Good morning, everybody. Thanks for coming out so early. It's really an honor to give this lecture for Dr. Richard S. Irwin. Dr. Irwin is still actively practicing. He's a professor of medicine in the Division of Pulmonary Allergy and Critical Care Medicine at the University of Massachusetts T.H. Chan School of Medicine. If I went through his CV, we'd all be here till tomorrow, but I do want to highlight all of the amazing contributions he's made to the American College of Chest Physicians. He was honored as a giant in chest medicine in 2020, which he really deserves when you see all that he has done. He gave a really inspiring video interview for that presentation, and I would encourage you to watch it if you have not. He was president of CHEST from 2003 to 2004, and really notably was the editor-in-chief of the journal CHEST for 14 years, from 2005 to 2019. You are probably aware that he was the force behind one of the original COUGH Guidelines and COUGH for ACCP that started in 1998 and is still being kept up today. As John pointed out, his career really has been focused on patient-centered care, and the COUGH Guidelines really speak to that. Just earlier this year, he and his group published in the Annals of Allergy, Asthma, and Immunology the updated evidence base for those guidelines, and again, he's so active and has been really a model for excellence in patient-centered care now for many, many years. So thank you for coming and being here today to honor Dr. Irwin with this lecture. So I'm going to speak on lung cancer, the evolution and changing presentations of a modern disease. I have no disclosures related to this lecture. Let's see. Is this going to work? Okay. So lung cancer is a modern disease. It's really a disease of the 20th century. This is a group of autopsy studies back in the early 1900s, and you can see that lung cancer was really rare, certainly as a cause of death and even as an incidental finding at autopsy. And that was true for the early part of the 1900s, but you can see a signal starting here in the 1930s with the number of lung cancer cases noted in autopsy series starting to rise, although still very low. But if we look at American Cancer Society data looking at causes of cancer death in the United States, these data go back to about 1930. And you can see that in 1930, lung cancer as a cause of death in men, a cause of cancer death in men or above and women below, was really uncommon. But that is the beginning of this unbelievable lung cancer epidemic in men, followed later by the epidemic in women, shown here in the curves in red, that the country experienced, particularly from about 1940 to about 2000. And so you can see that lung cancer is still the most common cause of cancer death in men and in women, though thankfully these curves are now declining. But this is really a disease of the 20th century, and it's going to be with us through the rest of our medical lifetimes. So lung cancer is also the most common cause of cancer death around the world. And these are WHO data from 2020. This is men on top and women on the bottom. And the color of the country indicates the leading cause of cancer death. And for lung cancer, it's blue, and for breast cancer, it's pink. And so you can see in men that most countries around the world do have lung cancer as the leading cause of death. All of North America, lots of South America, most of Western, Eastern Europe, and Asia and Australia. And that has been the case now for many years. In women, breast cancer is still the most common cause of cancer death in many countries, but in the United States and Canada, the countries of Scandinavia, the United Kingdom, and importantly, China, with its very large population, lung cancer is now the most common cause of cancer death in women, and this map gets bluer every time it's published. So this is a huge problem. It is a problem, really, of our generation. I'm going to talk to you today about why lung cancer actually is changing and the ways we're going to need to learn to recognize it. And specifically, I'm going to talk about multifocal lung cancer and lung cancer with air leucency. So we'll start with a case. This is a 70-year-old male who presents with persistent cough and several weeks of scant daily hemoptysis. He has a history of hypertension, COPD. He's a current smoker of a pack per day for 55 years. He was given antibiotics a couple months ago for cough and purulent sputum with clearing of the sputum but persistence of the cough, and his chest X-ray that was done because of that showed left upper lobe collapse. His chest CT that was triggered by the chest X-ray confirmed the left upper lobe collapse and noted that it appeared to be related to a proximal central nodule. That led to a PET scan, and you can see on the PET scan the collapsed left upper lobe as well as this very hot 2.5-centimeter nodule. The left hyaline nodes were also mildly FDG-AVID, and there were no other FDG-AVID sites seen. And as this case was being discussed in our tumor board because this patient has stage III lung cancer and is potentially eligible for many of the new approaches. My first thought was, wow, this is a classic case of lung cancer. And my second thought was, we don't see this much anymore. So this patient had bronchoscopy with EBUS. There was tumor obstructing the left upper lobe bronchus at the level of the secondary carina. This is the left lower lobe. And the pathology from the endobronchial biopsy showed squamous cell carcinoma PD-L1 greater than 50% with negative molecular profiling. The 11L and 7 nodes were positive for tumor and none other. And so in summary, this is a 70-year-old male with a heavy smoker presenting with cough central endobronchial tumor causing post-obstructive liver collapse and stage III squamous cell carcinoma. So the typical lung cancer phenotype was really defined by the epidemic in men that, as I said, occurred from the 1940s to the 1990s. These were middle-aged, older