Non-Malignant Liver Lesions

Welcome to First Incision, the podcast about preparing for the General Surgery Fellowship exam. I'm your host, Amanda Nikolic. Let's get started with our team timeout. Our patient today is the hepatobiliary module from the general surgical curriculum. And the operation or topics we'll be covering today in the curriculum are...

entitled incidental liver lesions, but I think we should call these non-malignant liver lesions. And specifically, we'll be talking about hepatic cysts, focal nodular hyperplasia, hepatic adenomas. and hemangiomas, as well as a couple of other benign liver lesions just briefly that we also may need to know about.

So in general, most of the liver lesions we're going to talk about today are asymptomatic, unless they're very large or causing a complication such as hemorrhage. These lesions are... classified as non-malignant. So we're not going to be talking about liver cancers such as hepatocellular carcinoma, intra-hepatic cholangiocarcinoma, or metastatic.

lesions from other malignancies. I will briefly mention these though at the end because a lot of what this talk is going to be about is the appearance of these lesions on imaging and I would highly recommend that you have a look up some of the pictures. of these lesions and how they appear on different imaging modalities as we're going through each of them in order to get a better idea of what they actually look like as I'm describing them.

In general, the approach to liver lesions should start with a question about how it was identified. Was this incidental and therefore asymptomatic, or was the patient having symptoms? Relevant history should be taken, including a history of liver disease and cirrhosis, risk factors for liver disease such as hepatitis and non-alcoholic fatty liver disease or alcohol.

use of the oral contraceptive pill in women, and a history of any known malignancies. Typically, the next step then would be an imaging assessment, and there's a number of different imaging modalities we use for looking at liver lesions. This includes ultrasound, which can give you information about whether the lesion is solid or cystic, can allow you to have a look at the vascularity and also whether there's any nodularity. A CT scan or MRI is typically the next step.

When looking at liver lesions, it's often very helpful to get multiple phases of contrast as the characteristics of enhancement and washout of the contrast help you identify what this lesion may actually be. PET scans can also be used if there's a question about whether the lesion is malignant with a lot of these lesions being PET-AVID if they are malignant and not PET-AVID if they are not.

Biopsy has a limited role in these lesions as it's often possible to identify what they are based on their imaging characteristics. And often if it's not clear, further imaging with a timeframe and seeing how the lesion changes. over time may be better than doing a biopsy. saying that a biopsy might be considered if it's going to change your management. But it's definitely contraindicated in hemangiomas and insists suspected of being echinococcal in origin.

If a solid tumor is biopsied, there can be sampling error, a misdiagnosis, and there's also a risk if it's a malignancy of needle tract seeding.

So let's get started with our first non-malignant liver lesion, which is going to be a liver cyst. Like cysts found in other areas of the body, liver cysts are typically lined by a single layer of cuboidal or columna epithelial cells, and they are filled with simple fluid. In the liver on imaging, an ultrasound can be diagnostic because you'll be able to see a circular area with a well-defined border. There won't be any vascularity in the cyst and there should be posterior acoustic.

shadowing. In addition there shouldn't be any nodularity or septations in the cyst as this may make you more concerned about an underlying pathological process. An MRI or CT scan may be performed to have a better look at the cysts if there's concern about nodularity or septations. On CT scan, the cyst will be hypodense compared to the surrounding parenchyma and it won't enhance or have any uptake on the arterial phase because it's avascular.

On MRI, in the T1-weighted images, the cyst will be hypo-intense compared to the surrounding parenchyma. And in the T2-weighted images, because there's fluid in them, The cyst will be very bright or hyper-intense compared to the surrounding parenchyma, and a simple cyst, as I've mentioned, shouldn't have any nodularity or septations.

In regards to cysts in the liver, cysts can be single or multiple, and there is a condition called polycystic liver disease, which is an inherited condition thought to be autosomally dominantly inherited, where... Patients get more than 10 cysts in the liver, which can be very, very large and can cause symptoms and even progress to liver failure.

An important thing to know about polycystic liver disease is that it's associated with berry aneurysms in the brain and an increased risk of subarachnoid hemorrhage. If cysts are very large, they can cause compression and atrophy of the surrounding liver parenchyma. They can also be palpable or cause symptoms such as early satiety. Or if they have a hemorrhage into them, they can cause acute pain or even sometimes rupture.

Saying that though, simple liver cysts are not malignant and they have no malignant potential. So if they're asymptomatic, then no further treatment needs to be undertaken. If they're symptomatic, then there are a couple of options. The first one is a formal anatomical resection, and this should be considered if the cyst is very, very large, if there's a concern about nodularity or septations, or if there's been intracystic hemorrhage.

The reason intracystic hemorrhage is a concern is that a simple cyst shouldn't really have a bleeding episode. And so that raises the suspicion that there was a malignant component that maybe has eroded into a blood vessel. For those that are smaller than five centimeters, then you may be able to de-roof the cyst, which I've seen done through a laparoscopic procedure, but also could be done as an open procedure as well.

It's important to consider the differential diagnoses for a cystic lesion in the liver. There are some infectious processes that can cause cystic lesions, including echinococcus or hydatid cystic disease of the liver. And we'll talk about these in an episode on liver infections. There can also be some neoplastic processes that can present with a cystic lesion.

These are very rare, but are very aggressive tumors. So if you're worried about any abnormalities or something about the cyst that doesn't make it look just like a simple cyst, these diagnoses need to be considered. The first is a cyst adenoma, and this can progress into a cyst adenocarcinoma.

And you can't tell which one of these two pathologies it is really until you look at it under the microscope. So you should assume that it's malignant until proven otherwise. And as I've mentioned, if there's a thick wall, nodularity or septations, they should all increase. your concern that this is a cyst adenoma or a cyst adenocarcinoma. And these tumours should be managed with an oncological anatomical liver resection.

A couple of other rarer cystic lesions include an IPMN of the bile duct, a primary liver cancer with cystic degeneration, such as a cystic hepatocellular carcinoma. And cystic metastases to the liver, so colorectal, neuroendocrine, gist, squamous cell, breast, and other types of tumors can have cystic metastases. And then a couple of other things include hepatic pseudocysts and post-traumatic cysts, which are all included in the list of differential diagnoses for cystic lesions.

Let's talk about the three main non-malignant solid liver lesions you're going to need to know about for the exam. This includes focal nodular hyperplasia, hepatocellular adenoma, and hemangioma. So let's start with focal nodular hyperplasia. FNH is a benign condition of the liver that has no malignant potential.

The pathophysiology is that it is a proliferation of hepatocytes, and it's thought to be a hyperplastic process resulting from an arterial malformation, potentially related to hyperperfusion. It's more common in women compared to men and it's not got a relation to the oral contraceptive pill.

The natural history of these lesions is that most of them don't really change in size and they're typically found asymptomatically and identified on imaging. Up to 20% of patients will have more than one area of FNH. Under the microscope, these look like a well circumscribed, unencapsulated. solitary mass of hepatocytes with a central fibrous scar. And the hepatocytes are hyperplastic and arranged in nodules with little fibrous scepter coming from the fibrous central scar.

Focal nodular hyperplasia has characteristic features on imaging. So starting with a CT scan. On the unenhanced imaging, you might see a hypo or isodense lesion. Typically, the central scar is hypodense compared to the surrounding liver parenchyma. On the arterial phase, you'll get homogenous strong arterial enhancement which is described as centrifugal filling but the central scar will remain not enhanced.

In the portal phase, again, you'll see enhancement of the lesion. And in the delayed phase, the lesion will become the same color as the rest of the liver. So it'll fade into the rest of the liver on that delayed venous imaging phase. Next, we'll talk about the MRI appearance. For the MRI imaging, typically this is done with primavist contrast. And you want to have a look at the T1 weighted images in all of the different arterial contrast phases. This gives you a picture that's...

closest to the arterial contrast phases on a CT scan. So on the non-enhanced T1 image, the lesion should look iso-intense. So basically the same color as the surrounding liver and then the scar in the middle may be hypo-intense. On the arterial imaging, you'll get enhancement of the lesion, and again, the scar will remain hypo-intense. And on the portal venous phase, you'll get an iso-intense lesion. So it fades back into the liver like it does on the CT scan with an enhancing scar.

On the T2 images, you might see a iso-intense lesion, but the scar will be a high signal. And the key to MRI imaging of FNH is that the FNH is made up of... pretty much normal liver cells. So if you do a... MRI with primavist contrast. The primavist is taken up by normal hepatocytes. So if you look at the hepatobiliary phase, the cells should be taking up the contrast like the surrounding liver cells. This is unlike hepatocellulose.

adenomas or hepatocellular carcinomas or non-hepatocellular tumors, which won't take up the primavist contrast. So this is probably the key imaging modality that's going to help you differentiate what lesion it is that you're actually looking at. comes to an FNH. If the lesion has characteristic features on imaging, then you don't need to do a biopsy. That can be diagnostic.

A biopsy should only be done to prove a lesion that doesn't have the typical features on imaging is definitely not malignant. Tumor markers with FNH are usually normal. So how do we manage these lesions? If this is asymptomatic, it is a benign non-malignant lesion with no malignant potential. So you should do nothing.

There's no evidence to stop the OCP or avoid pregnancy, which we'll talk about with another one of these lesions. And if there's no issues and it's really convincing on your imaging, then you could consider leaving it alone or do a scan in six months. or a year to make sure that there's no change in the lesion. If there's any diagnostic doubt a really important differential diagnosis

for these lesions are a fibrolamella HCC. This is a rare type of HCC, but is really aggressive. So if you don't have the typical features on imaging of an FNH, then this should be discussed at a specialty HPB. MDT, and they may consider interval imaging or a biopsy. But obviously, if it does end up being a HCC, there's a risk of tumor seeding through the biopsy tract. These lesions are very, very low risk of becoming symptomatic.

If they were symptomatic, then you could consider treatment. And this may include resection, TACE, or percutaneous RFA, although there's limited evidence for these options. And as I've mentioned, it's very unlikely that this will be required in an FNH lesion.

Okay, so now we've warmed up with focal nodular hyperplasia, let's move on to the meatier hepatocellular adenoma, also called hepatic adenoma or liver cell adenoma. Essentially, this is a type of liver cell tumor. So it's a monoclonal proliferation of hepatocytes. These tumours are much more common in women than they are in men, and they have an increasing incidence associated with use of the oral contraceptive pill and anabolic steroid use.

They also have an increased incidence in patients who are obese, have diabetes, glycogen storage disease, galactosemia and iron overload. They typically occur in women in their third to fifth decade of life and are thought to be a hormone sensitive tumor. And that's why there is increased risk with the oral contraceptive pill, but also an increased risk with pregnancy.

So how do these tumours present? They may present completely asymptomatically and have been identified incidentally on imaging. They can present with slightly abnormal liver function tests and sometimes with abdominal pain. These tumours have a risk of spontaneous hemorrhage, so they can present with acute onset pain, and they also have a risk of malignant transformation, which is why we're really worried about these tumours.

So macroscopically, these tumors are usually solitary and they typically have a round appearance and sometimes can even have a capsule. They look pale yellow macroscopically and they can have central hemorrhage or necrosis. In terms of microscopic, they look like a uniform mass of benign-appearing hepatocytes, and they may have intracellular fat.

Interestingly, it used to be thought that all liver cell adenomas were precancerous, but there's been some interest recently in the molecular subtypes of hepatocellular adenomas. And there's four main groups. or molecular subtypes, which have been identified. The first of these is HNF1-alpha germline mutated hepatocellular adenomas. The second group are inflammatory hepatocellular adenomas. The third group are beta-catenin-activated hepatocellular adenomas. And the last group are sonic hedgehog.

hepatocellular adenomas, with the last group being unclassified. So of these different subtypes, the HNF1 alpha germline mutated account for about 30 to 35%. And these have a low risk of progression to malignancy. The inflammatory hepatocellular adenomas occur about 30% to 35% of the time. And these are more commonly found in obese patients or those with non-alcoholic steatohepatitis. And these are most likely to be complicated by hemorrhage. The beta-catenin activated.

occur about 10% of the time, and these have a much higher incidence of turning into a malignancy. The sodic hedgehog and unclassified are much rarer. So what does a hepatocellular adenoma look like on imaging? Let's start with CT scan. Due to their mixed components of fat, hemorrhage, and necrosis, these lesions often look quite heterogeneous.

