Charles A. Forscher and Dennis A. Casciato
I. EPIDEMIOLOGY AND ETIOLOGY. Primary mesenchymal tumors localized outside the skeleton, parenchymatous organs, or hollow viscera are generally designated as soft tissue sarcomas (STSs). Sarcomas of the mediastinum, heart, and blood vessels are discussed in Chapter 19.
A. Incidence. Sarcomas constitute about 1% of all cancers and will account for an estimated 11,000 new cases of STS and 2,800 cases of bone sarcoma in the United States in 2011. These will be associated with 3,900 and 1,500 deaths, respectively.
1. STSs outnumber bone sarcomas by a ratio of 3:1. In children, most STSs are rhabdomyosarcomas or undifferentiated tumors originating in the head and neck regions. In adults, STSs occur most frequently on the extremities or retroperitoneum and least frequently in the head and neck region.
2. Bone sarcomas occur mostly between 10 and 20 years of age (osteogenic sarcoma) or between 40 and 60 years of age (chondrosarcoma).
3. Most sarcomas show no sexual predilection. Incidence peaks during childhood and in the fifth decade.
B. Etiology. Certain kinds of sarcomas are associated with exposure to specific agents or with underlying medical conditions:
1. Lymphangiosarcoma. Prolonged postmastectomy arm edema (Stewart-Treves syndrome)
2. Angiosarcoma and other STSs. Polyvinyl chloride, thorium dioxide, dioxin, arsenic, and androgens
3. Osteosarcoma. Radium (watch dials) exposure, postmastectomy irradiation, Paget disease of bone
4. Fibrosarcoma. Postirradiation: Paget disease of bone
5. Kaposi sarcoma. Cytomegalovirus and human immunodeficiency virus type 1 (HIV-1; discussed in Chapter 36, Section IV)
6. Leiomyosarcoma. HIV-1 in children
7. Genetic diseases and syndromes
a. Li-Fraumeni syndrome. Various sarcomas (especially rhabdomyosarcoma) and carcinomas of breast, lung, and adrenal cortex (p53 gene)
b. Neurofibromatosis. Schwannomas (NF1 gene)
c. Familial retinoblastoma. Osteosarcoma (RB1 gene)
8. Chromosomal aberrations are found in nearly all sarcomas. Some of these may be limited aberrations such as specific translocations, (e.g., the X;18 translocation in synovial sarcoma, the 11;22 translocation in Ewing sarcoma, and the 12;16 translocation in myxoid liposarcoma). Other sarcomas have complex chromosomal abnormalities as occurs in myxofibrosarcoma and pleomorphic liposarcoma.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology and nomenclature. Sarcomas are given a bewildering variety of names that do not indicate biologic behavior and usually do not influence therapeutic approach. The multipotential capacities of the mesenchymal tissue and the appearance of several histologic elements in the same tumor often make clear-cut histologic diagnosis difficult.
1. Sarcomas are named for the tissue of origin (e.g., osteosarcoma, chondrosarcoma, schwannoma, liposarcoma).
2. Tumors are also named for special histologic characteristics or given a nondescriptive name because the tissue of origin is unknown (alveolar soft parts tumor, Kaposi sarcoma, Ewing sarcoma).
3. Pathologists recognize several features in determining the grade of a sarcoma. These include the degree of cellular differentiation, the presence (or absence) of mitotic activity, spontaneous necrosis, and vascular invasion. The other descriptive terms for the tumor are far less important. Expert pathologic evaluation is crucial.
4. The presence of osteoid formation by the tumor cells suggests the diagnosis of osteogenic sarcoma. This must be distinguished from reactive or metaplastic bone formation by the pathologist.
5. Immunohistochemistry may be helpful in confirming the diagnosis of rhabdomyosarcoma and leiomyosarcoma. Expected immunophenotypes for the various sarcomas are shown in Appendix C4.III and C4.VIII.
6. Cytogenetics can be useful in the diagnosis of Ewing sarcoma, synovial sarcoma, and rhabdomyosarcoma. Newer techniques, such as fluorescent in situ hybridization (FISH) analysis, are also becoming increasingly useful.
