Dr. John Crary-Neuropathologist
*To read an article based on this interview, go to the Blog.
“These patients, we see their biopsies. So my perspective will be quite different from the people that see brain tumor patients in the clinic.”
Me: To what extent are you involved in brain tumors? Because I know you said your focus is in neurodegenerative diseases. So what is your knowledge of brain tumors?
Dr. Crary: So, 80% of my time is devoted to neurodegenerative research, and 20% of my time is devoted to clinical service. So of that 20% of my time, I spend basically spend it looking at brain biopsies and I try to figure out if they are tumors or not tumors. And every week I go to a tumor board conference, where they have the neurosurgeons, neuroradiologists, neurologists, neuro-oncologists, and the neuropathologists and we have a discussion about every single patient about what the diagnosis is. Even though it’s only 20% of my time, it’s every week I’m at these meeting.
Me: Regarding the parents, what would you have them know about a neuropathologists role in their child’s treatment?
Dr. Crary: A neuropathologist’s role is essential in dictating what the treatment is going to be. Before the biopsy, they don’t know if it’s a tumor or something else. They don’t know the degree of the tumor; they don’t know how aggressive it is going to be. So it is a key branch point in clinical decision making. If the neuropathologist says it’s a benign tumor, you’re going to go off in one direction for treatment. Whereas, if the neuropathologist says it’s a malignant tumor, you’re going to get a more aggressive treatment. The neuropathologist may help to decide, even at the time of the biopsy, while the patient is still in the operating room, the neurosurgeon will often ask the neuropathologist to come down and do a quick read, which we call a frozen section. So the surgeon will hand over small pieces of tissue to the neuropathologist. They’ll freeze it, and cut slides quickly under the microscope. They can usually finish this in about 20 minutes. But the frozen tissue is not ideal to making a diagnosis because of water frozen in the tissue. It’s a tricky read but it can help you triage the patient. During the frozen section, we might tell the neurosurgeon that it is benign region, in which case it might be more aggressive during surgery. Which is counterintuitive, but the logic is the benign region is more aggressive, and the malignant tumor is more likely to spread throughout the brain, there will be a less radical surgery. Because they’ll know if there’s going to be additional treatment later on, after the fact. So that’s the first time the neuropathologist comes into play. Then, sometime over the next couple of days, they’ll study the tissue under the microscope. It’s very important that you get an actual neuropathologist to look at the tissue. There is often a hospital generalist, who specializes in pathology but may not be an expert in the brain. And most centers do not have an active neurosurgical unit. You really need to be at a center where they treat a lot of the infected patients. Then you can be sure that a neuropathologist has actually looked at the slides. Now, if there is any question, you can always request that the slides be read by a second neuropathologist to get a second opinion. If you ever have a biopsy, always ask that it be reviewed at a major center. They do this all the time. Just ask for a second opinion. You may get a different wording, from different styles and customs, and pretty much a different diagnosis, the treatment is often the same. The thing about pathology that is important for everybody to know is that it’s the gold standard for making a diagnosis.
You brain is a vital organ. No one wants a neurosurgeon to dig a hole in your brain. But if there is a tumor in there, more people are willing to do it. If the tumor is in a hard to reach spot, the neurosurgeon may be reluctant to take out a large piece of tissue, and can only take out a really, really small piece. And the neuropathologist will have a really tough time deciding if it’s a high-grade tumor, a low-grade tumor, or if it’s a tumor at all.
Me: When my sister was getting her treatment, there were doctors on the east coast saying it was a juvenile pilocytic astrocytoma, and doctors on the west coast saying it was an grade 3 oliogodendroglioma. But a week later after they said that, the tumor quintupled in size. But the doctors on the east coast still saying it was a JPA. So what do you do in situations like that?
Dr. Crary: It’s very frustrating when dealing with uncertainty. In biopsies, you don’t have the whole thing. So you’re looking at a small piece of what’s happening. The pathologist can only make a diagnosis on the piece of the tumor that they have. Now, why wouldn’t they be able to know what the rest of it looks like? Well, tumors are all different. Everyone is a little bit different, but even in one person’s tumor they could have parts that are more aggressive and parts that are less aggressive. So even within something that seems like it would be a benign tumor, there would be parts of it that would be aggressive. And what a tumor basically is one cell that is trying to divide uncontrollably. And so all of the offspring, all of the daughter cells, of the cell that is dividing, all of the daughter cells are undergoing changes of their own that could potentially make them more aggressive. If one of those daughter cells “takes off”, you could have a very ugly tumor, but just in a subset of the cell. But when a surgeon takes out a biopsy, they grab the less aggressive part of the tumor. That’s why those clinical-pathological correlations are so important. Because what happens is a radiologist will say “This looks very, very aggressive” and the neurosurgeon says “Well, this is what I took.” And the pathologist will say “This is what you gave me, and what you see under the microscope is not aggressive.” So then they say A plus B does not equal C, even though it’s supposed to, so what’s missing? And then they’ll have to fill in the details.
Me: How important is getting the correct diagnosis to determining the proper treatment?
Dr. Crary: Right now there are only a couple things we can do for a patient with a brain tumor. We can do surgery. Surgery is great if you can remove the whole thing. There are certain types of tumors that are outside the brain that are immune to surgical resection alone. Unfortunately, in the brain the tumors can’t always be removed completely. Surgery alone works if the tumor is benign. If it’s a malignant tumor, they’ll require often chemotherapy and or radiation. Now it’s important, as a neuropathologist I don’t do these treatments, but I do know that there are a lot of side effects. It’s important to know that there are a lot of side effects, and people are scared of the side effects. And they should be! For example, radiation in the brain. It can get rid of tumors, but it can also cause tumors. Radiation is good because it is very effective at killing cancer cells. So it’s a balance. You don’t want to radiate a benign tumor. There’s a major source of medical liability in neuropathology. There are cases of misdiagnoses when a pathologist thought they were aggressive and called it a malignant tumor and they get it radiated and they turn a benign tumor into a malignant tumor. You don’t want that to happen. The other thing is chemotherapy. Chemotherapy also has side effects associated with that, like bleeding in the brain, nausea, vomiting, losing your hair. So making that decision, that’s really essential. You don’t want to treat a benign tumor with all these aggressive treatments with all these side effects. And with an aggressive tumor, it’s also the best chance that you have for extending life.
Me: How does understanding the pathology dictate the treatment?
Dr. Crary: The idea is pathology is all about prognosis. Pathologists are labelers, they’re namers. They will attach a label to every tumor. In the textbooks, it’s really nice and clean. But it’s not always like that in the real world. In the real world what matters most is the behavior of the tumor. We do our best to fit every tumor into the artificial categories that we have created. But there’s the whole idea of coming up with the prognosis. If there’s a patient with a tumor, and we tell them patients with similar molecular profiles generally live for about two years, that’s a bad prognosis. It’s nice to know that versus if we have another set of patients with another set of features with another set of molecular profiles, but those patients live on average up to five years, and we know it’s a benign tumor, we can pass that information onto the clinician. The clinician, being the neurologist and neuro-oncologist, will be able to better balance the side effects of the treatment versus the extension of life. So they know that the treatment will extend life a certain number of years on average paved on previous clinical research. So it’s all about us prognosticating on what the chances of living and being cured are.
Me: What is your role with the patient after their treatments are done?
Dr. Crary: Once they’ve been treated, brain tumor patients are generally followed; they really need to be. You need to have a relationship with your oncologist, neurologist, and neurosurgeon. You really need to come back and get rescanned periodically to see if the tumor has come back. The pathologist, after the first diagnosis is made, if the tumor comes back then they may need a second surgery. And we can be useful to determine whether the features of the tumor have changed. We’ll compare the original tumor with the second resection. That’ll be useful for a couple of reasons. Number one, it’ll tell you if it’s taken off, so to speak, if it’s done worse. If the tumor has evolved it can become more aggressive. We can give that information to the clinician and they can alter the treatment. The other thing that happens is that some patients, not all (it’s a minority, but it’s not insignificant), have cancer syndromes in their family, and they’re prone to multiple tumors. So they may have a new tumor that is now rising up, and that is important to know. We can diagnose a second tumor; usually that doesn’t happen though. The other thing is they may have a recurrence that can be many many years later, and the neurosurgeon comes in and takes out the tumor. And when we look at the histology, there’s no tumor there. It’s kind of a trick. What happens is these are almost always patients who were treated with radiation. And the radiation can have a side effect of damaging the tissue, we call it radiation necrosis. It can appear to the radiologist of being a recurring tumor. But in reality it’s just a small piece of tissue dissolving, so to speak, as a result of the radiation treatment. That’s really useful, because if it’s a recurring tumor, the patient may want to get another round of chemotherapy.