men who were heavy cigarette smokers. Typically, their symptoms reflected endobronchial disease with hemoptysis, cough, and fever related to post-obstructive pneumonia, or they might present with metastatic symptoms like weight loss or pain. The chest X-ray typically would show a central mass, although peripheral nozzles were certainly described. And the histology was dominantly squamous cell carcinoma. And this phenotype really was the classic lung cancer in the days of my training and in the early days when I was attending. But this actually is changing, and yet when you look at textbooks and even up to date, what's embedded in there is this phenotype. But lung cancer is changing, and for a lot of reasons. Cigarettes have changed. The distribution of histology has changed. There have been changes in population smoking patterns. There's an increasing number and proportion of women with lung cancer. Our world is changing, and the way we diagnose is changing. There's been a proliferation and a lot of technical advances in imaging studies. All this also contributes to an increasingly sophisticated ability to understand the biological mechanisms of oncogenesis, and so now we have amazing therapies for cancer. But we have to recognize that cancer first, and so it's really important that we understand what cancer looks like at the present time and what it may look like in the future. So first, let's look at cigarettes. So cigarettes really are a product of modern times. Prior to 1900, if you wanted to smoke a cigarette, you took raw tobacco, stuck it in a piece of paper, rolled the paper, spit on it, and then smoked it, and so socially it wasn't like a super acceptable habit. But the Industrial Revolution changed all of that, and with the ability to mass-produce cigarettes that were neat little tubes that you'd put in a box and carry around, more people started to smoke, and certainly the marketing campaigns of tobacco companies have been quite brilliant. So the early cigarettes were unfiltered, and the smoke coming out of those cigarettes was really harsh. It was hard to inhale and certainly hard to inhale deeply, and so most of the injury was done in the proximal airways, leading to squamous dysplasia and metoplasia, and then squamous cell carcinoma. In an effort to help people smoke more, filters eventually were developed in the 1940s and 1950s, allowing more people to smoke more easily. The smoke wasn't so harsh, so you could inhale it much more deeply and hold it in your lung to absorb more nicotine, and so more people were able to smoke. Along with that, the advertising campaigns included this image of the rugged male, and the cigarette companies, the tobacco companies really capitalized on the fact that nicotine is an appetite suppressant, and so this whole image of American beauty as being slender really is embedded in some of these marketing campaigns. You know, five years from now, do you want to be fat or do you want to be thin? And if you want to be thin, you should smoke. And so what we see then is that cigarettes become easier to smoke. You can inhale the smoke more deeply and get more, quote, satisfaction from the nicotine, and there's heavy marketing over the 1940s, 50s, and 60s and on to women and to children. And so whole new populations of smokers are developed, and smoke gets easier and easier to inhale with the introduction of flavorings, development of genetically engineered tobacco plants that the smoke is less harsh, and what we get is a world full of people who are smoking, but the cigarettes are different. And what that has contributed to is a difference in histology, and so if we look over time at histologic patterns of lung cancer in men, again, on the top, and women on the bottom, I don't know why the men are always on the top, but they are, what you can see is the splenocell histology in men, which is a dotted line, starts to decline with adenocarcinoma increasing because as the smoke gets lower and lower and exposes the terminal bronchioles and the alveoli to carcinogens, you get different histology of cancer. In women, the histology has always been dominantly adenocarcinoma. And so if we look at lung cancer histology in the United States at the present time, what you see is that of the non-small cell carcinomas, adenocarcinoma now accounts for a little over half of all non-small cell lung cancers in men, and a little bit more than 60% of all non-small cell lung cancer in women. And when you get lots of adenocarcinomas, you get much more heterogeneity of disease because we understand that adenocarcinoma is a very heterogeneous disease. And this chart is already out of date, but we know that for the majority of adenocarcinomas, there's an identifiable driver mutation. This has created tremendous amounts of opportunity for disease targeted at individual genetic abnormalities, but has also introduced tremendous amounts of heterogeneity of disease, most of which we really don't understand at the present time, but certainly gives opportunity for improvement in treatment. And then let's talk about who's smoking in the United States. And it turns out fewer and fewer people are smoking, and we're happy about that. But that creates a different population of patients who will get lung cancer. And so this is an interesting chart that's from a report that was published last year by the Early Detection and Screening Committee of the International Association for the Study of Lung Cancer. On the left is the population of the United States, divided by current in the dark green, ever in the light green, and never in light green smokers. And what you can see is this is a study looking at 100 years, looking back in 1964, which is the date of the first Surgeon General's report, up to projecting to 2065. And in 1964, more than half of the population in the United States was either currently or had smoked. And the population of never smokers was actually the minority of the populations. It's