By Joe Munch
Desmoid tumors are among the rarest of tumors—they occur in only 2–4 people per million per year in the United States. Although desmoids have a benign histologic appearance and lack the ability to metastasize, they can invade locally—often aggressively—and recur repeatedly. Physicians therefore face challenges in both the diagnosis and treatment of these tumors. At The University of Texas MD Anderson Cancer Center, a multidisciplinary team is working to address these challenges.
A question of malignancy
Desmoid tumors, also known as aggressive fibromatoses, are soft-tissue tumors that arise from connective tissue and typically present as a single, slowly growing mass. Most desmoids are sporadic tumors, but some occur in the setting of Gardner syndrome, a variant of familial adenomatous polyposis. Desmoids can occur anywhere in the body but generally occur in the root of the mesentery (intraabdominal desmoids), in the abdominal wall (abdominal desmoids), and outside the abdomen, primarily in the shoulder or pelvic girdles (extraabdominal desmoids).
Dina Chelouche Lev, M.D., an assistant professor in the Department of Cancer Biology, said that until about a decade ago, it was unclear whether desmoids should be considered a reactive proliferation—a “scarring process that has gone wild”—or a neoplastic process. Once it was determined that desmoids could be considered neoplasms, the question became whether to classify them as benign or malignant. A universally accepted answer has not yet been established. Some oncologists, citing the tumors’ inability to metastasize, consider desmoids to be benign. But at MD Anderson Cancer Center, desmoids are viewed as a malignant disease, a designation, Dr. Lev said, that hinges on the definition of malignancy.
“Per the book, malignant cells are cells that can metastasize from the primary tumor to a different site. If that’s how you characterize malignancy, then desmoid tumors are not malignant,” Dr. Lev said. “But if you consider desmoids based on the patient outcomes—death, deformity, effects on quality of life, significant recurrences mandating hospitalization, and so forth—in my mind, I would call that a malignant disease.”
Their benign histologic appearance and lack of metastatic potential notwithstanding, desmoids can be highly infiltrative, invading along fascial planes, destroying adjacent vital structures and organs, and obstructing blood vessels and ureters. Intraabdominal desmoids, for example, can grow so large that they compress the small bowel, causing abdominal pain, changes in bowel habits, and rectal bleeding.
According to Raphael Pollock, M.D., Ph.D., a professor in and head of the Division of Surgical Oncology, each of the major treatment modalities—systemic therapy, radiation therapy, and surgery—plays a potential role in the treatment of desmoid tumors, and finding the right therapy or combination of therapies for each patient involves an entire team. “All desmoid cases are presented at our weekly soft tissue sarcoma planning conference so that treatment plans can be discussed by specialists in each treatment modality before we embark on any specific therapeutic approach for the patient,” Dr. Pollock said. “What comes out of the conference is a truly integrated multidisciplinary approach that represents our best collective thinking.”
Surgery, the mainstay of therapy for most desmoid tumors, is performed with the goal of obtaining tumor-free—negative—margins while preserving functionality. However, obtaining negative margins can be difficult.
“Desmoids tend to be very infiltrative on a microscopic level,” Dr. Pollock said, “and a surgeon can be fooled into thinking that there is an adequate margin of resection when in fact there might be microscopic disease that’s just penetrated up to the edge of the resected specimen.” Positive surgical margins increase the risk of recurrent disease; if the desmoid recurs, repeat surgeries may lead to excessive scarring or even amputation in some patients. For this and other reasons, the role of surgery in some patients with desmoid tumors is being reevaluated.
“Rather than performing an operation that could damage the patient’s quality of life, we would try to use other types of treatments prior to surgery in the hope that we could avoid such a quality-of-life–defining situation,” Dr. Pollock said.
The natural history of desmoids varies from patient to patient: some desmoids grow unceasingly; others grow, stop growing, and then start growing again; still others grow and then regress without intervention. Because the tumors cannot metastasize, there may be a role for observing the patient if the lesion is not causing functional difficulty. And if the lesion is causing functional difficulty, there may be a role for nonsurgical therapy before surgery is considered. For example, in patients in whom surgical resection is not feasible, radiation therapy can be given as the definitive therapy.
“We can give radiation therapy as the sole treatment modality and expect to achieve local control in 75% of patients, which is similar to the control rate for surgical patients,” said Ashleigh Guadagnolo, M.D., M.P.H., an assistant professor in the Department of Radiation Oncology. “For instance, we would give radiation therapy to treat a desmoid in the neck, where it would be difficult to take out the tumor with negative margins, or to treat a desmoid deep in the low pelvis, which would require a full pelvic exenteration to extirpate the tumor.”
In rare cases, radiation therapy is given to shrink a tumor prior to surgery; more often, radiation therapy is administered after surgery to reduce the risk of recurrence in patients with positive surgical margins. Although desmoids are sensitive to radiation, the tumors’ slow cell cycle ensures that the effects of radiation therapy will not be seen until 6–8 months after treatment, with tumors continuing to shrink for years in some cases.
Good imaging and avoidance of critical structures are always important in delivering radiation therapy, Dr. Guadagnolo said. She added, “Radiation therapy for desmoid tumors needs to be done by someone who is familiar with the disease because it’s a rare tumor with distinctive behavior and potential to be locally aggressive.”
Medical treatment usually comes to the forefront when surgery and radiation cannot be used or have failed. Occasionally, however, systemic therapy is given before surgery to shrink large, potentially resectable desmoids that would otherwise incur excessive surgery-related morbidity in patients for whom radiation therapy would be inappropriate—for example, in patients with a desmoid deep in the pelvis or abdomen, sites prone to high radiation toxicity. Medical therapy for desmoids usually involves individualized combinations of antihormone agents, typically tamoxifen or raloxifene; nonsteroidal antiinflammatory drugs such as ibuprofen or naproxen; targeted chemotherapy with imatinib mesylate; and/or traditional cytotoxic chemotherapy.
“The major question in treating patients with desmoids is, how urgently do you need a response to therapy? If the tumor is not causing significant morbidity, then we’ll take a very conservative approach,” said Robert Benjamin, M.D., a professor in and chair of the Department of Sarcoma Medical Oncology. “But if we need a response to therapy right away, then we’ll give more intensive chemotherapy to start with, typically doxorubicin and dacarbazine.”
Although it is generally avoided because of its high toxicity, cytotoxic chemotherapy has a surprisingly high rate of success in treating desmoids.
“Desmoids can be considered very low-grade sarcomas. Conventional wisdom would indicate that such tumors would not respond to chemotherapy at all, but that is anything but the case,” Dr. Benjamin said. “Chemotherapy that is effective in treating high-grade sarcomas is also effective in treating desmoids, particularly those associated with Gardner syndrome, and that’s not something I think anyone would have predicted.”
Owing to this team approach, the rate of recurrence in desmoid patients treated at MD Anderson is less than 20%, which is on the low side of the 20%–40% rates reported in the literature, even though most desmoid patients referred to MD Anderson have already undergone surgery and experienced a recurrence necessitating a more aggressive approach to therapy.
Exploring new pathways
Desmoid tumors are difficult to diagnose for several reasons. Because desmoids can arise anywhere in the body, their location does not provide any clues to their identity. In addition, the type of cell from which desmoids arise is unknown. Most confounding, especially in the setting of suspected recurrent disease, is desmoids’ resemblance to scar tissue, which effectively eliminates frozen-section analysis as a method for evaluating the surgical margins of resected desmoids. And because virtually any mass that grows will have a rind of fibrosis that looks like scar tissue and has features of a desmoid, it is sometimes unclear whether a mass biopsied to establish or confirm additional disease in the setting of desmoid fibromatosis was inadequately biopsied (i.e., the fibrous rind surrounding the mass, not the mass itself, was biopsied) or is in fact a desmoid.
Investigating the molecular mechanisms underlying desmoid tumors may provide better ways to identify and treat the disease. About 85% of sporadic desmoids (i.e., desmoids not associated with Gardner syndrome) harbor mutations of the CTNNB1 gene encoding b-catenin, a cell adhesion cofactor and nuclear signaling factor that is part of the Wnt signaling pathway. The dysregulation of the Wnt pathway is implicated in the tumorigenesis of a number of cancers.
Seeking to confirm these findings, Dr. Lev, along with Dr. Pollock and Alexander Lazar, M.D., Ph.D., an associate professor in the Department of Pathology, and other MD Anderson researchers, began sequencing desmoids for b-catenin mutations and identified three specific mutations in two different codons of CTNNB1. The researchers then looked for correlations between specific mutations and clinical outcomes.
“To our surprise, we found that tumors that had one particular mutation, S45F, showed a remarkable propensity to recur very rapidly,” Dr. Lazar said. “If this finding can be corroborated, b-catenin sequencing can be a prognostic tool. There are more and less aggressive ways to treat desmoids, so if we know that a patient has a particular mutation associated with more aggressive disease, we may make different decisions in terms of whether to suggest surgery, radiation, or other treatments.”
Dr. Lev and her colleagues are working to validate the study’s findings, which have already proven valuable in definitively diagnosing desmoid tumors in some patients. Dr. Lazar said, “If we’re not sure whether a case is a desmoid tumor but can demonstrate a characteristic CTNNB1 mutation in it, we can be highly confident that it is in fact a desmoid.”
Desmoids do not become genetically complex; that is, they do not seem to acquire more mutations with time. “This suggests to me that b-catenin is the only thing, or the major thing, that is disrupted in the tumor,” Dr. Lev said. “Once we find a way to manipulate this pathway, we can find more effective treatments for these tumors.”For the time being, Dr. Lazar said, “The team approach we take to treating patients with desmoids—the pathological analysis to get the right diagnosis, genotyping, and involving surgeons, radiation oncologists, and medical oncologists—appears to make a real difference in how well these patients do.”
For more information, contact Dr. Benjamin at 713-792-3626, Dr. Guadagnolo at 713-563-8400, Dr. Lazar at 713-563-1843, Dr. Lev at 713-792-1637, or Dr. Pollock at 713-792-6928.
Other articles in OncoLog, November-December 2010 issue: