If you have been diagnosed with breast cancer, the treatment that has been planned for you almost certainly will be based on a breast cancer pathology report. This would have been produced by a pathologist, who analyses the breast specimen and subject it to different kinds of complex processes, before looking at it through the lens of a microscope.

In this episode, I interview Dr Peter Davis, who is a consultant in breast pathology.

During this conversation, we dissect and unpick the processes that take place from the moment a piece of breast tissue is taken, all the way to the various steps that are needed that allow the specimen to be examined underneath the microscope. The complexity of the process was certainly evident and in this episode, you will find out exactly what it involves.

WHAT WILL YOU LEARN?

• What is the role of a breast pathologist?
• How is a breast specimen transported to the lab?
• What happens to it when it arrives in the lab?
• Why do you embed it in a block of wax?
• How does the staining process of specimens help oncologist?
• What does cancer look like underneath a microscope?
• What does the grading of cancer mean?
• What is the difference between invasive cancer and insitu cancer?
• How can you tell if breast cancer is ductal or lobular?
• What are ER / PR and Her2 receptors?
• The role of artificial intelligence (AI) in breast cancer pathology

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Transcript #003

Note: transcription of episodes are generated using a combination of speech recognition software and human efforts, and as such may contain errors.

Tasha Gandamihardja
Welcome to the My Breast My Health podcast. My name is Tasha Gandamihardja, and I’m a breast cancer surgeon with over a decade’s worth of experience. I created this podcast as a place where those who have been affected by breast cancer can connect with each other, share experiences, and learn from each other’s life stories. I will also have conversations with experts in the field of medicine, as well as the health and wellness space. So if you want to learn more about this topic, then this is the place to be. The aim of this podcast is simple, to create a community where everyone feels empowered to help each other and support one another. This is because I truly believe that together we are stronger. I’m really happy to spend this time with you, so let’s start building community.

Tasha
Hi, and welcome to the podcast. Thank you so much for being here today. If you already subscribed to the show, thank you so much. I’m really, really grateful. And if you’re here for the first time, then make sure you subscribe to the show because that way, you won’t miss any of the future episodes.

Today I’ll be talking to Dr. Peter Davis, who is a breast pathologist. The role of a pathologist is extremely vital in the diagnosis of breast cancer. Have you ever thought how a breast cancer diagnosis is made just by taking a biopsy or sample of breast tissue? You’d be forgiven to think that it simply involves taking the specimen and looking at it down a microscope. In fact, the whole process is actually a little bit more complicated than that. In this conversation, we explore in more detail what happens when the specimen arrives in his lab. The complex steps that need to be taken before that piece of breast tissue is ready to be inspected by him through the lens of a microscope. It was an absolutely fascinating conversation and one that highlights the amount of work that takes place behind the scenes, which we don’t always appreciate. I hope you enjoyed this episode as much as I did interviewing Dr. Peter Davis.

Hi, Peter.

Peter Davis
Hello, there.

Tasha
Thank you so much for coming on to the podcast today.

Peter
Pleasure.

Tasha
You are a consultant pathologist.

Peter
That’s right. Yeah.

Tasha
For those who don’t know what a pathologist does, could you explain to us what it is that you do?

Peter
Okay, so I’m a doctor medically trained just like all of the doctors. So I have the same training as as other kinds of doctor and then I disappear off into pathology training, which after coming out of medical school is probably a sort of three years of junior doctorship and then another six years of training in histopathology then continually learning as you go along, basically. But what we do is we are particular kinds of pathologists who study disease by looking at tissue, and cells. And there are lots different kinds of pathologists. microbiologist look at infection, haematologist look at blood,

Tasha
Right

Peter
We look at tissue and by looking at it down the microscope, we work out what’s going on in a patient’s body. We do that through small samples that might be taken through a narrow needle, or sometimes a punch biopsy from the skin and then also in bigger surgical specimens. And the idea is that we look at tissue, examine it with the naked eye, dissect a specimen, if it’s a big specimen and turn that into something that we can look at down a microscope. And from that, we aim to work out, in essence, what the diagnosis is, and what does it mean. And the what does it mean bit is something that we spend an awful lot more time doing these days. In the past, pathology reports will be quite simple things..

Tasha
Right now they’re they’re complicated.

