Transcript:Brian A. Van Tine, MD, PhD: Dr. Randall, as our lead surgeon and one of the lead surgeons in the world, I think it’s always very important that our surgical colleagues are dramatically involved with the treatment of sarcoma because usually you’re the gatekeeper in a lot of this. It would be good to ask you what your typical workup is for a patient suspected of having a sarcoma.

R. Lor Randall, MD, FACS: Sure. Generally, a patient will present to a primary care doctor or an orthopedic surgeon or a general surgeon with a mass that is growing, something that is changing, or maybe there is abdominal distension and discomfort. Like we all learned in medical school, a good history and physical is the first thing we do. If the mass has been there for a long time, it’s less likely to be a malignant process or an aggressive malignant process. If it’s rapidly changing, the acuity is obviously there and something needs to be done about it. It’s very important to stress the history and physical. I always joke with my trainees that it’s the most important test we order.

With that being said, we generally do recommend plain film imaging or radiographs, particularly orthogonal views in the extremity, because that can shed a lot of information in the era of cost containment. If it’s completely radiolucent on an extremity film, it is very likely to be a lipomatous, well-differentiated liposarcoma at the worst, versus if it has some calcifications, the acuity is probably there and it’s a synovial sarcoma or, potentially, a higher grade liposarcoma.

So, radiographs are important and they’re inexpensive. Beyond that, we do think that advanced imaging is important. Before any biopsy is done, we would generally recommend an MRI in the extremity—sometimes in the pelvis—but often a CT scan is adequate. If we really suspect that it’s a sarcoma, we prefer getting a chest CT first before any intervention is done.

If you’re seeing the patient in the clinic and you’re going to do a biopsy because it’s amenable to that, you can hold off on some of that advanced imaging. We certainly recommend getting advanced imaging of the primary tumor before any intervention is done. As we all will talk about, the most common site for these to metastasize is the chest, and so we do think chest imaging is of paramount importance.

Brian A. Van Tine, MD, PhD: I agree. It’s always important to remember that we hear lots of interesting things—car doors do not cause hematomas unless you’re on a blood thinner. It’s very important to always do that history and physical because these masses sometimes just get found by car doors. Otherwise, surgeons go in and explore the middle of a sarcoma. If you don’t do these right, you could have inferior outcomes. As we’re moving through from the history and physical to imaging, I think the next most important thing is really an understanding of diagnosis and grading of these tumors and really what that means. Dr. Jones, can give us a little insight about how to approach that?

Robin L. Jones, MD, MRCP: Thank you. As Dr. Patel mentioned, these are heterogeneous and a complex group of diseases, so it’s very important to obtain a clear and accurate histological diagnosis prior to starting treatment. Each histological subtype can have different clinical behavior, different underlying biology, and a different treatment approach. It’s important to have an experienced pathologist make the diagnosis prior to starting treatment.

The World Health Organization classification system is generally regarded as the standard, and it’s very important that the newer techniques, such as molecular techniques, are incorporated into the diagnosis, as well. In terms of grading, the most common grading system that is used is the so-called French grading system, incorporating 3 grades—high, intermediate, and low—based on tumor differentiation, necrosis, and mitotic count. The grading system has implications in terms of prognosis.

Brian A. Van Tine, MD, PhD: I think that’s really, really important. In the year 2015, with our ability to sequence everybody and our ability to look at all sorts of molecular markers, we’re involved in a very complex world and a very rare group of tumors. Jonathan, what are the goals of molecular testing, and how do you incorporate that into your practice?

Jonathan C. Trent, MD: Good question. And thank you for the invitation to participate in the panel. I agree with Shreyaskumar and Robin regarding the complexity of sarcomas. In fact, there’s over 200 different types if you look at the pathology textbooks.

Molecular testing is underutilized in the world of sarcoma, and it can help in diagnosis. For instance, there are a number of histologies that have specific genetic abnormalities, such as gene amplification and MDM2 in liposarcomas. This testing can not only help make the diagnosis, but there could also be therapeutic relevance. For instance, in the era of targeted therapies, we are now able to pair specific molecular events, such as a mutation in a gene called KIT in gastrointestinal stromal tumor with a therapy, such as imatinib, sunitinib, or regorafenib, to precisely treat patients based on the molecular rearrangements or abnormalities. This is particularly pertinent to sarcoma, since we have so many histologic subtypes that have a very high frequency of molecular abnormalities.

Andrew J. Wagner, MD, PhD: I think it has been well stated that sarcoma is a huge number of different tumors, and just like you would never classify carcinomas as one disease, you wouldn’t lump breast carcinoma and prostate carcinoma into the same bucket. However, we do that in sarcomas where we have different diseases that we lump together as sarcomas because they’re so rare and they can have similar presentations, but markedly different genetics and different behavior. One of the key parts is to make sure, as Robin was saying, that an expert in sarcoma pathology is reviewing the biopsy material, especially when it’s obtained at a community hospital where pathologists may only see a few cases of these in the course of their career. The hierarchical testing that they do is based not just on the specimen they have, but also based on the presentation of the patient. So, it’s also very important that the medical and surgical teams are in communication with the pathologist about the location of the tumor, the behavior of the tumor, and those other aspects.

A multidisciplinary approach is really important! Their testing often looks at the shape of the cells first and where it is located; then that helps drive other testing, such as immunohistochemistry and other molecular testing. We’re still in the very early stage as far as wide-scale genomic testing that’s performed either for research or for commercial purposes right now. In our experience—and I think a lot of the other centers are doing this as well—when we’ve sequenced large panels of genes, we’ve seen a disappointingly few number of mutations that we didn’t already expect in sarcomas. I think it’s still a very important area for research.

But, personally, I’m not yet ready to order huge screening panels for genetic mutations, but instead to stay focused, as Jon was just talking about, based on the appearance of the tumor or suspected appearance of the tumor and the possible mutation types.

R. Lor Randall, MD, FACS: An illustrative example is in the pediatric realm, a very practical fusion product, the fusion-associated tumors, rhabdomyosarcoma, where historically they have been classified as alveolar versus embryonal. Now, the diagnosis is actually fusion gene—driven and that’s the gold standard. If there’s a PAX- or FOXO-associated tumor that may have some embryonal features, they’re still going to call it an alveolar rhabdomyosarcoma. It’s really that way in the clinical trials moving forward through the Children’s Oncology Group, etc, who all are doing this. I think synovial and Ewing’s tumors are following suit. It really is boots on the ground—this is happening today, not just as some academic ivory tower concept.

Robin L. Jones, MD, MRCP: I’d like to just highlight the importance of a multidisciplinary team in making the diagnosis, as Andy said. Very often, it’s important to have the clinical features and the radiological features, together with the pathology report, to make the diagnosis. That’s really, really important to highlight!

Brian A. Van Tine, MD, PhD: It’s important to highlight the fact that the one thing that these tumors are all mistaken for are melanomas, and melanomas are mistaken for sarcomas. If you make that error, you’ve radically altered a treatment path for a patient. This is why having a highly experienced sarcoma pathologist confirming what you are seeing is really that important. It’s very hard to have the discussion we’re having today because we’re talking about at least 80 different diseases that probably break up into 6 different categories of each one. And we go from probably one of the best understood tumors on the planet, which is the gastrointestinal stromal tumor, where we understand what mutations go with what drug, to the undifferentiated pleomorphic sarcoma where we’re still doing lots of clinical trials which we’ll get into later.

Transcript Edited for Clarity