“Carcinoid Tumors - What's A Patient To Do?
The latest data on diagnosis, follow-up, and therapy”
By Professor Kjell Öberg, M.D
Saturday November 1, 2003, 10:00 a.m. - - approximately NoonGeorge Washington University
Ross Hall, Room 117
2300 Eye St NW
Washington, DC 20037-2336
Note: Dr. Öberg is professor (and now Dean), Medical Faculty, Uppsala University, Sweden. He is the head of the Endocrine Oncology Unit and specialist in Endocrinology and Internal Medicine. He’s the founder of the Endocrine Oncology Unit, with more than 20 years experience in the field of Neuroendocrine Tumors. Between 1986 and 1992, Dr. Öberg was Clinical Associate Director of the Ludwig Institute for Cancer Research and Coordinator of the European Neuroendocrine Tumour Network (ENET). He pioneered the treatment of carcinoid tumor patients with interferon and somatostatin analogues, and described for the first time (1988) the genetic deletion in MEN-1. Dr. Oberg received in 1991 the European Interferon Research Award. He has given more than 100 lectures at international meetings and published more than 300 papers within the research field.
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Good morning, everybody. I am really honored to be here. Usually to be invited to different scientific seminars and other meetings is an honor. But to be invited to the patients, I think that is an even greater honor. So thank you for inviting me.
What I will do this morning is to talk to you about some new features on how to diagnose and how to treat these neuroendocrine tumors. And I am not only going to talk about carcinoid - - because usually we include in neuroendocrine tumors the carcinoids and pancreatic tumors, lung tumors, and so forth.[1]
[slide 2: Neuroendocrine-GEP tumors]
These are actual tumors, and of course it’s necessary to concentrate these patients to doctors that are interested and also to different centers. We expect the neuroendocrine gastroenteropancreatic (gastro-entero-pancreatic) tumors to be about 1% of all tumors that are diagnosed a year. This high figure, 8.4 per 100,000, was done in Malmo, Sweden, where they autopsied all patients dying during a couple of years. And then they found that the incidence is very high - - indicating that a lot of patients are not dying from the carcinoid, but they are dying with the carcinoids. And a number of these patients were also those with appendiceal carcinoids, which are rather benign.
In the first SEER study (a U.S. National Cancer Institute series of surveillance studies), the incidence was 1.2 per 100,000. We did a study in 1990 on endocrine pancreatic tumors (another member of this group of neuroendocrine tumors), with an incidence of 0.3 per 100,000. And the prevalence of MEN1 (multiple endocrine neoplasia type 1), which is an inherited form of neuroendocrine tumors, is about 0.2 per 100,000.
[slide 3: Incidence of Carcinoid Tumors]
Next is a newer compilation of data done by Irv Modlin (from Yale) and published in the journal Cancer (volume 97, page 934) in March 2003, and it was a fine detailed analysis, and the incidence for white people is 2.58 per 100,000. That is the same as in Sweden when we look at clinically significant carcinoids. But you can see that black people, particularly black males, have a significantly higher rate (4.48 per 100,000).
If we look at the different types of carcinoid tumors, about 42% are found in the small intestine, 27% in the rectum, 25.3% are bronchopulmonary, and stomach tumors are 8.7%. The small intestine is still the most common area for development of carcinoid tumors.
[slide 4: The Neuroendocrine Cell]
This is a complicated slide just showing you that these are the cells where the tumor starts to develop. This is a normal neuroendocrine cell, and this cell has the capacity to produce a lot of different hormones. They are taking up precursors, like tryptophan, coming into the cell, and then they make a hormone called serotonin, and serotonin is then going out from the cell to the bloodstream, but it can also be sent into the gut lumen, and we don’t know exactly what activity it might have in the gut lumen.
In this process, of course there are a lot of enzymes which are involved in packaging hormones. And I’m coming back to chromogranin A (CgA), which is an important marker. It’s a packaging hormone within the cell.
