Jason, thanks. Our original diagnosis was a low grade mucoepidermoid carcinoma. And, you know, in retrospect, probably not. But this case sat on our shelves for those of you who, and many of you have been to Scottsdale, Arizona, or you've been to visit Tom and Kevin and known the little white boxes. We had a visitor about a year and a half ago who was going through the boxes, and he said, you know, I don't think this is a low grade mucroepidermoid carcinoma. I said, oh, OK. There was a case that I had looked at. No, I mean that happens, right? And things change over the years, so. Uh, it was a case that I had signed out actually with Tom. Tom, uh, I had just gotten to Mayo about that time, and Tom Colby had already been there, and both of our names were on all three of these reports. So, the visitor pulled the box off and I thought, hmm, I don't know what this is. He said, Well, I think maybe I know what this is, so we did some additional stains. So here was a CK 7. P63, androgen receptor, S100 protein and SOS 10. So I don't know if that changes anybody's ideas about the case. But we thought maybe this was an introductal carcinoma of a minor salivary gland. Something that I had not heard of either. So, at least in the lung. So these are, you know, go by a variety of different names, low grade salivary duct carcinoma, salivary gland, duct carcinoma in situ, low grade, cribiform cys adenocarcinoma, they occur generally in the major salivary glands. Like our case, they have micropapillar and cribiform architecture arising within ducts and surrounded by an intact myoepithelial layer. There's a variety of types based on, you know, not surprisingly, the sites of cells that we see in the salivary gland. Most of these cases have a benign course, even if there's a little bit of apparent invasion. So, Doctor Lester Thompson, head and neck pathologist, was kind enough to give me a few examples out of the parotid gland. Here's an African type. Here's Little bit of a higher power, here's the sort of central necrosis, as you can sometimes see. These are often androgen receptor positive. Here's a mixed type, there's actually a fairly elaborate. Classification scheme for these and in fact, I was working out my talk along these lines, thinking, OK, that's what this lesion is. And There have been reports, there's only been one report in the lungs, so with the visitor, we were working on submitting this as a case report. Excuse me. The only other report was one in a 63 year old woman who had a right middle lobe tumor that was the mixed intercalated duct and oncocytic variant, and mhm. That patient had a rat gene fusion. So we tried to do testing on ours. We did a large panel DNA and RNA NGS, but it failed, that the tissue was too degraded, it was from the 1990. Mammal 2 was negative by fish, so probably not muccoepidermic carcinoma, and there was no ret mutation by fish. But we did, we did send this in as a case report. And got the reviewer's comments back. The classification of bronchiocentric glandular lesions in the lung is becoming increasingly complex, with greater correlation of molecular and morphologic data. Recently, more than one group has proposed that a subset of these tumors represent analogs to silo on the papiliferum of the salivary glands. So, The findings in this case overlap greatly with those reported cases, as well as those with this expanding spectrum of yoma papiliferum intraductal papillary tumor. Assessment of breath mutations in this case by immunity chemistry, maybe since NGS failed, could be very informative. So we took those reviewers' comments seriously. Unfortunately, Braff was negative. So now, I ask you, what is this? Well, we're trying again. We've revised the manuscript and sent it in as a style adenoma Papiliferum. I told you I made a mistake twice, so, you know, 3rd time's a charm, we'll see what the next reviewer has to say. And we've already heard a little bit about these lesions earlier today uh exophytic component with which I think really fixed, so I, we also added a head and neck pathologist to our papers. So Doctor, uh, Jim Lewis, who was at Vanderbilt recently joined us, uh, head and neck pathologist, and he really feels this is probably a yodenoma papiliferum, mostly because there's such an exophytic component and that was was what was being biopsied on those first two biopsies. So, um, I'll have to go back and look in our case, Doctor, uh, you know, Jason Chang also mentioned the CSino luminal secretion. I'll have to go back and look for that. I didn't really pay attention to that when I was putting the talk together. Um, they pulmonary cyano papiliferums look can look like conventional or, you know, the head and neck has a lot of variants as well of oncocytic types of SP. BAF mutations are present in about 40% of the pulmonary ones occasional HRAS mutations as well. So there have been 14 prior pulmonary and bronchial cases. The first case was reported by Bobos. Our case would be the 15th reported case and the youngest, so ours was in an 11 year old child. So Not mucoepidermoic carcinoma. And Probably silo and Omaappiliferum. The patient