Round cell sarcoma is a group of rare and aggressive cancers that primarily affect bone and soft tissue, mainly in children, adolescents, and young adults. This category is defined by the uniform appearance of the tumor cells when viewed under a microscope. These cells are characteristically small, undifferentiated, and “round,” giving the cancers their collective name. Their shared physical appearance makes initial diagnosis challenging, necessitating advanced testing to determine the specific disease and the most effective treatment plan.
Defining Round Cell Sarcomas
Sarcomas are malignancies that originate in the body’s connective tissues, such as fat, muscle, bone, cartilage, and blood vessels. Round cell sarcomas are distinguished from other sarcoma types by their unique cellular morphology. Under a pathologist’s lens, these tumor cells appear small, blue, and round, with a high ratio of nucleus to cytoplasm.
The cells are often described as primitive and monotonous, lacking the distinctive features of mature, specialized cells. This undifferentiated appearance causes many aggressive cancers to look alike, leading to the collective term “small blue round cell tumors.” Although they share a common physical appearance, this is an umbrella term for several biologically distinct diseases, each with its own unique genetic signature. Therefore, microscopic findings serve as an important initial clue but are not sufficient for a definitive diagnosis.
The Major Subtypes
The classification of round cell sarcomas is primarily based on the specific genetic change, typically a chromosomal translocation, that drives the cancer.
Ewing Sarcoma
Ewing sarcoma (ES) is the most recognizable example, often arising in the bone, but it can also occur in soft tissue. This cancer commonly affects children, adolescents, and young adults. The defining feature is a specific genetic rearrangement, most often a translocation between chromosomes 11 and 22, written as t(11;22)(q24;q12). This translocation creates the \(EWSR1\)–\(FLI1\) fusion gene, which is present in about 85% of cases and is considered the pathognomonic marker for this disease.
Desmoplastic Small Round Cell Tumor (DSRCT)
DSRCT is a rare and highly aggressive malignancy that mainly affects adolescent and young adult males. This tumor typically develops as masses within the abdomen and pelvis, often spreading across the lining of the abdominal cavity. The unique genetic signature is a translocation between chromosomes 11 and 22, specifically t(11;22)(p13;q12). This results in the \(EWSR1\)–\(WT1\) fusion gene, which is a key element for distinguishing DSRCT from other round cell sarcomas.
Alveolar Rhabdomyosarcoma (ARMS)
Rhabdomyosarcoma is a cancer with differentiation toward skeletal muscle, and the alveolar subtype is defined by its small round cell appearance. ARMS commonly arises in the extremities and often affects adolescents and young adults. This subtype is characterized by specific translocations involving the \(FOXO1\) gene, such as t(2;13) leading to the \(PAX3\)–\(FOXO1\) fusion gene, or t(1;13) resulting in the \(PAX7\)–\(FOXO1\) fusion gene.
Other Emerging Subtypes
Beyond these classic entities, molecular testing has identified other distinct round cell sarcomas that previously might have been misdiagnosed as Ewing sarcoma-like tumors. These include sarcomas with \(CIC\) gene rearrangements, most commonly involving a \(CIC\)–\(DUX4\) fusion, and sarcomas with \(BCOR\) genetic alterations. These genetically defined entities are recognized as biologically separate diseases, highlighting the complexity within this group.
Specialized Diagnostic Testing
Because the definitive diagnosis cannot rely on morphology alone, a precise diagnosis requires a sequence of specialized tests to identify the specific molecular signature of the tumor. This process is necessary because the exact genetic alteration dictates the choice of treatment.
The first step beyond standard histology often involves immunohistochemistry (IHC), a technique that uses antibodies to detect specific proteins on the tumor cells. For instance, Ewing sarcoma cells typically show strong positivity for the CD99 protein. However, IHC markers can sometimes be variable or non-specific, meaning they are also found in other tumor types, which necessitates further molecular confirmation.
Molecular Testing Techniques
The most definitive diagnostic step is molecular testing, which identifies the characteristic chromosomal translocations.
Techniques used include Fluorescence In Situ Hybridization (FISH), which uses fluorescent probes to visualize gene rearrangements, such as the break-apart of the \(EWSR1\) gene. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next-Generation Sequencing (NGS) are also employed to detect the actual gene fusion transcripts. NGS is particularly valuable because it can simultaneously screen for multiple known and novel gene fusions, helping to resolve complex cases.
Therapeutic Approaches
The aggressive nature of round cell sarcomas necessitates a comprehensive, multi-step treatment strategy. Treatment is typically multimodal, combining systemic therapy with local control measures. The specific regimen depends on the exact molecular subtype and the extent of the disease.
Systemic chemotherapy is a primary component of treatment for nearly all round cell sarcomas, often administered before local treatment in a process called neoadjuvant therapy. For Ewing sarcoma, a standard protocol involves alternating cycles of several different chemotherapy drugs, such as:
- Vincristine
- Doxorubicin
- Cyclophosphamide
- Ifosfamide
- Etoposide
This systemic approach is designed to shrink the tumor, control microscopic spread of the disease, and assess the tumor’s sensitivity to the drugs before surgery or radiation.
Local control measures are then employed to physically remove or destroy the primary tumor site. Surgery, with the goal of complete resection, is generally the preferred method when possible while preserving acceptable function. Radiation therapy is often used in conjunction with surgery, or as the sole local treatment when complete surgical removal is not feasible. Treatment protocols for other subtypes, like DSRCT, also involve multimodal therapy, including combination chemotherapy, surgery, and radiation.