We have another one called VMAT [vesicular monoamine transporter] (VMAT-1 and VMAT-2). Actually, what we are doing today is trying to develop a vaccine against midgut carcinoid. And this vaccine is seeing [targeting] VMAT-2, and we hope that this new vaccine will stimulate the immune system to attack this target.
[slide 5: Carcinoid Tumors/Secretary Products]
The carcinoids, if they are located in the midgut, have a very uniform secretion pattern: tachykinin, serotonin, chromogranin A are the most common secretory products. But if you go to the foregut, which means the lungs, the thymus, and the stomach, and so forth, you can see that they can produce almost every known peptide or amine, so these patients can develop different clinical syndromes; they can develop Cushing’s syndrome, acromegaly, and they can get the severe flushing due to secretion of histamine, and so on.
The hindgut, the rectal carcinoids, are more indolent. They produce hormones CgA, PP [pancreatic polypeptide], and HCG-alpha [human chorionic gonadotropin-alpha], but these hormones do not produce any clinical symptoms (carcinoid syndrome).
[slide 6: Carcinoid Syndrome]
If you look at the carcinoid syndrome, you know that it includes flushing, diarrhea, right heart failure, and bronchoconstriction. About 40% to 45% of patients present with the carcinoid syndrome. And we know that some of these agents are causing some of these symptoms. The flushing is mainly related to tachykinins. These belong to the family of neurokinins, and they give this reddish or blue-reddish color in the face. Diarrhea is related to serotonin and also to the prostaglandins, which are sometimes secreted. The right heart failure that we’ve studied quite extensively at our unit, and we know that TGFb (Transforming Growth Factor beta) is up-regulated on the right side of the heart, and might be responsible for the fibrotic process seen on that side. And then bronchoconstriction: in the only 10-15% of patients developing it, tachykinins might be responsible.
[slide 7: Two Views of Same Man]
This is a patient with typical carcinoid flushing (see slide) - - this is before and during flushing. You can see that he is more red in this area now. And this is often due to pentagastrin. You can provoke this flushing by giving the patient pentagastrin.
This is a patient with constant flushing. The problem for this guy is that he was a salesman traveling in Baltic countries selling table-tennis equipment, and when he wanted to do some business, every time he started to flush, the other person on the other side of the table thought he was doing wrong. That’s bad business [audience laughter]. But we solved that problem for that guy by giving him Sandostatin - - I can promise you.
[slide 8: Red-Faced Male]
Now this is constant flushing, but if you ask this guy “Are you flushing?” he says “No - - I can’t feel anything.” He is not feeling the flushing attacks.
[slide 9: Endocrine Pancreatic Tumors & Their Products]
I said that we have endocrine pancreatic tumors, other members of the neuroendocrine tumor group, and these are patients with different clinical syndromes. I will not discuss these in detail, but some of them are very spectacular. Those patients get multiple gastric ulcers, insulinoma, low blood sugar. This one, the Verner-Morrison syndrome, gives severe diarrhea. Some of the patients might have 15 liters of diarrhea [per day]. And of course they are the patients in intensive care.
The glucagonoma patients present with a special necrolytic migratory erythema, and you have also patients developing acromegaly and Cushing’s syndrome.
[slide 10: Back View of Gaunt Man]
This is a patient with a tiny, small glucagonoma - - only a 2-centimeter tumor in the pancreatic tail - - producing glucagon. He is a 42-year-old farmer from the southern part of Sweden. And what we see is the significant effects of glucagons, with this muscle wasting. It’s a catabolic hormone. You get a skin rash down here, also loss of hair, and loss of muscle. This is a farmer, 42-years-old, and what we did was we resected this tumor - - it was a tiny, small tumor, 2 centimeters - - and he became quite healthy afterward. I’ve seen him for 10 years now, and he is still working on his farm; he has recovered completely from the loss of muscle. So as you can see, these tumors produce a lot of factors which are so active in the metabolism in the body.
