1 Clinico-pathologic Considerations

The diagnosis of musculoskeletal and soft tissue neoplasms involves a multidisciplinary approach between clinicians, radiologists and anatomical pathologists. Histologic examination remains the gold standard in the diagnosis of mesenchymal tumors. However, the adjuvant diagnostic techniques of electron microscopy, immunohistochemistry and more recently genetic evaluation of neoplasms via conventional cytogenetics or a variety of molecular genetic techniques are increasingly used in the diagnostic workup of patients’ tumors. Appropriate clinical information must be made available to all members of the diagnostic team since it forms an invaluable component of the diagnostic algorithm used in the work up of patients.

2 Classification Criteria

The World Health Organization’s International Histological Classification of Tumours is used to classify neoplasms of bone and soft tissue (Reference). Two points need to be emphasized regarding these neoplasms

1. Neoplasms of mesenchymal tissues are classified based on the microscopic resemblance of the neoplastic cells to known mature or immature mesenchymal cells. It is not based on the tissue site of origin of the neoplasm. For example, sarcomas that demonstrate skeletal muscle differentiation are classified as rhabdomyosarcomas because the individual neoplastic cells demonstrate cytoplasmic evidence of skeletal muscle differentiation. In fact, rhabdomyosarcomas rarely arise in the large skeletal muscles and commonly develop in regions which normally contain no or scant numbers of mature skeletal muscle cells (the lower genital tract).

   This raises the question as to what is the "cell of origin" of the various neoplasms that constitute the mesenchymal tumors. In the vast majority of cases the answer to this is unknown. Current theories suggest that there are ubiquitously distributed mesenchymal cells throughout the skeleton and somatic soft tissues that have the capacity to differentiate into a variety of different mesenchymal cell types. These "pluripotential" cells likely represent the population that result in the majority of mesenchymal neoplasms. Most of the time the circumstances or signals that result in the development of the neoplastic phenotype are unknown. A proportion of mesenchymal neoplasms are composed of cells that do not resemble any known immature or mature mesenchymal cells. These latter neoplasms are typically designated in a descriptive manner (e.g. alveolar soft part sarcoma).

2. Unlike epithelial neoplasms in which there is a clearly recognized and biologically understood pathway that explains the development of malignant neoplasms on the background of pre-existing benign neoplasms (the adenoma-carcinoma sequence), the development of a sarcoma in the setting of a pre-existing benign mesenchymal neoplasm is rare. There are a number of uncommon hereditary syndromes in which benign mesenchymal neoplasms have a recognizable risk of "malignant degeneration", (Neurofibromatosis type I, multiple hereditary osteochondromatoses, multiple enchondromatosis). However numerically the sarcomas arising in these conditions constitute a tiny fraction of all sarcomas. The more usual circumstance in sarcoma is for the malignancy to develop de novo. On occasion, low grade, slow growing sarcomas may transform into high grade, biologically aggressive sarcomas. This phenomenon is known as "dedifferentiation" and most characteristically arises in low grade osseous chondrosarcomas and low grade soft tissue liposarcomas. Under these circumstances the behavior of the neoplasm, and by extension, the management of the patient, will be significantly altered by the presence of the high grade component of the neoplasm.

3 Diagnostic Pathology

• Histologic evaluation remains the gold standard in the classification of mesenchymal neoplasms. In the majority of instances this requires appropriately fixed biopsy tissue. 10% buffered Formalin is the fixative of choice for all tissue samples.
• On occasion fresh tissue is preferable, particularly if cytogenetic or molecular genetic investigations are anticipated in the work up of a neoplasm (for example in the setting of "blue cell tumors" of children and young adults). Under these circumstances direct communication between the clinician and pathologist should occur to ensure appropriate "triage" of tissue samples.
• Immunohistochemical techniques that allow specific recognition of nuclear, cytoplasmic and membranous antigens within neoplastic cells are a useful adjuvant to aid in the precise classification of mesenchymal neoplasms.
• Ultrastructural examination using electron microscopy also may aid in defining specific lines of "differentiation". Recently cytogenetic evaluation of selected mesenchymal tumors has demonstrated consistent reproducible abnormalities that serve as markers for subgroups of these neoplasms. These include chromosomal translocations, deletions and acquisition of marker chromosomes. These "genetic abnormalities" are typically identifiable only within the neoplastic cells and are not present in patients’ germline. In addition to having diagnostic relevance these genetic abnormalities may help explain the acquisition of the neoplastic phenotype although presently the pathogenesis of this is not understood.
• Grading of sarcomas: Histologic grading of sarcomas attempts to stratify specific neoplasms into groups of similar biologic behavior based upon their microscopic appearance. In general four parameters are evaluated in an attempt to apply a numerical grade (one to three) to individual neoplasms. These include the relative cellularity of the neoplasm, the presence or absence of necrosis, the degree of nuclear atypicality and the mitotic rate. Using these parameters it is considered that low grade sarcomas (histologic grade 1 of 3) have a low risk of metastasis whilst intermediate and high grade sarcomas (histologic grades 2 and 3 of 3) have significant metastatic capability.

4 Synoptic Report Form

The reporting of soft tissue sarcoma biopsy and/or resection specimens should include in addition to all of the patients demographic information the following points

1. The tissue site, including a statement as to the relationship to fascia (i.e. whether the tumor is superficial or deep).
2. The procedure (biopsy or resection).
3. The histologic type of neoplasm.
4. The (numerical) grade of tumor if it is a sarcoma.
5. The size of the tumor in centimeters.
6. The status of the surgical margins including a measured distance to the closest margin. The microscopic composition of the tissue between the neoplasm and the margin should also be included (i.e., adipose tissue, skeletal muscle, pseudocapsule, fascia etc.)
7. An estimate of the percentage of tumor necrosis.
8. A statement as to the presence or absence of vascular invasion.
9. The results of adjuvant diagnostic techniques including immunohistochemical staining panels, ultrastructural findings etc.