is alive, greater than 24 years later without any additional recurrence. So, a benign lesion to, to be sure that the patient is still a Mayo Clinic patient. So, um, this is my granddaughter who is now smiling because we've got victory, I think. So what did I learn from this case? Well, failure of imagination, can't diagnose what you don't know times 2. Listen to your visitors, learn more about head and neck pathology. Reviewers can sometimes be right. And maybe I should stick to non-neoplastic lung disease. So anyway, thank you very much. T Thank you, Henry, for a very nice presentation, and I'd like to call the next speaker, Marie Aubry. Mistakes I made. Thank you uh for the organizers, uh, to have invited me, uh, and to be presenting in a wonderful venue. Um, my case is a case of a misdiagnosis that did not need to happen. I basically did a series of errors in judgment and you will see that these errors will be self-evident, but yet I stand here, having been humbled by this case and therefore what better case to share with you all um in terms of tales of cautions and lessons learned. So it starts with a needle core biopsy of the lung that we got in consultation. And we had two cores that are obviously involved by a neoplasm. It was mostly a spindle cell neoplasm, a little vari variability in the cellularity, but overall mostly a cellular lesion at higher power, um, the uh cellecia was also variable, but there were many areas that were not only cellular but also had significant cellecia. So overall, a spindle cell malignancy that did not have any dis distinguish distinguishing features. The clinical history that we got was pretty brief. 90 year old woman, lung nodule, and a history of tumor of the right toe. On the other hand, we did get a lot of immunostains, and unfortunately they were not very revealing. We had a bit of CD 34, a bit of smooth muscle actin, everything else was negative. There was a lot of them. These were probably the pertinent negative ones. But we had seen the right toe in the past and I had access to all these pathology reports. So, um, in 2017, this patient had a punch biopsy and the diagnosis at the time was CD34 positive epithelioid and spindle cell meenomal neoplasm. A month later, she had another uh excisional biopsy that showed the same diagnosis, except this time we're favoring malignancy. A month later, she has her toe resected and now this is called undifferentiated sarcoma intermediate to high grade, there's patchy CD 34 and S100 positivity. And then two years after that, she gets a recurrence involving the 2nd and 3rd toe. Now it's called malignant S100 positive spindle cell neoplasm. There's still CD 34 positivity and there the discussion is around melanoma versus S100 positive sarcoma. So when I took all this information together, I said, ha ha, we're dealing with a spindle cell sarcoma that's co-expressing CD34 NS 100 and now probably metastatic to the lung, and I had an epiphany I had remember reading this article a few months ago about intra rearrange spindle cell neoplasm, and nowadays I can hardly remember what I read the day before, so if I remember this article, it had to be fate. This was the diagnosis I had solved the problem for this patient. This is what she had, period. And with all this knowledge, I went ahead did other stains including uh uh N uh immunostains, and this is what it showed, so it's kind of positive, I guess. I mean there is staining across most of the cells, not a very strong staining, but. Nothing was gonna deter me from my diagnosis. I had solved the problem, so I went ahead, signed out spindle cell malignancy consistent with metastatic and tra your arranged spindle cell neoplasm, didn't bothered to. Consider anything that had been said in the prior reports so I did that and yes by then uh I had done a lot of errors uh first I had jumped to conclusions about a diagnosis on which I had little evidence and I was quite convinced about that diagnosis actually I was quite proud of myself at that time um I didn't share the case and I have normally a low threshold for sharing the case but uh this did not even cross my mind at the time. I didn't talk with the referring pathologist. I love talking to the pathologist that sent cases for many reasons, and one of those reasons is it's another opportunity sometimes to reflect on a case and be able to revisit a case, uh, but in this case, um, I did not talk with the referring pathologist, and I didn't really read in depth on the topic. I had that article, I skim through it, kind of had vague recollections about it. And if I had read about and track rearranged the cell neoplasms, I would have learned a few things. I would have first learned it's a tumor mostly childhood and young adults. Now there's a wide age range, but 90 years old was starting to push it a bit. Um, these tumors though are not that easy to recognize because they can have a very wide morphologic spectrum. Um, they have a low grade end of, uh, monomorphic spindle cells that are haphazardly arranged. They have a high grade and vesicular Minist do you like. They can have overlapping features with