On an unenhanced CT scan, they'll look hypodense compared to the surrounding liver parenchyma. Usually they will enhance on the arterial phase and then they will usually become isodense or sometimes stay hyper. dense on the portal venous and delayed phase imaging. On the MRI, on T1 imaging, they're often hyper intense compared to the surrounding liver parenchyma and same on T2 imaging. But again, they often look heterogeneous with different components, meaning that they don't look.

smooth and homogenous on imaging. With the arterial phase, they will also enhance and then again, like the CT scan, remain hyper intense or become iso intense compared to the surrounding parenchyma on the portal venous and delayed phase. The difference here between a hepatocellular adenoma and a hepatocellular carcinoma is that a HCC has washout. So it will become hypodense or hypo-intense on the portal venous imaging rather than...

staying hyper intense or just becoming iso intense or iso dense on the portal venous imaging. Tumor markers for these lesions are typically negative. So in general regarding malignant potential. The malignant potential is higher in the beta-catenin mutated HCCs. The malignant potential also increases with the size. So up to five centimeters, it's less likely it's going to be malignant, but over five centimeters, the risk of malignancy increases.

And the other major risk factor for a malignant hepatocellular adenoma is when they occur in men. So how do we manage these lesions? So if a diagnosis of a hepatocellular adenoma is made, then... A decision needs to be made about whether it needs to be resected or whether it can be monitored. The features that may push you to resect a hepatocellular adenoma are if the lesion has had hemorrhage. if it's a beta-catenin mutated tumour, if it's in a man, and if it's more than 5 centimetres in size.

If none of those risk factors are present, then women who are on the oral contraceptive pill should stop the oral contraceptive pill and undergo yearly MRI surveillance to make sure that it decreases in size. If after coming off the oral contraceptive pill or the woman isn't on the oral contraceptive pill, there's a persistent adenoma more than five centimeters in size, then you can consider surgical resection.

If it's less than five centimetres, then you can just monitor it as most of these in women will remain stable in size, decrease or even disappear. Women who are wanting to become pregnant should also be counseled about the risk of the tumor increasing in size and also having a hemorrhagic issue during pregnancy.

In terms of resection, it depends on the size of the tumour and the location of the tumour and obviously making sure that you can have a sufficient functional liver remnant after surgery. And these are other features that need to be factored into decision making. In terms of resection, you don't need a wide margin, so they don't necessarily need a formal anatomical resection, but it should be completely removed.

The last thing to mention is that you can also monitor patients with AFP levels as the risk of this tumour turning into a malignancy is that it's going to turn into a HCC. So if you're monitoring these patients with imaging, you can also... monitor the AFP levels.

So we've made it to the last of our three main non-malignant solid liver lesions that we need to know about. And this one is a hemangioma. Hemangiomas are the most common benign liver tumor.

They have no potential and are thought to potentially have a congenital origin. They can be very small or very large and can be... classified as cavernous hemangiomas, which I've seen various definitions of what size cutoff is required to make them be called cavernous, anywhere between one and four centimeters.

They can be single or even multiple hemangiomas in the liver. The natural history of these lesions is that they can increase in size with pregnancy, but that they don't seem to have an association with the oral contraceptive pill. How do patients with hemangiomas present? Well, as with most of these liver lesions, the majority of them are benign and are picked up incidentally on imaging.

They can, however, be very large and cause local compression of surrounding organs, leading to pain, a feeling of fullness or early satiety, nausea, vomiting and even obstructive jaundice. There are very, very small risks with hemangiomas of spontaneous rupture, with about 30 reports of this occurring in the literature. So although everybody worries about rupture of a hemangioma, the risk of this is pretty negligible.

So let's get into the imaging characteristics of hemangiomas on CT scan and on MRI. So on CT, a hemangioma on the non-contrast phase is usually hypodense. On the arterial phase, you get nodular peripheral enhancement. And on the portal venous phase, this enhancement continues towards the center of the lesion. And this pattern of enhancement is called centripetal filling.

And on the delayed phase, there's typically ongoing filling or enhancement of the lesion compared to the surrounding parenchyma. For MRI the typical finding is that on T2 imaging because there's fluid in the lesion the hemangioma looks bright compared to the surrounding liver parenchyma. And this is actually often described as a light bulb sign because it looks like a really bright light bulb in the liver parenchyma.

It has a similar contrast enhancement pattern as the CT. So again, it'll look hypodense on the non-contrast. On the arterial phase, we'll have nodular peripheral enhancement, which slowly fills in towards the lesion on the portal venous phase and then has enhancement ongoing in the delayed phase imaging.

And on T1 imaging, it'll look hypo-intense compared to the surrounding liver parenchyma. Macroscopically, looking on the outside of the liver, you might see a well-circumscribed reddish-coloured... hypervascular lesion and it can have lots of little lobules or look quite lumpy on the surface of the liver. Definitely don't biopsy these as they will bleed everywhere. Imaging should give you enough information to make the diagnosis.

So in terms of management, typically once a diagnosis is made with the imaging studies, no further intervention is required. For asymptomatic lesions, even if they're very large, they have no malignant potential and you don't really need to monitor them with serial imaging. Intervention should only be required in the case of a symptomatic lesion or if there's diagnostic doubt.

Relative indications for intervention include growth on follow-up imaging, tumours that are more than 10 centimetres, or patients that play contact sports. But as I've mentioned, the risk of anything happening with these lesions is pretty negligible. In terms of management,

Surgical resection is an option with enucleation of the lesion to save as much liver parenchyma as possible, with the alternative being an anatomical liver resection. And this really depends on the size and location of the tumor. There is some evidence that arterial embolization may be attempted. However, there's no good long-term evidence for this procedure.

The other thing to know about patients with multiple hemangiomas is that there's a risk of a consumptive coagulopathy where basically the coagulation factors and platelets can get chewed up in the hemangioma due to turbulence. flow. And this is called Casabac Merritt syndrome and might be something that could come up in the exam. So you might see liver imaging suggestive of hemangiomas and they would give you a blood test showing low platelets and low fibrinogen levels.

And you would say, well, I know what this is. This is a consumptive coagulopathy or Casabac Merritt syndrome.

So let's briefly summarize the appearance of those different lesions. So a cyst is going to be hypovascular, non-enhancing, and on MRI is going to be bright on the T2 imaging. Focal nodular hyperplasia is characterized by a central scar. It's going to look hypodense on the pre-contrast imaging. And then it has rapid diffuse enhancement with centrifugal filling with that central scar not enhancing. And then it becomes isodense and fades.

to the rest of the liver on the venous delayed imaging. Focal nodular hyperplasia can be confirmed with a primavist MRI, which demonstrates uptake similar to the surrounding liver cells in the lesion. Hepatocellular adenomas are again going to look hypodense on the pre-contrast phase, and they then have enhancement on the arterial phase with...

hyper intensity or iso intensity on the portal venous and the delayed phase. It may also appear heterogeneous depending on how much fat and hemorrhage there is in the lesion. And then last but not least is the hemangioma. Hemangioma is often hypo-intense or hypodense on the pre-contrast imaging, and then it has nodular peripheral enhancement on the arterial phase, with further filling described as centripetal filling on the

the portal venous phase and then usually continued filling on the delayed phase. And it has a light bulb sign on MRI in the T2 phase given there's blood or fluid within it. And just briefly, this...

is relevant when talking about trying to differentiate it from malignant tumors of the liver. So for example, a hepatocellular carcinoma is often hypo-intense or hypodense on the pre-contrast imaging, but has brisk arterial enhancement and washout, meaning that it is darker than the surrounding liver parenchyma on the portal venous. And if you're going to talk about contrast washout and use that term, you're basically saying this is a HCC. So be careful about that nomenclature.

Colangiocarcinoma is often again hypodense on the original pre-contrast imaging, and it may have some rim enhancement. And then in the delayed portal venous and delayed phases will often be hypoenhancing. And metastatic cancer can pretty much do what it likes. So in general, they're usually hypodense and don't have a lot of enhancement or just have rim enhancement with rapid washout. But you can also get hypervascular tumors, including renal cell.

carcinoma melanoma and neuroendocrine tumors in the liver that can behave differently so that's why the history and appearance of the lesions put together is what's really important to make a diagnosis

For the last part of this episode, I'm just going to talk a little bit about some other non-malignant solid liver lesions that you may find in the liver.