B. Natural history. Generally, sarcomas arise de novo and not from pre-existing benign neoplasms. Tumors can “dedifferentiate,” however, from a lower grade to a higher grade. Sarcomas spread without interruption along tissue planes; they invade local nerve fibers, muscle bundles, and blood vessels. Histologic sections usually show much greater local extension than is apparent on gross examination.
1. Histologic grade. The biologic behavior of sarcomas can usually be predicted by their histologic grade. Low-grade tumors tend to remain localized; high-grade tumors (especially those with a marked degree of necrosis) have a greater propensity to metastasize. Most osteogenic sarcomas, rhabdomyosarcomas, Ewing sarcomas, and synovial sarcomas are high-grade malignancies.
2. Site of origin. The site of origin of the sarcoma may suggest the cell type as follows:
a. Head and neck
(1) Rhabdomyosarcoma (in a child)
(2) Angiosarcoma (in an elderly person)
(3) Osteogenic sarcoma (jaw)
b. Distal extremity
(1) Epithelioid sarcoma
(2) Synovial sarcoma
(3) Clear cell sarcoma
(4) Osteogenic sarcoma (femur)
c. Proximal tibia or humerus. Osteogenic sarcoma
d. Mesothelium. Mesothelioma
e. Abdomen, retroperitoneum, and mesentery
(1) Leiomyosarcoma
(2) Gastrointestinal stromal tumor (GIST; gastrointestinal sarcoma)
(3) Liposarcoma
(4) Desmoplastic small round cell tumor
f. Genitourinary tract
(1) Rhabdomyosarcoma (in a child)
(2) Leiomyosarcoma (in an adult)
g. Skin
(1) Angiosarcoma, lymphangiosarcoma
(2) Kaposi sarcoma
(3) Epithelioid sarcoma
(4) Dermatofibrosarcoma protuberans (on trunk)
3. Metastases. Sarcomas typically spread hematogenously. Lung metastases occur most commonly. Hepatic metastases can be seen from primary gastrointestinal or gynecologic sarcomas. The retroperitoneum can be a site of metastasis for extremity liposarcomas. Other sites, such as bone, subcutaneous tissue, and brain, are less common and are often detected only after pulmonary metastases have developed (tertiary metastases).
a. Sarcomas that metastasize to lymph nodes
(1) Rhabdomyosarcoma
(2) Synovial sarcoma
(3) Epithelioid sarcoma
b. Sarcomas that rarely metastasize and are associated with a favorable survival
(1) Liposarcoma (well-differentiated types)
(2) Fibrosarcoma (infantile and well-differentiated types)
(3) Malignant fibrous histiocytoma/myxofibrosarcoma (superficial type)
(4) Dermatofibrosarcoma protuberans
(5) Parosteal osteosarcoma
(6) Kaposi sarcoma when not related to acquired immunodeficiency syndrome (AIDS)
4. Paraneoplastic syndromes associated with sarcomas
a. Hypoglycemia (particularly with retroperitoneal fibrosarcoma)
b. Hypertrophic osteoarthropathy (sarcoma of pleura or mediastinum)
c. Hypocalcemia
d. Oncogenic osteomalacia
C. Clinical aspects of specific STSs
1. Alveolar soft-part sarcoma
a. Tissue of origin (incidence). Unknown (rare)
b. Features. Unique histology with no benign counterpart; often indolent even with lung metastases, which are common. The sarcoma most associated with brain metastases. Commonly affects the thigh in adults and the head and neck in children. The 5-year survival rate exceeds 60%.
2. Angiosarcoma (hemangiosarcoma, lymphangiosarcoma)
a. Tissue of origin (incidence). Blood or lymph vessels (2% to 3%)
b. Features of hemangiosarcoma. Affects the elderly; aggressive. Arises in many organs, notably the head and neck region, breast, and liver; especially affects the skin and superficial soft tissues (whereas most STSs are deep). Dedifferentiation from a hemangioma is rare. The 5-year survival rate is <20%.
c. Features of lymphangiosarcoma. Affects older adults; aggressive. Arises in areas with chronic lymphatic stasis (especially postmastectomy). The 5-year survival rate is 10%.