infantile fibrosarcoma or lipo fibromatosis like neural tumor. The cytology grade can be variable. It could be low grade, high grade. So, uh, that having that information would have probably been less helpful, but there's another feature that can be helpful, uh, in recognizing this tumor when it's present is the haloid-like fibrosis that could be stromal and perivascular. And of course Doctor Anniscu has written a lot about a lot of spindle cell tumors, but, uh, this is one paper that looks specifically at the Ntra rearranged ones, but there's similar morphology for the NRC 1 and 2. And it kind of highlights really the variation in morphologic appearance. This picture really highlights more of that keloid fibrosis, but it could also look very high grade, um, in appearance also, and that article that I'd remembered had showed mostly high grade sarcoma, uh, sarcoma looking uh lesion, although one of their case also had that colloid like fibrosis that you can see in these tumors. Now, of course, what I had remembered was that coexpression of CD 34 NS100, and each of these markers can be focal to diffuse. You can have some smooth muscle lactin, um, and oxin and decimine is typically negative. Now, what about the uh immunostain? So this immunostain for NAC typically covers all three genes, but the sensitivity and the specificity for these three genes is different. So it's not as good as detecting uh uh rearrangements involving NTR 3. Now we know that Amtrak does uh not only involve uh sarcomas or spindle cell uh neoplasms you can see Atrak rearrangements and other tumor types including carcinoma and melanoma, and the sensitivity and specificity of that immunostain also varies with the tumor type and for sarcomas it can be as low as 80% and 74% in terms of sensitivity and specificity. And that is why genomic confirmation of course is highly desirable. um, there's many ways of identifying and track rearrangement and um the best way is NGS uh with an RNA based uh essay or uh with or without DNA. Those are the ones that provide us with the highest sensitivity and specificity of 100%. And this is an example that we actually had in our pulmonary teaching files. I was aware of it, and it was another missed opportunity. I could have looked at it. That was a case that my colleague Jen Bolin had put in our teaching file. This was more of a maybe a little lower grade looking spindle cell tumor that haphazard arrangements with a nice convincing CD34S100 expression. And this is what we would like our intra immunal stains to look like, uh, very strong and diffuse, and of course, um she actually had confirmed her case with uh Ntra fusion. So back to our case, um, I got lucky. I had a very uh uh a curious pathologist who, of course, when he got my report, decided to call me and we had the conversation that I should have had from the beginning and as we were talking, I started realizing, 00, I think I really screwed up this case. So when our conversation was done, um, I did what um I should have done. I went to my colleagues and started discussing this case with them. We actually did our inaction gene fusion panel and there was no reportable fusion, not completely unexpected. And the other thing that I hadn't done that normally I would have done and I should have done is not only read pathology reports, but actually see with my own eyes what the tumor had looked like from the beginning. And if I had done that, this is what it looked like. So these were the initial two biopsies and the tumor doesn't look spindled um it's more polygonal round cells oval, um uh and uh this one is a little more cellular but a similar morphology, um, the CD 34 was strongly positive in those two with not a lot of other markers staining. And the great toe excision was um a dermal tumor that extended into the uh soft tissue with no connection of the overlying epidermis. It was lobuated again it was mostly oval cells uh to elongated, uh, slightly, um, there's some cell atypia that was uh present kind of looked a little nested pattern, kind of enceophilic cytoplasm. The CD 34 is still strong, but now we're seeing more of the S100 protein. So this tumor is kind of evolving a little bit in its morphology. By the time the tumor recurs, it's still a dermal tumor extending into the soft tissue. Now it's clearly spindled with these fascicle, and then, um, um, the CD 34 by then is not staining as strongly and the S100 is starting to be more positive and then of course now we have this long tumor that looks yet a little different, uh, still more spindled, high grade. So looking at all that, um, now we're starting to think, well, could it have been melanoma all along. So we did uh a BRAF uh immunostain, and um this was the recurrence that showed strong and diffuse staining, um, and then the tumor in the lung was convincingly positive. Uh, but we're not gonna jump to conclusions. We know very well that there's a lot of tumors that can have the RV 600 mutations, um, and therefore express the immunostain, um, but when we, you know, when you think about all the tumors that do that. Um, sounded like melanoma fit more the bill