DR. BRENNAN: Jonathan, why don't you sit down for a moment, because I think this subject is so different from what you are going to talk about, that we should have one or two questions. This is going to come up again in the group that looked at local therapy. Bob, do you want to comment already? You overlapped significantly.

DR. BELL: I am Bob Bell, Toronto, Princess Margaret Hospital. We have also got a recommendation regarding best practice around the issue of tumor banking and biopsy.

My concern is that, if the pathology group recommends that freezing core biopsies is sufficient for further studies later, especially with respect to tumor banking, that we are fooling ourselves.

I think that current practice in terms of cDNA microarrays, for example, for sarcoma requires that each specimen is assayed for appropriateness with a frozen section prior to extracting RNA from that.

If you are going to do a frozen section from a core sample to ensure it is not necrotic or it does represent tumor, you are going to have nothing left.

I am just concerned, with the increasing use of neoadjuvant therapies, if we have this recommendation out there that frozen core biopsies are sufficient as a tumor banking resource, that IRBs are going to shut down the potential for doing open biopsies to obtain material, and that we are just fooling ourselves when it comes to quality control of tumor bank material. We are going to have nothing that is going to be valid for microarray studies.

DR. BRENNAN: Bob, let me take the chairman's prerogative. I think we should have that specific discussion after you say what we think, and we will fuse those two together, because I think we can easily come to agreement. They are very complementary.

DR. WEISS: Let me just pop one other thing up. I think we realize that, if it is going to be a core biopsy, it is going to have to be several of them, so that we have some aliquot of tissue.

This was, of course, designed for expediency, cost, and all the other issues that I think confront us.

DR. BRENNAN: We did address that in Bob's group in a little bit different way. That is, obviously you don't need other than a diagnostic core for the patient coming immediately to operation, where they will give you the ultimate biopsy. I think it is a matter of just how we phrase it. Other specific questions for Sharon?

I had one. In your reporting, you described histological type. I see nothing about subtype and yet, liposarcoma --

DR. WEISS: Well, histologic typing includes subtyping of liposarcoma.

DR. BRENNAN: For the pedestrian people, I think you need --

DR. WEISS: Liposarcoma, myxoid type.

DR. BRENNAN: I think you need to say that, if that is really what we want. Did you come to struggle with what is grade?

DR. WEISS: Well, what is grade. We all, I think, grade lesions. I think many of us do it by our own systems. I suspect the French system is the most reproducibly used grading system currently.

My own feeling is that probably pathologists by almost any grade can separate something that is low -- that is, grade 1 -- from grade 2 and 3. Given the current AJCC recommendations that Raph was the chair to, we did suggest that all grade twos and threes become high-grade. So, it may be less of a problem now.

DR. BRENNAN: Grade is a little bit, in my mind, like class. It is easy to recognize and hard to define.

DR. BENJAMIN: Going on to the question, the last time I looked at the AJCC system, there are four grades of sarcomas.

I have never seen the four-grade sarcoma system. The French system doesn't use it.

DR. BRENNAN: The gentleman to your left will correct that, Dr. Benjamin.

PARTICIPANT: Functionally, there are three grades.

DR. WEISS: And 2 and 3 are high-grade. So, it is real easy. There are two grades.

DR. BRENNAN: In New York, we call that low and high.

DR. HEALEY: What is an acceptable major error rate in diagnosis? If we are accepting 30 percent, I think this is, just once, a recommendation that has legal consequences.

DR. WEISS: I think the 30 percent -- I believe it was Paul Sorensen who gave that number. That would be a patient that gets referred to one of their protocols, and the case is reviewed and the diagnosis revised. In a sense, the patient gets salvaged under those circumstances by having the diagnosis revised appropriately, at least one would hope.

I would like to see far, far less than that as a tolerance level for major diagnoses. I think it should probably be less than five percent, probably well under five percent.

DR. HEALEY: How do we achieve that?

DR. WEISS: My personal bias is that a lot of these lesions should be sent off for second opinions. I think people like Chris and myself and Christina and Marc, who see large numbers of consult cases, feel a little bit squeamish here, because it is a bit of a conflict of interest for me to say, you should all be sending your cases to me because you don't know what you are doing. That has, I think, some ramifications for us.

So, at the moment, our group, I think, felt that second opinions should be used judiciously. This is an area where I think they should be used more generously than, say, for example, lung cancer or colon cancer, where I think people see a lot of it and they can do it very easily. This is not the same case.

DR. BAKER: Sharon, as I remember, when you chaired the Pathology Committee of the Southwest Oncology Group, there was an analysis -- I mean, getting to the definitions that you showed, I think it is probably time to redefine them.

The first kind of error is a major error, meaning that the patient didn't have any kind of sarcoma. They had a carcinoma or a lymphoma. There is no question that that actually is destructive to many efforts, including therapeutic trials. That was around five or 10 percent as I remember it.

Then there were about 20 to 30 percent that were called errors, and these were changing histological subtype.

Sometimes, however, that was very important. And as we think about therapeutic trials today, if you were designing a trial for synovial sarcomas -- and let's imagine a monophasic synovial cell -- suppose that wasn't synovial cell. Then, that minor error becomes gigantic. So, I might urge that the pathology community become even more specific about what that error rate is, to tack onto John's question.

DR. WEISS: That is an excellent point. I think all studies in the past have dealt specifically with what you say, a major change from a major diagnostic group, lymphoma to sarcoma, or a change from benign to malignant, or a change of more than one grade, such that low comes to high.

You are right, with tumor-specific therapies, a change in what we previously said was a minor change -- synovial sarcoma to fibrosarcoma -- may, in fact, buy the patient an important therapy and, hence, that is a major error.

DR. BRENNAN: This can be addressed and I think it will come up again in the third session. We can't tell people what to do. We can't tell you that you cannot be treated by Dr. X or Y.

What we can do, I think, is to say that at the time of the primary identification of a tumor suspected of being a sarcoma, that that should be dealt with at an institution that has the facilities for appropriate imaging, pathology, treatment, outcome analysis. In other words, more and more moving the opportunity that, before you even see it, that would ensure the appropriate biopsy.

I think, Robert, if you brought that up in your session, we might be willing to come to grips with this difficult question of referral, but done in the context of the patient should be allowed the opportunity to be cared for at an appropriate facility that has all the appropriate diagnostic tools, would help solve that.

DR. LADANYI: Actually, getting back to the question of frozen tissue, before we even get to the issue of whether we should be using core biopsies or open biopsies, I think we need to issue a strong call out to the community that we need to get frozen tissue, any frozen tissue.

There are so many cases that come in with only paraffin. As you know, it really makes the molecular diagnosis much harder.

So, I think before we even get to what kind of frozen tissue is best, I think we really need to emphasize to the community, where a lot of the initial biopsies are done, that we need to get frozen tissue in all the cases. It is like what is already common practice in pediatric surgery, to get frozen tissue on virtually any tumor that they operate.

DR. BRENNAN: We will address that later this morning. Other specific questions for Sharon?

DR. HOGENDOORN: Dr. Hogendoorn, Leiden. Addressing the question of grading -- as you said in one of your slides, there is a discrepancy in grading of high numbers in fine needle aspirations and core and needle biopsies.

When we stick to the French criteria, it is simply impossible to put them on needle biopsies. So, the figure given is, I think, a bit wrong because you simply can't grade according to the French system on any biopsies, because they are too small.
DR. WEISS: I think if you read the French paper, they say they devised the whole grading system based on excised specimens.

DR. HOGENDOORN: Just saying there is a grading problem in needle biopsies is not acknowledging the fact that you can't grade on needle biopsies.

DR. WEISS: I would modify it a little bit. I think if you stick a needle into a mass and you get out sheets of highly pleomorphic cells, like type A with necrosis, the chance that that needle went through a very small microscopic focus in what was otherwise a low-grade legion is very low. I think you can, with a pretty good level of accuracy, say that is probably a high-grade lesion.

I think the flip side is less true. If you put your needle in a low-grade lesion, you can't assure that there aren't higher-grade areas.

DR. HOGENDOORN: I just make my comments for the notes, because your slide is saying there is a discrepancy percentage in needle biopsies. That is a logical point.
DR. BRENNAN: We will address it in the recommendations. Thank you.

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