Musculoskeletal Oncology: Introduction
Tumors of the musculoskeletal system are an extremely heterogeneous group of neoplasms consisting of well over 200 benign types of neoplasms and approximately 90 malignant conditions. The relative incidence of benign to malignant disease is 200:1. The tumors uniformly arise from embryonic mesoderm and are categorized according to their differentiated or adult histology. Current classification schemes are essentially descriptive. Each histologic type of tumor expresses individual, distinct behaviors with great variation between tumor types. Benign disease, by definition, behaves in a nonaggressive fashion with little tendency to recur locally or to metastasize. Malignant tumors or sarcomas, such as osteosarcoma and synovial cell sarcoma, are capable of invasive, locally destructive growth with a tendency to recur and to metastasize.
Neoplastic processes arise in tissues of mesenchymal origin far less frequently than those of ectodermal and endodermal origin. In 2004, soft-tissue and bone sarcomas had an annual incidence in the United States of more than 8600 and 2400 new cases, respectively. When compared with the overall cancer mortality of 563,000 cases per year in 2004, sarcomas are a small fraction of the problem. However, although a relatively uncommon form of cancer, these mesenchymal tumors behave in an aggressive fashion with reported current mortality rates in some series greater than 50%. According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, approximately 8600 new soft-tissue sarcomas developed in the United States in 2004 with over 3600 sarcoma-related deaths. The associated morbidity is much higher. These tumors inflict a tremendous emotional and financial toll on individuals and society alike. Furthermore, sarcomas are more common in older patients, with 15% percent affecting patients younger than 15 years and 40% percent affecting persons older than 55 years. Accordingly, as the population ages, as it is doing at a rapid rate, the incidence of these tumors will increase.
Etiology of Musculoskeletal Tumors
Tumorigenesis is a complex multiple-step process by which healthy tissue progressively transforms from a normal phenotype into an abnormal colony of proliferating cells. During this process, cells acquire genetic abnormalities in oncogenes, tumor suppressor genes, and other genes that directly or indirectly control proliferation. Such a process may progress beyond the controlled state of benign disease to become a dedifferentiated, aggressive, and immortal phenotype by genomic instability. It is this instability that allows the cell to progress to fulminant malignancy. DNA regulation and, correspondingly, integrity is ultimately lost and a cancer is born.
To appreciate how bone or soft-tissue tumors develop, one must have a basic understanding of the cell cycle during which cell division occurs. The cell cycle is divided into four distinct phases: G1 (gap 1), S (DNA synthesis), G2 (gap 2), and M (mitosis). DNA synthesis occurs during the S phase, with chromosomal separation and cell division occurring in the M phase. The majority of cell growth takes place during G1. The mature state for mesenchymal tissues is normally in a resting, nonproliferative phase designated G0. It is the factors that affect the exit of the cell from G0, with entrance into G1, that is the hallmark of neoplastic disease.
Control of the cell cycle is a function of numerous regulatory proteins and checkpoints. The checkpoints allow for the monitoring and correction in the genetic sequence. The proteins are encoded by two basic gene types: oncogenes (stimulatory) and tumor suppressor genes (inhibitory). The retinoblastoma (Rb) protein and its phosphorylation state are critically important in regulating cell cycle progression (from G1 to S phase). Therefore, the activation state of Rb is a highly regulated cellular event. In addition, multiple cyclins and cyclin-dependent kinases are being studied actively to elucidate their role in regulation of the cell cycle.
Oncogenes, encoding a variety of growth factors, promote progression of the cell through G1, effecting a mitogenic signal. Suppressor genes, such as wild-type TP53, act to arrest the cell cycle. Specifically, TP53 acts to stop the cell cycle at the G1/S border as a final attempt to abort proliferation. Other suppressor genes work earlier to keep reproduction at bay. A complex array of molecules can serve as either an induction or suppressor function. When this pathway is not orchestrated properly, a given cell obtains the potential for limited or even immortal proliferation. A normal cell progresses through a preneoplastic state on its way to becoming neoplastic via the accumulation of mutations. A critical step during tumor progression is the loss of suppressor gene function, which occurs by a variety of defects, including deletions, translocations, promoter silencing, loss of heterozygosity, point mutations, microsatellite changes, and telomeric associations. The degree to which the daughter cells dedifferentiate into a malignant phenotype is a function of the amount of genomic instability that arises with each subsequent mitosis. Mutation begets mutation as the checkpoints and regulatory machinery continually fail to repair the genetic code.
Factors that influence these mechanisms include both inheritable genetic conditions (eg, Li-Fraumeni syndrome, retinoblastoma) or environmental factors. It is well established that oncogenic viruses, radiation, and chemical carcinogens can affect these processes, ultimately compromising genomic stability.
The neoplastic process may arrest in the so-called benign state, with further genomic instability curtailed, or it can almost progress to a sarcomatous state. For example, if the cell type of origin is a lipocyte, then a lipoma or liposarcoma may develop. Furthermore, a liposarcoma can progress in its dedifferentiation such that its phenotype, as a high-grade lesion, minimally reflects its lipocytic origin. This possibility does not imply, however, that all benign lesions are necessarily at risk for malignant degeneration. It is not a surgical indication to remove a lipoma because of concern over developing a liposarcoma.
Although a plethora of molecular markers are being studied, understanding the details of genomic instability and subsequent tumor formation is lacking. The initiation of the neoplastic process and subsequent disease progression is a complex multistep process in gene expression and deregulation. There is no single pathway by which all neoplasms arise; instead, multiple genetic targets are altered in a variety of sequences with the common result of cellular proliferation that is tumorigenesis.
Evaluation & Staging of Tumors
History & Physical Examination
When evaluating a new patient with a possible tumor, the workup must commence with a thorough history and physical examination. Prior to ordering any diagnostic studies, particular questions must be answered, and the physical characteristics of the mass in question must be assessed. This procedure prevents unnecessary tests and better enables the physician to determine which tests will be most helpful in diagnosing the condition as well as facilitating therapeutic interventions if needed.
The clinical history is of paramount importance (Table 6–1). The age of the patient permits the generation of a list of potential diagnoses (Table 6–2), which, when combined with the history and a few additional studies, should permit establishing a diagnosis. The duration of symptoms, rate of growth, the presence of pain, and a history of trauma can help elucidate the diagnosis. A careful past medical history, family history, and review of systems must not be overlooked