for this case. Um, what was interesting, um, is these S100 CD 34, uh, spindle cell tumor can have other rearrangements besides N track, so not all of these are N track rearranged, whether N2 uh 12 or 3, you could actually find a rearrangements and raf one, ret, and also Braf, but they're usually rearrangements. What about mutations? Well, um, it seems like, uh, in a couple of reports, a large series of sarcomas, this theory actually had almost 2000 sarcomas. Um, they did find, uh, genomic abnormalities involving BRAF and up to 1%, well, a little over than 1% of their sarcomas, um, and actually half for mutations involving BRAF's V600E. So, um, No, we could maybe add sarcoma to our long list of tumors that can uh be positive for the immunostains. So what did we do at the end? Well, my colleague, uh, bone and soft tissue with who I was dealing with that case, basically said the simplest explanation is usually the best one, and um it's a 90 year old woman with an acral tumor um that uh ultimately was S100 and BRAF positive. Um, so by then we were making a very descriptive diagnosis and we made a very long comment, um, to say that we would favor uh melanoma, uh, that this might have been melanoma from the beginning, and that, uh, perhaps, uh, now we were dealing with the most likely a metastasis uh from the lung. We hadn't done anything more at this point because unfortunately the patient. Was not doing very well, but comfort care and the pathologist wanted uh us, we were planning on doing all sorts of genomics, but the pathologist asked us not to do. So that's how this case ended and uh I guess lessons that I should say are relearned, um. Don't be attracted by a shiny new diagnosis. Basically I was like a magpie. It was shiny. It was new, and I thought I had uh found a solution and yet I, and I jumped to conclusions um of course reviewing the prior material, sharing the case, reading, those are all seems like I said, self evident, but each of these are so easy not to do if you're busy trying to get out of town. There's all sorts of reasons to not do these, and each one of these steps will. Has the potential of avoiding a misdiagnosis, so they're so critical at to do and I just kind of relearned that so it's never too old to learn a lesson I guess and um and it really takes a village um to do pathology and I'm very thankful to my village, so. And the next speaker will be Andre Moira. For his mystery case. OK, so when I got this topic, I thought like, Andrew, am I too old? And then I discussed with my colleagues and they said, no, you're not that old, you're just senior. So I like, I prefer the senior pathologists title. And then the question was which mistake because uh. Uh-huh. And uh so I decided to do one mistake that at least has some sort of discussion that we can all think about. So the history is a 53 year old woman, heavy smoker, uh, one pack a day for 20 years. She presented with cough, and she was treated empirically for that cough with steroids, and then she reported that she improved, but then the symptoms came back. They did an X-ray and there was a right lobe consolidation and right sup uh hyal mass. A CT scan confirms those findings. And she went for a bus to DNA of the mass in the lymph node. And this is the image that we see. Most of the material was dispersed like this. It's a little bit too low, but that's fine, dispersed cells and other areas we had cells that were clustering like this and a little bit of a nested appearance. It gave me the vibe of neur endocrine. And this is a high magnification. These cells have more cytoplasm. They have nucleolus. So, you know, let's looks like a carcinoma. Let's do these things. Positive for TTF1. I thought it had a neuroendocrine marker or neuroendocrine vibe, and I did synaptophy and it was positive, but it was negative for chromogrunin. It's OK, it's a sample. Uh, let's look for the KI 67 because I don't see any mitosis here. And it was highly proliferative, so very high grade. So with that, I call you to see what is your diagnosis. Small cell, Merkel cell, large cell, adenocarcinoma with neuroendocrine differentiation or non small cell carcinoma NOS? Let's see. So yes, so that is uh. Exactly where I was. So I call this large cell neuroendocrine carcinoma because I don't like the term modern carcinoma of neuroendocrine differentiation. It doesn't exist in the WHO, so, you know, but That's it. That's exactly what I did. So I went back to the definition. Large cell neuroendocrine carcinoma is a high grade non-small cell carcinoma with neuroendocrine morphology and a mitotic count of more than 10 or 2 milli square, which we cannot do because it's a biopsy. The AS 67 shows high that express one or more neuroendocrine immunosse comarca. I'm right, that's what the diagnosis. Everything is good. So. An MRI of the brain was negative. There was no other metastasis, and the clinician, because the patient was young. Sent for a molecular piano, which is not really indicated in large external endocrine. Maybe he said, no, I don't trust this guy. And then the uh patient was starting carboplatin and a topocyte. And then came the molecular results. No mutation, but there was a fusion. A BRG 3 and not fusion. So I did the IHC for not and in fact it is positive. I did additional IHCs and it is NMS1 negative, P40 negative, focal positive 1 cell here, one cell there, and PDL1 is completely negative. So the final diagnosis is a not carcinoma. So not carcinoma the histologist, we have the sheets of homogeneous cells with abrupt carinization, which not always we see, especially in a biopsy and sometimes even in an excision, we don't see the abrupt cartoonization, but the morphology can also vary, they can be basilloid, spindled, monomorphic, or neuroendocrine appearance. This is a uh two papers that uh dealt with the effect of the spectrum of not carcinoma. And this is the IHC positivity that they report, uh. uh, the majority of the tumor cells are positive for P63 followed by P40. Our case they were not very single cells. Synaptophyin can be positive in about 17-20%. chromogranin in the. First paper was 0 in the second paper they did find some chromogranite positivity in some of the cells, INSM1 can be positive, TTF 1 can be positive. So again, not carcinoma can look like anything and can stain like anything. So that is one lesson to learn. If you don't think of it, it doesn't, you miss a diagnosis. So the patient was enrolled in a clinical trial for not, but she did not tolerate the procedure and then she went back to carboplatin etopozide and progressed with liver metasis that we have here. So the clinical pitfalls here is that, you know, the age could be a clue because in general it's younger individuals, but it can occur at any age. Uh, not is not strongly associated with smoking while large cellar endocrine carcinoma is, and that is the clinical pitfall there. And not carcinoma can occur at any site, especially tor in media sino and lung, what are the most common sites. So again, if you don't think of the diagnosis, we don't make the diagnosis because it can look like anything. This is another case. Um, it's a 71 year old former smoker also present with the with a 3.2 lung mass, TTF positive, synapopizing in positive, chromogramine positive because it gave me this neuroendocrine vibe. I only do the neuroendocrine markers if I think morphologically, it looks like neuroendocrine, because if you do neuroendocrine for everybody, you're gonna find it in a lot of stuff, so we stay to that rule. So again, is this a large cell endocrine carcinoma? It follows the criteria in the definition of the WHO. But then I said, OK, let's be careful with large cellur endocrine. Let's do more stains. And I did this thing. That is positive. And that is naps in a. So this is not a large cell endocrine carcinoma. Not, of course I learned my lesson. Not is there, and I include not in a lot of cases that I, they sort of wish wash into the diagnosis. ISM1 is also negative, so it is a carcinoma and the data expressed near thequeen Marcus and olecular showed that division has a Kra G12c mutation. So again. Pitfalls here that uh I want to bring to you is that uh for not morphology and mono chemical variability can be a big problem. Overlaps with adenocarcinoma, neuroendocrine, large cell, even large cell carcinomas, and squamous cell carcinomas. Enlarged cell carcinoma, it is a problem that we're dealing now. The definition and the diagnostic criteria are a little bit outdated when you compare with the molecular material that is coming up, and we have already referred to it today that it can be a spectrum of diseases then uh it is a little bit more variable than it used to be, uh, at least when I started. Uh, so before making the diagnosis of large cell endocrine carcinoma, you really must exclude another carcinoma, add more stains there, not carcinoma, and even small cell carcinomas, because again, the differential diagnosis, morphologically, they can be the same. The only difference from small cell is the presence of nucleolus, which can also be a little bit tricky, correct? So, I don't have time to show you, but I just want to talk about this thing. Can we have a PA 2F3 positive that is largely on endocrine carcinoma? I had a case like this. Looked like neuroendocrine. Everything is negative, but it had nucleolus, so I said, I'm going to send for I'll do a pau just to be sure, and it was positive. So again. It doesn't fulfill any of the criteria for large cell or endocrine because it only looks near endocrine but is negative for the markers, has nucleolus, it is not a small cell. OK, Natasha, please solve this, uh, but it is a problem for us, correct? Because that we have now all these variations that we need to be aware of. So as I said, I still have a lot of problem with neuroendocrine carcinomas. I look at these tumors very carefully now, make sure that exclude all the possibilities before I make that diagnosis, OK? Thank you. The last speaker of this, uh, the panel discussion is uh Doctor uh Web Travis. Thank you very much for the meeting organizers. Uh, thank you, uh, Eric and Yasushi for moderating. I'm very happy to be here as I look out on all these, um, Wonderful faces, I think back to 30 years ago. When my wife and I were stuffing envelopes to mail out uh letters around the world, inquiring if people were interested in starting a pulmonary pathology society. And I see some of you who were there when we had our first meeting at SSCAP, uh, deciding if we. Really wanted to have a society and uh. We're at 30 years now, uh, next year will be the 30th anniversary of the society. And in 2026 will be the first, uh, will be the 30th anniversary of the companion meeting at a Scout. And I was talking with Victor, who was there in the beginning, uh, he hosted the first uh PPS meeting uh at Asheville, North Carolina, and it's wonderful to have Victor here with us. So sorry for a little sentimental beginning, but uh this is my dream and I'm just so excited that the leadership of this organization has continued in the spirit in which it was uh this organization was started. So thank you for all your doing uh uh PPF uh leaders. OK, the experience is making mistakes and learning from them. And as has been alluded to, the longer you live, the longer you work, the more mistakes you're gonna make, and uh the question is, can we learn? So how do we do this? There we go. I have nothing to disclose. This was a 79 year old male with stage 3C, locally advanced hylarcholangio uh carcinoma, resected 18 months previously, uh, status post adjuvant chemotherapy. And on surveillance was found to have a solitary right lower lobe 1.600 m part solid nodule. And as you look at the CT, you can see it's a beautiful part solid, it's got ground glass at the uh periphery and a solid component in the middle. It would fit uh very well for a primary lung adenocarcinoma, and this is the biopsy which uh. Shows preservation of alveolar architecture, and as you look more closely, you can see these uh tumor cells looking nice uh low cuboidal, very much like uh type 2 pneumocytes and Clara cells. Um, Here's another view, and as I looked at this. I said that's a lipidic adenocarcinoma. And it's TTF positive, so this is a uh primary lung adenocarcinoma. And so I did the our usual primary lung adeno workup. And uh, you know, adenocarcinoma with lipidic pattern, no uh concern about that. Uh, Alc and PDL1 were negative. So then, uh, what's your diagnosis? I don't know if you all did the QR code, did you? No one put it in. So you can answer the question in your mind. You know that I'm setting you up because I was set up. Uh, and, uh. So I get an email after I signed this out from the clinician. Hello, you read the pathology on his lung uh uh biopsy his adenocarcinoma with lipidic pattern. Is this similar to his biliary primary, and I have to make a confession, uh, MCI. Didn't look at the primary, I didn't even think it was an issue, um. And I'm not sure if looking at the primary would have helped me at all. Uh, I see the specimen is sent for EGFR. Is there any more tissue left for impact, and impact is our memorial Sloan Kettering, uh, NGS panel. So this was my reply. This is a long primary. By morphology and TTF positivity, it's not a me from the biliary tumor and uh I was so confident in that. And uh and then here comes the uh. Comparative impact, so we were able to do it on both the bile duct primary and the lung, and as you can see, it's uh clonally related with these identical four genes. So, I said I was just in complete shock, thinking I had to go back and to pathology 101 and do a residency all over again. Uh, maybe I needed to take a, uh, thoracic pathology fellowship. Uh, so we went and we did a, a, a naps in. Which very oddly was negative, uh, you would really expect any. Lepitic aero, a primary in the lung with TTF expression to express napsin. And this is the uh uh biliary primary, which. You know, I, I have to say there is some morphologic overlap. But I really, even after looking at this, don't think I would have regarded it as likely to be a med, given everything I knew at the time, uh, only because of the NGS. So then we did Uh, TTF and absent on the biliary primary and it was just like the lung. Uh, so it really clinched the diagnosis. Because we had now uh overlapping morphology, uh, we had PTF positivity in both with Naps and negativity. And identical genetic alterations. So again, sorry, the uh they were supposed to set this up, but I guess it it didn't happen. Uh, so this is metastatic biliary adenocarcinoma, so I amended my report. And uh I have conversations with my fellows, I try to be an example. Uh Don't be shy about making amended reports, I mean. We, we do this all the time when it. Uh, ends up, uh, making the final diagnosis that clinicians see to be the correct one. And, and so this was uh metastatic adenocarcinoma with lipidtic growth consistent with metastasis from primary uh biliary adenocarcinoma, and then there's this long note explaining what I just it's very kind of apologetic but sort of justifying how did I screw this up so badly. Oh my goodness. So, uh. So actually there there is some literature, it was hard to find about uh uh TTF and Napsen and cholangiocarcinomas. And I'm not sure these are the most definitive of articles. But uh this one published in AGSP in 2014. Uh, they