Sarcoma and Bone Cancer Awareness Month

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Becca Battisfore:

Welcome to the latest edition of the College of American Pathologist CAPcast. I'm Becca Battisfore, Content Specialist with the CAP. In this episode, Doctors Edgerton and Fanburg-Smith will be talking about bone and soft tissue cancers.

July is Sarcoma and Bone Cancer Awareness Month. Sarcomas are rare cancers in which malignant cells form in the bones or soft tissues. There are currently 70 different subtypes of sarcomas divided into two categories, soft tissue sarcomas and bone cancers. Medical News Today has found that 1% of all new cancers diagnosed each year are bone and soft tissue cancers. The American Cancer Society estimated that of the sarcomas diagnosed each year approximately 13,000, are soft tissue with another 3,500 as bone cancers. And now I'll let our guests introduce themselves and dive into the questions.

Dr. Mary Edgerton:

I am Dr. Mary Edgerton. I am an anatomic pathologist. I worked at MD Anderson for, I think 17 years before I retired recently. But I didn't completely retire. I have moved to the University of Nebraska where I'm heavily involved with pathology informatics and some breast pathology. Talking about the electronic cancer protocols and cancer is a subject that I am fascinated by and I have worked on for many years. I am actually the chair of the Pathology Electronic Reporting Committee, which formulates the electronic models for the cancer protocols. We are coming out with some updated protocols for bone and soft tissue, and so we have invited Dr. Julie Fanburg-Smith to tell us a little bit about osteosarcoma and soft tissue tumors. Yes, those tumors that strike fear in the heart of every resident. Oh my gosh, it's just some pink stuff with just a few nuclei. What is this? So let me let Dr. Fanburg-Smith introduce herself and then we'll talk about osteosarcoma and soft tissue tumors.

Dr. Julie Fanburg-Smith:

Great. Well thank you Dr. Edgerton for this kind invitation to speak with you today. Just to give a little background about myself, I'm currently a professor of pathology pediatrics in orthopedics at the Penn State Health College of Medicine Children's Hospital, Milton S. Hershey Medical Center. There, I do a lot of things. I wear a lot of hats. So I'm actually a senator, the chair for the academic affairs and I direct the musculoskeletal pathology unit. I really love teaching and we have a lot of trainees, anywhere from visiting high school students to college students to medical students and residents, of course, I teach every day. We also do research together. And we collaborate on several types of interesting areas, anywhere from non-neoplastic sarcoma neuropathic arthropathy mouse model to studying tumors including these very new tyrosine kinase fusion sarcomas. We can talk about these in a minute as we go through some of the newest and targetable sarcomas that are really interesting.

I usually have a very specific approach to diagnosis and we'll talk about that also as we go along. And I'm involved in several committees, but most importantly for the CAP I have been involved with CAP for many years. I've given soft tissue seminars, but I also notably was a member of the search path committee and wrote some of the PIP cases and that was very enjoyable, a great group. And currently I am part of the cancer committee and I also help with the biomarker reporting. And we're currently working on, this very minute, we're working on the bone and soft tissue protocol. So this is going to be an exciting time for bone and soft tissue.

Dr. Mary Edgerton:

Oh, excellent. Well, to start, bone and soft tissue tumors are not very common. Can you just tell us a little bit? And you also mentioned you're a pediatric pathologist, and I know that the pediatric soft tumors are a completely different textbook than the adult soft tumors. Can you just tell us a little bit about the population's most affected by, and let's start with osteosarcoma and focus on that?

Dr. Julie Fanburg-Smith:

Sure. Thanks for asking. There's many bones in the human body, 206. And probably almost all of them can develop osteosarcoma. And osteosarcoma is the most common type of primary bone malignancy in children and young adults, so that's the age population. Osteo we know is the word for bone for the Greek word, and sarcoma is a malignant tumor that involves connective tissue, including bone, cartilage, fat, vessels, nerve and muscle.