Peter
Now they’re much more complicated and takes a lot more time. And what we’re trying to do is we’re trying to work out, what is the likely prognosis? What can we tell oncologists and surgeons about what they’ve done? Is a tumour, for example, completely out, does the surgeon need to go back and take a bit more tissue maybe. Does the tumour have features that make it more aggressive? And how likely is the tumour to recur? Increasingly oncologists want to know what sorts of factors there are in a tumour that will guide how it’s likely to respond both to traditional drugs, that they’ve always used ….. chemotherapy, and then some newer agents that are coming online now,

Tasha
Right. So you play an extremely important role not only in the diagnosis of a disease, and that is essentially anything where a tissue specimen and has been taken from the patient because that is the thing that we send to you for analysis. But also you help us formulate a best treatment plan for the patient because you tell us exactly what we’re dealing with, which will, in turn, help us decide how to treat them. Is that correct?

Peter
That’s right.

Tasha
So let’s have a scenario. A patient comes to the breast clinic, and they will get assessed they’ll get clinically assess. So in a triple assessment clinic, they get clinically assessed, they have a lump or they have an area of abnormality in the breast which we want to investigate further. So we do a biopsy. This specimen is then put into formalin and sent to the lab. So you can tell me why we need to put that in formalin… but also, if a patient has a cancer, which we remove in surgery, as you said before, that surgical specimen is then also sent to the lab to you to to look at. Whether that’s a lumpectomy or if it’s a breast, having had a mastectomy all of whatever it is that was removed from a patient was sent to you. What happens to that specimen when it arrives in your lab?

Peter
So yeah, we receive a specimen in formalin, as you say and formalin sort of rather lightly call it pickling fluid is basically the first thing that it does, is it preserves tissue. It’s not like vinegar, it’s horrible to smell. It gets right up your nose. Yes, it is quite nasty stuff. But what it does do is it very, very quickly preserves that tissue. And what we mean in particular, with relevance to breast cancer with fixation is not just preserving the tissue physically, but also fixing or stopping the turning over of living cells.

Tasha
I see.

Peter
And when cells are alive, they divide and they grow. And that’s something that normal tissue does, but obviously that’s something that cancer does a lot. Because one of the problems with cancer is that cells grow too quickly,

Tasha
So that one of the definitions of cancer, isn’t it, that it continues to multiply and it doesn’t, it doesn’t die.

Peter
Yeah, that’s right. So one of the things that we need to know about cancer is how aggressive it is. And to do that, we give it what we call a grade. And a grade is really a measure if you like a reproducible measure, of how aggressive that tumour is. And one of the things that is its aggressiveness is the speed at which is dividing.

Tasha
Okay, so the formalin stops that

Peter
It does, it stops those cells dividing quickly. And why we need that to to happen really quickly is because one of the things we look at down a microscope is a thing called a mitosis. And that’s a thing that a cell does that we can see, which is where the chromosomes are actually dividing, to turn one cell into two. So it really helps us to see how many cells in a tumour or sample of the tumour, have a mitosis in them. If we don’t fix a sample quick enough, a lot of those mitosis continue. And then they become invisible.

Tasha
Even when it’s outside of that body.

Peter
Even outside the body, even outside the body, which is a bit of a thing to get your head around isn’t it? What the formalin does is it actually acts almost like a snapshot.

Tasha
Right, so it just freezes it in time?

Peter
So it just freezes that moment in time.

Tasha
Right

We talked about why we put this specimen in formalin

And then I guess the aim is for you to be able to look at these underneath the microscope.

Peter
Yeah.

Tasha
And to make them into slides.

Peter
That’s right.

Tasha
So then what happens to the specimens after you’ve taken the out of the formalin?

Peter
Sure. So we get them in the in the lab and if there is a core biopsy a very small core breast tissue that we’ve received, then that’s very simple. We just put that into what we call a cassette, which is like a little holder. And what we need to do is we need to be able to cut off that core into a very thin slice. A little bit like a meat slicer at a supermarket deli counter. But of course, it’s very tiny. So we need to have a way that we can hold it. Because you can’t hold it with your fingers because you cut your finger as well.

Tasha
Right Of course. Yeah.

Peter
It’s so what we need to do is we need to find some way of holding that tissue firm. And the way we do it is by solidifying it into a block of wax, paraffin wax.

Tasha
Right, that makes sense. So you embed it into the wax.