used the less specific SPT 24 TT up clone, uh, and it was positive in 27% of cases. All of these were extra hepatic, uh, 3 also were Napsin A positive. And then in a follow-up study, uh, using the more specific uh HG7G3 clone, uh and naps and all of the tumors that were studied were negative, and these were gallbladder cholangiocarcinomas. For what it's worth, the TTF clone that we used uh is the more specific uh deco uh clone. So Lynette uh Scholl's group published this nice paper uh a few years ago, uh, showing. That in 12 out of 1,0007 cases of suspected non-small cell lung cancer. Uh, I think. Attention was drawn to the cases primarily by NGS, but in correlating it also with the clinical information. They reclassified the cases as metastases from extra pulmonary primaries. And uh Uh, UV radiation associated mutational signatures, uh, were seen, I think 6 of the cases reclassifying them as melanomas and also uh gene fusions and mutations, and they uh found also cutaneous squamous and basal cell carcinomas, urothelial carcinomas, hepatocellular, pancreatic, and hepatic cholangio. A thyroid and synovial sarcomas. Uh, so, uh, metastatic melanoma is something that can also present as a lipidic, uh, growth, and I'll never forget when this case coming across. I think I got this one right though, uh, uh, with the melanoma markers, and, uh, uh, Natasha uh put together with one of our fellows and very nice study showing uh uh that 10 cases with lung only. Uh, melanomas, uh. Were found to have by our NGA uh NGS a uh UV mutational signature, uh, so they reclassified cases previously thought to be primary uh pulmonary melanomas as meta metastatic. So in summary, metastatic tumors can uh rarely show lepetic growth, even uh TTF positive metastatic carcinomas can resemble uh lapitic adenocarcinomas. In patients with biliary adenocarcinomas, keep in mind that uh you can have TTF positive cases, uh. Uh, you may want to try a napsson if you encounter such a situation. Um, and I, I just have to say, uh, when I started pathology some 40 years ago. Uh, immunohistochemistry did not exist. And it's just mind boggling to imagine working in an environment now where we have these incredibly powerful tools to classify tumors and solve problems that uh in the past, I'm sure we were making all kinds of mistakes, we were just uh. A little bit uh ignorant that we were doing so, so. How do you deal with a mistake? When you make a mistake, there are only 3 things you should ever do about it, according to Bear Bryant, the famous uh football coach from Alabama. First thing is admit it, uh, second, learn from it. And 3, don't repeat it. And I can't uh finish this talk without uh just telling you how wonderful my day is to go to work and work with these amazing colleagues, and you're hearing from a few of them, some in the audience you're not gonna hear from, uh, but it's just a dream for me to have such incredible colleagues, uh, Natasha Rchman, Jennifer Sauder, Marina Bain, Darren Bonnicore, Jason Chang, Stu Yang. And also we have incredible fellows and Susan Armstrong, I believe is here in the back, uh, some of you uh who send cases uh have gotten to know her and Melissa Byle, and then Rania Ali is here as a research fellow and uh. So Our field has come so far in 30 years. It's absolutely amazing, and uh I thank you all for being here and your interest in thoracic pathology. Thank you very much. Mm Well, thank uh all the presenters for their excellent presentations. It's uh. Time for questions. I did not see questions on digital, so you're allowed to go to the microphone. I've, in the meantime, one question to Bill. You showed an intriguing case with probable growth of the tumor cells on the ovular walls. And I imagine that you those tumor cells must meet somewhere the preexisting epithelium. And the second thing I imagine is that they grow then in between the pre-existing epithelium. And the basal membrane, have you looked at that point? No how No, I was just so, I was just so embarrassed that I um screwed the case up. I, I didn't get into the science of it. It's a good question. By, uh, this is a project for you. Uh, we'll start tomorrow. Victor, yeah, I, I just have two quick comments. One is that seeing uh mistakes admitted by such an incredible panel of diagnostic pathologists makes us all feel better about ourselves and the mistakes that we've made in the past. The other is that your Bryant, your uh Bear Bryant quote reminded me of a of a sign which my assistant has on her door which says, I never lose either I win or I learn. Thank you, Victor. And Victor is one of the giants of our field. We give a big hand for. All of you young people need to go spend a little time chatting with him, he's amazing. Uh, Andre, uh, I will, I will show my residents the table from the WHO, uh, showing how to say, how to diagnose biopsies, how to diagnose resections. So right now, how do you diagnose a biopsy that has the endocrine features with large nucleoli, but it's not small cell but also has some, so how to sign out the day after this case. So there are several things. Number one, directly, we should