pretty amazing. In 1964, 75% of adult American males were habitual smokers. And as we project out over 100 years, and we're kind of right now in here, what you can see is that the population of current and ever smokers is falling and eventually is expected to plateau. But the proportion, the absolute number and proportion of never smokers is really increasing. And that gets reflected in lung cancer deaths when you look at lung cancer deaths by smoking status. So back in 1964, most patients who got lung cancer were current smokers. There was a group of ever smokers getting lung cancer that was smaller. And there was this tiny, tiny sliver of people who never smoked but got lung cancer. And over time, with these population changes, what we see is that we're kind of right in here, right after the peak of this lung cancer epidemic. And while most of the lung cancers are still occurring in current or ever smokers, because the population of never smokers is getting bigger, the population of never smokers with lung cancer is also getting bigger. And over time, I'm sorry, this is kind of awkward, this arrow, that population will stay stable and then grow. So current smokers who get cancer are different than ever smokers who get cancer are different than never smokers who get cancer. And so the heterogeneity just of the population in terms of smoking is also going to grow and the number of patients we will see in the future who are never smokers proportionately is going to grow. And then what about lung cancer in women? And again, the epidemic in women was later than in men because women didn't start smoking in great numbers until the 1930s and 40s. There's a famous picture of Eleanor Roosevelt in an open car with a cigarette, which caused a lot of stir at the time. But the concept that smoking cigarettes was liberating, emancipating, and associated with sophisticated life certainly was embedded and reinforced by tobacco advertising in our communities. So the historical male lung cancer phenotype, like with all diseases, should not be summarily generalized to female lung cancer. Lung cancer in women occurs with lower smoking intensity at younger age. Twenty percent of women who get lung cancer are never smokers. There's always been an adenocarcinoma predominance. Patients who are women who have lung cancer are more likely to demonstrate driver mutations in their tumors, and the high prevalence of adenocarcinoma always raises the question of the influence of hormones on the development of those cancers. This is a signal that family history of lung cancer may be a stronger risk in women than in men, and that's particularly strong in Asia. And we've seen for decades that women with lung cancer have better survival outcomes. If we look at lung cancer in women in the United States, last year for the first time more new lung cancer cases were diagnosed in women than in men. That has become a trend because the same thing is true this year. 20,800 cases in women and 117,000 cases in men. And you can see in the graph on the right, which is 2014 to 2023, that these lines have crossed and likely are going to diverge even further. And in terms of deaths from lung cancer, this gap used to be much wider in decades ago, and that gap between the number of deaths in men and women is closing, and if this trend in number of cases continues, that those graphs will eventually also cross. So much more likely that you will see women with lung cancer in your practices in the future. And then what about the world around us? Well, we know that lung cancer has a lot of risk factors. There are the non-modifiable ones like family history of lung cancer, personal history of lung cancer, sex, geography, and the presence of nonmalignant chronic lung disease. But there are lots of modifiable risk factors that change as the world changes. Cigarette smoking certainly is an individual choice, but we don't have individual choices about occupational, environmental, and domestic exposure to carcinogen because we actually don't know in most cases what we're being exposed to. So things like diesel exhaust, radon, therapeutic or diagnostic radiation, indoor and outdoor air pollution, these are not things that we can necessarily control, and certainly outdoor air pollution is a huge problem in countries like China and is felt to be a major factor in contributing to disease. These sorts of exposures will change as the world around us changes, and certainly our planet is under stress at the current time. And then technology has made a difference. In 1980, there were 3 million body CT scans done in the United States. In 2020, that number had increased to over 80 million. And the imaging quality now is super high and sufficient to identify easily 1 to 2 millimeter nodules and early changes in the lung chronicoma. And so the question always comes up, how much of what we see now is new and what was there all along? Are ground glass nodules a new phenomenon, or were they just invisible before we couldn't see them because the technology wasn't present? And so at present time and looking forward, the phenotype of lung cancer will change and it will become more diverse. More patients will be asymptomatic. They'll be found because of incidental findings related to the proliferation of CT imaging, and we've all seen that. And hopefully, as lung cancer screening becomes more embedded in the community, we will see more asymptomatic patients because of early detection. The histology has already changed. Adenocarcinoma, more common than squamous small cell or large cell, and we know because of that there's increasing tumor heterogeneity. Neversmokers will become a more important portion of the lung cancer population because of the increasing absolute number and proportion of them among lung cancers. And there'll be more lung cancers in women than men. And so for the rest of my talk, I'm going to talk about two new, somewhat new presentations of lung cancer, multifocal