One of the classification systems I came across split these up into epithelial tumors, mesenchymal tumors, mixed and miscellaneous. So under epithelial tumors, tumors that come from the hepatocytes include nodular transformation, focal nodular hyperplasia, which we've already talked about, and hepatocellular adenomas, which was already talked about as well. Colangiocellular tumors include bile duct adenomas and biliary cyst adenomas.

Then we go into the mesenchymal tumors, and there's quite a few of these. So tumors of adipose tissue can occur in the liver, including lipomas and myelolipomas and angiomyolipomas. Tumors of smooth muscle can also occur in the liver from blood vessels, for example, and these are leiomyomas. You can also get hemangiomas, as we've already talked about. and also tumors of the mesothelial tissue such as benign mesothelioma. These are all, as you might expect, very rare.

In terms of mixed mesenchymal and epithelial tumors, you can get mesenchymal hematomas and benign teratomas of the liver. Again, very, very rare. And miscellaneous includes pancreatic heterotopic tissue and inflammatory pseudotumours. I have some notes on some of these. I've never come across them in clinical practice, but again, with the exam, they could pretty much ask us anything. So just briefly to go through a couple of these.

Angiomyelipomas are rare mesenchymal tumours that can happen in the liver, and they come from smooth muscle cells, adipose tissue, and proliferating blood vessels. They can be associated with a condition called tuberous sclerosis, but most of these are sporadic and they affect women 30 to 50 years old.

They are often found incidentally, and there's only very rare cases of malignant transformation associated with these tumours. Because of the three different... tissue components, smooth muscle, adipose and blood vessels, they can have very strange imaging findings and they may be confused for adenomas or HCC.

Given there's only a very rare risk of malignant transformation with these lesions, if they're small, such as less than 5cm, you'd leave them alone. But if they were more than 5cm, then they have a higher risk of malignant transformation and liver resection.

may be suggested in that situation. Billoryhamatomas are the next one to talk about. These are also known as von Mayenberg complexes and they are basically... little abnormal developmental clusters of small intrahepatic bile ducts, and then they lead to little ulcerated areas with inflammatory cells and fibrosis. They usually present as multiple lesions that are all very small, sort of one to five millimeter nodules scattered throughout the liver.

An MRI would see that on the T2-weighted signals, they appear as multiple small lesions that are really hyper-intense, and these don't need any treatment. A bile duct adenoma is the next one to briefly mention. This is also known as a benign cholangioma. And these are proliferation of non-cystic biliary structures within a dense fibrous stroma.

are traditionally not malignant and don't have a malignant potential, so are left alone. Inflammatory pseudotumors are a rare benign lesion with no malignant potential. They're thought to be a response or a type of exaggerated inflammatory response, maybe due to an underlying infectious process.

These can be difficult to differentiate from cholangiocarcinoma and therefore is often diagnosed on a resection specimen. If it is diagnosed preoperatively, then there's no role for surgery because they're benign and they don't have malignant. potential. And for these, there is actually medical management such as steroids, especially if it's an IgG4-related disease or patients have IgG4-related sclerosing cholangitis.

And potentially antibiotics can also cause regression of these tumors. Again, that fits in with the idea that maybe they are an infectious or inflammatory process. Lyomyomas are a type of rare benign liver tumor which originates from smooth muscle cells of the vessels or the bile ducts. They are more common in women and interestingly are associated with EBV and HIV infection as well as organ transplants. They are hypoechoic lesions on ultrasound and on CT.

will have varying enhancement with contrast. On MRI, they are hyper intense on T1 and strongly hyper intense on the T2 weighted images. If they are able to be confirmed, then they're usually left alone as they're benign. But sometimes it's not possible to identify them or they're misdiagnosed for other lesions, in which case they are identified on the post-operative pathology specimen. Bye.

And that's it for today's episode on non-malignant liver lesions. I hope you learned something. And like I said, definitely go and have a look at some images of what these lesions look like on CT and MRI. I think this is definitely something we could be asked about in the exam. As usual, please remember to rate the podcast

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