Sarcomas are a heterogeneous group of malignant tumors that develop from connective tissue (fat, muscles, nerves, joints, blood vessels, bones, and deep skin tissues) and result in mesoderm proliferation. They are difficult to differentiate from other malignancies when they are found within organs; for this reason, sarcomas are frequently misdiagnosed and highly underreported.
According to the National Cancer Institute, approximately 13,000 Americans will be diagnosed with sarcoma and 5,200 will die from the disease in 2008.1 In addition, since sarcomas often affect young patients, the number of years of life lost is substantial despite this relatively low incidence. The limited number of cases available for follow-up at any single institution is reflected in the paucity of definitive guidelines in the management of patients with sarcoma. Over the past thirty years, tremendous progress in diagnostic techniques and treatment alternatives has favorably improved the survival and quality of life of patients with sarcoma.2,3 Despite these new discoveries and the development of new techniques and materials, limited collaborative effort among comprehensive cancer institutions around the world has been a constant.
Professional societies such as the Connective Tissue Oncology Society (CTOS) Musculoskeletal Tumor Society (MSTS) European Organization for research on Treatment of Soft Tissue and Bone Sarcoma (EORTC) have provided the setting for multidisciplinary and multicenter discussions on the management of sarcoma. Despite these attempts to create consensus, several issues regarding the pathophysiology, diagnosis, staging, and treatment of sarcoma remain controversial and a matter of debate.4-7 The present report is a brief description of few of the many controversies in the evaluation of patients with sarcoma in order of increasing advancements.
Atypical Lipoma vs. Liposarcoma
When an abnormal proliferation of mature fat exhibits at least some grade of cellular atypia, and magnetic resonance imaging shows a large heterogeneous mass of fatty tissue with prominent fibrous banding and/or necrosis, a diagnosis of "atypical lipoma" can be made.8-11 This particular type of sarcoma has been described over the years with multiple terms that include "well differentiated liposarcoma", "lipoma-like liposarcoma", "pleomorphic lipoma", "sclerosing liposarcoma", "inflammatory liposarcoma", "lymphocyte rich liposarcoma", "spindle cell liposarcoma", and many others. The terms "well differentiated liposarcoma" and "atypical lipomatous tumor" are currently the most frequently used to describe this type of sarcoma. One argument in favor of the term "well differentiated liposarcoma" is that when present in deep locations, recurrences of the tumor may be difficult to control. Also, these tumors may dedifferentiate and in some cases, metastasize. On the other hand, arguments in favor of the term "atypical lipomatous tumor" include that in the absence of dedifferentiation, such tumors do not metastasize. Also, the mentioned "uncontrollable recurrences" are rare and never present when the tumor is in non-central locations. Another concern voiced by several authors is the fact that the term "sarcoma" given to non-central lesions may result in over-aggressive surgical interventions.8-11
Brachytherapy vs. External Beam Radiotherapy
Radical surgery, such as amputation or massive soft tissue resections at the expense of function and cosmesis, was the standard of care before the early 1980s. Since then, multiple prospective randomized trials have shown that limb-sparing surgery combined with adjuvant external beam radiotherapy (EBRT) is possible without compromising survival compared with amputation alone.12-17 Postoperative radiotherapy is most commonly given as either low-dose-rate brachytherapy (BT) or EBRT, or a combination of the two. The potential benefits of BT alone include a reduced treatment time, higher doses to the tumor bed, and the sparing of overlying skin.
Several authors have proposed the addition of EBRT to BT when surgical margins are positive. The rationale is to use BT for control of the tumor bed and to add EBRT for wider coverage to minimize the potential for marginal failures. Another related controversial topic regarding radiation treatment is the timing (pre or post-operative) of the therapy and the supplementation of chemotherapy. In many centers, neoadjuvant chemotherapy is sequenced with preoperative EBRT.18
Surgical Management of Low Grade Chondrosarcoma
Surgical intervention is the preferred treatment option for chondrosarcoma because radiation and chemotherapy are ineffective.19,20 The local recurrence rate and potential for metastasis of grade 1 chondrosarcoma are low. For these reasons, limited surgery (intralesional resection) with adjuvant therapy (cryosurgery, phenol-alcoholization) has been proposed for less aggressive-appearing lesions. However, in some studies, the outcome when treated with intralesional surgery has been associated with increased incidence of local recurrence and subsequent disease progression. In general, tumors that do not erode the cortex or have associated soft tissue masses have a favorable outcome when treated with limited intralesional surgery. The addition of adjuvant therapy such as phenol, liquid nitrogen, alcohol, cement, etc, is surgeon/center dependent with confounding reports in the literature.19 21,22
Learn more in "Management in Low-Grade Chondrosarcoma."
Low Grade Chondrosarcoma vs. Enchondroma
The diagnosis of cartilage lesions requires three key elements. First, clinical and radiographic features such as the age of the patient, symptoms, localization in the skeleton, and the pattern of bone destruction or mineralization should be documented. Second, low-power histological features must be carefully investigated to accurately describe the growth pattern of the lesion. Third, the cellularity and degree of nuclear atypia must be analyzed. A key factor in making the correct diagnosis between low-grade chondrosarcoma and enchondroma is a close communication between the surgeon, the pathologist, and the radiologist.23,24
Enchondroma and low-grade chondrosarcoma are distinguished by how they behave, and histological features alone do not always predict clinical behavior.24-26 The behavior of a cartilage lesion is appreciated using clinical and radiographic features before a biopsy is done. The histological features are then interpreted in the light of this clinical information. Serial radiographs and close clinical follow-up over several months provide invaluable information regarding growth of the lesion, a fundamental factor used in the distinction between these two conditions. Exceptions to this approach include the cartilage lesion of Oilier's disease, cartilage lesions of the hand, or in children. In these cases, slow growth does not always indicate malignancy (ie low grade chondrosarcoma).27-29
Immunotherapy for Sarcoma
For decades, physicians have been studying the concept that tumor cells are foreign to the local host and that the immune system has the potential to recognize the key differences and respond by rejecting the tumor cells.30-33 The surface membranes of sarcoma cells have markers that can act as antigens labeling the cells as abnormal and allowing recognition by the immune system.
There are two broad classes of immunotherapies, active immunotherapy (vaccine therapy) and passive immunotherapy (antibody therapy). Active immunotherapies stimulate the immune system of the patient to ideally "detect" and "react" to the cancerous cells.34 Passive immunotherapies do not rely on the immune system to attack the disease; they use external/synthetic immune system components (such as antibodies) to fight the disease.35
One of the main points of controversy has been to delineate the ideal antigen that the immune system can target and that is only present on the sarcoma cells. Other controversial issues in sarcoma immunotherapies are the scientific effort and cost of creating new, unique vaccines for each cancer patient, the mutations in the cancer cells that result in the vaccine becoming less effective over time, and the wide antigen variation in primary and metastatic tumoral cells.31
Learn more in "The Difficulty and Promise of Immunotherapy for Sarcomas."
Stem cell in pathogenesis of Ewing Sarcoma
A basic issue in cancer research is the isolation and identification of the cell that gives rise to a clinically apparent tumor.36-39 In common epithelial tumors, such as breast and colon cancers, the search can be directed to the cell types that are present within the target organ. Rare neoplasias such as sarcomas that may occur in a variety of anatomic sites will not arise from a particular tissue.
Ewing's sarcoma is an uncommon tumor that has a high probability to metastasize and remains lethal in a significant percentage of patients. The tumor frequently appears to arise in bones, but several extraosseous sites have been described. Ewing's sarcomas are typically described in textbooks as composed of small round blue cells that may express neural markers. These cells, however, can not be placed clearly in any developmental lineage.
The discovery of specific chromosome translocations [t(11;22)(q24;q12)] and oncogenic proteins [EWS (EWSR1)] has allowed further classification of diverse tumors into the Ewing's sarcoma family of tumors (ESFT). However, these breakthrough advances have not answered the question of the progenitor cell problem. Recent animal studies have supported the possibility that Ewing's sarcoma may be derived from mesenchymal stem cells.38 These cells can be derived from either bone marrow or soft tissue (muscle or adipose tissue) and retain the ability to differentiate along a number of connective tissue lineages (adipocyte, muscle, tendon, bone, or cartilage).
Several controversies on this hypothesis are still a matter of debate. First, mesenchymal stem cells are defined by their pluripotentiality. Unlike hematopoietic stem cells or embryonic stem cells, there are no accepted markers for the mesenchymal stem cells. Another source of debate is the fact that cultures of glioblastoma and other neuroectodermal tumors have also been induced to differentiate along adipocyte or other mesenchymal lineages (a relationship between neural stem cells and mesenchymal stem cells?). In addition and crucially important, is the fact that no premalignant precursor of Ewing's sarcoma has been observed in humans.
Read more in "Cancer Stem Cells in Sarcoma."
Role of PET scans in the treatment of Sarcoma
For the past twenty years, several authors have supported the association between glucose uptake and the tumor grade in patients with sarcoma. It is well known that the glycolytic metabolic activity of high-grade tumors is higher than that of low-grade or benign tumors. The metabolic data acquired by PET scans may facilitate accurate grading and have prognostic value in the management of sarcoma. Currently, there are no accepted guidelines regarding the indications for the use of PET scans in patients with sarcoma.
Controversial issues include the use of PET to differentiate benign from malignant sarcomas, the degree of uptake as a potential prognostic value and a predictive tool for recurrence-free survival, and its widespread use as a valuable diagnostic and staging modality.40-44 Fueling the controversy is the fact that several studies have shown conflicting results using the metabolic rate as a parameter to distinguish between benign and malignant sarcomas and the high rate of false positives (such as with giant cell tumors which typically show a relatively high metabolic activity. The controversy regarding the role of PET scans in the evaluation of sarcoma emphasizes the need for collaboration between institutions (establishing homogenous imaging protocols and evaluation algorithms).
Limb salvaging procedures, radiation therapy and chemotherapy have dramatically improved sarcoma survival rates and reduced the incidence of recurrence. Today, surgery remains as the primary treatment option for most types of sarcoma. With the current treatment options, the majority of patients who will die from sarcoma have chemotherapy-resistant metastatic disease. One of the pitfalls in the management of patients with sarcoma is that only a few chemotherapy drugs are effective, and the relatively infrequent presentation and heterogeneity of sarcoma make testing new agents challenging.
As previously briefly discussed in this report, the lack of a uniform standard of care, the difficulty in diagnosis, the lack of new treatments, and the paucity of collaborative inter-institutional guidelines explain why sarcoma continues to be an underserved pathology by the medical and research communities. We strongly believe that collaborative efforts and guidelines, and constructive multidisciplinary discussions with the supervision of professional associations are of paramount importance in providing state of the art care to patients with sarcoma.