Peter
So we embed it into the wax. But what we need to make sure is that the wax doesn’t just surround the tissue, but actually goes all the way through it. Because otherwise when we cut it, the tissue jumps out. It’s like trying to embed something like a like a grape in wax. You need to hold it rather than just surrounding it. So we have to go through a chemical process that dehydrates the tissue, impregnate it with wax, and then by the time that’s happened, tissue has actually been a little bit chemically changed in that it’s still the shape that it was. It’s still microscopically made of the same stuff. But it’s chemically changed. So it’s ready to be cut. So it’s dry enough to cut, thoroughly dehydrated. And then it’s ready to stain. Because if you imagine if you cut a very, very thin slice through something delicate, like human tissue, it’s so thin that it’s almost translucent. You can see through. It’s much thinner than a human hair.

Tasha
Wow, so you slice them that finely. And how many slices would you get from a biopsy?

Peter
Well, we have to be careful, we have to make sure that each slice we can’t add value. Because sometimes we need to do more tests on a piece of tissue than we initially think. Usually, we can get at least 16 or so slices as a piece of tissue. It depends how big the core biopsy is, of course. But usually, we can get enough out to do the work we need to do. And keep some in file for future use just in case we need to. So we cut these very thin slices. And they’re the things that we then slide onto a piece of glass called the slide. And the tissue is so thin that it sticks to the glass. But what we need to do is do a few more things to it before we can actually look at it, we need to stain it in some contrasting colours. So we can see the difference between the various bits of tissue that make up breast. And that often looks like various shades of pink and purple. Yeah, it’s nice. It’s nice is that it’s amazing. Actually, the human body is a fascinating thing. And it’s actually quite a beautiful thing too.

Tasha
So that’s the H and E stain.

Peter
That’s what we call the H and E, which is haemotoxin and eosin which is just the name of the two kinds of ink we use. And then we put another thin piece of glass over the top to protect it. And that’s the slide.

Tasha
And how long does that whole process take?

Peter
It takes somewhere between 24 and 48 hours. It depends on the size of the piece of tissue that we’ve received. Because the fixing process with the pickling fluid, the formalin takes a little while to get seep through tissue. If it’s a very thin piece of tissue, like a core biopsy will fix very quickly. If we receive a surgical specimen, a big excision, that’s going to take quite some time to pickle.

Tasha
And how can you tell whether it’s ready?

Peter
Because it’ll feel solid. And it starts to look before we stain it, of course, it starts to look a kind of a homogenous kind of brownish colour. It looks a bit cooked if you like.

Tasha
Okay, so a little bit shrivelled up.

Peter
Yeah, it shrivels up.

Tasha
So it’s in formalin, then you embed it in wax. Then you slice them to very finely, to fine slices and then you stain them. And then you put them on slides and then you look at it anything right underneath the microscope. Yeah. And that’s when everything becomes clear for you.

Peter
This is when the magic happens. Yeah, this is well, the misconception I think about pathology is that we are very clever.

Tasha
You are

Thank you very much.

Peter
But we’re very clever. We can look at tissue under the microscope and immediately make a diagnosis.

It’s not quite true. For some diagnoses, it is true. Some diagnoses are very characteristic.

Tasha
And very straightforward.

Peter
Very straightforward. And I can look at it, I can say, this is a malignant tumour. And this is its name. And this is how it’s likely to behave. But often we’re dealing with things that are precursors to cancer, or even precursors to the precursor. So they may be changes that you see in breast that are not quite normal, but aren’t malignant.

Tasha
Okay. So there’s bit more complicated than, you know, that we may think.

So, how can you tell whether a cell or you know, a specimen contains cells that are cancerous?

Peter
Well, the earliest changes in the cell that are moving towards cancer are probably things we can’t see. They’re probably mutations, that we have ways to pick up through looking at the genetics of the cell. But in terms of daily diagnosis, that’s too small for us to see. So what we’re looking for is changes in the cell that change what the cell actually looks like. And the way it grows. And breast tissue is made up of a number of different components. There’s a fatty stroma, which is essentially the tissue in the background that makes up the bulk of the breast, which is fat. And then within it, it has tubes, what we call ducts. And it has lobules and lobules are the parts that basically produce the milk that goes through the ducts, that

Tasha
goes through the nipple.

Peter
Exactly. There are other elements of tissue within the breast, but those are the basic components. And each one of those can develop benign proliferative processes, which is where they grow too much. And then when that growth becomes uncontrolled that’s when cancer can start.