lung cancer and lung cancer with air leucency. And I want to give a particular shout out to Frank Detterbeck, who's sitting here in the front of the auditorium, because much of this is work that he has led over the past 10 years. Frank has been my colleague at Yale for the past 20 years. The best thing I ever did for the thoracic oncology program was steal him from the University of North Carolina, and Patricia Rivera, who's sitting here in the front, has still not forgiven me for that, but it made all the difference to our thoracic oncology programs and development. So we'll go to another case. This is a 76-year-old woman with hypertension, hyperleukemia, and coronary artery disease. She has a distant history of smoking and a positive family history of lung cancer. She had CT imaging performed because of a thoracic spine meningioma, and so this was the lung incidental. And what she demonstrated was multiple pure ground glass lesions scattered around the lung. This is one of the largest here in the right upper lobe, and you can see that it is pure ground glass, and if you look hard, you can see there's actually a second one in that same cut. The recommendation was made to her for watchful monitoring with serial CT imaging without invasive intervention, and the question is, does this patient have lung cancer? And I think the answer to that is yes. I told her that, and she was a little shocked that I told her in one breath she had lung cancer and in the next breath that we weren't going to do anything about it except watch her, and I'll come back to that later. And here's the next case, a 61-year-old white female who presented for first pulmonary evaluation in 2012 requesting follow-up for lung nodules. She had a history of cigarette smoking of a pack per day for 20 years that she had stopped in 2005 when she was first told of the presence of a lung nodule. She has no COPD or pulmonary symptoms. In 2005, when she stopped smoking, she had a panic attack with severe dyspnea that had prompted the infamous PE protocol chest CT in the ED. The CT demonstrated no PE, but she was told that she had, quote, a few spots in her lungs. No follow-up was done until 2011 when another chest CT was done because of another panic attack with dyspnea. She was told again that there were, quote, a few spots in the lungs and advised to follow up with a pulmonologist at some point in the future. She was at that time in the process of moving to Connecticut from California, and when she had set up residence, she came to our thoracic oncology program for nodule evaluation. When I saw her in 2012, this was her chest CT, and she had multiple subsolid nodules that were too numerous to count. In this cut, you can see there's one there, there's one up here that's much fainter, and there's actually another one here. And on the rest of her CT, the nodules are actually much easier to see. She has a nodule in the right middle lobe that looks pretty solid, another one in the right middle lobe that's relatively dense, and another one in the lingula, which are in the lingular nodule that was cut up to show that it was actually the biggest one measuring 24 millimeters. And the one we were concerned about was this one, the 15 millimeter nodule in the right middle lobe with a 12 millimeter solid component. So this CT triggered a PET scan, and what you can see is that on the PET, that nodule with the solid component actually is hot, it's taking up FDG. And so this patient has lung cancer, and she has multifocal lung cancer. In anticipation of the 8th edition revision of the International Staging System for Lung Cancer, Frank led a group addressing the sticky issue of lung cancer with multiple sites of pulmonary disease. And those of you who have dealt with lung cancer patients know that this can be a really difficult area to determine what the patient actually has. Do they have synchronous separate primaries? Do they have tumor nodules that are related to a cancer in the chest but not independent cancers on their own? Do they have multifocal disease, which I'm going to show you, which is a very distinct pattern of ground glass leading to subsolid nodules? Or do they have pneumonic type adenocarcinoma? This framework actually has been incredibly useful to me over the years thinking about this population of patients, and I'm going to focus on patients with multifocal disease who have multiple ground glass or part solid nodules. So what is a ground glass nodule? It's defined as a focal nodular area of increased lung attenuation on CT scan through which normal structures like blood vessels and airways can be seen with no solid component. A subsolid nodule that persists over time is much more likely to be an adenocarcinoma than inflammation or infection. Our radiology colleagues love to call these subsolid nodules adenocarcinoma spectrum, which drives the patients who are now reading all their reports really crazy because they look that up on Dr. Google and they say, I have lung cancer. The pathology of these subsolid nodules includes atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lipidic predominant adenocarcinoma. And it'd be much easier to show you what that is and to read all those words. So atypical adenomatous hyperplasia correlates, we think, with these pure ground glass nodules. And what you see under the microscope is a proliferation of atypical cells along the alveolar structures respecting that architecture. And what you see under lower power is those cells that are scattered along the alveolar walls. Adenocarcinoma in situ is the next step in the lineage leading to invasive adenocarcinoma. Radiographically, these, we think, look like this. They are denser than this ground glass nodule, but they are still predominantly ground glass. They may have components within them that look more solid. The American College of Radiology would call this nodule part solid. We tend to do this trick where we switch to mediastinal windows, and