PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Gauging the anatomic extent of soft tissue sarcoma requires an understanding of compartmental anatomy by investing fascia, which applies mainly but not exclusively to limbs.
PERSPECTIVE AND PATTERNS OF SPREAD
Soft tissues sarcomas are thought to originate exclusively from mesenchyme, which is also the origin of connective tissue. The mesenchyme is an embryonic stem cell that can have a variety of connective tissue elements, any and all of which can undergo malignant transformation. Soft tissue sarcomas are not common and represent 1% of all malignancies. Because of their rarity and their slow onset, they are often identified secondary to incidental trauma. Therefore, any suspicious soft tissue mass that increases in size or has associated pain should not be dismissed but investigated. The challenge is to achieve local control without sacrifice of a limb or vital axial part and yet early enough to avoid metastatic dissemination. Exciting advances in understanding the genetic determinants of this disease have allowed for new insights in its management. The incidence of musculoskeletal tumors is estimated at 10,000 new patients annually; only 25% occur in bone (2,500 cases). For every malignant soft tissue sarcoma, there are 100 benign neoplasms. The ratio is slightly higher in males than in females. By far, the most common sites are in lower and upper extremities, followed by axial and head and neck locations, with other sites such as retroperitoneum and pelvis being least common.
Patterns of spread tend to invade the compartment in which they arise. Superficial soft tissue sarcomas, that is, fibrosarcomas and liposarcomas, that arise in subcutaneous tissues spread along sagittal planes before invading underlying muscle. New muscle sarcomas invade within their muscle compartments initially, then the adjacent neurovascular bundles as they advance, and eventually bone (Fig. 52.1; Table 52.1).
The histopathologic types are highly varied and include malignant fibrous histiocytoma (40%), liposarcoma, synovial sarcoma, and neurofibrosarcoma as common types (each >10%); other varieties are infrequent (each 10%). Accurate assignment of histopathologic grade is the central component in staging of the patient's sarcoma. The essential features of establishing grade are nuclear and cellular morphology and pleomorphism. The number of mitoses per high-powered field, the presence of necrosis, and the degree of cellularity all affect establishing grade by a pathologist with familiarity of soft tissue sarcomas. With modern molecular biology technology, cytogenetics and molecular genetics have been added to cytochemistry, immunohistochemistry, electron microscopy, and flow cytometry, supplementing routine hematoxylin and eosin staining microscopy. Grade has typically been assigned in terms of four grades, and the American Joint Committee on Cancer (AJCC) recommendation is into two tiers: low and high grade. From perusing the stage grouping it is evident that pathologic grade dominates the anatomic extent.
ETIOLOGY
Most soft tissue sarcomas occur sporadically. Their etiology is undefined, although, in rare cases, there is an association with familial disease syndromes:
• Desmoid tumors among patients with familial polyposis.
• Sarcomas of soft tissue and bone in patients with hereditary or bilateral retinoblastoma.
• Neurofibromatosis type 1, in which benign neurofibromas and malignant neurofibrosarcomas are seen.
• Bone and soft tissue sarcomas in patients with Li–Fraumeni syndrome.
In addition to genetic causes, soft tissue sarcomas are occasionally associated with exposure to carcinogens.
For example, radiation therapy has been linked to the development of bone and soft tissue sarcomas, although this occurrence is uncommon, and cohort studies of this phenomenon are rare. The frequency of radiation-induced sarcoma is higher following treatment in children, particularly those with Ewing's sarcoma and retinoblastoma. In addition to radiation, exposure to chemicals, such as chemotherapeutic agents, phenoxyacetic acid, chlorophenols, and vinyl chloride, is similarly related to the development of sarcomas.
An interesting feature of soft tissue sarcomas is that some of these tumors display stable chromosomal translocations; these translocations eventually may serve as diagnostic criteria. For example, a study in the Netherlands found patterns of structural and numeric imbalances in a series of malignant fibrous histiocytomas, the most common subtype of malignant soft tissue sarcomas. Through the use of comparative genomic hybridization and conventional cytogenetic and Southern blot analyses, researchers have found increases in 1q21-q22 (69%) and 20q (66%), and decreases in 9p21-pter (55%) and 11q23-qter (55%), along with loss of TP53 and amplification of MDM2 genes.
Figure 52.1 | Patterns of spread. The spread pattern of sarcoma is both horizontal and vertical and is color coded for stage: T0, yellow; T1, green; T2, blue; T3, purple; and T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern (SIMLAP, Table 52.1).
