Dr. Matushansky is Assistant Professor of Medicine at the New York Presbyterian Hospital, Columbia University Medical Center in New York City.
OncologySTAT: Would you discuss diagnosis and classification of soft tissue sarcomas? How are adult sarcomas different from childhood sarcomas?
Dr. Matushansky: Pathologically, soft tissue sarcomas are still classified as they were in the twentieth century. Usually patients will present with a soft tissue mass, which they will feel either as a bump or a lump. Or, they will present with a sign or symptom that will lead their physician to order a CAT scan or MRI, which will show a mass that is radiologically consistent with soft tissue. Usually what follows then is a core biopsy or a large incisional biopsy, and that material goes to a pathologist, who looks at it and makes a morphological determination. In other words, he will define it by the type of normal tissue that it resembles the most. Not surprisingly, soft tissue sarcomas tend to resemble various types of connective tissues. For example, rhabdomyosarcoma, or skeletal muscle tumor, resembles normal skeletal muscle. On the other hand, leiomyosarcoma, which is smooth muscle cancer, resembles smooth muscle; and liposarcomas resemble fat, and so on.
After the pathologist determines the type of tissue, he uses immunohistochemistry to look for certain markers, most often proteins, that are known to be expressed in specific tissues. For example a pathologist would look for proteins that are specifically found on normal skeletal muscle and would hope to find that the protein is also expressed in the corresponding skeletal muscle sarcoma, resulting in a fair degree of correlation and validation of their initial morphological based conclusion. Of course, the more undifferentiated or poorly differentiated the cancer is, the less chance it will resemble normal mature connective tissue. Sometimes, all the pathologist can say is that it is derived from some kind of connective tissue; but, it really doesn’t resemble any mature connective tissue well enough to say specifically which connective tissue it is. So, a common diagnosis of soft tissue sarcoma is "sarcoma not otherwise specified" or "high-grade pleomorphic sarcoma", or what used to be called "malignant fibrous histiocytoma"—an antiquated term that is still occasionally used, although it has largely been eliminated in modern staging and diagnostic literature. These are all fully undifferentiated sarcomas which cannot be better delineated because they look uncharacteristically like any mature connective tissue.
That is pretty much how we diagnosis and classify soft tissue sarcomas. The other component that comes into it is the grade, which is basically how aggressive the tumor appears. It has to do with how mitotically active it is, how fast it is proliferating, how normal or abnormal the nuclei are looking. As in any other cancer, if the tumor looks poorly differentiated, that is not good. If it has a high-grade component to it—say, the nuclei look really aberrant—that also is not good. Usually differentiation and grade are inversely correlated. The more poorly differentiated, the higher the grade.
As far as how sarcomas differ in children and adults, there are a couple of differences. The most is the spectrum, or subtypes, of sarcomas that occur. Children tend to get a lot more skeletal muscle tumors, such as rhabdomyosarcomas and osteosarcomas, than adults. Adults tend to get more smooth muscle sarcomas, such as leiomyosarcomas, and more liposarcomas. Exactly why there is a difference in the spectrum is somewhat unclear. There are some who have hypothesized that it has to do with the fact that children are growing and their skeletal muscle and bones are rapidly developing. Children then may be more prone to getting tumors arising from the types of connective tissues that are actively developing. Adults tend to develop more fat than muscle; maybe that is why they get liposarcomas. These are theories, which have never actually been supported by factual data; so, it is really hypothesis at this point.
Childhood sarcomas are also, on average, more responsive to chemotherapy than adult sarcomas. Again, why that is so is unclear? It may be because the spectrum of sarcomas that develop in children are inherently more chemotherapy- sensitive; but that theory also hasn’t been formally looked at. If you compare a specific sarcoma subtype, such as rhabdomyosarcoma, in children vs adults, who does better? Children with rhabdomyosarcoma do better than adults; but, that may have to do with the fact that children tolerate a lot more chemotherapy because their bone marrow recovers faster. So it is difficult to directly compare even the identical subtypes because the amount of chemotherapy received is different simply because children can tolerate more.
OncologySTAT: Are there known molecular or genetic characteristics of soft tissue sarcomas?
Dr. Matushansky: There are actually many. The problem in answering that question is that there are 70 different types of sarcomas. Approximately 50% of them are characterized by specific translocations in these translocation-related sarcomas specific genes from different chromosomes fuse pieces of themselves creating new functional proteins with hybrid properties of their progenitors. Translocation-related sarcomas are characterized, or molecularly defined, by these translocations. So, cytogenetic analysis in sarcomas is fairly common because so many of the sarcomas are characterized by specific gene fusion translocation events that define them. Common sarcomas that have characteristic genetic abnormalities include Ewing sarcoma, which carries the EWS/FLI-1fusion product; myxoid round-cell liposarcoma, which carries TLS-CHOP fusion; the alveolar rhabdomyosarcomas, which carry PAX-FKHR rearrangement; and there are many others. All carry specific translocations that can be used diagnostically to help us figure out which sarcoma we are dealing with. The remaining 50% of sarcomas do not carry these translocations. They are characterized as complex karyotype sarcomas, and tend to more closely resemble the classic carcinoma, such as lung and pancreatic adenocarcinoma, which are associated with massive chromosomal damage and lots of gene amplifications and deletions.
OncologySTAT: What are available prognostic strategies for risk assessment in patients with soft tissue sarcomas?
Dr. Matushansky: Unfortunately, we can’t predict who is going to get a soft tissue sarcoma. Very few genetic syndromes predispose someone to develop a sarcoma de novo. For example, people with Li-Fraumeni syndrome, which is a p53 familial deletion syndrome, are indeed prone to getting osteosarcomas; but that is so rare. The majority of sarcomas develop sporadically. They are not hereditary. I tell all of my patients that their children are not at increased risk for getting a sarcoma just because the mother, father, brother, or sister had a sarcoma. In terms of patients who have sarcoma, and in terms of the treatment options, assuming they present and assuming a large surgery has been done and they are rendered tumor-free, their prognosis depends on several factors. The first is size of the primary tumor; the larger the primary tumor, the larger the risk of recurrence. Second, prognosis depends on the grade of the tumor; the higher the grade, of course, and the more poorly differentiated the tumor is, the higher the recurrence rate. And third, it matters whether the tumor is superficial or deep. Sarcomas can occur anywhere where there are connective tissue elements, and cutaneous and subcutaneous sarcomas do show up. The latter carry a better prognosis than, for example, the retroperitoneal or abdominal sarcomas. The rule of thumb when we talk about prognosis for sarcoma patients is that a high-grade tumor, which is 8 centimeters or more, usually carries an approximately 50% chance of recurrence over the following 3 years.
OncologySTAT: Would you talk about multidisciplinary care for patients with newly diagnosed and also recurrent disease, and also the challenges involved in treating these patients?
Dr. Matushansky: I usually tell all of my newly diagnosed patients that the most important thing to do, assuming the tumor is not metastatic, is to be seen by a surgeon who specializes in sarcoma resections, because sarcomas tend to grow a little bit differently than carcinomas. A lot of surgeons have experience with carcinomas because they are much more common than sarcomas. Sarcomas grow differently in the sense that they grow a little bit more like weeds. Despite the circumference of soil, there are still little weedlings that can be found at the periphery, no matter how wide you make the border. Carcinomas tend to grow a fashion that is a little bit more circumscribed. Surgical resection of sarcomas requires specific expertise in sarcoma resection. This may sound obvious but is an often overlooked and underappreciated point. There are several good surgeons across the United States who specialize in sarcomas. They are usually the first people to consult, in my opinion, as to whether or not surgery is feasible. If it is feasible, there are questions like, “Should we do it now?” “Should we try to do some chemotherapy up front and shrink the tumor down a little bit, or not?”
This prompts involvement early on by other cancer specialists:; the medical oncologist, to see if getting chemotherapy can or cannot provide some shrinkage; and a radiation oncologist, especially for the primary tumor, to determine the area where radiation therapy can be delivered safely.. The reason to consider this is because it has definitely been shown that radiation therapy, either before or after, decreases the chance of local recurrence by approximately 50%. So, radiation should definitely be considered at the same time that surgery is being considered. There are a lot of surgeons who either prefer to operate or do not prefer to operate on radiated fields or pre-irradiated fields. This sort of preference needs to be taken into account. Therefore, it is important that a patient see all three specialists, and, preferably, in one center where a disease management team can interact, present the case, and develop a uniform, long-term plan to get the patient through the next couple of years.
OncologySTAT: Would you discuss treatment in both neoadjuvant and metastatic settings?
Dr. Matushansky: Neoadjuvant chemotherapy, for the moment, remains experimental and should only be used in the realm of clinical trials. Several places have tried giving patients neoadjuvant therapy to look for an effect on overall survival. So far, there has been no indication that neoadjuvant therapy affects overall survival. The only time most of us consider providing neoadjuvant therapy is when a surgeon says, “You know, I think I can get it, but it is close.” In other words, the tumor is either close to a blood vessel or close to a nerve, and can’t truly be operated on successfully without significantly affecting the patient’s morbidity, to the extent that a leg must be amputated, or something of the sort. If, for example, we can shrink the tumor by some minimal degree, 10% or 15%, with a little bit of neoadjuvant therapy, and surgery can be more successful, while it may not fully translate into an overall survival advantage, it may translate into a quality of life advantage. For the moment, neoadjuvant therapy remains highly appropriate in the situation where, as I have indicated, a surgeon says he can do a better surgery, with less morbidity and achieve a better quality of life for the patient without compromising overall survival with a little bit of neoadjuvant therapy. Interaction between the surgeon and the radiation oncologist is critical in terms of when to give neoadjuvant therapy— when to give radiation therapy, if radiation therapy should be given or not, when to give it, and for what reason. It is important that the reasons are clear. We are not giving it because we think it actually increases overall survival. We are giving it predominantly because it decreases tumor burden to the point that the tumor is more surgically amenable, and, thus, increases the quality of life for the patient.
This is in counterbalance to adjuvant therapy because, for adjuvant therapy, we in the sarcoma community have been exploring its utility for 30 years without much success. Today, I think most oncologists who treat sarcoma would say that there really is no benefit to adjuvant therapy for sarcoma, despite the high recurrence rate, and they do not offer it. The adjuvant setting remains highly controversial only because there were some limited data 30 years ago that showed that there might be something to it. It has subsequently fallen out of favor, but the old data still pop up now and again. The majority of oncologists who currently treat sarcomas do not give adjuvant therapy A lot of my patients are referred to me having received adjuvant therapy at some point from a community oncologist. I always say we should stop doing this. If there was one message I would send out to oncologists that do not specialize in sarcomas, it is that we should get out of the habit of giving adjuvant therapy for sarcomas simply because we do it for breast and colon cancer. That is not a good rationale. There are plenty of data suggesting it doesn’t work at this point.
In the metastatic setting, the majority of treatment for sarcomas remains doxorubicin-based, with a response rate somewhere between 25% and 33%. Clinical trials are fair game at all stages. First-line clinical trials should be compared to a doxorubicin backbone at all times. Second-line regimens—and there are plenty—all have approximately 20% efficacy.
OncologySTAT: What role does the community oncologist play in the management of the patient diagnosed with sarcoma, and should patients always be referred to high-volume centers?
Dr. Matushansky: My feeling on this is that all oncologists should treat what they feel comfortable treating and what they know how to treat. What we all, as clinicians, feel comfortable doing are the things that we do most frequently. A decade ago, I was certified to do bone marrow biopsies as part of hematology–oncology fellowship training; but, that was 10 years ago. Today, I don’t think I am qualified to actually do a bone marrow biopsy, even though I have a certification. As doctors, we have certifications attesting to our competence in much more than what I think time and practice supports. For just because as a doctor I have a license to practice "medicine and surgery" in the state of New York does not imply that I should be practicing general medicine and surgery? I do not believe I am qualified at this point to do either. I think the same reasoning should apply to the situation of oncologists and rare tumors. Everyone should do what they are comfortable with and what they know. I really do feel that patients with rare diseases should be referred to those specializing in those rare diseases. Mistakes in managing diseases that are very uncommon are more likely to occur.
What is the role of community oncologists? I would say that it is to recognize what they can treat and what they can’t treat and to treat what they can, treat what they know, and treat cancers for which there are standard guidelines. Community oncologists should, treat cancers for which ASCO, ACS, and ACR have put out unquestionable guidelines for first-line and second-line therapy that is commonly available. These organizations have good experience, and they do provide guidelines. I actually think all patients with rare diseases—not just sarcomas— should be referred out to places that have experience in treating them and that see a fair number of them. Partially, I worry that mistakes will be made, as are made by all of us all the time when confronting the new and unknown. However, I also think that patients with rare diseases need to be grouped, their treatments standardized (either as part of a clinical trial or not) so that medically relevant conclusions about the whole group can be made which would help us all improve our understanding of the disease. Rare diseases are hard to evaluate even in clinical trials because patients are scattered. So referring patients to a high-volume center not only avoids mistakes, but also facilitates formal learning for the greater good. Without this, the entire field remains one of anecdotal medicine due to a lack of resources. I do think it is important, for many reasons, that these patients with rare diagnoses across the board be referred to high-volume centers that have the experience of seeing them and treating them.
We see about 100 new patients a year. That is considered pretty good, if you think about how many patients there are in the United States every year. There are approximately 10,000 cases of new sarcomas diagnosed every year across the entire country. Most centers do not see a new patient with sarcoma once a week. That is how extremely rare this cancer is.
Sometimes I get phone calls from various places across the country where a clinician has seen a new patient, but this patient can’t travel to New York or Boston or Texas. The oncologist will ask what to do with the patient. There are a lot of patients across the country, but they simply can’t get to a center where there is volume. It is important that we get the word out about what needs to be done. What I usually tell them is, if you can’t get the patient there, at least communicate with somebody at the institution who has experience I am more than happy to speak with anyone at all times.
OncologySTAT: What are the most promising targets and targeted agents in soft tissue sarcomas?
Dr. Matushansky: The drug that everybody has been talking about is Yondelis (trabectedin), which is a novel compound derived naturally from a marine sponge. Its mechanism is not yet fully characterized, and work is ongoing. This drug has received a lot of attention, especially for treating liposarcomas. It has been approved in Europe for the treatment of sarcomas, but it has not been approved in the US. There are several trials being run primarily to look at its efficacy in various sarcoma settings; but, everyone who has used this drug has seen dramatic responses in some patients. It is still probably the most promising agent out there for sarcomas.
OncologySTAT: What type of monitoring of late effects should be put into place for childhood and adolescent survivors?
Dr. Matushansky: I usually tell patients that they should receive CAT scans every 3 months for at least 3 years following initial surgery. If there is going to be a recurrence, 75% of all recurrences for high-grade sarcomas will be in the first 3 years after the first surgery. And 90% of all recurrences will occur in the first 5 years. If a patient has had no recurrences in the first 5 years, then I usually monitor him or her with CAT scans every 3 months for the first 3 years, and then every 4 to 5 months for years 4 and 5. After 5 years, if there has really been no indication of disease recurrence, we stop monitoring. There is still a 10% window throughout the patient’s lifetime of increased risk for sarcomas across the board; but, as I said earlier, unfortunately nothing can change that. Imaging with CAT scans hasn’t really been shown to be effective for long-term surveillance. Patients will tend to re-present at some point later in life with some sign and/or symptom that will then prompt some kind of imaging that may identify a recurrence. The only other additional thing that I would say is that patients who have received chemotherapy at some point for sarcoma, whatever side effects associated with that chemotherapy need to be specifically heeded. For example, doxorubicin carries a cardiac side-effect profile. It can drop the ejection fraction of the heart; so, patients may present at any point with some kind of heart symptoms, shortness of breath, and dyspnea on exertion, et cetera. Physicians outside of oncology who treat these patients really need to pay close attention to the fact that they may have some late chemotherapy side effect.
References
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2. E Charytonowicz, et al. Alternate PAX3 and PAX7 C-terminal isoforms in myogenic differentiation and sarcomagenesis. Clin Transl Oncol, 2011. 13(3): p. 194-203.
3. J Mills, et al. Chromatin structure predicts epigenetic therapy responsiveness in sarcoma. Mol Cancer Ther, 2011. 10(2): p. 313-24.
4. I Matushansky,et al. MFH classification: differentiating undifferentiated pleomorphic sarcoma in the 21st Century. Expert Rev Anticancer Ther, 2009. 9(8): p. 1135-44.
5. E Charytonowicz, et al. Alveolar rhabdomyosarcoma: is the cell of origin a mesenchymal stem cell? Cancer Lett, 2009. 279(2): p. 126-36.
6. I Matushansky, et al. A developmental model of sarcomagenesis defines a differentiation-based classification for liposarcomas. Am J Pathol, 2008. 172(4): p. 1069-80.
7. I Matushansky, et al. Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. J Clin Invest, 2007. 117(11): p. 3248-57.
8. E Hernando, et al. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med, 2007. 13(6): p. 748-53.
9. I Matushansky and RG Maki. Mechanisms of sarcomagenesis. Hematol Oncol Clin North Am. 2005. 19(3): p. 427-49, v.
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