Tasha
So when you look at them underneath the microscope, there are, you know, certain characteristics that make up the cell like the nucleus and the cytoplasm. These terms come to haunt me from my medical school days, but you can decide whether a cell is I guess, more active than normal by looking at certain things. Is that right?

Peter
That’s right. So the cells individually can start to look wrong. When a cell is growing too fast, it grows from its nucleus because its nucleus provides it with the instructions to grow or not grow. So nuclei tend to become bigger. And they tend to exhibit disorderly growth, which is one of the characteristics of cancer. So the nucleus starts to look irregular, because it’s no longer growing in a tidy, tidy manner. We talked a little bit about mitosis earlier, and we can start to see more mitosis because the cells are dividing more. So on an individual level, there are characteristics that tells me that the cell is growing out of control.

Tasha
And you can look and you can see that underneath the microscope? And it’s quite obvious, isn’t it?

Peter
It is, it is. But we also see changes in groups of cells. So normally a group of cells will produce a structure. So they will all be growing because their program to grow to form a duct or they may be cells within a lobule that are programmed by genetics to grow a duct. And when they start to go a bit wrong, you can have too many ducts, for example. Or you can have a duct that has too many cells within its wall. So it starts to expand, and it starts to have too many cells piled on top of each other.

Tasha
So there is a disorganisation of cellular growth, that becomes quite obvious to see underneath the microscope. So that’s how you can tell the difference between a cancer versus a benign specimen. When we give a diagnosis to patients, you know, it contains lots of terms and words that are quite medical, and can be quite confusing. So I thought it might be a good thing to maybe dissect those terminologies a bit more. The first things that we would say to a patient if they had breast cancer would be the type of breast cancer. So it’ll either be, you know, a ductal carcinoma or lobular carcinoma. What are the commonest types of breast cancer that you see and what you know, what are the other non, the other cancers that are not that obvious and not that common? Because they’re quite many.

Peter
Yeah, exactly. Well, the main groups in the traditional sort of anatomical way of looking at this are that there are ductal carcinomas, and those are tumours which are derived from the duct. So if we go from having a normal duct growing normally, as it should be, to too much proliferation within the duct, to uncontrolled proliferation within the duct, and if that gets to the point where that’s growing a tumour, it becomes a ductal carcinoma. And ductal carcinoma is a good way of looking at…the other thing people might have heard of is its insitu. So ductal carcinoma insitu means a malignant proliferation within the duct, but it hasn’t yet got the ability to break out of the ducts, because the error in its genetics that grows from a mutation that allows it to do that hasn’t happened yet.

Tasha
Okay, so it’s confined within the duct.

Peter
It becomes confined within a duct.

Tasha
Okay, so that’s a ductal carcinoma, DICS really. Yes.

Peter
Now, that’s insitu in that, it’s not broken out into the surrounding breast. But what it does tend to do is creep along the tube..

Tasha
Right…along the ducts..

Peter
Along the ducts.. so that’s one of the characteristics of DCIS. It tends to be associated with calcification, often, not always, that’s the problem. So that’s can be one of the ways that you guys follow it. Once a ductal carcinoma has moved beyond that, it can develop the ability to invade.

Tasha
Right, that is where a cancer is known to be an invasive cancer or an invasive ductal carcinoma. So you can tell whether a cancer is an invasive cancer by virtue of it going through the ducts, beyond the ducts, or the confines of the ducts..

Peter
Exactly, into the breaking out into that surrounding fatty tissue. Now, lobular carcinoma is a pretty similar process, but it grows its thought from cells within the lobules. So, these two tumours when they’re relatively early stage, they look quite distinctive. And for a long time, they look distinctive, and the way we tell one from the other is by looking for what they seem to be trying to do. Which is looking at what they look like they’ve come from. So an invasive tumour that looks like it’s forming tubes, is probably a ductal carcinoma. Whereas an invasive lobular carcinoma tumor…..a tumour that’s made of lots of little cells that looked like the ones you see in a lobule, is probably a lobular carcinoma. The problem comes, when tumours get more advanced and more aggressive, they can start to look worse and worse down the microscope to the point where it becomes really difficult to work out.

Tasha
Distinguish between the two…

Peter
Just by eyeball… to distinguish between the two.

Tasha
So then what do you do to distinguish between the two? You do other staines?

