Hi, my name is Jeff Myers. I'm in the Department of Pathology at the University of Michigan. And I'm here to talk to you about some new concepts in the pathological classification of lung adenocarcinomas. We have only two objectives for our time together. At the conclusion of this lecture, it is my hope that you will be able to apply current terminology to primary adenocarcinomas of the lung. And importantly, you'll be able to articulate the clinical and biological significance of selected adenocarcinoma subtypes. Let's start with a question to which we'll return at the end of our time together. A CT-guided core needle biopsy from a 2.7 centimeter spiculated peripheral lung mass in a 59 year old woman yielded a diagnosis of adenocarcinoma with a predominantly micropapillary component. Which of the following statements regarding her lung carcinoma is true? A, it's a variant of adenocarcinoma in-situ. B, this is a tumor type referred to historically as bronchioloalveolar carcinoma. C, micropapillary architecture is unique to primary lung adenocarcinomas. D, this is a poor differentiated, meaning high grade adenocarcinoma, with higher likelihood of lymph node metastases. Or E, these tumors lack EGFR sensitizing mutations and therefore should not be subjected to molecular testing. Adenocarcinoma, as you may know, is the most common incident lung cancer in the United States. Lung cancer incident rates in the United States peaked in the early 1990s, but adenocarcinoma rates continued to rise up until 2010. Adenocarcinoma rates are uniformly higher than rates for squamous cell carcinomas across virtually all demographic categories. If we compare males to females across whites and blacks, the incident rate ratios have been approaching parity over the last several years, so that now the incident rates are equivalent. Adenocarcinoma is a member of the larger category of non small cell lung carcinomas that in general is a term applied to adenocarcinomas, squamous cell carcinomas, adenosquamous carcinomas, and large cell carcinomas. We will not consider the latter three categories in the course of this lecture. Adenocarcinomas in the newest 2015 WHO classification for tumors of the lung are defined on the basis of both their histology and cytology, as has been true in previous iterations of this classification scheme. But we will also see that there are now immunohistochemicals staining criteria that can put tumors into this category. The historical criteria for the diagnosis of adenocarcinoma were that tumors had to show either evidence of an ability to make glandular structures and/or produce mucin to qualify as adenocarcinomas. The image on the left shows a tumor forming glands and therefore an adenocarcinoma, while the illustration on the right shows a tumor that is elaborating mucin, much of it in the extracellular space. The current WHO classification also stipulates that carcinomas that could not otherwise be subclassified as adenocarcinoma belong in this category if they stain positively with antibodies directed against either TTF-1, that stands for thyroid transcription factor 1, or napsin A. That this immunophenotype, in the absence of glandular architecture or mucin production, is sufficient to establish the diagnosis of adenocarcinoma. In February 2011, this paper transformed the language applied to adenocarcinomas of the lung. This was an international multi-disciplinary effort led by Bill Travis at Memorial Sloan Kettering to codify the language regarding this evolving category of lung carcinomas. The proposed classification scheme divides adenocarcinomas into these three main categories, preinvasive legions, minimally invasive legions, and fully invasive adenocarcinomas. And we'll talk about the differences between these groups in turn. The categories of preinvasive lesions and minimally invasive lesions collapse what had historically been referred to as bronchial alveolar carcinomas, a term that they suggested no longer be used. If we think about non invasive adenocarcinoma, the criteria proposed in the current WHO is that first of all, this language only applies to solitary tumors that are no greater than 3 centimeters in greatest dimension. And under the microscope, they're defined by a peculiar growth pattern that has been referred to as a lepidic, L-E-P-I-D-I-C, growth pattern, illustrated in the small photo micrograph on the right, in which neoplastic cells are distributed along the surfaces of alveolar septa. When this histology applies to 100% of well sampled small lung adenocarcinomas, then the term adenocarcinoma in-situ is appropriate. That means that these tumors have no stromal vascular or pleural invasion, and no other histologic patterns affiliated with invasive growth. That includes the categories of acinar carcinoma, papillary carcinoma, micropapillary carcinoma, and solid carcinoma. This term is also not appropriate for those tumors demonstrating a micropapillary architecture, in which tumor cells easily spread into adjacent air spaces, as illustrated in the photo micrograph in the lower left. So small adenocarcinomas, no invasion, meaning they have a purely lepidic growth pattern, and there is no spread of tumor cells through the air spaces. The term lepidic has been debated and was clarified in this review by Kirk Jones at UCSF in 2013, who after some scholarly research, discovered that the term lepidic had been invented by a Canadian pathologist, John Adami, in 1902, when he presented to the Toronto Pathological Society. And he used the term to apply in general, not just to the lung, to tumors that appeared to be derived from surface lining cells. In an early edition of Spencer's Pathology of the Lung textbook, he suggested that tumors grow into alveoli by either filling them with a solid mass of malignant cells, which he called a hilic growth pattern, or by lining their walls, which he described as a lepidic growth pattern. So, lepidic is a neologism that was inherited from Dr. Adami in the early 20th century. Defined in this way, the sitology of the neoplastic population lining the alveolar septa can be either non-mucinous or mucinous. The non-mucinous variance far outweigh the mucinous category of adenocarcinoma in-situ. And both strictly defined are rare. This illustrates at low magnification a classical example Of a non-invasive, non-mucinous adenocarcinoma in-situ, a lesion that historically would have been referred to as a bronchiolalveolar carcinoma. At low magnification, you get the sense that the lung architecture is relatively unperturbed. But you can see a marked cutoff from the normal tissue at the lower left and the tumor on the right, in which the interstitial structures, while slightly thickened, are most abnormal in that they are lined by a population of neoplastic cells that depart significantly from their benign counterparts in being much larger with atypical, enlarged, and more darkly staining nuclei. The presence of a small focus of invasive carcinoma, small defined as no greater than half a centimeter, in fact, does not change the survival advantage in low stage, meaning 3 centimeters or less, adenocarcinomas. For this category of tumor, the current WHO classification scheme, modelled after the 2011 February paper that I referenced, has adopted the term, minimally invasive adenocarcinoma. A number of studies have illustrated that a little bit of invasion in what would otherwise be an adenocarcinoma in-situ does not affect the prognosis in small adenocarcinomas. In this study from Japan, Dr Sakurai and colleagues looked at a series of small adenocarcinomas that have been resected. In this study, the tumors were less then 2 centimeters in size. They graded the tumors into these categories. Grade 0 tumors were those that had a purely lepidic, or what in those days was called a bronchiolalveolar growth pattern, what today we might adenocarcinoma in-situ. Grade 1 tumors were those tumors that were mostly noninvasive, but had small foci of invasion in an area of otherwise lepidic growth. Grade 2 tumors were tumors that had a central scar in which there was a small focus of invasion. And Grade 3 tumors were tumors in which there was clear-cut invasion in the center of the fibrotic focus. When they compared the survival in these groups, the presence of a little bit of invasion, meaning Grade 1 and Grade 2 tumors, they had the same survival as purely in-situ lesions. And disease specific mortality was seen only in those with clearly invasive disease. This study was repeated using slightly different criteria at NYU by Dr. Yim and associates when they divided their tumors into four categories based on the presence or absence of invasion. Their Group 1 patients were purely in-situ lesions, what in those days was called bronchiolalveolar carcinoma, today would be called adenocarcinoma in-situ. Their Group 2 patients were patients who had no more than half a centimeter of invasion. Their Group 3 patients were patients who had that lepidic growth pattern at the periphery, but at least half a centimeter of invasion elsewhere. And their Group 4 patients were patients who had purely invasive tumors, with no areas demonstrating the lepidic pattern illustrated previously. And when they compared survival across these categories, mortality was seen only in their Group 3 and Group 4 patients, who had invasive tumor of at least half a centimeter in size. And there was no disease related mortality in those with purely in-situ lesions or those with invasion that measured no more than half a centimeter in greatest dimension. The study was repeated by Alan Borczuk and colleagues and showed exactly the same results. So the conclusion from these studies was that a little bit of invasion in an otherwise in-situ adenocarcinoma of the lung, in tumors that are no greater than 3 centimeters in size, is still a very good prognosis lesion. In fact, in this more recent data from Memorial Sloan Kettering, those tumors that had a lepidic growth pattern accounting for at least 50% of the sampled tissue had zero disease associated recurrence. Their conclusion was that small, meaning no greater than 3 centimeter, well differentiated lepidic predominant tumors have a good prognosis, as long as there are no other adverse prognostic features. Meaning a micropapillary growth pattern that we're going to get to, angiolymphatic or visceral pleural invasion, sublobar resection, and close margins. So the truth is, those well differentiated tumors, in which a lepidic growth pattern is predominant, are good prognosis tumors. This is the lepidic predominant category that is included under the invasive adenocarcinoma group. The language in this invasive adenocarcinoma group means that if a particular histology accounts for the highest percentage of sampled cross-sectional area, then the label lepidic, or acinar, or papillary, or micropapillary, or solid predominant is appropriate, depending on which of those components predominates. It's a simple system. So here is an invasive adenocarcinoma in which a lepidic bronchiolalveolar historically growth pattern predominates, in which you see at the periphery neoplastic cells, spreading along the surfaces of intact interstitial structures, in this case, alveolar septa. Acinar predominant invasive adenocarcinomas are those adenocarcinomas in which the highest percentage of sampled tumor falls into this category, in which neoplastic columnar cells form these tubules, often affiliated with a desma plastic stromal reaction. Papillary predominant adenocarcinomas refer to those in which the highest percentage of tumor shows this histology in which neoplastic cells are lined up on the surface of these papillary structures, characterized by central connective tissue cores, often with an associated vessel. Micropapillary predominant tumors are those tumors in which this histology is the most predominant. And in this pattern, which differs from the papillary pattern in that the neoplastic