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Disease Factors Influencing Initial Treatment Approaches in NETs

Insights From:Jennifer Eads, MD, Case Western Reserve University; Matthew H. Kulke, MD, Harvard Medical School; Diane Reidy Lagunes, MD, Memorial Sloan-Kettering Cancer Center; Eric H. Liu, MD, FACS, Rocky Mountain Cancer Center; James C. Yao, MD, The University of Texas MD Anderson Cancer Center
Published: Monday, Feb 22, 2016


Transcript:

Matthew H. Kulke, MD:
If we take a step back from the genetics, which we’re all very excited about, for years we have also noted some just differences under the microscope. And these tumors have been classified as well differentiated, as moderately differentiated, as poorly differentiated. And that’s also something that’s shifted over time. Jennifer, can you explain your view of how you think about tumor differentiation and the histologic classification of neuroendocrine tumors?

Jennifer Eads, MD: I think, first of all, it’s important to take a step back and look at the primary site first and determine, is this something of pancreatic origin versus of bowel origin? And then, under the microscope, making a distinction between a well-differentiated tumor versus a poorly differentiated tumor is pretty significant because the treatment options are much different. In the well-differentiated population, we use agents, as James was alluding to, such as VEGF inhibition, mTOR inhibition, and cytotoxic therapies based on primary tumor site.

But in the poorly differentiated setting, we really only use systemic chemotherapy, and no targeted agents are useful in that disease. So I think that, histologically, we’re learning a lot more over the past few years that there really is a difference—not just among well-differentiated versus poorly-differentiated, but also amongst the poorly-differentiated group of tumors—that there’s large cell and small cell and that those may also not be the same disease entity.

Matthew H. Kulke, MD: If you have a patient in front of you and you’re looking at the pathology report, what are the key things you look at to help you decide if this is well differentiated or poorly differentiated?

Jennifer Eads, MD: The first thing that I look for is what the pathologist called it: well differentiated, moderately differentiated, or poorly differentiated. And then to make sure that it’s being classified as a truly well-differentiated tumor versus a poorly-differentiated tumor, I look at supplementary features such as the Ki67 proliferative index and the mitotic rate to make sure that it seems that a tumor is really more in one class over another, and then that again the primary site is also critical.

Matthew H. Kulke, MD: So you mentioned the Ki67, which is the proliferative index. In your mind, what’s the cutoff that should be used or that is used? This is an area of controversy.

Jennifer Eads, MD: The current definition would say that a poorly differentiated tumor has to have a Ki67 of greater than 20% all the way up to 100%, which is a very broad range. Whereas the well- and moderately-differentiated tumors would be less than 20%. There’s sort of this borderline in between where sometimes patients can have a well-differentiated histology but may have a Ki67 that technically classifies them as a high-grade or poorly-differentiated tumor. And so, I think that gray area is difficult and is the area of controversy that you’re speaking of.

Matthew H. Kulke, MD: Yeah. It’s hard to know these high-grade, well-differentiated tumors, an emerging class, and it’s tough to know what to do with those. James, do you know what to do with those patients?

James C. Yao, MD: That’s always a tough one. I think that sometimes the clinical features will help you. If the patient is coming in, 60% of their liver is replaced with the tumor and the LDH is a bit elevated; usually we want to treat the component that you cannot afford to leave untreated. So even though sometimes there’s some question, we may decide to go with a poorly differentiated regimen.

We had one case recently where the patient three, four years ago had a grade 2 small bowel carcinoid resected but now is back with a metastasis which got resected again, biopsied again, got called grade 3 or poorly differentiated, just over the line, Ki67, 30%. That’s a patient, especially in the setting of lower-volume disease, you’d like to just follow, observe, and the patient is fine. The tumor is behaving like a well-differentiated tumor; it is stable.

Matthew H. Kulke, MD: Another way that people have classified these tumors is whether or not they secrete hormones. There’s this term about functional versus nonfunctional tumors. I’m going to turn to Diane. Do you treat these patients differently whether they’re so-called functional or nonfunctional? Is this a real difference?

Diane Reidy-Lagunes, MD: Absolutely. One of the first things I tell my patients when I see them, particularly when they have hormone-secreting or functional tumors, is that, unfortunately, that’s generally when they come to me in the stage IV setting. Now, there are functional tumors, for example, that start in the pancreas that can be resected for sure and those should go to the surgeon. But in the setting of a stage IV metastatic or hormone-secreting functional tumor, my job is to control their disease but also maintain their quality of life. And some of these hormone-secreting tumors can be quite debilitating. So we really need to get on top of those patients so that we can better improve their quality of life.

Unfortunately, many of them have come after being undiagnosed for many years, and it can be very frustrating for them. So there’s very different hormones that can actually be secreted depending on where the cancer started. If the cancer, for example, starts in the pancreas, a pancreatic neuroendocrine tumor, those tumors can produce insulin. So they can have potentially life-threatening hypoglycemia, a pro-insulin, the derivative. If you have someone with low sugar, you should think about insulin and pro-insulin; glucagon, which is pretty uncommon; gastrinoma, which can have high morbidity with a potential for severe ulcers. And then the rare, the VIPomas and some other very uncommon hormones. Those hormones, decisions as to what biomarkers I decide to take, are really driven by the clinical symptoms that the patient comes in to the office with.