Me: What do you find most rewarding about your job?
Dr. Crary: The thing is there are two different aspects of it. The research is the most rewarding. The opportunity of making a lasting difference that can affect everybody is really really valuable. It’s what keeps me going. It’s very hard to be a scientist and a doctor at the same time. And there aren’t that many fields where it’s easy to do it. Unfortunately, it’s sad as a pathologist that we never see the patients, we never see their faces. They never get a chance to thank you. There’s a classic story of the tumor board. And the neuropathologist shows up at the tumor board. When it happened, there was a frozen section the previous week and it was really tricky. The neuropathologist said “This doesn’t look right” and the neurosurgeon thought it was a glioblastoma. And the neuropathologist put in all this extra work and did all these extra levels and figured out that it wasn’t a glioblastoma, and figured that it was some other tumor that was benign and he was very proud of himself. He went home patting himself on the back. And the next week at the tumor board, all the fellows have new watches. And the neuropathologist said “Why are you guys all wearing new watches?” And they said “Well remember that guy last week who had a really tough case? Well he owns a watch store and he gave us all new watches because we cured him.” And the neuropathologist said “Does anyone want to give me their watch?” and nobody did. Nobody knows about the neuropathologists, no one really knows that they even exist. So we do get a lot of satisfaction, but it’s not directed from patients. But it’s knowing that you’re doing science that’s the most important thing. Because your impact could potentially be beyond what you’re doing that that moment. It has the potential to reverberate to change care across the whole country. And that is a great feeling.
“These patients, we see their biopsies. So my perspective will be quite different from the people that see brain tumor patients in the clinic.”
Me: To what extent are you involved in brain tumors? Because I know you said your focus is in neurodegenerative diseases. So what is your knowledge of brain tumors?
Dr. Crary: So, 80% of my time is devoted to neurodegenerative research, and 20% of my time is devoted to clinical service. So of that 20% of my time, I spend basically spend it looking at brain biopsies and I try to figure out if they are tumors or not tumors. And every week I go to a tumor board conference, where they have the neurosurgeons, neuroradiologists, neurologists, neuro-oncologists, and the neuropathologists and we have a discussion about every single patient about what the diagnosis is. Even though it’s only 20% of my time, it’s every week I’m at these meeting.
Me: Regarding the parents, what would you have them know about a neuropathologists role in their child’s treatment?
Dr. Crary: A neuropathologist’s role is essential in dictating what the treatment is going to be. Before the biopsy, they don’t know if it’s a tumor or something else. They don’t know the degree of the tumor; they don’t know how aggressive it is going to be. So it is a key branch point in clinical decision making. If the neuropathologist says it’s a benign tumor, you’re going to go off in one direction for treatment. Whereas, if the neuropathologist says it’s a malignant tumor, you’re going to get a more aggressive treatment. The neuropathologist may help to decide, even at the time of the biopsy, while the patient is still in the operating room, the neurosurgeon will often ask the neuropathologist to come down and do a quick read, which we call a frozen section. So the surgeon will hand over small pieces of tissue to the neuropathologist. They’ll freeze it, and cut slides quickly under the microscope. They can usually finish this in about 20 minutes. But the frozen tissue is not ideal to making a diagnosis because of water frozen in the tissue. It’s a tricky read but it can help you triage the patient. During the frozen section, we might tell the neurosurgeon that it is benign region, in which case it might be more aggressive during surgery. Which is counterintuitive, but the logic is the benign region is more aggressive, and the malignant tumor is more likely to spread throughout the brain, there will be a less radical surgery. Because they’ll know if there’s going to be additional treatment later on, after the fact. So that’s the first time the neuropathologist comes into play. Then, sometime over the next couple of days, they’ll study the tissue under the microscope. It’s very important that you get an actual neuropathologist to look at the tissue. There is often a hospital generalist, who specializes in pathology but may not be an expert in the brain. And most centers do not have an active neurosurgical unit. You really need to be at a center where they treat a lot of the infected patients. Then you can be sure that a neuropathologist has actually looked at the slides. Now, if there is any question, you can always request that the slides be read by a second neuropathologist to get a second opinion. If you ever have a biopsy, always ask that it be reviewed at a major center. They do this all the time. Just ask for a second opinion. You may get a different wording, from different styles and customs, and pretty much a different diagnosis, the treatment is often the same. The thing about pathology that is important for everybody to know is that it’s the gold standard for making a diagnosis.