if the nodule disappears, it may still have a solid component, but it's certainly not as dense as a nodule where that does not disappear. Histologically, you can see that there's more proliferation of these, what are neoplastic cells along the alveolar structures. In both of these cases, you can see that the air is maintained in the alveoli, and that presumably is what leads to this ground-gap glass appearance of these nodules. And on higher power, you can see these neoplastic cells proliferating along the alveolar structures, with retained alveolar architecture. And then, lipidic predominant adenocarcinoma correlates with the development of a true solid component within the ground glass nodules, so this is now sub-solid with a solid component. And what this looks like under the microscope are areas of lipidic adenocarcinoma. Lipidic means they're spreading along those alveolar structures, but now there is an invasive component where there's an invasion of the normal alveolar structures and obliteration of the normal lung architecture. Minimally invasive adenocarcinoma looks like lipidic predominant adenocarcinoma, but with a very small component of invasion, less than 5 mm. And so what is the natural history of these sub-solid nodules? And there's good literature about this, and the paper I tend to turn to is this one by Kakinuma and colleagues, because it's a really big study. They had 795 patients with 1,229 sub-solid nodules who were followed up for a mean of over four years. Most of the nodules are identified by lung cancer screening. This study was done in Japan, where they've been all over lung cancer screening for a long time. Notably, 60% of the cases were never smokers, and only 40% of these patients were current or former smokers. 70% of the nodules were solitary, and 31% of them were multiple. So there were a lot of multifocal lung cancers patients in this study, and 8% had prior history of lung cancer. You know what, these slides are slightly out of order, but I'll just go with it. And so they looked at the natural history, and this is a busy graph, but basically all three charts are the probability of something occurring against time, and time here is in years. And the graph at the upper left is growth. The graph on the upper right is the appearance of a solid component, and the graph at the bottom is solid component growth. Pure ground glass nodules are shown in red, and what you can see is for all of those metrics, if a growth happened, a solid component happened, or a solid component grew, that occurred with very low likelihood and very slowly. And so the natural history of ground glass nodules is they are indolent. For heterogeneous nodules, which are what would correlate to the nodule I showed you for adenocarcinoma in situ, the findings were very similar. That growth of the nodule, the appearance of the solid component, and solid component growth happened, these patients are shown in green. But again, the probability of those three things happening and the rate at which they happened were both low and slow. For nodules that already had a solid component, you can see that the natural history was different. They tended to be more likely to grow, and they tended to have growth of their solid components. And so the bottom line of this and other studies is that indolent lung cancer is not an oxymoron. These are patients who have lung cancer, but their natural history is really quite indolent. The Kakinuma group did look at the patients in their group who had resection, and resection was decided at the level of the local hospital. 91, actually it's 123 nodules were resected, of which 12 were invasive adenocarcinomas with a short doubling time, volume doubling time, and that's shown here on the right. And so that's 1% of that entire population, so this was actually a very uncommon occurrence. If we look at the population of patients who had either pure brown glass or nodules that didn't really have identifiable true solid components, there were some resections of those patients, but what you can see is that their volume doubling time was really quite long, you know, two years on average. And those are cancers that are probably not destined to hurt, not destined to progress to clinically meaningful disease, and these nodules essentially would be under the umbrella of overdiagnosis, nodules that we've addressed but were never destined to cause harm. So tumors should be considered multifocal, if brown glass, lipidic predominant, adenocarcinomas if the following criteria are met, and this was the definition that was adopted by the 8th edition of the Lung Cancer Staging System. Clinically there should be multiple sub-solid nodules, either pure brown glass or part solid, that are greater than 5 millimeters in total diameter, with at least one suspected or proved to be cancer, including adenocarcinoma situ, minimally invasive adenocarcinoma, or lipidic predominant adenocarcinoma. Pathologically they should be considered multifocal lung cancer if there are multiple foci of those three types of cancer, at least one of which has to be proved. And on the basis of the Strength of Franks Committee, the multifocal lung cancer T descriptor was added to the 8th edition TNM classification for lung cancer in 2017, so this really defines a new type of lung cancer. So in our, at Yale we've been looking at this in our own lung cancer biorepository, and this is the work of Andres Mora-Carpio, who is one of our stellar senior fellows. In our biorepository there are 862 cases of predominantly surgically resected lung cancer with at least five years of follow-up. Andres has gone through that entire group of patients and identified 72 cases of lung cancer with multipulmonary sites of involvement. And this is preliminary data, but what you can see is that the majority of them, actually 60%, are multifocal lung cancer. So among this group of patients, this is actually a very common type of cancer. 