Peter
We do other stains. Yeah, I mean we have, when we talk about stains, what we’re talking about is the first of all the H and E stain, which shows us morphology. But we have certain things that we can do where we use, we call immunohistochemistry or IHC. All abbreviations for the same thing. And what we’re doing now is we’re using, in essence, an antibody, which has a, an ink on it, or an enzyme on it that activates an ink. Now that antibody people might think of antibodies is something you see in an infection and you might have an antibody to nuts. Which is why you have a nut allergy. So we’re borrowing that reaction and we’re saying we want to know if this unidentified cell that might be ductal might be lobular has a particular protein on it, that’s too small to see with our eyes, even with a microscope. But we want to know if it’s there because if it’s there, it’s more likely to be lobular. So we try an antibody on it. And we’ll try a range of antibodies on it. And the antibody that picks up that particular protein will activate an enzyme which lights up an ink.

Tasha
Right? And then you can tell …

Peter
that cell changes colour. So we look for the cells that have changed colour. And we say if a certain proportion of them have changed colour, they’re positive for that particular protein. Yeah, yep. And that allows us to say, more likely than not, these particular cells that we’re looking at, have probably come from a lobule rather than a duct.

Tasha
So that’s extremely helpful for you to decide whether it’s ductal or lobular

Peter
It is, it’s not always as clear cut as that makes it sound because tumours don’t always behave the way the book says they do, which is why sometimes test results aren’t entirely comparable and you have to look at them in the setting of an individual patient.

Tasha
Sure, or it might change from… a core biopsy might say something. But then, you know, after the patient’s had an operation and you look at the specimen in its entirety, you might change. Exactly. Because you have more specimen to look at.

Peter
That’s right. I mean, the core is only ever a tiny sample..

Tasha
Yeah

Peter
…of tumour. And the core when you think about it might be 12 millimetres long, one millimetre wide. And the tumour might be 35 millimetres across.

Tasha
Yeah. So that’s much, you know, sometimes more helpful. Well, it can be. Yeah, and I think.. I also warn my patients that when you get a diagnosis of something, at the time of your core biopsy, looking specifically at grading, for example, we can talk about that in a minute. That grading can change depending on… it depends on the final histology of that specimen because you are looking at only a small area of that cancer, which is the biopsy. And you might give that a grade 2, for example, but that grading might be upgraded to a grade 3 based on the outcome of that specimen. So we know that there are three grades 1, 2, and 3. What are the differences in those three? And what is a grade I guess?

Peter
Sure, yeah, well, a grade is a way of trying to identify some features that we can see down the microscope that allow us to reproducibly identify three different sets of likely outcomes for patients. So we try to identify a group who are likely to do quite well, a group who have a more aggressive tumour and a group that have a more aggressive tumour still. And to do that, it’s a product of a lot of researchers over the years that’s identified features that we can use for this. But what we look at is we look at the degree to which a tumour makes tubes or tubules. And we give that a score. So if the tumour is making lots of tubules, and we give it a one, because it’s a good feature. If it’s not making many tubules we’d give it a three, because it’s a bad feature. So it goes in that direction…one, two, three. We then look at what we call there’s another technical term.. pleomorphism, which is really the irregularity of the nucleus. So nuclei of a tumour as we said before, nuclei of tumours that are quite aggressive tend to be quite irregular. And this is a way of saying one is very nice, neat and tidy, almost like normal. Two is somewhere in the middle and three is nasty, irregular looking, angry nuclei.

Tasha
So it’s more pleomorphic, right. Okay.

Peter
And then the last thing we look at is mitotic activity. And that is measured by the number of mitoses you see per a fixed area and that requires you to calibrate your microscope. So you know, you’re always measuring a fixed area, so everybody’s range that you use to count is slightly different depending on what kind of microscope you’ve got. But we all calibrate our microscopes so that we measured the same area. And then it’s just a matter of counting the mitosis.

Tasha
So the more mitosis you see, the more aggressive that tumour type is

Peter
Exactly, so not only mitosis is a one, lots of mitoses is a three.

Tasha
Okay. So you look at those three factors.

Peter
And we put those together. And then the number that we get then affects whether you’re in grade one, two, or three. So the higher the number, the higher the grade.

Tasha
Right, and I guess that’s the surrogate to how aggressive a cancer might be.