You brain is a vital organ. No one wants a neurosurgeon to dig a hole in your brain. But if there is a tumor in there, more people are willing to do it. If the tumor is in a hard to reach spot, the neurosurgeon may be reluctant to take out a large piece of tissue, and can only take out a really, really small piece. And the neuropathologist will have a really tough time deciding if it’s a high-grade tumor, a low-grade tumor, or if it’s a tumor at all.
Me: When my sister was getting her treatment, there were doctors on the east coast saying it was a juvenile pilocytic astrocytoma, and doctors on the west coast saying it was an grade 3 oliogodendroglioma. But a week later after they said that, the tumor quintupled in size. But the doctors on the east coast still saying it was a JPA. So what do you do in situations like that?
Dr. Crary: It’s very frustrating when dealing with uncertainty. In biopsies, you don’t have the whole thing. So you’re looking at a small piece of what’s happening. The pathologist can only make a diagnosis on the piece of the tumor that they have. Now, why wouldn’t they be able to know what the rest of it looks like? Well, tumors are all different. Everyone is a little bit different, but even in one person’s tumor they could have parts that are more aggressive and parts that are less aggressive. So even within something that seems like it would be a benign tumor, there would be parts of it that would be aggressive. And what a tumor basically is one cell that is trying to divide uncontrollably. And so all of the offspring, all of the daughter cells, of the cell that is dividing, all of the daughter cells are undergoing changes of their own that could potentially make them more aggressive. If one of those daughter cells “takes off”, you could have a very ugly tumor, but just in a subset of the cell. But when a surgeon takes out a biopsy, they grab the less aggressive part of the tumor. That’s why those clinical-pathological correlations are so important. Because what happens is a radiologist will say “This looks very, very aggressive” and the neurosurgeon says “Well, this is what I took.” And the pathologist will say “This is what you gave me, and what you see under the microscope is not aggressive.” So then they say A plus B does not equal C, even though it’s supposed to, so what’s missing? And then they’ll have to fill in the details.
Me: How important is getting the correct diagnosis to determining the proper treatment?
Dr. Crary: Right now there are only a couple things we can do for a patient with a brain tumor. We can do surgery. Surgery is great if you can remove the whole thing. There are certain types of tumors that are outside the brain that are immune to surgical resection alone. Unfortunately, in the brain the tumors can’t always be removed completely. Surgery alone works if the tumor is benign. If it’s a malignant tumor, they’ll require often chemotherapy and or radiation. Now it’s important, as a neuropathologist I don’t do these treatments, but I do know that there are a lot of side effects. It’s important to know that there are a lot of side effects, and people are scared of the side effects. And they should be! For example, radiation in the brain. It can get rid of tumors, but it can also cause tumors. Radiation is good because it is very effective at killing cancer cells. So it’s a balance. You don’t want to radiate a benign tumor. There’s a major source of medical liability in neuropathology. There are cases of misdiagnoses when a pathologist thought they were aggressive and called it a malignant tumor and they get it radiated and they turn a benign tumor into a malignant tumor. You don’t want that to happen. The other thing is chemotherapy. Chemotherapy also has side effects associated with that, like bleeding in the brain, nausea, vomiting, losing your hair. So making that decision, that’s really essential. You don’t want to treat a benign tumor with all these aggressive treatments with all these side effects. And with an aggressive tumor, it’s also the best chance that you have for extending life.