In contrast, if the tumor starts outside the pancreas or in the small bowel—or certainly in the lung, as well—those patients can have hormone-secreting cancers that are traditionally what we call the carcinoid syndrome. We thought that maybe it’s serotonin, but, in fact, there’s probably other tachykinins and other types of hormones that contribute to those carcinoid syndromes, which is also quite debilitating. And those patients will have flushing and diarrhea as their main symptoms.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
If we take a step back from the genetics, which we’re all very excited about, for years we have also noted some just differences under the microscope. And these tumors have been classified as well differentiated, as moderately differentiated, as poorly differentiated. And that’s also something that’s shifted over time. Jennifer, can you explain your view of how you think about tumor differentiation and the histologic classification of neuroendocrine tumors?

Jennifer Eads, MD: I think, first of all, it’s important to take a step back and look at the primary site first and determine, is this something of pancreatic origin versus of bowel origin? And then, under the microscope, making a distinction between a well-differentiated tumor versus a poorly differentiated tumor is pretty significant because the treatment options are much different. In the well-differentiated population, we use agents, as James was alluding to, such as VEGF inhibition, mTOR inhibition, and cytotoxic therapies based on primary tumor site.

But in the poorly differentiated setting, we really only use systemic chemotherapy, and no targeted agents are useful in that disease. So I think that, histologically, we’re learning a lot more over the past few years that there really is a difference—not just among well-differentiated versus poorly-differentiated, but also amongst the poorly-differentiated group of tumors—that there’s large cell and small cell and that those may also not be the same disease entity.

Matthew H. Kulke, MD: If you have a patient in front of you and you’re looking at the pathology report, what are the key things you look at to help you decide if this is well differentiated or poorly differentiated?

Jennifer Eads, MD: The first thing that I look for is what the pathologist called it: well differentiated, moderately differentiated, or poorly differentiated. And then to make sure that it’s being classified as a truly well-differentiated tumor versus a poorly-differentiated tumor, I look at supplementary features such as the Ki67 proliferative index and the mitotic rate to make sure that it seems that a tumor is really more in one class over another, and then that again the primary site is also critical.

Matthew H. Kulke, MD: So you mentioned the Ki67, which is the proliferative index. In your mind, what’s the cutoff that should be used or that is used? This is an area of controversy.

Jennifer Eads, MD: The current definition would say that a poorly differentiated tumor has to have a Ki67 of greater than 20% all the way up to 100%, which is a very broad range. Whereas the well- and moderately-differentiated tumors would be less than 20%. There’s sort of this borderline in between where sometimes patients can have a well-differentiated histology but may have a Ki67 that technically classifies them as a high-grade or poorly-differentiated tumor. And so, I think that gray area is difficult and is the area of controversy that you’re speaking of.

Matthew H. Kulke, MD: Yeah. It’s hard to know these high-grade, well-differentiated tumors, an emerging class, and it’s tough to know what to do with those. James, do you know what to do with those patients?

James C. Yao, MD: That’s always a tough one. I think that sometimes the clinical features will help you. If the patient is coming in, 60% of their liver is replaced with the tumor and the LDH is a bit elevated; usually we want to treat the component that you cannot afford to leave untreated. So even though sometimes there’s some question, we may decide to go with a poorly differentiated regimen.

We had one case recently where the patient three, four years ago had a grade 2 small bowel carcinoid resected but now is back with a metastasis which got resected again, biopsied again, got called grade 3 or poorly differentiated, just over the line, Ki67, 30%. That’s a patient, especially in the setting of lower-volume disease, you’d like to just follow, observe, and the patient is fine. The tumor is behaving like a well-differentiated tumor; it is stable.

Matthew H. Kulke, MD: Another way that people have classified these tumors is whether or not they secrete hormones. There’s this term about functional versus nonfunctional tumors. I’m going to turn to Diane. Do you treat these patients differently whether they’re so-called functional or nonfunctional? Is this a real difference?

Diane Reidy-Lagunes, MD: Absolutely. One of the first things I tell my patients when I see them, particularly when they have hormone-secreting or functional tumors, is that, unfortunately, that’s generally when they come to me in the stage IV setting. Now, there are functional tumors, for example, that start in the pancreas that can be resected for sure and those should go to the surgeon. But in the setting of a stage IV metastatic or hormone-secreting functional tumor, my job is to control their disease but also maintain their quality of life. And some of these hormone-secreting tumors can be quite debilitating. So we really need to get on top of those patients so that we can better improve their quality of life.

Unfortunately, many of them have come after being undiagnosed for many years, and it can be very frustrating for them. So there’s very different hormones that can actually be secreted depending on where the cancer started. If the cancer, for example, starts in the pancreas, a pancreatic neuroendocrine tumor, those tumors can produce insulin. So they can have potentially life-threatening hypoglycemia, a pro-insulin, the derivative. If you have someone with low sugar, you should think about insulin and pro-insulin; glucagon, which is pretty uncommon; gastrinoma, which can have high morbidity with a potential for severe ulcers. And then the rare, the VIPomas and some other very uncommon hormones. Those hormones, decisions as to what biomarkers I decide to take, are really driven by the clinical symptoms that the patient comes in to the office with.

In contrast, if the tumor starts outside the pancreas or in the small bowel—or certainly in the lung, as well—those patients can have hormone-secreting cancers that are traditionally what we call the carcinoid syndrome. We thought that maybe it’s serotonin, but, in fact, there’s probably other tachykinins and other types of hormones that contribute to those carcinoid syndromes, which is also quite debilitating. And those patients will have flushing and diarrhea as their main symptoms.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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