cells, while forming these papillary structures, have no central connected tissue core or vessel. The solid predominant pattern refers to those tumors in which the most common histology shows neoplastic cells forming solid sheets with any of the other differentiating architectures to which we have previously referred. It would be difficult to separate this histology from a high grade squamous cell carcinoma without the use of immuno stains. To be an adenocarcinoma, it would have to be positive for a TTF-1 and or napsin A. The distribution of the histologic types depends on the population explored. In this series of over 1,000 stage 1 lung adenocarcinomas resected at Memorial Sloan Kettering Cancer Center, published by Kadota and colleagues, the acinar predominant adenocarcinomas accounted for nearly 40% of cases. The second most common category were papillary predominant tumors, accounting for about a quarter of cases. And notice that purely noninvasive in-situ lesions accounted for less than 1%, while minimally invasive cancers accounted for about 3% And lepidic predominant tumors about 10%. Invasive adenocarcinomas predominate in series of even small adenocarcinomas. When they looked at the influence of the histologic category to outcome, they segregated their tumors into these three larger groups, low grade tumors which was the category that included adenal carcinomas in site two and minimally invasive adenal carcinomas had a 100% five year disease free survival as you might have guessed from the previous studies that we shared. The intermediate category, which was the largest category, were those tumors that had a lepidic predominant, an acinar predominant, or a papillary predominant growth pattern, and the five year disease free survival in this group was 84%. Their high grade category included micropapillary tumors, solid tumors, and mucinous tumors, which had a five year disease free survival of 71%, illustrating that in low stage, small adenocarcinomas, histologic subtype matters. A similar study showed a different distribution of invasive subtypes. In this study, papillary invase adenocarcinomas predominated, acinar was a much smaller subset. But the low grade tumors were again a small fraction of 440 tumors resected in Japan, and yet with similar findings in terms of the influence on outcome. This grading scheme differed a little in that they moved the lepidic predominant tumours into the low grade group and they moved the invasive mucinous tumours into the intermediate group. And based on their data they showed similar differences in five year disease free survival based on the predominant histologic type. Both studies would agree that the micropapillary and solid histologies tend to be affiliated with the worst outcome in small resected adenocarcinomas. So when it comes to histologic grading of adenocarcinomas of the lung, low grade or well differentiated adenocarcinomas are those that are in situ minimally invasive or have a lepidic predominant growth pattern. The terms adenocarcinoma in situ and minimally invasive adenocarcinoma should only be applied to tumors no greater than three centimeters in greatest dimension. Intermediate grade adenocarcinomas are those in which acinar histology, papillary histology, or invasive mucinous histology predominates. And high grade or poorly differentiated adenocarcinomas are those in which a solid growth pattern or a micropapillary growth pattern predominates. More recently it's been demonstrated that even a little bit of a micropapillary growth pattern can influence the outcome in patients with primary pulmonary adenocarcinoma, showing that a micropapillary architecture as demonstrated in the two previously cited studies predicts for a poor outcome and a greater likelihood of metastatic disease. Histology cannot predict genotype in adenocarcinomas of the lung, so to know whether an adenocarcinoma of the lung has a sensitizing mutation in EGFR, and the same applies to and translocations. You have to do the tests. While there are certain tumor types more likely than others to be affiliated with sensitizing mutations, in any individual patient you can only know the answer if you do the tests. So let's get back to our question. A CT-guided core needle biopsy, from a 2.7 centimeter spiculated peripheral long mass in a 59-year-old woman yield a diagnosis of adenocarcinoma with a predominantly micropapillary component. Which of the following statements regarding her lung carcinoma is true? It is my hope that after our conversation you would choose D, poorly differentiated adenocarcinoma with a higher likelihood of lymph node metastases. As we've talked about, a micropapillary growth pattern is a distinctive histology seen in a broad range of predominantly adenocarcinomas arising in various sites including not only the lung, but also breast and other organ sites. And interestingly in any site, this micropapillary histology tends to be affiliated with higher stage at presentation and serves as a poor prognostic factor independent of stage. So what I would like for you to remember as a consequence of this conversation? First adenocarcinomas of the lung are defined by a combination of histopathologic and immunophenotypic features. Small adenocarcinomas, meaning those no greater than three centimeters in size, in which all of the tumor or most of the tumor has a lepidic growth pattern are affiliated with a nearly 100% disease free survival. The language may be different for these various categories, applying the term adenocarcinoma in situ to those with no invasion, or lepidic predominant to those in which the tumor has more than half a centimeter of invasion, but in any of those categories for small tumors it is an excellent prognostic group. The same cannot be said for solid adenocarcinomas and those with a micropapillary component, which are the bad actors when it comes to adenocarcinoma of the lung. Thank you for joining me today, I hope you've enjoyed this lecture.