[slide 11: Neuroendocrine GEP Tumors - - List of Topics]
So what I will talk to you a little bit about is a tumor biology program we have developed in our unit; the importance of correct histopathology, biochemical diagnosis, and some neuroimaging procedures.
[slide 12: Molecular Genetics in Neuroendocrine Tumors]
This is a slide showing a lot of genetic changes in the tumor. People are asking how these tumors develop. We don’t know exactly how it happens. But we know that there is a range of different changes in the genome, in the genetic material inside the cells.
One area is the so-called MEN1 area on chromosome 11, where you have, in at least 30% of the patients, mutations of the gene. You have what we call loss of heterozygosity. A fragment of the gene might be lost, or also one of the chromosomes, or a part of one of the chromosomes might be lost. And as you can see, there is a lot of different changes within the cell. So there is not just one genetic change in these tumors. I think that is very important to remember.
[slide 13: Growth Factors in Neuroendocrine Tumors]
These tumors secrete a lot of growth factors. These are factors that stimulate the cells to divide and to continue to grow. Usually a regular cell is dividing 20 to 22 times, but then they start to grow. But these cells can then continue forever to divide, stimulated not only by growth factors, but also other factors.
[slide 14: The Emergent Integrated Circuit of the Cell]
And this is, I think, the most busy slide; someone called it a map of the Underground in London [audience laughter]. But actually this is a cartoon of how a tumor cell is regulated by a lot of different factors. So just to give you an idea, it’s not one factor that is stimulating; it’s a number of factors, and the endpoint is that they are stimulating the genome to split off and to make new tumor cells. So there are a lot of influences, and we call this thing the “signal transduction pathway.”
We have sorted most of this out at the moment, so now it’s for the medical industry to start to target different parts of this signal transduction pathway. What you will see in the future is that you will see a lot of new treatments coming which are actually targeting different important junctions in this signal transduction pathway.
[slide 15: Two Graphs of CgA and 5-HIAA for Two Patients]
I like to show this slide because carcinoids are not always the same. These are two patients coming to our ward at the same time - - two males the same age - - and they have a similar extent of disease, both [have] liver metastases, and you can see that they have also increased levels of urinary 5-HIAA. The level is also the same in this guy, but the scale is different because he had some high levels in the end.
And this guy was started on alpha-interferon and has now been treated for 15 years and is still controlled and is working full-time, and is doing wonderfully.
That other guy started on the same type of treatment, but he didn’t do so well. He continued to progress, so we had to do chemoembolization, and had to add somatostatin. We had to add cytotoxic agents, but despite all these efforts, he died within 7 years.
[slide 16: Two ki-67 Stains, One Above the Other]
And what was the difference between these guys? I think this is one of the explanations: this is the [top tissue] good guy doing well on alpha-interferon, and we can see some dark spots here. This is the ki-67 stain, which stains dividing tumor cells, and the first guy has very low proliferation; he has only a few dividing cells, and of course he is responding quite well to biological treatment.
This [bottom tissue] was the bad guy who didn’t do well on the treatment, and you can see a lot of dark spots indicating that he has a lot of dividing cells, a more aggressive tumor than the [other] one. With this [top tumor], you can live for 25-30 years. With this [bottom tumor], you have to have very significant treatment from the very beginning.
[slide 17: Neuroendocrine Tumors: Histopathology - - Tumor Biology]
So what we are doing at our center today is that we are doing tumor biology profiles on each patient. We take a biopsy the first time they come to us, and we analyze for the general neuroendocrine markers (chromogranin A, synaptophysin, neurospecific amylase). And of course we also analyze for the specific markers (gastrin for gastrinomas, serotonin for carcinoids), but we take these markers, proliferation marker ki-67, adhesion molecules (I will not try to talk about that, but CD44 is an adhesion molecule), and then we have angiogenic factors, VEGF [vascular endothelial growth factor], bFGF [basic fibroblast growth factor], TGF [transforming growth factor]-alpha, and what we are rather proud about is that we can analyze all the somatostatin receptors, the expression on the tumor cells, we have specific antibodies for receptors type 1 to type 5.