3. Clear cell sarcoma
a. Tissue of origin (incidence). Now recognized as a form of malignant melanoma (rare)
b. Features. Affects adults <40 years of age; painless, firm, spherical masses on tendon sheaths and aponeurotic structures of distal extremities. The 5-year survival rate is about 50%.
4. Epithelioid sarcoma
a. Tissue of origin (incidence). Unknown (rare)
b. Features. Affects young adults; aggressive; typically appears on distal extremities. Epithelioid sarcoma and synovial sarcoma are the most common tumors of the hand and foot. Differs from other STSs by having a greater tendency to spread to noncontiguous areas of skin, subcutaneous tissue, fat, draining lymph nodes, and bone. The 5-year survival rate is about 30%.
5. Fibrosarcoma
a. Tissue of origin (incidence). Fibrous tissue (5% to 20%)
b. Features. Affects all age groups; arises in many mesenchymal sites; usually involves the abdominal wall or extremities. Ninety percent are well differentiated (desmoid). Dermatofibrosarcoma protuberans (rare) develops on the skin of the trunk and almost never metastasizes. Fibromyxosarcoma affects any soft tissue site but usually develops on the extremities. Ten percent are poorly differentiated (high grade). Survival is directly related to tumor grade (also see Section II.D.5).
6. Malignant fibrous histiocytoma (MFH)/myxofibrosarcoma. Many pathologists now prefer the term myxofibrosarcoma for these tumors. Some tumors previously felt to represent MFH are now classified as pleomorphic liposarcomas or pleomorphic sarcoma, not otherwise specified (NOS).
a. Tissue of origin (incidence). Unknown (10% to 23%)
b. Features. Age > 40 years (<5% of affected patients are <20 years of age). MFH has become a common histologic diagnosis. Develops in extremities (especially legs), trunk, and retroperitoneum. Superficial MFH develops close to the skin surface and is often low grade; the 5-year survival rate is 65%. Deep MFH usually is high grade; the 5-year survival rate is 30% to 60%.
7. Hemangiopericytoma/solitary fibrous tumor
a. Tissue of origin (incidence). Blood vessels or fibrous tissue (<1%)
b. Features. Affects all ages. Develops under finger tips (glomus tumors), on lower extremities or pelvis, in the retroperitoneum, and elsewhere. Benign and malignant versions. The 5-year survival rate is about 50%.
8. Kaposi sarcoma (KS). All varieties of KS are associated with human herpesvirus type 8 (HHV-8). KS typically presents as purplish blotches or nodules that may be painful or pruritic. Treatment of KS in patients with AIDS is discussed in Chapter 36, Section IV.
a. Tissue of origin (incidence). Controversial (varied)
b. Features of classic KS. Classically affects older adults with Mediterranean ancestry; extremely indolent lesions arise on lower extremities (occasionally on hands, ears, and nose) and rarely cause death.
c. Features of epidemic KS. The epidemic and aggressive variety is associated with AIDS (see Chapter 36, Section IV), African children, renal transplant recipients, immunosuppressed nontransplantation patients, and Eskimos. These patients develop a widely disseminated, aggressive, and usually fatal form of the disease. Generalized cutaneous involvement, generalized lymphadenopathy, and visceral or gastrointestinal involvement are typical.
9. Leiomyosarcoma, gastrointestinal stromal tumor (GIST), and metastasizing leiomyoma
a. Tissue of origin (incidence). Smooth muscle for leiomyoma and leiomyosarcoma; interstitial cell of Cajal for GIST (7% to 11%)
b. Features. Affects all age groups. Develops in gastrointestinal tract, uterus, retroperitoneum, and other soft tissues. Generally refractory to chemotherapy and radiotherapy. The 5-year survival rate is 30%.
c. Gastrointestinal stromal tumors (GISTs) are morphologically similar to leiomyosarcoma but have different immunohistochemical staining characteristics (see Appendix C4.III). GISTs do not stain for actin (as leiomyosarcomas do), and most express CD117 (c-kit protein). Treatment of GIST is presented in Section VII.C.7.