not make the diagnosis of large cell or endocrine in a biopsy, correct? But we can if it fulfills all those criteria, so it has to look near endocrine has to have prominent nucleolus and positive for neuroendocrine markers. So that is the classical and the the definition that we have. But with all these advances in molecular pathology that we have, we now must exclude. That we're not dealing with an adeno carcinoma, that you're not dealing with another carcinoma or even with a PA positive tumor. So it becomes a bit more complicated and I think our field is going to become more and more complicated with this interaction between morphology and molecular. Uh, I'm not, uh, I, I'm not, I'm not being critical. It's just that I think we need to be very open minded on how we are dealing and navigate this, all these diagnosis now, because if there is a moleculteration, it will trump, uh, in my opinion, whatever we, we see morphologically. Out all the questions, then I like just to. Make on one of the differential diagnosis of benign and malignant lesions. What I used when diagnosing is, I compared the size of the tumor cell nuclei with the preexisting size of the nuclei of the stromal cells, the lymphocytes, and granulocytes. And you know that the the perimeter from a neutrophilic granulocyte, it's about 15 mic. And from a lymphocyte about 10 micron. If those tumor cells were in the range of that size, then I could not exclude a benign lesion, although the number of cells might be very large. So That's how I looked at the size of the cells and the differential diagnosis, which might be. A possibility. Oh that's your comment or your question or what? No. I, I wonder if I, if somebody else uses this approach to the tumor diagnosis. Oh, yes, certainly, actually, if you have a small cuboidal cells in the background of other walls, and then you have to wonder up maybe the active process, of course, uh but uh I am not sure whether we can definitively exclude the malignant uh based on the nuclear size. You know, constellation of multiple morphology, right? So the nuclear size, nuclear irregularity, hyperchromysia, or architecture and so on and so so we have to think about to differentiate benign malignant as well. I heard another uh trick that is the abrupt transition from the linear hole between the proliferation and the preexisting size, but if you see a gradient of changes. Over a long length of the over wall that might still be benign. So if there are no other questions, then I'd like to think. And gives microphone. So I have a question uh to Mari. So you, you mentioned about the, you showed the two the uh bronchiol uh bronchiolar adenoma and uh IgG4 related disease. So, uh the uh bronchiolala can uh occurs, uh, I mean the multiplex lesion. So I mean, uh, Are there any chance to show the uh multi lesion with the IgG for related disease? So I mean uh uh multiple lesion. So what's kind of the lesion show the multispleural lesion in the lung? Uh sorry, I, I, I, I don't, I'm not sure that I, I understand what your question because a uh uh adenoma can occur as a multiple lesion, so several lesions in the neck. So how about the IgG4 related disease? Are there multiple lesions? Yes, yes, and we can see the multiple lesions. So that means lesions can uh um make a uh narrow the diagnosis. Right. Oh, to mean to be benign? To, no, I mean, to, to, to make a list of the uh differential diagnosis. In that point, could you explain that uh what's kind of the type of the lesion show the part lesions in the lung? So IgG 4 in a benign disease. Uh, so in the benign lesions in the multiple lesions, yes. Oh, OK. So that's a sort of a, yeah, tricky question, I think. And then Yeah, so IDG4 is one thing. Uh, the, uh, BA usually is solitary, but they can be multiple. Yes, uh, I think squa pneumocytoma is usually solitary lesion, right? And then, um, what else? Hm. Yeah, so longha cell histiocytosis, uh, is usually multiple in my experience because of the smoking related, uh, you know, sort of a bronchialocentric lesion, it could be multiple, yes. Um, anything else? From the floor? Uh, yeah, organizing pneumonia, organizing pneumonia is, uh, on multiple lesion is organ mature, um, well, I don't know, team effort. So that's, can be helped to the differential diagnosis in the case of the Marsproot diseases. Yes, but, uh, you know, we can see malignant, sort of semi-malignant lesion is a multiple as a multiple lesions, right? You know, EHE or some other, you know, lesions can be multiple. So, uh, if you have a multiple lesions, it may indicate B but it cannot be definitive differentiation, right? OK. So some other questions from the floors. So we still have a several time. You have a which, so we thank the. So we have some time left, but it's also time to. Go out and sing first all the speakers with their very interesting errors which we all can make. Anytime during our practice, so. Thank you very much. Published June 20, 2024 Created by Related Presenters Marie Aubry, MD Andre Moreira, MD, PhD View full profile Henry Tazelaar, MD William Travis, MD
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