We're continuing with the same patient who has an unusual two-centimeter mass and an unknown cirrhotic, but the information that is not currently available to us includes the patient's AFP level, prior tumor history, last alcohol intake, presence of comorbidities, and additional information in terms of how the lesion appears. The first question is, what are the specific therapies that are available to this patient given the diagnostic workup? In a patient with known cirrhosis and a new liver lesion, the first diagnostic consideration is the development of hepatocellular carcinoma. In patients with early HTC, there are three potential curative options which are listed here, and include ablation, resection, and liver transplantation. Highlighted are potential contraindications to each of these therapies, specifically in ablation, the size and the location, in resection, decompensated cirrhosis, the presence of clinically significant portal hypertension, and an inadequate future liver remnant, which is defined as less than 40% in a cirrhotic. In patients being evaluated for liver transplantation, the Milan criteria have been the tumor burden that we have used. Patients with advanced age, comorbidities, or significant psychosocial issues can be of concern. All of these options provide over 50% five-year survival, and recurrence is known to be higher post-ablation and resection compared to liver transplantation due to the persistence of a cirrhotic liver. Now, our patient has a two-centimeter lesion, but I do want to point out for the audience that in patients who have a lesion that is solitary less than two centimeters, which is defined as a very early HTC, that these patients are not candidates for HTC MELD upgrade. In patients with a very early HTC who are well compensated, the treatment of choice is either an ablation or a resection based on this algorithm, and transplantation should be reserved only for patients who develop recurrent HTC or decompensation after resection or ablation. Now, back to our patient who has an early HTC. This is a solitary lesion. However, we do not know if this is an optimal surgical candidate, and when one is assessing the risk for resection, one has to look at many factors, which includes, is there clinically significant portal hypertension present? What is the extent of the surgery, and what is the MELD score? In a patient with no clinically significant portal hypertension who is undergoing a minor hepatectomy and has a MELD that is not greater than nine, this is very low risk of decompensation. In contrast, a patient who has known portal hypertension and the extent of the hepatectomy is major, which is defined as greater than three segments, this patient carries a very high risk of decompensation and a 25% chance risk of mortality. Radiofrequency ablation is a known treatment option for patients with a single lesion less than three centimeters and has been shown to have outcomes similar to resection. However, five-year recurrence rates remain high due to the fact that there is underlying cirrhosis that remains, and most of these patients develop new lesions. In the last few years, there has been a surge in the popularity of microwave ablation over RFA due to some of its advantages, which include shorter ablation time and that there's less concern for heat sink, and there may be able to achieve a larger ablation zone, which may allow larger tumors to be successfully treated. There have been several randomized control trials that have specifically looked at ablation versus resection in early HCC, and all of these have shown that there is no significant difference in overall survival in ablation versus resection, except for the one that is highlighted in pink. The one in dark blue closely simulates what we see in our patient in terms of tumor criteria, and there is no significant difference in overall survival. However, disease-free survival is significantly prolonged in patients who are treated with resection. Now, there have been no randomized control trials that have specifically looked at, excuse me, this is a SIRS retrospective trial that is looking at patients with very early, or early HCC, ablation versus resection, and what they did here that was a little bit different was they stratified patients by age and tumor size. Age was a cutoff of 65, and tumor size was up to five centimeters, and after performing a propensity score matching, they came up with three recommendations. The patients who are over the age of 65 with a very early HCC that RFA has recommended, and patients over the age of 65 who have a larger tumor up to five centimeters, their resection is recommended, and in younger patients less than 65, regardless of the size of the tumor, the resection is a treatment of choice, and this is where our patient would fall into. Now, there have been no randomized control trials that have specifically looked at RFA compared to transplantation, and it is not anticipated that there ever will be. This is a retrospective study from the University of Toronto that looked at RFA as a first-line treatment for patients with a single lesion less than three centimeters who otherwise would have been considered a transplant candidate. All patients had evidence of complete response by M-resist, so no evidence of enhancement after RFA, and the primary endpoint of this trial was looking at the recurrence of HCC post-successful RFA greater than the Milan criteria. Lesions were divided based on pretreatment size with a cutoff of two centimeters, as well as the AFP level, and there were a total of 301 patients who were included. Sixty-six percent of patients ultimately developed evidence of recurrence after a successful RFA, and the initial tumor size was not predictive recurrence itself. However, you will see that those who did develop recurrence beyond the Milan criteria, predictors included greater than a lesion of two centimeters or more at the time of RFA, or an AFP greater than 100 at the time of RFA. When patients did recur, there was no significant difference in having these patients listed for transplantation. However, in patients who had an original lesion greater than two centimeters at the time of RFA, they were significantly more likely to drop out due to tumor progression and less likely to undergo transplantation. Now this would suggest that potentially patients with a lesion greater than two centimeters or an AFP greater than 100, that transplantation would be the better treatment option for these patients. And if this is not feasible based on limitations of organs, that patients