Peter
It is to a degree, it is only… it is only one way of looking at cancer off course. There are other prognostic scales that look at the mutations that tumours have and use that to put people into different groups, for the likely outcome. There are also scoring systems that involve both pathological factors and things like nodal count… how many how many nodes the tumour might have spread to. So there are other…

Tasha
other factors that might determine whether a patient’s cancer is more aggressive than somebody else’s. Because of course, we treat patients depending on their cancer. So somebody’s cancer will be very different to another person’s cancer and their treatment will be entirely different.

Peter
Yeah, I mean, we’re moving… we’re moving from an age when cancer therapy was was quite mechanical, it was about digging it out, and then poisoning the person and the tumour. And you kind of hoped that the tumour would, would be killed.. quite quickly. But what we’re moving now is we’ve moved through into much less toxic chemotherapy regimes and specialized treatments… immunotherapy…new treatments that are coming on

Tasha
..more targeted really.

Peter
they are much, much more targeted… and they really are targeted at the tumour rather than the tumour and the person.

Tasha
Right, yeah that’s very that’s very true. So, another kind of factor that we look at when we determine how best to treat a patient is whether the cancer expresses hormone receptors. So, you know, a cancer might be what’s called ER-positive which is oestrogen receptor-positive, PR positive, which is progesterone. And there’s another receptor called the HER2 receptor. So can you explain a bit more about these receptors and why they are important?

Peter
Yeah, so we know….we know that a lot of breast cancers are driven by responses to hormones, and they will often but not always expressed estrogen receptors, and progesterone receptors.

Tasha
So that’s the ER and PR to abbreviate them

Peter
Those tumours are being fed, if you like by oestrogen and progesterone, which opens the ability to either select use drugs to either selectively block that drive, or actually to modulate the hormonal environment itself. So it opens a therapeutic option for those patients who have enough responsiveness to estrogen and progesterone. So what we have to do as pathologists are we have to use some of those IHC immuno tests to try to identify how positive a tumour is for oestrogen receptors and progesterone receptors. And we have another scoring system that we use for that …. we like scoring systems, giving us reproducible ways of doing things. And so what we’ll do is we’ll look at … so there is a lot of counting involved as a pathologist. And we’ll look at a sample of cells within that tumour, and we’ll assess how many of them are staining, and to what strength. Now at the moment, that’s all done by the human eye, which means you have to regularly recalibrate yourself and check that you’re scoring reproducibly. And we have to check that we’re scoring against positive and negative controls. So we know what a negative stain looks like and what a positive stain looks like. But what we’re trying to do, and this is a sort of at the forefront of technology is trying to teach computers how to do that.

Tasha
Right…AI

Peter
AI. And this is this is where actually AI has a lot of possibility within pathology because yeah, I know for a lot of us, we we would probably like to think that a highly trained doctor was assessing your tumour. So would I, but highly trained doctors get tired, and machines don’t get tired.

Tasha
Yeah, so maybe they perhaps maybe more accurate because fatigue doesn’t come into it.

Peter
Exactly, they can be accurate they can be potentially quicker.. now a lot of research is going into this at the moment and the results are actually very, very good. Now if you can be better than a tired human, why wouldn’t you do it? So it’s it’s certainly something which is on the cusp of technologies is where we what we tend to be where we’re going. Obviously, a lot of the decision making and interpretation has to be done by a human, but the actual counting…

Tasha
..kind of the automated tasks that you the pathologists do can be delegated to, to a machine. So how, so we will get you know, an ER score of eight out of eight or seven out of eight or three out of eight or zero out of eight. How do you determine whether you know the oestrogen receptor positivity is eight out of eight versus three versus zero.

Peter
So this is basically counting, and there are a number of different ways of doing it. The quick score or Allred score, it has two names, is that it’s relatively quick. And what it looks at is it looks at the percentage of cells, which stain, weakly, strongly or moderately. And each one of those gets a score. And that score the two together, so you might say, you might score if you have less than 1% of cells staining it scores a one for example.

If you have 100%, it scores four or five anyway, half… And the other half comes from the intensity. And basically what we do is we check and the intensity of the cell staining and the percentage that are staining combined

Tasha
becomes the score.

Peter
Where we set the cutoff is two and three, so two is regarded as negative. Three is regarded as positive. Now three is still very weak staining. So you say you call it weekly positive, or we call it weekly positive. And those are the kinds of cases where there may be some sort of discussion with the oncologists. You know, which which way they think is the best way to proceed. The alternative way of doing it is to look for less than or greater than 1% of staining in any intensity. And that usually aligns with the two three cut off, but not always. So what we do is we tend to get both.