80% of these patients are women. Most of them, nearly all of them, were ever smokers. And interestingly, three-quarters of them have more than five nodules. And so these are challenging patients. You end up following them a long time because they have so many nodules. The overwhelming histology is adenocarcinoma. Four of these patients had a prior surgery for lung cancer. 18 of them went on after that index entry into our biorepository to have another cancer treatment intervention, either surgery or SBRT for another lung cancer, but in the meantime to that second treatment of 33 months. And four patients had a third lung cancer treatment intervention, with meantime to that intervention another 16 months. And several patients actually have had more interventions than that. So of these 42 patients, there were at least 68 cancer interventions. So they kept busy over time, and some of their nodules continued to evolve. But strikingly, 60% of them are alive at 10 years. And so their prognosis is good. And so multifocal lung cancer is a distinct type of lung cancer. It has a strong female predominance. 60% to 80% of patients in the literature who have multifocal lung cancer are women. Generally, what's seen is that there's an increased proportion of never smokers. That wasn't seen in our series, but that is typically what is reported, with a prevalence of 30% to 80%, with the higher end being in Asia. The histology is adenocarcinoma, with predominantly lipidic features. And one important thing is that every one of those nodules should be treated as a separate primary. The biologic behavior in multifocal lung cancer for each of those nodules mirrors the indolent behavior of solitary, sub-solid nodules, where we know that the prognosis is good. 60% to 95% of pure ground glass nodules stay stable. 20% of sub-solid nodules increase in size or become more solid. And at the time of intervention, resection typically, nodal involvement is low. So again, an indolent course. Distant recurrence is highly unusual. And the five-year survival after resection is approximately 90%. So we'll go back to our cases. And so the first one I showed you of multifocal was the woman who had had the lung cancer And the second one I showed you of multifocal was the woman who had had the thoracic spina meningioma, and this was an incidental finding. We had a long discussion about indolent lung cancer and why I was recommending to her that we monitor her watchfully and not intervene, and that I would watch her carefully. But the course of her disease was likely to be very slow. And you can see that is what turned out to be. I initially saw her in 2014, and I showed you those two nodules. And what you can see, fast forward seven years to 2021, is that right upper lobe nodule is still there. It may be a couple millimeters bigger. It remained the largest one in all the nodules she had. And at that point, she was 83, and she elected to stop coming to see me for serial monitoring. And for the other case, the woman who had the history of lung nodules dating back to 2005, and fast forward to when I saw her initially in 2012. We were concerned that this nodule in the right middle lobe, which really had not been very visible in 2005, was actually progressing with development of a solid component that we could see in 2011, and that had gotten bigger a year later, and was FDG AVID. And this patient underwent a right middle lobectomy, which showed lipidic predominant invasive adenocarcinoma, 2.3 sonometers in largest dimension, which was staged at that time in 2012 under the seventh edition as PT1BN0M0, stage one. Five years later, she had two more nodules that were getting bigger and denser, and she had linguelectomy and left upper lobe resection to take those two out. They both showed invasive adenocarcinoma. At this point, though, the eighth edition lung cancer staging system was in place with the multifocal designation. And so her stage was based on the size of the solid components, and she was staged at pathology T1AM to designate multifocal N0M0, stage one. And I'm not going to go through all the other surgeries she has, but the bottom line is 17 years after her nodules were first identified in 2005, she has had five invasive adenocarcinomas resected and one treated with SBRT, and she is alive, active, and without limitation, and still being followed for the other gonglass sub-solid nodules she still has. Okay, so we've talked about the classic phenotype, the central solid speculated lung cancer, and I've talked to you now about multifocal lung cancer, and I want to end with a discussion about a newly described entity. Frank, again, led this group that delved into this topic, lung cancer with air lucency. And you can see that that abnormality is a gonglass nodule with air densities within it. So this is our last case. He's a 74-year-old male with a history of hypertension, coronary artery disease, status post-CABG. He has a remote history of smoking for several years in his youth, and he's without any pulmonary complaints. He had a chest CT done a couple of years ago. He doesn't recall why, but he was told he had glass in his lung and not to worry. He's a retired machinist without workplace exposure, and his chest CT showed a left upper lobe nodule that was 22 millimeters gonglass with these air lucencies within it. He was followed every six months with a chest CT, and what you can see over time is that the nodule remains gonglass, but the cystic spaces within it got bigger and bigger, and the nodule also got bigger. And so after this approximately 20-month period of follow-up, he was referred to our thoracic oncology program. This nodule remained pure gonglass except for the air spaces. And so Frank put together another committee. Sometimes I feel like we're the honking geese, and he's got a small stick to keep us in line. There was a systematic review done of 49 studies that each had at least 10 cases of lung cancer with cystic, cavitary, bulla, pseudo-cavitary, or