who do have these risk factors, when they initially have recurrence, they should be immediately sent for transplantation. Radiation segmentectomy has emerged as another treatment option. This notion is that large doses of radiation, VOI-90, are placed into one to two segments of liver. This has particularly been done in patients who are deemed not a ablation candidate due to location. This is a study that looked at a single center at Northwestern looking at a solitary lesion less than five centimeters that was not amenable to ablation. All these patients were well compensated and they all received what was considered ablative doses into the tumor, which is greater than 190 gray. And when you look at patients who had up to three centimeter tumor, five year survival rate was 75%, which was comparable to what is accepted as curative options of resection, transplantation, and ablation, leading the authors to conclude that radiation segmentectomy is a potential therapeutic option in patients who cannot undergo ablation. Our next question is, what would be the therapy if this patient had a different phenotype genotype of their tumor? And the next tumor that comes to mind is intrapatic langiocarcinoma, which is increasing in incidence, similar to what we are seeing with HTC. However, the prognosis for intrapatic langiocarcinoma is dismal with five year overall survival is generally less than 5%. I've highlighted the risk factors for this type of tumor. It needs to be pointed out that one does not need to have cirrhosis to develop intrapatic langiocarcinoma. Those highlighted in blue are similar risk factors for what we see with the development of HTC. It is also very important to point out that if this patient is biopsied and it's proven that this is intrapatic langiocarcinoma, that this patient currently would not be given a MELD upgrade on the basis of this tumor due to the inferior overall survival post-transplant compared to hepatocellular carcinoma. This is generally a tumor that is made by biopsy. We've heard from our prior speaker that there are clues in radiology findings including capsular retraction shown in blue, bile duct dilatation shown in yellow, and persistence of enhancement with a lack of central washout. In this tumor, the treatment of choice is resection. However, in patients who are not resectable, there are local regional therapy options. As I've stated, liver transplantation has largely been considered contraindicated worldwide. We've seen this from Dr. Jovet's talk. This is from easel and this is a patient who the treatment of choice would be to undergo resection. Ablation has also been performed for intrapatic langiocarcinomas. However, in a comparison to HCC, the numbers in these trials are relatively small and there is quite a heterogeneity in that some patients were treated as first line for unresectable intrapatic langiocarcinoma whereas others were treated with ablation after undergoing recurrence post-resection. And I will draw your attention to the five year survival which you can see is inferior to what has historically been reported for patients with HCC. Radioembolization is also being used for intrapatic langiocarcinoma similar to ablation. It suffers from small numbers of patients as well as heterogeneity in the trials. Here you see that there are patients who receive chemotherapy prior to undergoing treatment with radioembolization. Very recently in the last two weeks there has been the report of the first prospective trial that is looking at intrapatic langiocarcinoma being treated with first line chemotherapy as well as Y90 and median overall survival was 22 months and probably the most promising result from this trial was that nearly a quarter of these patients were able to be downstage to resection and hopefully a potential cure. As I've stated, resection is the treatment of choice for intrapatic langiocarcinoma and this was a very interesting paper that looked at what is the probability of being cured after one undergoes resection. And cure is defined as when the mortality from the disease which in this case is intrapatic langiocarcinoma returns to that of the general population. Over 500 patients underwent resection. The median overall survival was 27 months with five year survival of 22%. And when they constructed models they found that the time to be cured after resection was 10 years with less than 10% of patients achieving that goal. However, a quarter of the patients who had more favorable risk factors were able to be cured. This include a solitary tumor, well differentiated, less than five centimeters without evidence of vascular, perioductal, or lymph node invasion. Patients who were minus all of these, their risk of cure was 0.1%. This is another study that was retrospective. It's from Japan looking at resection and doing a multivariate analysis based on pathology to look at factors that are associated with improved survival. They clearly showed that tumor size up to two centimeters is associated with improved survival. And in patients with a very early intrapatic langiocarcinoma without evidence of lymph node invasion or vascular invasion, five year overall survival was 100%. However, with the same tumor size, once there was vascular invasion, there was a sharp decline in overall survival at two years which was 60%. Now there has been a keen interest in the use of liver transplantation for patients with early intrapatic langiocarcinoma. This is a retrospective study from 17 international transplant centers. All patients who underwent transplantation did so in the thought that they had HCC or they had an incidental intrapatic langiocarcinoma. Patients were grouped as having intrapatic langiocarcinoma alone versus patients who had mixed. We will concentrate on intrapatic langiocarcinoma. Early stage was, or very early was one, a single lesion up to two centimeters whereas advanced was a single lesion greater than two centimeters or greater than one lesion. Those with very early disease had a five year survival of 65%. This is in line with what had been reported from a prior cohort from Spain at which 73% at five years. And five year survival in those with advanced was diminished at 45%. On multivariate analysis they found that the risk for recurrence was poorly differentiated tumor and microvascular invasion. The authors using this information then did a sub-analysis at patients with advanced disease and defined an intermediate stage which was a lesion of 2.1 to three centimeters without poorly differentiated gradation and found that five year survival was 61% so there may be room to increase the size of these lesions for transplantation whereas all others had an overall survival of 42%. Our final question is what are the differences in treatment monitoring depending on specific tumor markers? And I really want to frame this discussion in looking at transplant survival benefit. To really demonstrate this if we take the extremes, if we have a patient who develops HCC recurrence post-transplant we know that they have a diminished survival post-transplant and therefore a decreased benefit of transplant. On the other hand if you have a patient who is treated with a complete response with HCC and is otherwise compensated you will also see a decrease in benefit of transplantation. AFP is the biomarker that has been looked at the most in terms of prognosis. We know that an elevated AFP specifically greater than 1,000 portends a poor prognosis with over 50% of patients developing recurrence. Recently UNOS has acted on this data and has made changes to the MELD upgrade that in patients who meet the Milan criteria at the time of listing if they have an AFP greater than 1,000 they are not candidates for standard MELD exception. However if their AFP is able to be driven down to less than 500 with local regional therapy then patients would then potentially become a candidate for a MELD upgrade. The French AFP model has replaced the Milan criteria in terms of selection for transplantation for HCC in France since 2013. There are points for tumor size, tumor number and the AFP level. More than two points is considered high risk. This model has allowed patients who are low risk who are otherwise outside Milan criteria to be candidates for transplantation and has also identified a group within the Milan criteria who are high risk of recurrence at approximately 40%. This is a retrospective analysis from the Mayo group looking at the use of a combination of biomarkers to estimate the risk of recurrence post transplant. They used a cutoff for AFP of greater than 250 and DCP greater than 7.5. You can see if both of these were met that the risk of recurrence was highest with a higher hazards ratio of 5.2. They then looked at these markers in combination with Milan status and what I will point out is that if you are outside the Milan status but your AFP or DCP falls below this cutoff then your risk of recurrence is lower than someone who is within the Milan status who has an AFP greater than 250 or a DCP greater than 7.5. So this shows that a combination of biomarkers used in conjunction with Milan criteria may be able to optimize our selection for transplantation compared to Milan criteria alone. There are known risk factors for dropout for transplantation while awaiting with an indication of HCC. These include a size greater than three centimeters, greater than one lesion, lack of complete radiographic response after initial local regional therapy and an AFP greater than 20 after initial local regional therapy. And in patients who have none of these factors present they have an exceedingly low chance of dropout at less than 2% at two years. However, if any of these factors are present then this increases to 26.5% at two years. Now there have been various studies that have aimed to address if we can identify factors that will show us what patients will benefit and what patients may not benefit from transplantation. And I highlight two of these studies. The first is from Europe and it looked at over 2,000 patients who were listed for transplantation with the indication of HCC. They were able to construct a model looking at overall survival with and a separate model without transplantation. And they found four variables that were able to distinguish patients who would benefit versus those who would not benefit from transplantation. These included the MELD score, Milan status, response to local regional therapy. And I'm missing one here. And if they had progression. And you can see that the patients who had the best overall survival in terms of gain in life of 60 months is here. These are patients that we should prioritize for transplantation. However, patients who had no gain in life expectancy with transplantation compared to no transplantation, these are patients that we should consider delisting. The second study is taken from areas in the United States that have long wait lists. And they were able to identify four factors were associated with a low risk of dropout including a lesion up to three centimeters, an AFP less than 20, well compensated cirrhosis, and a MELD sodium less than 15. And these are patients that you would predict to have a long wait list expectancy. And so the author stated that these patients should either have a lower or no priority for transplantation. Just to finish up briefly on intrapatic cholangiocarcinoma, there are several candidate markers in the serum. Most of these have been used in the research forum. The one that is clinically used the most is CA1919. However, it has issues in terms of it's not detected in 7% of the general population due to a lack of Lewis antigen. It can be elevated in benign liver biliary disease as well as cholangitis. And its levels can be significantly increased not only with development of metastatic disease due to intrapatic cholangiocarcinoma but also the degree of cirrhosis. PET scan is often used to determine receptability for intrapatic cholangiocarcinoma. In this retrospective study, they specifically looked at the difference between PET scan versus conventional imaging to look for detection of lymph node involvement or metastatic disease. They found that the PET scan was more sensitive than conventional imaging. There were six patients who were being slated for resection. However, based on the PET scan, these patients were then transferred to different treatments and these were not caught on conventional imaging. To summarize, my takeaway points are that tumor size and AFP may help determine higher rates of progression beyond the Milan criteria after successful RFA. Radiation segmentectomy is emerging as a treatment option for early HCC as well as being looked at in intrapatic cholangiocarcinoma. Very early intrapatic cholangiocarcinoma may be a reasonable indication for liver transplantation. However, further research is needed. And the survival benefit of transplantation for HCC needs to be better defined in terms of in order to offer organs to the patients with the highest gain in life expectancy. Thank you for your attention. Thank you.

liver lesion

cirrhosis

hepatocellular carcinoma

ablation

resection

transplantation