Tasha
OK… talk to me about HER2.

Peter
So HER2 is the human epidermal growth factor receptor. And it is one of the molecules that’s involved in cell growth. And what we do is we test for that in exactly the same way, a very similar way to the way we do Er and PR. It’s still done by immunohistochemistry, but it has a different scoring system. Of course.

Tasha
Of course, why would it make it any easier?

Peter
So we have we have a zero which is negative. We have a +1, which is negative. We have a +2, which is borderline. And then we have a +3, which is positive.

Tasha
Right. And then we know that if it’s borderline it goes for further testing, which is called the FISH testing.

Peter
Which is fluorescence in situ hybridisation.

Tasha
Okay, thankfully, it is abbreviated to FISH.

Peter
It’s gone fishing, it’s is gone fishing and that FISH.. FISH is one of those other things in histology which looks great. It does actually look like fluorescent dyes, staining different parts of the cell. It is as a result quite technical to report and so we tend to send it out to another specialist lab to do.

Tasha
And it does take a while for it to come back.

Peter
It does. The problem is at the moment in the UK, there are relatively few labs which are doing it. And of course, lots of patients need it.

Tasha
Right. Okay.

Peter
It can mean that there is a little delay in getting it. But I think most of our MDT teams tend to, you know, try to anticipate as much as you can.. how you may manage the patient in different circumstances of how that comes out. Okay. But obviously, it is a problem. As we move forward with technology, what we hope is that we can start to kind of bring a lot of these things in house. FISH itself is likely to be reduced in HER2 in the coming years because actually, the scoring system for immunohistochemistry is likely to change. Which will probably get rid of some of those problems around 2+.

Tasha
Okay, so get rid of that ambiguity and become either more binary,

Peter
Probably more binary. That’s right. I mean, the thing is, though, that the more we know about cancer, the more we know about the other mutations. Substances that are involved in the pathway of carcinogenesis, like cancers grow. So just when we think we have less testing to do we discover something else that needs testing for. And that really is the story of pathology because we have gone from really simple reports that say, cancer, completely excised, full stop, to great big, long, complex reports with lots and lots of data fields that take longer to do and the more complex to read, but they, they incorporate much more information that’s relevant to an individual patient.

Tasha
Right. So it’s becoming much more complex than years, you know, long, long time ago. And I think the receptor positivity is extremely important because that, as you said, guides us to, you know, say to a patient well your tumour is this… these are the characteristics of your tumour. And therefore we think you would benefit from, you know, anti-hormonal treatment like tamoxifen or letrozole or you may greatly benefit from chemotherapy, if you have, for example, a triple-negative cancer. So, you know, it is an extremely important part of the cancer treatment.

Peter
Well, this is where we talked earlier about an anatomical view of breast cancer. And that was the traditional view for a long time. You either had a ductal carcinoma or you had a lobular carcinoma or one of the other kinds that’s driven by where it’s come from. But now, of course, increasingly, we look at what is the receptor status of that tumour? Or what is it actually doing? Yes,

Tasha
the biology of the tumour. That’s right.

Peter
And that has become all-important because a lot of the decisions that are now made are based on the individual patients’ tumour biology.

Tasha
That’s right, and hence the more targeted approach to cancer treatment.

The other thing that we do obviously in breast cancer surgery is remove lymph nodes or glands from the axilla or the armpit. And anybody with an invasive cancer will also have what’s called a sentinel lymph node biopsy, which is removal of a few of the glands. If the node at time of presentation is normal. Is the process of analyzing lymph nodes the same as what you would do for the breast specimens?

Peter
It’s a little bit different. Well, first up the breast excisions, whether they’re breast-conserving, whether they’re a wide local excision or mastectomy, they they tend to be big. Whereas a sentinel node biopsy is usually quite small. It’s usually one or two nodes with a bit of fat around them. So it’s maybe a couple of centimetres …a pea size…yeah or something like that..

Tasha
or maybe smaller sometimes

Peter
And most of that’s fat and within that be a small lymph node which is a few millimetres across. It’s not very big, not very big. But what we’re trying to do is we’re trying to use that sample as a very high yield decision-making tool. So very important. We want to make the absolute best of that tissue. So what we do is we sample it across its long axis, like slicing up a sausage. So we don’t want to slice the sausage in its long plane. Yeah, because then we only just see two faces of sausage, But if we

Peter
slice it across, all the way along it, then we see as much area of sausage as we can. And that’s the way we stand the greatest chance of picking up tiny little metastasis, if they are there and that means that we can have great confidence that that lymph node or nodes are negative, if we don’t see anything down the slide down the microscope on the slide, and that really helps you guys make a decision as to what’s the likelihood of the other nodes being positive. The theory with the sentinel node biopsy is that you’ve taken the node which is the closest to the tumour. So any tumor that spreading really has to go through that node.

Tasha
Yeah, the most important node, the guardian of the axilla.

Peter
It is, it is the guardian of the axilla. So if we are confident that our way of doing our histology means that when we say it’s negative, it really is negative, then that gives you the confidence that you can reassure the patient that there isn’t or there is unlikely to be any tumour in the rest of the axilla.

Tasha
Yeah, no, that’s, that’s really helpful. And presumably, the slicing that you do is exactly the same in terms of the diameter and the thickness.

Peter
Yeah, yeah. it’s very very thin.

Tasha
Yeah.

Peter
Yeah. Well, we don’t look at the whole lymph node att that interval. What we do is we’ll cut it into sections which are about two millimetres to three millimetres thick. They go into one of our cassettes and then we embed them in wax and then what we do is we cut through each of those. And that’s what we see as a hairs’ thinness. And we’ll cut several sections through each of those. So what we then see is a whole load of glass slides, maybe eight. And each one is showing us a cross-section of the lymph node. And we’re looking for tiny deposit… for ductal carcinoma, the cells are usually quite big and chunky. So they’re relatively easy to see, whereas, for lobular cancer, the cells are quite small. And they can look like the background cells in the lymph gland,

Tasha
Right…it is trickier.

Peter
Cells in the lymph gland are also very small. So we have to then use antibodies with enzymes and stains to stain them up in different colours. And that’s how we pick them up.

Tasha
Okay, so it’s a bit more complex, complex. So thank you very much. I mean, that’s been really, really helpful. I think it just goes to show that what you do is so important. And I think you do all the work in the background because you essentially the bridge between, you know, us seeing the patient at the time of their presentation. And then, you know, at the time of giving them their diagnosis, and all of this work happens in your lab, by you and the rest of your team.

Peter
Well, yeah, I mean, we see ourselves as absolutely part of the whole team. And, you know, the way we see things is that we’re dealing with our patients, you know, we’re not doing something for your patients. Actually, they are patients too. And, we, we are doing this, I think because we’ve got a real passion for getting to the bottom of what’s going on and fundamentally helping patients receive the best treatment and the right treatment for them.

Tasha
Yes, and I think, you know, the information that you provide is absolutely pivotal in us being able to tailor the best care for our breast cancer patients. Any other things that you want to add that we haven’t covered?

Peter
Um, well, I think we really the thing that’s changing in pathology is that we’re moving more and more from traditional morphological work, which is, you know, looking at the shapes of things essentially, and the colour of things, to moving into molecular work. And getting to grips with the mutations that we see in different tumours is teaching us so much more about that tumour biology. And we don’t all have to be research scientists to be involved in research. Because our daily work with real patients is teaching us more and more about the patterns that we see. And that’s teaching us how to better tailor treatment to individual patients and we’re having to become much more technical, much more advanced. That’s coming in lots of different ways. And you know, we touched a little bit on AI and whilst I don’t think I’m going to be out of the job immediately, I’m really looking forward to a technological future. There’s gonna be a lot more genetics involved. a lot more computing power, but still with a human head-on, and a real human passion for getting it right.

Tasha
Well, on that note, thank you so much for giving me and the listeners your time. It’s been really, really interesting. And hopefully, it will help lots of our listeners today to better learn and better understand their cancer. Great. Thank you very much.

What an interesting conversation. Thank you so much to Dr. Peter Davis for his time and his expertise. And I hope you have enjoyed this episode as much as I did. It does highlight what happens in the background and all the work that happens that help doctors diagnose the disease but also help us design the best treatment plan based on that specific tumour characteristic. Different people’s cancers are very different, and it is because of the work of our pathologists that it enables doctors formulate specific and patient-centred treatment plans.

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Take care. Bye.

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