d. Leiomyoma peritonealis disseminata (LPD). A condition in women, usually in reproductive years. Myriads of asymptomatic benign leiomyomas are usually scattered throughout the peritoneal cavity and range from 1 to 10 cm in size; they are stimulated by estrogen. LPD causes occasional mechanical problems with bowel or pain. Generally, no treatment is required; when symptomatic, treatment is with estrogens or antiestrogens.
e. Leiomyoma, benign metastasizing. Histologically benign, these leiomyomas are typically discovered as persistent pulmonary nodules and possibly as a variant of LPD. Associated nodules in the pelvis are mostly in round ligaments of uterus and not as diffuse as in LPD. Treatment is surgical for symptomatic or progressive lesions.
10. Liposarcoma
a. Tissue of origin (incidence). Fat tissue (15% to 18%)
b. Features. Affects middle and older age groups, mostly men. Develops in the thigh, groin, buttocks, shoulder girdle, and retroperitoneum. Does not arise from benign lipomas. Low-grade tumors in the extremity are now called atypical lipomatous tumor. The designation of well- differentiated liposarcoma remains for tumors of the abdomen and retroperitoneum. The 5-year survival rate is 80% for low-grade liposarcomas and 20% for high-grade liposarcomas of an extremity. Survival rates are lower and local recurrence rates are high for abdominal/retroperitoneal liposarcomas.
11. Mesothelioma
a. Tissue of origin (incidence). Mesothelium
b. Features. Age > 50 years. Asbestos exposure is etiologic. Involves pleura and peritoneum; aggressively encases viscera. Highly lethal; the 5-year survival rate is <10% (see Chapter 8).
12. Myxoma
a. Tissue of origin (incidence). Mesenchymal tissues
b. Features. Usually found on extremities; has histologic appearance of umbilical cord. The 5-year survival rate is about 80%.
13. Neurofibrosarcoma (schwannoma, neurilemoma)
a. Tissue of origin (incidence). Nerve (5% to 7%)
b. Features. Affects young and middle-aged adults and patients with neurofibromatosis type 1 (von Recklinghausen disease; about 10% develop sarcomatous changes during lifetime). Histologically resembles fibrosarcoma. Presents with thickening of nerves and without anatomic predilection. Superficial variety is low grade, spreads extensively along nerve sheaths without metastasizing, and has a 5-year survival rate of >90%. Penetrating variety is high grade with nodular growth, vascular invasion, and lung metastases and has a 5-year survival rate of <20%.
14. Rhabdomyosarcoma
a. Tissue of origin (incidence). Striated muscle (5% to 19%)
b. Features. By definition in the G-TNM staging system, all are grade 3. All types can occur in any age group, but the typical onset and distribution is noted below (see Chapter 18, Cancers in Childhood, “Rhabdomyosarcoma”).
c. Features of embryonal rhabdomyosarcoma. Affects infants and children; sites are head and neck (70%) and genitalia (15% to 20%). Includes sarcoma botryoid. The 5-year survival rate is about 70%.
d. Features of alveolar rhabdomyosarcoma. Affects teenagers at any site; highly aggressive; histology resembles lung alveoli. The 5-year survival rate is about 50%.
e. Features of pleomorphic rhabdomyosarcoma. Affects patients >30 years of age, is rare, and develops in extremities. Often is highly anaplastic; microscopically confused with MFH. The 5-year survival rate is about 25%.
15. Synovial sarcoma
a. Tissue of origin (incidence). Unknown. Recent data suggests these tumors may arise from primitive muscle cells. Although these tumors can arise near joints, they are not composed of cells with synovial differentiation. The name is a misnomer that persists. They rarely arise within a joint space.
b. Features. Affects young adults but may occur from the second to fourth decade. Monophasic and biphasic subtypes are distinguished. Presents with hard masses, often painful, near tendons in the vicinity of joints of the hands, knees, or feet. Synovial and epithelioid sarcomas are the most common tumors of the hand and foot. Often calcified, with characteristic radiographic appearance. The majority of synovial sarcomas are high grade. Lymph node involvement may be seen in up to 20% of cases. The 5-year survival rate is from 30% to 50%.
D. Clinical aspects of specific bone sarcomas
1. Adamantinoma
a. Tissue of origin (incidence). Unknown; nonosseous (<1%)
b. Features. Osteolytic tumor; often develops on upper tibia; resembles ameloblastoma of mandible. Indolent behavior; the 5-year survival rate is >90%.
2. Chondrosarcoma
a. Tissue of origin (incidence). Cartilage (30%)
b. Features. Age 40 to 60 years; <4% of patients are <20 years of age. Usually develops in shoulder girdle (15%), proximal femur (20%), or pelvis (30%). Chondrosarcomas are the most common malignant tumors of the sternum and scapula. Most tumors are grade 1 or 2; higher grade tumors metastasize frequently; however, tumor grade does not appear to affect prognosis. Local recurrence is a major problem in management. Usually refractory to both radiation therapy (RT) and chemotherapy. Dedifferentiated chondrosarcomas may, however, respond to chemotherapy. Complete surgical removal is the main determinant of recurrence and survival. The 5-year survival rate is about 50%.
(1) Central chondrosarcomas (75%) arise within a bone; peripheral chondrosarcomas (25%) arise from the surface of a bone. Peripheral lesions can become quite large without causing pain; central lesions present with a dull pain but rarely with a mass. Pain means that the apparently “benign” cartilage tumor on radiographs is probably a central chondrosarcoma.
(2) About 25% of chondrosarcomas represent malignant transformation of a pre-existing endochondroma or osteocartilaginous exostosis. The presentation of multiple benign cartilaginous tumors has a higher rate of malignant transformation than the corresponding solitary lesions.
3. Chordoma
a. Tissue of origin (incidence). Primitive notochord cells (5%)
b. Features. Develops in the midline of the neural axis at base of skull or sacrococcygeal area. The physaliferous (bubble-bearing) cells are pathognomonic histologically. Indolent tumor with almost universal tendency for local recurrence. Low grade but eventually fatal after many years because of complications associated with invasion into neural tissues. Treated with surgery and RT. The 5-year survival rate is 50%.
4. Ewing sarcoma
a. Tissue of origin (incidence). Unknown; nonmesenchymal elements of bone marrow (15%).
b. Features. Affects children 10 to 15 years of age; rare in blacks; highly aggressive; arises in many bones, but especially the femoral diaphysis (see Chapter 18, Cancers in Childhood, “Ewing Sarcoma”).
5. Fibrosarcoma of bone
a. Tissue of origin (incidence). Fibrous tissue (2%)
b. Features. Affects middle-aged patients in major long bones; develops occasionally in conjunction with an underlying disease (bone infarcts, osteomyelitis, benign giant cell tumor, Paget disease, after RT). Resembles fibrosarcoma, but osteoid is detected in parts of the lesion. Often high grade, which correlates with metastatic potential and survival (see Section II.C.5).
6. Malignant fibrous histiocytoma of bone
a. Tissue of origin (incidence). Fibrous and primitive mesenchymal tissue (5%)
b. Features. Affects older patients; arises de novo or as a complication of Paget disease. Most common sites are metaphyses of long bones, especially around the knee. In contrast to osteogenic sarcoma, serum alkaline phosphatase levels are normal. Pathologic fracture is often the first manifestation. Aggressive with high rate of dissemination to lungs (also see Section II.C.6).
7. Giant cell tumor of bone
a. Tissue of origin (incidence). Unknown (<1%)
b. Features. Patients usually >20 years of age. Most common sites are around the knee, radius, and sacrum. Tumor is usually benign but can be locally aggressive. Rare malignant transformation can occur.
8. Osteogenic sarcoma
a. Tissue of origin (incidence). Bone (40% to 50%)
b. Features of classic osteogenic sarcoma. Affects any age, but the onset is usually between 10 and 20 years; more common in boys and men. