Other major prognostic factors are histopathology, and I’ll go over some of these at the end. Lymph node involvement, which is extremely rare, connotes a very poor prognosis. And you can see that with epithelioids, synovial, rhabdo and angio. For the most part though we don’t recommend doing lymph node dissections because for the most part sarcomas do not go to the lymph nodes. Age; those patients under 60 usually do better than over 60. Females, as for most tumors, do a little bit better than males. And then there’s some literature on P-glycoprotein and Ki-67 expression, and aneuploidy. Debatable literature. Ploidy, you can find in both directions, whether it has significance or not. P-glycoprotein is for measurement of MDR and Ki-67 expression, DNA synthesis. Obviously those patients who have a higher DNA synthesis do somewhat worse.

We have two major staging systems for soft tissue sarcoma. One of them is the Enneking system, put together by Dr. Enneking who is sort of the father of orthopedic oncology, who was at the University of Florida. It’s a bi-gradal system; low grade, high grade and then whether the tumor is either intra-compartmental or extra-compartmental, and then if the patient has nodes or metastases they would be stage III. This emphasizes compartmentalization. It is best suited for extremity sarcomas. It’s not good for other areas of the body, and size and depth are not included. It’s the system though that’s probably used the most by orthopedic oncologists. Now our other grading system is the American Joint Cancer Committee system and this again has been changed in 2006 from a tri-grade to a bi-gradal system. Putting well-differentiated and moderately- differentiated in one group, and poorly and un-differentiated in another. But in addition to that, it looks at size – less than or greater than 5 cm – and it also looks as to whether the tumor is superficial or deep. The tumors that specifically we want to look at, that have probably the highest rate of recurrence and where we possibly could look to give adjuvant therapy, would be in the high grades that are somewhat superficial, but more the high grades that are large and that are deep. Those are the ones that have the most potential for recurrence and where we would think possibly of giving adjuvant chemotherapy. Obviously those that do the worst are those who have nodal involvement or metastasis.

Now this is what a typical soft tissue sarcoma looks like, and I put this up to show to you that it’s critically, critically important that you get this patient to a surgeon who knows what they are doing the first time. Many of these tumors, the majority of these tumors, have a pseudo capsule around them and many many a time the patient gets the “oops” procedure. In other words, the surgeon goes in and sees, “Boy that capsule, this is easy. I’m just going to slide it right out” and the tumor is out. Then the pathology comes back and all the margins are positive. And why are the margins positive? Because there are satellite areas of tumor around that pseudo capsule, so you just don’t want to scoop it out. If possible, you want to get a wide excision with at least 1-2 cm of normal tissue around it. When we do a marginal resection, a shell-out, there is about a 90% incidence of local recurrence.

Even with wide excision, there can be about 50% in older series. When we do a radical, it is less than 15%. Sometimes we still have to do an amputation, and this is really based on the biopsy site and the biopsy being done properly, as I said before, whether there is neurovascular or compartmental involvement, the size of the tumor, and what the anticipated function is. If the patient, after the surgery, is left with very poor function then there is no point in doing a limb-sparing procedure. So in terms of surgical treatment, there has been a transition from doing a shelling out, where there is 90% local recurrence, to an amputation, to now limb-sparing surgery plus radiation, where there is about a 5-15% local recurrence rate. In a trial done at NCI comparing limb-sparing surgery plus radiation, versus amputation, there was no difference in survival.

Now we’ll first talk about the soft tissue sarcomas, and these are usually solitary, painless and palpable. The majority occur in the extremities. In the lower extremity, 40% of these are the highest amount and 75% of these are above the knee. They can also occur in the trunk where the most common area is the retroperitoneum, and then also rarely in the head and neck area. In terms of sites and histologies, usually in the extremity its MFH, synovial, lipo and fibro and most of these patients develop lung mets. The tumor usually avoids the liver. In the retroperitoneal area, lipos, leiomyosarcomas, there’s intraabdominal spread as well as liver and lung mets. In the chest wall, desmoid, lipo, leiomyo. The GI tract, leiomyosarcomas and then the newer-named GI stromal and GI autonomic tumors, which are extremely resistant to chemotherapy. In the GU tract, leiomyos and mesodermal mixed. Now what’s extremely important when you first see these patients, especially if this is an extremity sarcoma, is that you obtain the tissue in the right format. It’s really recommended that if possible you refer these patients to surgeons who have experience in doing the ultimate procedure. Really, if you are going to do a biopsy, you want to do an incisional biopsy, not an excisional biopsy unless it’s a very small lesion. And you want to make sure that the plane of that dissection is longitudinal to the muscle and not perpendicular. If you have the facilities, probably now at most major centers the majority of biopsies are done as a core true cut. I would say at our center about 95%, 98% of our biopsies are done by our radiologists. The advantage to that is that under CT guidance they can hit different areas of the tumor, because sometimes some of these tumors have necrotic areas and you may get no tissue or you may get a low grade tissue in one area and a high grade in another.

This is a study, an old study. There have been two other studies more recently. One from our institution, one from Memorial, looking at the value of core and needle biopsy compared to FNA. And you can see there is a much higher sensitivity, specificity and accuracy. Really it’s recommended to get at least three core and needle samples. We usually only use FNA’s to confirm a recurrence. Because it’s real important not only to determine, if possible, the exact histopathology of the sarcoma, but also to determine the grade. What’s critically important also is that you have a pathologist who has some experience in reading these and has some familiarity with the different immunohistochemical stains. You need to be aware that for some of these, in terms of helping delineating the type of sarcoma you are dealing with; angiosarcomas having CD34 factor 8; leiomyosarcomas having desmoid muscle-specific and smooth muscle actin; Ewings sarcoma having HB71013. None of these are absolutely specific but they can be very helpful in delineating the type of sarcoma you are dealing with. In addition, more recently now, there have been several different fusion genes based on different translocations that have occurred for some of these sarcomas, that are fairly diagnostic. One of them being the translocation of 11-22 for Ewings or primitive neurectodermal tumors. Also for synovial sarcoma, a translocation of X and 18. Looking at SID and SS-1 and SX-2 and we have found now that not only can these be somewhat diagnostic for diagnosing the sarcoma, but in this instance with synovial sarcoma it can tell whether you are dealing with a biphasic or a monophasic tumor. The biphasic being SS-1, the monophasic being SX-2 And not only is it helpful in delineating that but also in prognosis. The monophasic tumor being all spindle cell, having a much better prognosis than a biphasic tumor where there is an epithelial component as well.

Now what do we do in terms of a work-up? Well, first of all we want to find the local extent of the tumor and probably the best test for extremity, trunk and head and neck is an MRI. But in addition to that, if it’s in the retroperitoneal area or an intraabdominal sarcoma, we want to get a CT because we want to look at the abdominal contents and also evaluate the liver where the tumor can metastasize to. Then in addition, for all these sites, they have the potential to metastasize to the lung. So we want to get a chest CT as well. Now there are several major prognostic factors. Histologic rate is extremely important. Low grade tumors tend to stay locally, tend not to metastasize, tend to have a much better prognosis. We need to know the extent and location of surgical margins and those should be delineated by the surgeon. We want, if possible, to get margins of at least 1-2 cm. That is not always possible, depending where the tumor is. It’s much harder if it’s in the retroperitoneal area, much easier in the extremity area. Size becomes important. Those tumors greater than 5 cm and even greater than 10 cm are much more likely to recur and have a worse prognosis. The primary site becomes important. Distal tumors usually do better than proximal tumors, they are picked up earlier, usually easier to resect. Those tumors that are subcutaneous usually do better than deep. Those tumors that are intra-compartmental usually do better than extra-compartmental. Those tumors that are in the extremities usually do better than the trunk, and head and neck usually do better than the retroperitoneum. Retroperitoneum tumors are usually picked up late because they are usually very big, the patient doesn’t have any symptoms, then once they are picked up they are usually very near vital structures and it’s very hard to do an adequate full resection to remove all the tumor. In fact, for most patients who are at major centers getting surgery for retroperitoneal tumor, approximately 75% of the time a vital organ or part of a vital organ has to be removed in addition to the sarcoma.

Sarcoma
A sarcoma (from the Greek ‘sarx’ meaning “flesh”) is a cancer of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue. This is in contrast to carcinomas, which are of epithelial origin (breast, colon, pancreas, and others).
Sarcomas are quite rare tumors, tumors that you don’t see that often. There are approximately 7,800 soft tissue sarcomas occurring in the United States, and this is about equivalent to the number of non-Hodgkin’s lymphomas, a little bit more than Hodgkin’s disease, but it’s a much rarer tumor than colon, lung, breast which are 170,000 to 180,000 a year. There can be the classical type of extremity and trunk, visceral involving the GI tract the GU tract, also KS and mesothelioma, and then even rarer are the bone sarcomas, approximately 2,600. The major one being osteogenic sarcoma but also chondrosarcoma, Ewing’s and MFH of bone. Although these tissues arise from about 75% of the average body weight, the just represent less than 1% of all adult and 15% of pediatric malignancies.

In terms of etiologies, exposure to radiation is certainly a cause of the development of sarcomas. Anywhere from 2000 to 7800 centigray and mostly we see osteogenic sarcomas, but also MFH, angio and fibrosarcomas. There is literature on chemical exposure and this comes from Vietnam and also from the farm belt in which exposure to herbicides and dioxin and oxyacetic acid can increase your chances of developing sarcoma. But there is quite a lot of debate in the literature about this. Also exposure to vinyl chloride and arsenic evolving into an angiosarcoma. Patients who’ve had renal transplants, chronic lymphocytic leukemia, autoimmune hemolytic anemia, can develop Kaposi’s. Then in terms of viral etiologies, the Kaposi’s sarcoma virus, HHV8, and also some literature looking at Epstein-Barr virus in children. Those children exposed to Epstein-Barr virus having a higher incidence of smooth muscle cell tumors. There is some literature, small usually, case reports of different injuries; scars, burns leading to fibrosarcoma. Implants and bone infarcts leading to osteogenic. There is the postmastectomy lymphedema, Stewart-Treves syndrome in which you develop an angiosarcoma. There’s a higher incidence of osteogenic sarcoma in those patients who have had Paget’s disease, and then certain benign forms of bone disease can also lead to osteogenic sarcoma.

In addition, in terms of genetic predispositions, those patients who have had a retinal blastoma develop about one thousand times more incidence of osteogenic sarcoma, and there is even a further risk if those patients have been exposed to radiation therapy. But you can also develop osteogenic sarcomas outside of the radiation therapy site. Rp53 17P _ in which there is a high incidence of sarcomas, breast, leukemia, brain tumors. The murine double minute 2, which is an oncogene on chromosome 12, and this can inactivate both P53 and a retinoblastoma and therefore gives you similar effects. Neurofibromatosis, a higher incidence when you have both a genetic defect of 17Q, where there would be a higher incidence of neurofibromas, and then adding on the P53 17P with an increased incidence of malignant schwannomas and neurofibrosarcomas. Also with Gardeners, the APC5Q, there is a higher incidence of intraabdominal desmoids.