Me: How does understanding the pathology dictate the treatment?
Dr. Crary: The idea is pathology is all about prognosis. Pathologists are labelers, they’re namers. They will attach a label to every tumor. In the textbooks, it’s really nice and clean. But it’s not always like that in the real world. In the real world what matters most is the behavior of the tumor. We do our best to fit every tumor into the artificial categories that we have created. But there’s the whole idea of coming up with the prognosis. If there’s a patient with a tumor, and we tell them patients with similar molecular profiles generally live for about two years, that’s a bad prognosis. It’s nice to know that versus if we have another set of patients with another set of features with another set of molecular profiles, but those patients live on average up to five years, and we know it’s a benign tumor, we can pass that information onto the clinician. The clinician, being the neurologist and neuro-oncologist, will be able to better balance the side effects of the treatment versus the extension of life. So they know that the treatment will extend life a certain number of years on average paved on previous clinical research. So it’s all about us prognosticating on what the chances of living and being cured are.
Me: What is your role with the patient after their treatments are done?
Dr. Crary: Once they’ve been treated, brain tumor patients are generally followed; they really need to be. You need to have a relationship with your oncologist, neurologist, and neurosurgeon. You really need to come back and get rescanned periodically to see if the tumor has come back. The pathologist, after the first diagnosis is made, if the tumor comes back then they may need a second surgery. And we can be useful to determine whether the features of the tumor have changed. We’ll compare the original tumor with the second resection. That’ll be useful for a couple of reasons. Number one, it’ll tell you if it’s taken off, so to speak, if it’s done worse. If the tumor has evolved it can become more aggressive. We can give that information to the clinician and they can alter the treatment. The other thing that happens is that some patients, not all (it’s a minority, but it’s not insignificant), have cancer syndromes in their family, and they’re prone to multiple tumors. So they may have a new tumor that is now rising up, and that is important to know. We can diagnose a second tumor; usually that doesn’t happen though. The other thing is they may have a recurrence that can be many many years later, and the neurosurgeon comes in and takes out the tumor. And when we look at the histology, there’s no tumor there. It’s kind of a trick. What happens is these are almost always patients who were treated with radiation. And the radiation can have a side effect of damaging the tissue, we call it radiation necrosis. It can appear to the radiologist of being a recurring tumor. But in reality it’s just a small piece of tissue dissolving, so to speak, as a result of the radiation treatment. That’s really useful, because if it’s a recurring tumor, the patient may want to get another round of chemotherapy.
Me: What do you find most rewarding about your job?
Dr. Crary: The thing is there are two different aspects of it. The research is the most rewarding. The opportunity of making a lasting difference that can affect everybody is really really valuable. It’s what keeps me going. It’s very hard to be a scientist and a doctor at the same time. And there aren’t that many fields where it’s easy to do it. Unfortunately, it’s sad as a pathologist that we never see the patients, we never see their faces. They never get a chance to thank you. There’s a classic story of the tumor board. And the neuropathologist shows up at the tumor board. When it happened, there was a frozen section the previous week and it was really tricky. The neuropathologist said “This doesn’t look right” and the neurosurgeon thought it was a glioblastoma. And the neuropathologist put in all this extra work and did all these extra levels and figured out that it wasn’t a glioblastoma, and figured that it was some other tumor that was benign and he was very proud of himself. He went home patting himself on the back. And the next week at the tumor board, all the fellows have new watches. And the neuropathologist said “Why are you guys all wearing new watches?” And they said “Well remember that guy last week who had a really tough case? Well he owns a watch store and he gave us all new watches because we cured him.” And the neuropathologist said “Does anyone want to give me their watch?” and nobody did. Nobody knows about the neuropathologists, no one really knows that they even exist. So we do get a lot of satisfaction, but it’s not directed from patients. But it’s knowing that you’re doing science that’s the most important thing. Because your impact could potentially be beyond what you’re doing that that moment. It has the potential to reverberate to change care across the whole country. And that is a great feeling.