There's two age peaks for osteosarcoma, particularly for conventional high-grade osteosarcoma, which is the most common types. These mainly occur in children, teenagers, and young adults between the ages of 10 and 24. They arise in the metaphysis of the appendicular or long bones, usually around the knee. So a classic scenario is that a child will be playing soccer or something to get hit in the knee by a ball. They go in for radiologic imaging and unfortunately discover that they have a osteosarcoma only to think back that all that pain they had for the last several months was probably not sports related and most likely due to the tumor. And so that's the first group in the most common group.

The second group of osteosarcomas occur in the axial or central skeleton, which is the jaw, the spine, the pelvis, and these are usually in older adults, anywhere between 65 and 74. These also when we call something in soft tissue such as an extra skeletal osteosarcoma, these may even occur in an older age group like in the 80s. So that the types of osteosarcomas that we usually think about as separating high grade and low grade, and there's several different subtypes.

Dr. Mary Edgerton:

One of the other things that I remember from my residency is you need to have an x-ray of the specimen. So can you just tell us a little bit about how you start to evaluate the specimen once you get it?

Dr. Julie Fanburg-Smith:

Absolutely. Yeah, absolutely. We work very closely with our musculoskeletal radiologists On a daily basis. I usually talk with them or meet with them once a day and go over all of the bone and soft tissue cases. And so the diagnosis of bone tumors particularly requires a clinical radiologic and pathologic correlation diagnosis. We never make the diagnosis under the microscope without looking at the radiologic imaging and to get the clinical history. And this goes for many subspecialties, but particularly for bone and soft tissue. And we'll talk in a minute, when we talk about treatment, I'm going to talk about our team that we work with, the sarcoma group that we work with on a regular basis. And we meet together and go over all of the cases that we have, particularly sarcomas.

Dr. Mary Edgerton:

I know that this podcast is for pathologists, but I always like to mention that a lot of patients don't realize who pathologists are and what they mean to the patient and how integrated we are. It's as though you look at a picture of all your doctors and there's this missing face, which is us, the pathologists. But just you did mention something about different subtypes of osteosarcoma. So let's go into that a little bit.

Dr. Julie Fanburg-Smith:

So basically, we have the central conventional osteosarcoma, which is the most common type, and that's usually in the long bones. And then we have a low grade central, or sometimes it more commonly manifests on the surface. It's called a parosteal osteosarcoma, which is a low-grade osteosarcoma. And these have a very distinctive and characteristic finding. By FISH, we can see an MDM2 amplification to help make the diagnosis. These can be particularly tricky in a small biopsy, and so sometimes MDM2 can be very helpful in addition to the morphology. The difference between the two subtypes, high versus low grade, including the high grade to see features of malignancy, high grade malignancy in the background for a high grade osteosarcoma, including polymorphism, cytologic atypia, increased mitosis with atypical forms, or sometimes there's a round cell population or some other type of population that's making or producing a woven bone or osteoid, which is the characteristic malignant bone. The bone itself isn't malignant, but the production of the bone by malignant cells makes it a osteosarcoma or malignant bone tumor.

Then the low-grade variants look very bland deceptively. So they have spindle cells that are bland and run parallel to the longitudinal slabs of bone. Sometimes the bone is woven or even lamellar. There might be a rare mitosis, but not usually many mitoses. And in addition, there might be mild atypia like we see in a atypical lipomatous tumor or well differentiated liposarcoma that has the same MDM2 amplification. And we may see this in an osteosarcoma.

But if not, it's very bland and it can mimic other benign fibrosus lesions. There's several subtypes of that as well. Then the other types, including the central high and low grade and the surface parosteal osteosarcoma, PAR, is periosteal osteosarcoma, which is also a surface tumor bone and tends to be intermediate grade. It's the only place we actually give an intermediate grade to osteosarcomas. And it has chondroblastic or cartilage features. This is also on the surface of bone. Then there's also a high-grade surface osteosarcoma. And finally there are secondary osteosarcomas that may arise in patients with other either previous radiation or other bone lesions, including Paget disease, infarction, osteomyelitis, orthopedic implants, and these secondary osteosarcomas tend to occur in an older age group than the conventional central osteosarcomas.

Dr. Mary Edgerton:

I work in breast cancer and we're always looking for or certainly evaluating after someone's had treatment for a radiation induced angiosarcoma. And you have to imagine my surprise when I found a radiation induced osteosarcoma in the breast, and I talked to our imaging radiologist and she said, "Yes, radiation-induced osteosarcoma is the most common form of a radiation-induced sarcoma." And that was an interesting factoid to me.

Dr. Julie Fanburg-Smith:

Well actually, it's not the most common. The most common radiation-induced sarcoma is a very high grade pleomorphic, almost undifferentiated pleomorphic sarcoma, UPS, that is without bone formation and then followed by angiosarcoma and then finally osteosarcoma, malignant peripheral nerve tumor, et cetera. But usually it's a very high-grade tumor.

And it has elevated P53, which is interesting. These are found many years after the original radiation, sometimes up to 30 years later. It's very interesting. But it's rare. Osteosarcomas are rare, but osteosarcomas rising in radiation are exceedingly rare.

Dr. Mary Edgerton:

Oh, okay. I am corrected to the right path now. And this was actually a woman who had had Hodgkin's disease and had intensive radiation to the chest area, whereas the post-surgical or the adjuvant radiation in breast cancer is less radiation, but then can result in angiosarcoma.

You started to talk about the MDM fusions, and I want to go back to that because molecular testing is really changing the landscape of cancer diagnosis and cancer therapy. So what is the MDM infusion and tell me more about what's happening with molecular findings and how they're impacting precision medicine and therapy.

Dr. Julie Fanburg-Smith:

We use a lot more molecular and bone pathology than we ever have before. One of my colleagues, Adrienne Flanagan, whose name I'm mentioning now, Dr. Adrienne Flanagan from England, she has described many of the molecular events that occur in benign bone tumors as well as malignant. And it's helpful to separate these, especially if you have a benign bone tumor to make sure it's benign by their molecular signature.

MDM2 amplification has been well known to occur in a large subset of the low-grade osteosarcomas, whether they're intraosseous or central or if they're on the surface or paraosteal. And so we do use that quite frequently. It's the same amplification by FISH that we see in a group of liposarcomas, and so it's very helpful to use this method. At our place, we actually don't... currently, our molecular lab is being built again with a new pathologist and we're building up the use of these techniques, in-house. But right now we do the technical outside and we read the MDM2 FISH ourself on these cases.

But in general, moleculars use tremendous amount now. In fact, I have a case that is a very challenging case and I have markers for molecular events that I can use for both osteoblast and osteoblastoma and for chondroblastoma in separating it from an epiphyseal lesion, clear cell chondrosarcoma. So sometimes we use the benign molecular to exclude it from something malignant.

Dr. Mary Edgerton:

And this is a fascinating area. How does this molecular profile impact treatment?

Dr. Julie Fanburg-Smith:

Oh, tremendously.

Dr. Mary Edgerton:

Can you talk about that?

Dr. Julie Fanburg-Smith:

Yeah, sure. And going back to sort of a basic sort of 10 step approach to the diagnosis of bone and soft tissue tumors, I do usually take in all facts into consideration. I usually take into consideration the patient demographics, the age, you mentioned earlier that pediatrics, the tumors are different than the tumors that we see in young adults or even older adults, and location. And particularly location is which bone is it involving for bone tumors? And then of course, exactly where it's involving for soft tissue tumors, including the depth of involvement, and we'll talk about that a little bit later. Depth is very important in soft tissue tumors. And then we think about whether it's polyostotic, meaning multiple bones involved for bone tumors or one bone involved. All of these features can be identified by our radiologic colleagues. So the big picture really is our radiologist. We talked about radiology using that very heavily in bone tumors.

In addition, they can tell us whether the bone tumor is breaking through one compartment into another, and so therefore that also helps with our interpretation. We're more concerned about a very aggressive lesion with an aggressive periosteum and breaking into soft tissue from the bone. We also are concerned about larger size tumors. And so all of these things come into play by our radiologic interpretation, which is the big picture, especially if we only have a small biopsy.

Then we look under the microscope and try to make a histologic diagnosis. For most conventional osteosarcomas, it's an HD diagnosis alone. We don't use any special immunostains or techniques. There is an immunostain, SATB2 that can be used for high grade osteosarcoma, but it is only telling us that there is bone being formed and it's also positive and benign bone as well. So it doesn't help us make the diagnosis of malignant tumor. And so therefore we really don't have a specific finding.

We know that some of the osteo sarcomas are retinoblastoma gene involved or their P53 mutation involved, like Li-Fraumeni for the retinoblastoma gene. We don't do those markers for US sarcoma. It's really an H&E diagnosis, but when it comes to all of the other tumors in the differential diagnosis, most of those now have a molecular event. So for example, giant cell tumor bone has a mutation of H3F3A and chondroblastoma, H3F3B, and so on. And so this is very helpful. In fact, what you're asking is very important to the diagnosis and the CAP synoptic reporting. And so we are going to be updating the CAP synoptic reporting with clues and with tables as to how to work up some of these histologic diagnoses with proper immunostaining and also any type of cytogenetic or molecular studies to help with the diagnosis because the biomarker reporting is also something that we're working on as well.

Dr. Mary Edgerton:

That's a fantastic segue into the cancer protocols. I think you're very involved both, as a subject matter expert with the protocols for osteosarcoma and soft tissue and also for the biomarker protocols. Can you tell me how they affect your workflow and how you use the data from them after the fact?

Dr. Julie Fanburg-Smith:

Oh, absolutely. I would say with every tumor that we sign out, I do a lot of surgical pathology subspecialties as well as bone and soft tissue. We use the cancer CAP synoptic reporting protocols. We're also using biomarker protocols, and we started to, we just recently completed, I was one of the primary authors on the GIST protocol and its biomarker protocol, and we updated those.

And so we basically use these very heavily. When we're about to write up a case, not only do we do the workup, but I think going through the protocol can be very helpful to folks, a checklist, a mental checklist to make sure they haven't missed anything. And particularly going back to bone pathology, really, some of it can be made on H&E diagnosis, but it's helpful to, if we were going to get some additional markers, we would go ahead and report those also in our synoptic report, either by immunochemistry or by cytogenetics or molecular. So it's interesting because I think we're going to try to put in more clues. And also, the World Health Organization classification has been even more complex. There's many more new entities that we've discovered in the world of bone and soft tissue pathology, and this is largely due to molecular events, separating them into separate subtypes. And so now we have additional data that we're going to add to the CAP protocols to help make some of these nuance changes in diagnosis.

Dr. Mary Edgerton:

It's fascinating. So many people might say, "Cancer's been around since humans have been around." I look at the history of it, and they have found evidence of cancer in ancient Paweraa from the Egyptian society. And yet we're finding out new things about it all the time. It's an ever challenging and evolving topic. Let's talk a little bit about treatment and then we'll switch to soft tissue tumors.

Dr. Julie Fanburg-Smith:

Yeah, yeah, absolutely. So I, in preparation for this podcast asked one of my very esteemed colleagues who's an orthopedic oncologist at Memorial Sloan Kettering in New York City, Dr. Carol Morris. I asked her to give us a few words about the clinical management and team approach to patient care for bone and soft tissue sarcomas, and I'm going to go ahead and play this, the data that she recorded.

Dr. Carol Morris:

The clinical management and prognosis in osteosarcoma is highly dependent on grade. All tumors, regardless of grade, need extensive disease workups called staging, which includes CT of the chest, which is the most common site of distant metastases, followed by a nuclear medicine scan, either bone scan or PET scan, both of which are acceptable in 2023. Low grade osteosarcomas are treated with surgery only. High grade osteosarcomas are treated with a combination of chemotherapy and surgery.

Low grade osteosarcomas most commonly occur on the surface of the bone as opposed to intramedullary. In this example of this tibial low-grade osteosarcoma, given the low grade, we can perform a hemi-cortical resection taking out the tumor, but leaving the rest of the bone behind and fill in that defect with an allograft. Low-grade osteosarcomas are associated with good survival with most patients experiencing greater than 90% at five years.

High grade osteosarcoma, on the other hand, is associated with a high incidence of micrometastatic disease. The current treatment paradigm is to give preoperative chemotherapy followed by surgery, followed by postoperative chemotherapy. The most common chemotherapy protocol is a multi-drug regimen consisting of adriamycin, cisplatin and high dose methotrexate. A wide excision is performed with a cuff of normal tissue around the tumor and reconstructed with a mega prosthesis. The five-year survival for localized disease is approximately 65%.

Dr. Mary Edgerton:

It's amazing to me, and especially because our osteosarcoma has a pediatric peak that surgeries have moved from a complete amputation to actually carving out the bone tumor and then replacing it with, I guess I would say an intracorpular prosthetic.

Dr. Julie Fanburg-Smith:

Sure, yeah.

Dr. Mary Edgerton:

Some of the materials [inaudible].

Dr. Julie Fanburg-Smith:

Yeah, the limb salvage procedures are amazing. Yeah.

There's also a very interesting surgery, I don't know if you've heard about it, it's called the Van Ness turniplasty, where if there's a tumor around the knee, that they will take out the knee joint and the tumor and then they will put the ankle back onto the patient as a new knee. So now when they flex up your foot, it's like flexing back their knee. So it's turned around and the ankle joint becomes the new knee joint. So it's quite interesting. And the patients learn how to run, do normal activity on a new joint. So it's quite a great procedure.

Dr. Mary Edgerton:

That's amazing.

Dr. Mary Edgerton:

That is amazing. Let's switch gears to soft tissue. So can you tell us, let's start with who are the populations who are affected most commonly?

Dr. Julie Fanburg-Smith:

The soft tissue sarcomas are involving anywhere from very young, all the way to very old. And certain types of soft tissue sarcomas are more common in pediatrics like rhabdomyosarcoma or certainly in newborns, infantile fibrosarcoma. Whereas we have certain types that are more common in older, either I'd say like the mid-range of adults like myxoid liposarcoma or even very much older adults, undifferentiated pleomorphic sarcoma. And we tend to have the more aggressive high-grade things in both ends of the spectrum of age. Although some of the pediatric tumors including the new fusion sarcomas that are tyrosine kinase fusions, and these are targetable sarcomas, these tend to look a little bit lower grade, although they sometimes can't be graded. Their behavior is unpredictable sometimes. But we tend to have usually more very high grade and very aggressive tumors in both ends of the spectrum, but mostly in older adults, where there's complex cytogenetic abnormalities that form the tumor.

Dr. Mary Edgerton:

So that brings to mind a question. Do the pediatric cases have a simpler molecular phenotype in contrast to the adult cases?

Dr. Julie Fanburg-Smith:

Well, that's a good question. I think when we say pediatrics and young adults that I think several of these tumors will bridge both of them. So if we talk about Ewing sarcoma for example, that would be more around the teenage years, or the young adult. And those are, generally speaking, if they're intraosseous, and those are one of the prototypical simple or reciprocal translocation or fusion sarcomas. And those are the most common that we see. But we see several other round cell tumors that will occur probably around that young age group, mostly.

When I'm looking for fusions, I usually get the comprehensive sarcoma fusion panel in patients who are less than 50 years old. Not to stereotype, but usually we'll find more fusions in younger... reciprocal translocations or fusions in younger patients, although that's not true for everybody. Sometimes we just see them-

Dr. Mary Edgerton:

I find that fascinating. So how do you approach a soft tissue tumor for diagnosis?

Dr. Julie Fanburg-Smith:

Okay, great question. So going back to my sort of 10 separate approach, I also involve the clinical information, demographics, radiology. The gross pathology is so important for soft tissue and bone tumors. I like to see what the margins look like. For example, soft tissue tumors when they're in the subcutaneous tissue, they're very infiltrative and it's hard for the surgeon to get around the margin. Where is when they're intramuscular, they compress the adjacent normal tissue and form a fibrous pseudocapsule. And usually it's easier for a surgeon to completely excise it. And we can look at gross pathology and see if there's a smooth margin to see if it's been completely excised. I know that our margins are different from yours in breast pathology because we just have to have one fibroblast of a pseudocapsule as a negative margin in the sarcoma world. And if there's a pseudocapsule around the tumor then and it hasn't been transgressed by tumor, then that's a negative margin even if it's less than a fraction of a millimeter margin.

So then I look at my microscopic and decide what cell type I'm working with. Is it a round cell tumor, pleomorphic? Is it spindled or fascicular? Is it rhabdoid? Is it giant cell, rich or is it ovoid like these new myoparasitic, targetable fusion sarcomas? And once I decide that, I apply some immunostains. I have sort of a cookbook that I use to make sure I'm not missing anything. I make sure I'm not missing pleomorphic tumors and make sure I'm not missing a melanoma or a spindle cell carcinoma, as well as working up various immunostains to exclude sarcoma, particularly CD34 and desmin, just to make sure it's not along those lines. And then I will apply molecular or genetics if necessary, particularly in the round cell tumors. And now in some of these fusion sarcomas, we will get them all the time, especially as I mentioned in younger patients.

And then we arrive at what's called the phenotype or cell of origin. So what is it most resemble? Does it resemble a vascular tumor with all this information? Are the vascular markers positive? And if so, once I determine the phenotype or cell of origin, then I can assign a diagnosis, I can grade it and if it's malignant and assign prognosis, and we advise as pathologist treatment. But we know from what Dr. Morris would say in a second here, I can play her tape. But I can summarize that, if we're in a hurry, that basically low-grade sarcomas usually get complete excision, whereas the grade two and grade three, which are considered high grade sarcomas, usually have pre adjuvant therapy and post adjuvant therapy. Do you have a second for me to play what she-

Dr. Mary Edgerton:

Go ahead.

Dr. Carol Morris:

Soft tissue sarcomas are typically taken care of by a multidisciplinary team, consisting of a surgeon, a radiation oncologist, a medical oncologist supported by a pathologist and a radiologist. Collectively, this group makes up the multidisciplinary sarcoma tumor board. In large academic medical centers, each patient with a sarcoma is discussed in a tumor board setting where the size of the tumor, the grade of the tumor, the histologic subtype, the presence or absence of metastases and other clinical factors are weighed to come up with an individual treatment plan. In general, most low-grade sarcomas are going to be treated with surgery and in some instances radiation, whereas high grade tumors will be treated with surgery, in most cases radiation plus or minus chemotherapy.

Dr. Julie Fanburg-Smith:

And I can add that with the new targetable lesions, we have some really interesting cases where the tumor like in the hand around the fingers, was not amenable to surgical excision. It would've resulted in amputation. But now, because this example was an ALK fusion sarcoma, it could be treated, as a pediatric two-year-old instead of an amputation, they were treated with crizotinib, which is a target it's an anti ALK therapy. And so this tumor melted away within five months, and the patient is tumor free, radiologically and clinically tumor free, able to use the hand again. And this spared the patient from getting an amputation. So it's pretty remarkable now these novel fusion sarcomas that we actually can have some targeted therapy as well in addition to classic chemotherapy.

Dr. Mary Edgerton:

That's amazing. So we're going to go a little bit into the cancer protocols and how they help to keep pathologists on track. So you just mentioned how important the molecular findings are to guide the therapy, and I know that you're on the biomarker task group. Can you tell me a little bit about how the cancer protocols might help in making sure that this information is being collected and that the patient facing clinicians are able to access it for treatment purposes?

Dr. Julie Fanburg-Smith:

Absolutely. I think that the cancer protocols are helpful for everybody, including trainees, residents, staff, even experienced staff, because it makes us do a checklist and make sure that we haven't forgotten anything basically for the, I guess I can start with the bone protocol since we did that first, it's very helpful to know, of course, the radiologic findings as we talked about. And that's one of the features that is in the caps synoptic report. And it's helpful to put that into the report for everybody else to make sure, because let's say we think there's an osteosarcoma, we want to make sure that it's a metaphyseal big tumor that's breaking through into the soft tissue with a classic Codman triangle. Those are going to be features that we're looking for in order to support our histologic morphologic impression. It also puts in there to find out if the patient's been treated for resections.

Treatment is really an important thing in both bone and soft tissue. And treatment is measurable not only by necrosis, but also with some of these newer targetable therapies. We see more of a fibrotic picture. It changes the tumor, it makes it hypocellular, it sterilizes the tumor so there's less mitotic activity. And we'll see smudgy fibrosis sometimes instead of necrosis. And those all count as treatment effect that we will note the percentage of. So it's helpful to know what type of treatment the patient received before receiving one of our specimens, particularly for the resections. And this goes for soft tissue as well as for bone tumors. It's helpful to have the checklist because you need to know exactly in bone where the tumor's located. Is it in the epiphysis or metaphysis? And that helps our diagnosis to know these specific features. Where is it exactly located?

And then finally, there's a nice checklist of all of the malignant. And now in soft tissue, we're going to include the locally aggressive or low-grade borderline tumors in our synoptic report because these are also important. And these do get sometimes additional adjuvant therapy. Even tumors such as fibromatosis, which is a locally aggressive benign entity. But it can actually be so aggressive that it can wrap around vital structures and cause patient death. And therefore, sometimes these are treated with radiation or other modalities, other types of medical treatment. And so basically, we are including several tumor types in the new upcoming version. Once we decide the histology, together with our morphologic impression, the immunophenotype and any type of molecular or genetic studies that we do. And we can talk a little bit about new modalities maybe at the very end, but we can go into talking about the grade. The grade is important, particularly for guiding treatment.

In osteosarcoma, we really only have low and high grade, but we have intermediate or moderately differentiated in some of the other subtypes as well as some other sarcoma types. Mitotic rate is important, necrosis is important for grading purposes, lymphovascular invasion. Aside from a couple tumors that mimic melanoma and carcinoma, namely clear cell sarcoma and [inaudible 00:34:19] sarcoma, and also sometimes rhabdomyosarcoma. Most of the sarcomas are hematologically spread. So we don't actually see lymph node involvement, but we do comment if lymph nodes are involved, or if they happen to be in the specimen. They're not usually taken with the specimen. But sometimes if we have an amputation, we'll comment on the lymph nodes. They're usually negative because it's not lymphatically spread.

The most important that we're coming to from a pathologic standpoint is our PT pathologic stage score. And in bone tumors, this really depends on site and it depends on whether it's appendicular, skeleton, trunk, and facial bones versus whether it's in the spine. Those differences would be between measuring size versus measuring segment involvement. And the same goes for the pelvis that's separated out. And I think those are helpful for the pathologists and the trainees to look at these protocols in order to properly give a pathologic staging.

In addition, we look for metastases in these tumors often at the time of resection. The reason the resection was done is because there aren't any lung metastases. But we do occasionally get, and for example, in pulmonary, we would get maybe a osteosarcoma lung metastasis, and that would change the M staging for the pathologic stage.

Dr. Mary Edgerton:

So is lung the most common site of metastasis?

Dr. Julie Fanburg-Smith:

For osteosarcoma and most of the malignant bone tumors, lung is the most common site for metastasis because it is hematologist spread. Sometimes we have other soft tissue sites as a metastasis as well.

Dr. Mary Edgerton:

Yes, I know in breast, actually, I've encountered a few sarcomas besides the radiation induced angiosarcomas. I had the radiation induced osteosarcoma that I mentioned, and then I also recently had a malignant phyllodes tumor that had transformed into an osteosarcoma. It's pretty fascinating to see those. Quite something. But in breasts, it seems like it doesn't matter what your tumor is, they're going to do a sentinel lymph node. And I always think, and in these soft tissue tumors of the breast, why?

Dr. Julie Fanburg-Smith:

Yeah. Right, right.

Dr. Mary Edgerton:

Yeah, they've always been negative. I just want to mention that the College of American Pathologists is going to hold a really a user group summit for people who use or are thinking about using or wondering what the value is of the electronic cancer protocols. We're calling it Cancer Data Summit, and the title is Leveraging the Power of Pathology data. It'll be held this October 6th in Chicago just proceeding the CAP annual meeting. Do you reuse any of your data? Do you go back and say how many cases of this type, that type or for quality, how often was this molecular test performed?

Dr. Julie Fanburg-Smith:

Absolutely. We use these protocols all the time. And so basically this is one way that we can, in addition to the top line diagnosis, this is one way that we can actually search for research purposes or for data purposes. I know that we do sometimes use, we use this significantly, and I know that many of the epidemiology studies are based on some of the CAP synoptic reporting. The reason to do CAP synoptic reporting is really to have it standardized so that we can go back and look at some of this data, and it's all going to be standardized and easy to search for. And so I think that's also very helpful in addition to a checklist for people to make sure that they write all... don't forget anything in the diagnosis. And it's nice to have it all in one place in a synoptic reporting area, in the report.

I was going to mention that currently many of the systems that we use for pathology at various institutions, they all have vendors that will have the CAP synoptic report put into the system. And so when we update the reports, there might be a little bit of lag time. And so sometimes we will go on the CAP website to look for these protocols if we don't have the most updated version, although most of them are the most updated version. But there is a little bit of a live time after a protocol is updated. And so it is helpful sometimes to check the most recent protocol. I know that we just updated all the pediatric protocols recently, and also a few of the other ones.

I was going to mention for soft tissue pathology, we also have a similar importance in the PT score, or pathologic stage classification, particularly as to site, just like for the bone. So head and neck tumors get a different scoring system for T score than trunk and extremities, abdominal, thoracic, visceral organs, retroperitoneal, and even orbit. And so all of these from head to toe is really included in soft tissue pathology. And that's important for most folks like yourself and others who practice other subspecialties to know that they can use the soft tissue protocol or various other sites as well. If it's not in an organ, they're, they're often will be, this can be used for various locations in other subspecialties as well.

Dr. Mary Edgerton:

Yes, I guess it's the only other protocol I've used in the breast besides the breast protocols is when I have a soft tissue tumor or some kind of sarcoma includes that protocol. So before we close out, is there anything else you want to say?

Dr. Julie Fanburg-Smith:

Well, I just wanted to say that these two fields are rapidly evolving and I think the CAP protocols and their updates are going to be important to catch everybody up to the latest and the greatest. And we now have new techniques. When I first started practicing pathology many years ago, I started off at the Armed Forces Institute of Pathology for many years, and I worked with Dr. Enzinger. And he used to make the classification based on the morphologic impression alone. He didn't have any immunostains when he started doing soft... he is really the grandfather of soft tissue pathology, and he didn't have any stains back then. But his observations have withstood the test of time. We've just made a few tweaks based on some of the molecular and breaking things into some subcategories.

Along the way, while I was there, we developed more immunostains and we went from using mostly PCR to mostly FISH. And then the newer technique that we've used in the last 10 years has been NextGen sequencing, which has really tremendously changed our diagnoses and findings. And you'd be surprised, we're finding novel fusions all the time by using NextGen sequencing. And then also the newest modalities might include methylation profiling, which hasn't become very big in this country yet for soft tissue tumors. It's used for CNS and other areas, but several of our European colleagues are using methylation profiling for all of their tumors, bone and soft tissue. And so we're able to sometimes find out more information from those studies.

And finally, this whole role of AI, I think soft tissue and bone still is going to require a pathologist because it's really an art as well as a science to make a comprehensive diagnosis. And there's a lot of nuances in the field, and I think that certainly if this is probably one of the biggest areas that gets consulted on is the mesenchymal lesions because these are rare and often very challenging and reactive things can mimic malignant and vice versa.

Dr. Mary Edgerton:

And I want to underline that, rare and very challenging. So I admire you for persisting in this field and I want to thank you for letting us know about all the new changes. I do want to mention, you talked about the CAP protocols being updated and how there's a lag time before they're updated electronically in a vendor supported laboratory information system. But the paper protocols are updated usually about six to eight months before the electronic protocols are updated. But the vendors have six to eight months to implement them. But the paper protocols updated are available online on the CAP website. And if you're a CAP member and you have MyCAP app, you can actually find them on your MyCAP app. And I've used that quite a few times.

Thank you so much for taking some time out to teach us about bone and soft tissue tumors and to let us know what's happening molecularly, treatment wise. It's fascinating and wonderful to know. And for talking about how you use the electronic cancer protocols. So Dr. Julie Fanburg-Smith, we thank you for being our guest on this podcast.

Becca Battisfore:

I want to thank you both for joining the podcast to talk about Sarcoma Awareness Month. And I want to thank you all for listening to this CAPcast. You can find links to the Cancer Protocols that were mentioned in the episode description, and for more information about the CAP visit cap.org.