bubble-like features. The Fleischner Society defines cyst, cavity, and bulla quite clearly, and we are very familiar with what those benign air lucencies look like, and I've shown them to you on the bottom, but I don't need to talk to this audience about that. Pseudo-cavitary was defined as small, round areas of low attenuation within a solid area of consolidation or in a mass or a nodule, and I'll show you what that looks like. And bubble-like describes small air lucencies within a gonglass lesion. The most common of these is cystic lung cancer with air lucency, and what is meant by that are cysts that no longer have a very thin, discrete wall, but where the wall is thicker or where there's an eccentric, solid component in part of the cyst wall. These can show progression over time, as is the case in these boxes that are outlined in red, where this cystic structure with this irregular wall actually expanded over a relatively short period of time, again, irregular and with this thick wall, and this was a cancer. These actually may start out as ground glass nodules that then develop air lucency within them with expansion, in this case, of both the air space as well as the entire size of the nodule, and again, that thick, irregular wall. What's also observed sometimes is nodules where the wall, again, doesn't look like a normal cyst and where the empty space actually fills in, it can again develop air lucencies. If all we saw was this point in time, we might call this a cavitary nodule. It's just that in this case, there was the history seen on previous images of how this had evolved, in this case, over a year. So these cystic lung cancers with air lucency are predominantly adenocarcinomas. The series of the papers that were evaluated often were a series of case reports, and so age, sex, smoking distribution is really reported variably. What is pretty consistent is the report that has the solid component size of that wall of the cyst or the adjacent solid structure increases. The rate of nodal involvement, meaning spread to the original nodes, also increases. Signs of progression would include a ground glass nodule that develops air lucency with development of solid features, such as this one. It's generally observed that the appearance of a solid component heralds more rapid progression, which really mirrors what we've come to recognize in pure ground glass nodules that then develop solid components, which we see as the trigger for intervention, because the behavior is changing. And then there's much less clinical information out there about the other four phenotypes in this lung cancer with air lucency group. On the top, you see patients with Bullis lung cancer with air lucency. And we recognize a Bulli by their very discrete appearance with very, very thin walls. In this case, though, adjacent to the Bulli in these three separate cases are these solid appearing areas that over time grow, which in these three cases are lung cancer adjacent to a large air lucency. Cavitary lung cancer maybe is more familiar to us because we've all seen this, and we think of classic squamous cell carcinoma, though we know that adenose can cavitate also. In this case, on the left, the patient has a very thick wall with a large cavity. These two images are from the same patient. This lesion started out as what looked like a cavitary structure, but filled in and got bigger, interestingly surrounded by ground glass. And that ground glass component is very much seen with many of these lung cancers with air lucency. And then these are examples of pseudocavitary lung cancer with air lucency. This is an area of consolidation with the small air lucency sprinkled through it. It's not clear whether these are trapped bronchi or whether these are areas of lung destruction, but it has that characteristic appearance of not one cavity and these discrete roundish air spaces. And then bubble-like lung cancer with air lucencies. This is, now that I've seen it, I'll recognize it again. And I think the classic example is this one, where these small, round, cystic, multi, multiple in one ground glass nodule appearance. In this case, too, the appearance of a solid component is a herald of progression of disease. And so I think what came out of this work that Frank led was a framework for description. And if we can describe things in the same way, hopefully then they can be studied more effectively because we're all talking about the same thing. And now there's so many questions that need to be asked about these patients in the same way that multifocal lung cancer patients generated a lot of questions. Is lung cancer with air lucency truly a separate category of lung cancer? If it is, within that group, are these five distinct radiographic appearances distinct from each other biologically? What are the characteristics of the patients who have lung cancer with air lucency? And what is the natural history of disease? And then because this ground glass feature with development of solid components so much mirrors what we know about patients with subsolid nodules. Is there a biologic relationship between those two types of cancer? And as always, if you describe something, the next question is, well, what am I going to do about this? And even though we don't know the answers to all those questions, Frank's group provided a framework for clinical management. So if the cyst or the cavity or the solid area next to a bulla stays stable or gets smaller, certainly you can continue to monitor them. But if the cyst changes with a thicker wall, development of an eccentric solid component, or the development of multi-locules, or the cavity gets bigger, thicker, or the whole thing gets larger, or if that solid area next to a bulla also gets larger, that probably is a signal that intervention is appropriate. And I think as again, now that we have a framework for standardization of description, these entities can be studied separately. And as is often the case, when you're thinking about something, because you've seen it as potentially something new, somebody else has thought about it too. And independently, there was clearly an effort going on at the American College of Radiology, because in their last iteration of LUNG-RADS, LUNG-RADS version 2022, which is the reading protocol, the reporting protocol for screening low-dose CT, is newly included of reference to the reporting out of atypical pulmonary cysts. And so an atypical pulmonary cyst with a growing cystic component is now newly included in category three, probably benign, but keep an eye on it. And image it sooner than an annual screening low-dose CT. And abnormal pulmonary cysts that are thick-walled, have multilocular cysts, or develop those multilocular cysts, are now included in category 4A, suspicious for lung cancer, with the recommendation to do something sooner, you know, at the discretion really of the clinician. And so back to our patient who had progression of this, what appeared to be a lung cancer with air leucency. He had an uneventful left upper lobectomy in Frank's hands, and the pathology showed adenocarcinoma 3.6 centimeters, there was no nodal involvement, T2A, N0, M0, still early stage, stage 1B. So lung cancer with air leucency appears to be a distinct entity that merits further investigation. Now that it's been described, I see this all the time, and some other lucky fellow is going to undertake the evaluation of those patients in our lung cancer biorepository, because Andres has meticulously identified all of them in his search for the multifocal patients. Having a standardized descriptive framework that was established with this effort of Frank's group will enable organized data collection to better define patient characteristics, radiographic subgroups, and prognosis. Better defining patient population should facilitate the study of the biological relationship of lung cancer with air leucency to other processes that result in ground glass changes, the destruction of lung tissue, and the development of neoplasia, like multifocal lung cancer. And that information will inform better clinical management and treatment. So I'm going to leave you with some final thoughts. The phenotype of lung cancer is changing and will continue to change in the future. Classic lung cancers that were described back in the before 2000 will be increasingly less common as the population of current and ever smokers declines. The recognition of new patterns of lung cancers in never smokers, women, and other groups will be critical in guiding and evaluating approaches to management and therapy. And that includes multifocal lung cancer, lung cancer with air leucency, and who knows what other phenotypes will be discovered. And I'll quote Louis Pasteur, in the fields of observation, chance favors only the prepared mind. And so we have to come to our patients with open minds and not get stuck in what we were taught years ago based on different populations of patients. So I'm standing here not because I did a lot of stuff on my own, but because I've had the support of wonderful people throughout my career. And the first group of people I need to give credit to are my peers, friends, colleagues, and mentors in the section of pulmonary critical care and sleep medicine at Yale. This is a great group of people. When COVID hit, and I was in charge of the workforce management, there was never a question in my mind that this community would get us through that. And we did. I wouldn't say it was easy, but I could rely on this group of people to step to the plate, answer their mission, and take care of all these unbelievably critically ill people in the hospital. And they're amazing people, nice people, helpful, and it's just a wonderful tribe. And then my colleagues in the Yale Cancer Center Thoracic Oncology Program. In 2003, when this was started, there were exactly four of us, one pulmonologist, one medical oncologist, one radiation oncologist, and a cardiac surgeon. We recruited Frank, and the landscape changed. And basically, there's been an explosion of clinical programs and scientific effort. And this is our research retreat from, I think, five years ago. And that group actually is much bigger now, even than it was then. And then I really want to call out the women faculty of Yale Pulmonary Critical Care and Sleep Medicine. I borrowed this slide from Margaret Pisani, who received the Roger Bone Award this year and showed this at her talk. And I stole it from her. When I went back to Yale in late 1991, there was exactly one woman faculty, and that was me. And I have to give credit to Jack Elias, who was then section chief of pulmonary, became chair of medicine at Yale, and recently retired after being dean at the Alpert School of Medicine at Brown for over 10 years. And Jack and I, at that time, agreed that we needed more women in the section. And over time, the effort to consciously recruit great women faculty, in addition to the great men faculty, really turned into normal for us. And it has always been the case now for decades that the faculty in the section of pulmonary critical care and sleep medicine at Yale is half women, which is still the case. I want to give a shout out to all these wonderful women who have been my colleagues over many years. And then last and most importantly, I want to give a huge call of thanks to my family. My daughter, Marissa, and my husband, Larry, are in the audience. My sons, Grant and Robert, are busy working and going to medical school. They keep me honest. They take care of me and make sure I eat dinner. And they have been my joy for many years. And I'm so thankful that I'm part of their lives. And with that, I'll end. Thank you so much for being here with me today to honor Dr. Irwin.

lung cancer

changing phenotype

multifocal lung cancer

lung cancer with air lucency

rare disease

cancer death

adenocarcinoma

squamous cell carcinoma

women and neversmokers