And just a couple of reminders, in the U.S. uterine cancer is the fourth most common cancer in females, and it's the most common gynecologic malignancy. It's estimated that about 66,570 new cases will be diagnosed this year, accompanied by about 13,000 deaths. In Vietnam, based on the Global Cancer Observatory, it's the sixth most common cancer in females, and it is also the most common gynecologic malignancy. And in Vietnam, there were 5,354 new cases in 2020, accompanied by 1,319 deaths. So very common. And so endometrioid adenocarcinoma is the most common type of endometrial carcinoma, comprising approximately 70 to 80 percent. Most are diagnosed at low grade and present at an early stage, and they generally have an excellent prognosis, but there are about 10 to 20 percent that end up recurring and then behave quite badly. So predictive factors of poor prognosis include lymph node involvement, lymphascular space invasion or LVSI, deep myometrial invasion, so greater than 50 percent, and cervical stromal invasion. So five patterns of myo-invasion have been described. We don't usually comment on these except for the MELF that we're going to be talking about today, but there's diffusely infiltrating, which is the most common, broad front, adenomalignum, adenomyosis-like, and then the one we're talking about, the microcystic elongated and fragmented or MELF gland pattern. So in 2003, Murray, Young, and Scully coined the term MELF for this pattern of myo-invasion, and again, they saw microcystic glands, the glands were elongated, there were some fragmented glands and also single cell invasion as well, and the foci of tumor tended to be widely separated from each other, and often they were deeper in the myometrium than typical invasive glands. The lumina often contained neutrophils, and they were also often associated with the fibromyxoid stromal reaction. So they also noted that the glands could be missed at low power, and so depth of invasion may be underestimated, and when I show what these look like, you'll see why they're pretty easy to miss. And the combination of MELF and fibromyxoid stromal reaction was associated with the poroprognosis, but they thought that that was due at least in part to the greater frequency of vascular invasion that was associated with this pattern. So subsequently, greater than 50 studies have been published, and in these studies, incidence of MELF ranges from 7% to 48%. It occurs predominantly in FIGO grade 1 and 2 endometrioid adenocarcinomas. It is not a feature of serous carcinomas. It tends to occur deeply at the leading edge of the invasion, so you may have normal infiltrative glands, and then it transitions into this MELF pattern. And endometrioid adenocarcinomas with MELF more often show at least some mucinous differentiation. So if you see some mucinous differentiation, you want to just have your antenna up looking for this pattern of invasion. So as you can see here, this is kind of an elongated gland here. You get some fragmentation here with some single cells. And here you see that fibromyxoid stromal reaction around it. And what is typical of these glands is that the cells have a lot of eosinophilic cytoplasm, and because they're very irregular and fragmented, they can kind of blend in with the background or be obscured by the fibromyxoid stroma. So cytokeratin immunohistochemistry may be helpful if you detect these glands to make sure that you also detect the single cells and are able to accurately determine the depth of invasion. So there's also an LVSI pattern that's associated with MELF that consists of individual or small clusters of tumor cells. And again, they have abundant eosinophilic cytoplasm and sometimes vacuoles like you see here. And they can mimic histiocytes, as you see over in this area. And so cytokeratin, again, may be helpful just to distinguish the cells from histiocytes. But it also may be helpful to use a lymphovascular marker such as D240 to confirm LVSI. And then there's also a pattern of lymphnometastasis that's associated with this myoinvasive pattern. And again, you generally see isolated or very small clusters of tumor cells, and they're often in the subcapsular space here or in the sinusoidal areas. But sometimes, as you see over here, they can be interfollicular in the lymph node. And they are often very subtle. So again, cytokeratin immunohistochemistry may be helpful in this scenario as well. As a matter of fact, in reviewing 80 cases, Hertel and his colleagues found five cases with lymphnometastasis that were not seen at the time of the initial diagnosis because they can hide and look a lot like histiocytes. So these are just a couple more examples of some tiny little clusters here, single cells here. And then this is the more conventional metastasis that usually consists more of intact glands and larger clusters, so they're easier to see in the lymph node. And then this is just an example of a cytokeratin highlighting the single cells and tiny little clusters in a lymph node. So these glands that show this MELF pattern of evasion also tend to show a different immunoprofile than the conventional tumor areas. And the MELF glands are diffusely positive for cytokeratin AE1, AE3, and CK7, where they tend to be more patchy in the conventional tumor. Vimentin shows a reduction in staining in the MELF-type glands. ER and PR tend to be negative in this study. They did see focal reactivity in four cases, but 17 cases were negative for ER and PR, whereas in the conventional tumor, ER and PR are usually positive. And again, ECAD heron is usually diffusely and strongly positive in a membranous pattern in conventional tumor, but it's either negative or reduced in these MELF-type glands. So just want to talk a little bit about this epithelial mesenchymal transition, or EMT. It's thought to be an important means of tumor invasion and metastasis, and it tends to be associated with reduced ECAD heron, which makes sense because ECAD heron plays a role in maintaining contact and polarity. So EMT is characterized by loss of the epithelial features, including the polarization and adhesion, thus the loss of the ECAD heron, and acquisition of mesenchymal characteristics, including migratory capacity. So they suggest that the MELF IHC, as well as the differences in the IHC between the MELF and conventional glands, suggest that MELF does represent a specific tumor alteration and not just degenerative changes. And they also suggested that MELF may represent a form of epithelial mesenchymal transition. So even though quite a few studies have been published, the prognostic and predictive value remained unclear. So a systematic review was done by Prodomido and colleagues and published in 2018, and they were hoping to determine whether MELF could be established as a predictor of recurrence risk and or extra uterine disease. And they wanted to evaluate its role in prognosis and recurrence. So they included all articles with endometrial carcinoma MELF. And if there were more than 10 cases, the women were greater than 18 years of age. And there was also assessment of prognostic clinical and pathologic associations. Once they reviewed all the studies and applied the criteria, they were left with 14 studies that included 588 patients with MELF. But these were further divided into six studies, which actually looked at patients with and without MELF, so comparative studies. And there were 242 patients involved in those studies. And then eight studies where there wasn't a comparison between MELF and non-MELF. Most of those studies, they were looking at cases with lymph node metastasis versus no metastasis. And then they were looking at certain features, including MELF, to see how they correlate. So of the four studies where they looked at lymph node metastasis and the MELF versus not MELF, they did find that the patients with MELF were more likely to have lymph node metastasis. And in the six studies where they looked at lymph node involvement in the non-comparative group, they did find that lymph node metastases were more likely to have MELF compared to patients without lymph node metastases. However, multivariate analysis was done in five of these studies, and only two indicated MELF was an independent predictor of lymph node metastasis. And then as far as LVSI goes, four studies in the MELF versus non-MELF group did show higher rates of LVSI compared to those without the MELF. So as far as myoinvasion and cervical stromal invasion, four studies looked at myoinvasion, and three of those did show that myoinvasion, greater than 50%, sorry, myometrial invasion was more common in patients with MELF versus those without. However, one study found no difference. And then three studies looked at cervical stromal invasion, and two of those three found that it was more frequent in patients with MELF, but one study found no difference. So as far as survival goes, four studies found no difference in disease-specific survival or disease-free survival between patients with and without MELF. And then two studies did see a significantly lower overall survival rate in patients with MELF. And then one study did find that patients with MELF were more likely to present with extravaginal recurrence compared to no recurrence or vaginal recurrence. And then another study showed no difference in extravaginal recurrence rates. And then one study also looked at any recurrences, and they found no difference. And another study found no difference in recurrence-free survival rates when they looked at all stages and when they compared separately stages one to two and three to four. So overall, they concluded that MELF does seem to be an indicator of deep myometrial invasion, cervical stromal invasion, lymphascular space invasion, and lymph node metastasis, but the impact in survival and recurrence is still not well-defined. There have been a few studies since 2018, and I just wanted to mention this one. It's a retrospective study from this year, and what they looked at were endometrial carcinomas that had no gross involvement of the cervix. And cervical stromal involvement was present in 2.1% of cases without MELF, but it was present in 27% of cases with MELF. Now these numbers are not great as far as the number of cases, but it does further support the other findings that MELF tends to be associated with cervical stromal involvement. Also in this study, they did find that patients with extension to the lower uterine segment and LVSI also were more likely to have cervical stromal involvement. So overall, with this MELF-type myoinvasion, it does seem to be associated with deeper myometrial invasion, cervical stromal invasion, LVSI, and lymph node metastasis. So if MELF is present, you may consider doing cytokeratin IHC to help detect fragmented glands and single cells to make sure that the depth of invasion is measured accurately, and also cytokeratin IHC and possibly D240 to confirm LVSI since the cells can mimic histiocytes, and then also cytokeratin IHC can be helpful to detect the type of metastases that you see with this type of invasion. It was also suggested in that most recent study that if you see MELF and there's no grossly apparent involvement of the cervix, you may consider putting additional sections of cervix through since there is an increased risk of cervical stromal involvement with MELF, particularly if there is lower uterine segment involvement and or LVSI. And even with all these studies, MELF has still not been established as an independent predictor of recurrence or survival. So right now, it's probably most helpful in just recognizing if you have this pattern that you take these extra steps to look for deeper myometrial invasion, cervical stromal invasion, LVSI, and lymph node metastasis. And these are our Belted Galloway cows that we have at Farrington Village in Chapel Hill. Any questions?

MELF gland pattern

endometrioid adenocarcinoma

uterine cancer

prevalence

characteristics