Many of these chromosomal abnormalities have been characterized at the molecular level, and chimeric genes that are associated with these cytogenetic changes have been cloned. Some of these developments are providing clues to the molecular alterations that are fundamental to the development of soft tissue sarcomas:
• Myxoid liposarcoma displays a t(12;16)(q13;p11) translocation. The fusion gene, known as TLS/FUS-CHOP, fails to induce G1/S arrest, whereas the nononcogenic form of CHOP induces a normal G1/S arrest.
• Synovial cell sarcomas are characterized by the translocation t(X;18)(p11.2;q11.2), which has been cloned and has led to the identification of two novel genes, SYT and SSX.
• Alveolar rhabdomyosarcomas show a translocation at t(2;13)(q35;q14). This chimeric gene has also been cloned and has been termed PAX3-FKHR. Molecular determination of minimal residual disease in alveolar rhabdomyosarcoma is possible with this gene, but the clinical significance of this finding is uncertain.
• Clear cell sarcomas often exhibit a t(12;22)(q13-14;q12) translocation. This entity is sometimes referred to as malignant melanoma of soft parts, although it should be noted that the t(12;22)(q13-14;q12) translocation is not seen in cutaneous malignant melanoma.
• Alterations of the retinoblastoma gene (RB) are a common finding in the sporadic development of soft tissue sarcomas. Loss of RB immunoreactivity and RB loss of heterozygosity have been correlated with a poorer outcome.
• Somatic alterations of the TP53 gene are also common in soft tissue sarcomas. It is now well recognized that the high cancer incidence in patients with Li–Fraumeni syndrome, in which soft tissue and bone sarcomas are prominent, is the consequence of germline mutations on the TP53 gene.
• The MDM2 gene, located at 12q13-14, was observed to be frequently amplified in soft tissue sarcomas. SAS, another gene located at 12q13-14, was similarly amplified in soft tissue sarcomas.
Molecular characterizations of these chromosomal abnormalities serve as diagnostic criteria for soft tissue sarcomas. It is expected that diagnosis will be made on the basis of histology, immunohistochemistry, cytogenetics, and molecular biology in the near future. Indeed, genetic evaluation already is proving to be a useful complement to histopathologic assessment.
OVERVIEW OF HISTOGENESIS AND HISTOPATHOLOGY
The connective tissues are the derivatives of the mesenchymal stem cell. The derivative normal cells that can become malignant and give rise to a large variety of soft tissue sarcomas are given in Table 52.2. The composite illustration of loose connective tissue (LCT; Fig. 52.2) vividly illustrates the rich variety of cells and types of connective tissue fibers. LCT is constituted by the fibroblast, the fibrocyte, fat cells, mast cells, and macrophages in a rich matrix of extracellular materials such as collagen bundles, reticular fibers, and elastic fibers, along with abundant ground substance. This LCT constitutes the hypodermis and is the intermediate layer between the skin epidermis and dermis and the investing fascia, which is the initial tight wrapping around the musculature and neurovascular bundle and bone. This investing fascia is the dense connective tissue, which has more collagen bundles packed together with fewer cells and less ground substance. The “dense irregular connective tissue” defines the deep muscle compartment of limbs, the head and neck, and the trunk. The “dense regular connective tissue” constitutes the ligaments of muscles and joints. In dense connective tissue, fibroblasts and fibrocytes are the dominant cells.
The fusiform-shaped fibroblast synthesizes collagen fiber and ground substance. The fibrocyte is a resting cell, and the presence or absence of adipose cells determines whether the connective tissue is loose or dense, respectively. Macrophages and histiocytes are numerous in LCTs but are difficult to distinguish from fibrocytes unless they are phagocytic. It is for this reason that the malignant fibrous histiocytoma is the dominant soft tissue sarcoma. Mast cells, plasma cells, and lymphocytes permeate LCTs and occasional leukocytes owing to the rich network of capillaries and small vessels in the hypodermis. The collagen fibers are tough, thick proteinaceous bundles; the elastic fibers are fine, resilient, and, when stretched, return to their initial position; reticular fibers form delicate, netlike meshworks. Collagen is abundant in soft tissues, muscle compartments, and fascial layer tendons. Elastic fibers are abundant in blood vessels, especially arteries, lungs, urinary bladder, and Cooper's ligaments in breasts. They enable return to the original shape after stretching. Reticular fibers are the network mesh in liver, lymph nodes, spleen, bone marrow, and generally in lymphatic and hematopoietic organs (Table 52.2; Fig. 52.2A, C).
To complete the story of soft tissues, the largest bulk of soft tissue—muscle mass—needs to be presented. There are three types of muscle tissues: skeletal, striated muscle, and, to a lesser degree, smooth, nonstriated muscle, and cardiac muscle. Muscle cells are inactive mitotically, largely consisting of sarcoplasm, surrounded by sarcolemma membrane. Muscle contains numerous myofibrils, which contain two types of contractile proteins—actin and myosin. Skeletal muscle fibers are multinucleated cells with cross-striations. They tend to hypertrophy rather than undergo hyperplasia to increase muscle mass, which may account for the rarity of adult rhabdomyosarcoma. In children, embryonal rhabdomyosarcoma is more common. The smooth muscle layer lines the wall of hollow viscera such as the digestive organ, ureter, urinary bladder, and blood vessels. They tend to form benign leiomyomas more than leiomyosarcomas. Cardiac myocytes rarely give rise to any tumefaction and, in blood vessels, proliferation of myofibroblasts cause restenosis rather than angiosarcomas, which account for 1% of all soft tissue sarcomas (Table 52.2; Fig. 52.2B, D).
The last soft tissue element is nerve fibers of the peripheral nervous system, which consists of neurons, nerves, and axons. The peripheral nervous system is composed of various sizes of axons, surrounded by layers of connective tissue that partition several nerve bundles (axons) into fascicles. The epineurium is the thicker outer layer, whereas the perineurium is the thinner inner layer of nerve fibers. The supportive cell is the myelin-forming neurolemmocyte (Schwann cells) and satellite cells surround the neuronal cells in paravertebral and peripheral ganglia. Neurofibrosarcoma are among the more common soft tissue malignancies and constitute 12% of soft tissue sarcomas (Table 52.2).
Figure 52.2 | Overview of histogenesis. A. The mesenchymal cells give rise to a variety of LCT elements and include fibrocytes, fibroblasts, adipocyte, macrophages, and mast cells, including both collagen and reticular and elastic fibers. B. Muscle compartments are composed of muscle cells and, in addition, cardiac muscle. Muscle cells are multinucleated and tend to hypertrophy rather than undergo hyperplasia. C. Fibrosarcoma. A photomicrograph demonstrates irregularly arranged malignant fibroblasts characterized by dark, irregular, and elongated nuclei of varying sizes. D. Rhabdomyosarcoma. The tumor contains polyhedral and spindle-shaped tumor cells with enlarged, hyperchromatic nuclei and deeply eosinophilic cytoplasm. A few cells have clearly visible cross-striations. E. Alveolar rhabdomyosarcoma. The neoplastic cells are arranged in clusters that display an alveolar pattern.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
Gauging the anatomic extent of soft tissue sarcoma requires an understanding of compartmental anatomy, which applies mainly, but not exclusively, to the limbs. The depth of invasion of soft tissue sarcomas in limbs and the trunk is more important than size. The hypodermis is deep to the dermis and is the common location. The term “superficial” is defined as lack of involvement of the investing fascia, whereas “deep” implies deep to or involving the investing fascia. The relationship of the investing fascia is readily apparent in limbs. All intraperitoneal, retroperitoneal, intrathoracic truncal soft tissue sarcomas are considered deep. Head and neck tumors may be designated superficial or deep. There are two T stages based on size: T1, 5 cm; and T2, >5 cm. Each can be superficial (T1A or T2A) or deep (T1B or T2B) related to investing fascia. Grades I and II are low, and grades III and IV are high. Nodal invasion is less common than hematogenous spread, and N1 is equivalent to M1 or stage IV.
Grade is a very important criterion and has been extensively revised from a two-grade system to three tiers based on the National Institutes of Health and the French systems. The grade is determined by three parameters that are scored (Table 52.3A, B):
• Differentiation (1–3)
• Mitotic Activity (1–3)
• Necrosis (0–2)
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• Gastrointestinal stromal tumor (GIST) is now included in Chapter 16; fibromatosis (desmoids tumor), Kaposi's sarcoma, and infantile fibrosarcoma are no longer included in the histological types for this site (Fig. 52.3).
• Angiosarcoma, extraskeletal Ewing's sarcoma, and dermatofibrosarcoma protuberans have been added to the list of histologic types for this site.
• N1 disease has been reclassified as Stage III rather than Stage IV disease.
• Grading has been reformatted from a four grade to a threegrade system as per the criteria recommended by the College of American Pathologists.
• Kaposi's sarcoma, fibromatosis (desmoid tumor), and sarcoma arising from the dura mater, brain, parenchymatous organs, or hollow viscera are not included.
SOFT TISSUE SARCOMAS
Figure 52.3 | TNM staging diagram. Soft tissue sarcomas are resected with the goal of limb preservation and are defined by compartmental anatomy. There are four stages when histologic grade is added to the T stage. N1 is equivalent to distant metastases. Color bars are coded for stage: stage I, green; II, blue; III, purple; IV, red; and metastatic disease to viscera and nodes, black. Note the importance of tumor grade in addition to anatomic extent.
T-ONCOANATOMY
ORIENTATION OF T-ONCOANATOMY
The ubiquitous distribution of connective tissue and muscle presents a challenge to defining this compartment anatomically. The major anatomic sectors are explored as functions of the frequency of soft tissue malignancies. The logical emphasis in oncoanatomy is on the limbs.
The three-dimensional and three-planar oncoanatomies are presented for each site, starting with the superficial investing fascia located deep to the skin in the hypodermis.
THREE-PLANAR ANATOMY
The upper limbs are presented in this chapter although the frequency of soft tissue sarcomas are in the lower limb. Because compartmental anatomy is the key concept, the axial or transverse planes of limbs are the focus of the primary-site anatomy more than coronal or sagittal planes.
• Upper limb (Fig. 52.4ABC): The investing fascia is the superficial fascia and consists of the brachial fascia in the arm and the antebrachial fascia in the forearm. The brachial fascia is also the deep fascia of the arm and divides the muscle compartments into anterior (biceps) and posterior (triceps) compartments by its extensions, namely, the lateral and medial intermuscular septa. In the forearm, the antebrachial fascia is the superficial fascia, and its extension in the interosseous membrane divides the anterior from the posterior compartments, which is the deep aspect of the staging system for soft tissue sarcoma.
Figure 52.4 | Orientation of T-oncoanatomy of the upper limb. A. Anterior view of investing fascia. B. Transverse through arm. C. Transverse through forearm.
The anatomic and age distribution by pathology of soft tissue sarcomas is essential to understanding the challenges in diagnosis and treatment of these sarcomas which can occur in any site throughout the body. The majority are located in the extremities (41%), with 29% of all lesions occurring most commonly in the thigh of the lower limb; the intradominal location accounts for a third of the sarcomas and they are equally divided between visceral (21%) and retroperitoneal (15%) locations. Another 10% are truncal and 5% are in the head and neck region (Fig. 52.4D). Soft tissue sarcomas, as are most cancers, are most common with increasing age; the median age at diagnosis is 65 years.
However, median age varies by histologic type and subtype. Alveolar rhabdomyosarcoma and desmoplastic small round cell sarcomas occur in young adults, whereas leiomyosarcomas, liposarcomas, and angiosarcomas occur most commonly in the 50–60 year old age group (Fig. 52.4E).
Figure 52.4 | D. Distribution by histologic subtype and site of soft tissue sarcomas in 8,328 patients aged 16 years or older admitted to the Memorial Sloan-Kettering Cancer Center from 1982 to 2009. The retroperitoneal/abdominal category excludes visceral sarcomas. E. Age at diagnosis for sarcoma subtypes. The boxes show median and interquartile range and the whiskers show range (with outliers excluded) for 7,212 patients aged 16 years or older admitted to Memorial Sloan-Kettering Cancer Center from 1982 through 2009. Sarcoma subtypes with simple genotypes, shown in red, are associated with younger median age at diagnosis than those with complex genotypes, shown in blue.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
N-oncoanatomy of the soft tissues beneath the skin surfaces emphasizes the anterior location for most if not all lymph node stations (Fig. 52.5).
• The axillary nodes are the recipients for lymphatics of the upper extremity and upper half body, including both anterior and posterior thoracic abdominal walls.
• The femoral and inguinal nodes drain the lower extremity and the lower half of the body on their anterior and posterior surfaces.
• The face and scalp drain into the superficial ring of nodes at the junction of the mandible and neck: submental, submandibular, preauricular, mastoid, and occipital nodes. Once involved, the rest of the lymph nodes in the neck along the carotid arterial sheath and internal jugular vein are at risk.
Figure 52.5 | N-oncoanatomy of the upper limb.
M-ONCOANATOMY
There is a rich network of venous channels in the hypodermis of all skin surfaces that allows for hematogenous spread once the dermal and hypodermal layers are invaded by soft tissue sarcoma. Collateral venous channels and plexus are rich and rapidly appear once obstruction occurs (Fig. 52.6). Pulmonary metastases are the most common site.
Figure 52.6 | M-oncoanatomy of upper limbs. Venous plexus and drainage.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Whenever feasible, physical examination in conjunction with imaging should establish size of the tumor: T1, 5 cm; or T2, >5 cm. Modern cross-sectional imaging is essential, and spiral computed tomography (CT) and magnetic resonance imaging (MRI) are of value and are complementary (Fig. 52.7; Table 52.4).
Pathologic Staging
Pathologic staging is an essential aspect of staging; histopathologic grading is critical. Imaging is valuable for orientation of surgical margins (ink markings), particularly for conservation surgery with reliance on postoperative radiation to ablate any residuum of tumor. Immunohistochemical staining and cytogenetics may be helpful for subtyping tumors.
• Accurate measurement of tumor size is important because it is regarded as a continuous variable, with 5 cm as an arbitrary dividing line between T1 and T2. Radiologic imaging can be used when resected specimens are difficult to interpret.
• Depth is very important to staging; superficial is designated A, and deep is designated B for each T category and stage. Superficial soft tissue sarcomas are in the hypodermis and do not involve the superficial investing fascia, which is the dividing line between the hypodermis and the deep muscle compartments. Note that all visceral soft tissue sarcomas are considered deep, as are retroperitoneal or intraperitoneal soft tissue sarcomas.
• Grade is critical to stage and is referred to as low or high. Low refers to grades I and II. High refers to grades III and IV.
• Recurrent soft tissue sarcomas are restaged following the same rules as the primary soft tissue sarcoma.
• Nodes, when enlarged, need histopathologic confirmation because they are so uncommon.
Oncoimaging Annotations
• Ultrasonography cannot discriminate between benign and malignant soft tissue tumors and is not recommended for their classification.
• Ultrasonography is useful in guiding percutaneous biopsy and may be useful in answering specific concerns in posttreatment follow-up.
• CT tends not to add value to the workup of the primary soft tissue tumor site compared with MRI.
• MRI is the primary modality in the pretreatment assessment of these tumors. Surface coils are necessary, and axial images are required. The utility of gadolinium enhancement is controversial.
• Hemorrhage, hematoma, and inflammatory changes can be confused with tumor on MRI.
• MRI has disappointing accuracy in assigning benign or malignant tumor status and even less reliability in predicting histology in most cases.
• MRI is the dominant imaging modality for determining intracompartmental and extracompartmental extent of a soft tissue sarcoma and its relationship to critical neurovascular structures.
• Sarcomas treated before limb salvage surgery with chemotherapy should be restaged with MRI before operation.
• The role of positron emission tomography in evaluating tumor response to neoadjuvant chemotherapy is still being explored.
• Systemic metastatic disease, usually to the lungs, and local recurrence have their maximum hazard rates within the first 2 years, defining the most frequent follow-up intervals for the first 2 years and tapering over a total of 5 years for osseous sarcomas.
PROGNOSTIC FACTORS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
Required for staging:
• grade
Clinically significant:
• neurovascular invasion as determined by pathology.
• Bone invasion as determined by imaging. If pM1, source of pathologic metastatic specimen.*
Anatomic extent and histologic grade determine the stage.
The TNM staging matrix is color coded for identification of stage group once T and N stages are determined (Table 52.6).
*Preceding passage from Edge SB, Byrd DR, and Compton CC, et al, AJCC Cancer Staging Manual, 7th edition. New York: Springer, 2010, p. 298.
Figure 52.7 | Transverse MRI through the distal forearm.
CANCER STATISTICS AND SURVIVAL
Soft tissue sarcomas account for 10,520 cases annually (male, 5,680; female, 4,840). The number of deaths is 10% of these (1,460 annually). When compared with primary cancer sites, the current gains in survival over five decades dramatize the reversal of incurability of musculoskeletal sarcomas (10%) in the 1940s and 1950s to its present 60% to 70% survival. This is a 700% increase in survival with limb preservation. The majority of these patients are pediatric and adolescent patients (Fig. 52.8; Table 52.5).
Figure 52.8 | A. Trajectory of soft tissue sarcoma curability. B. Five-year survival for patients with soft tissue sarcoma. Data taken from Table 56.6. (Data from Edge SB, Byrd DR, and Compton CC, et al, AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 295, Table 28.2.)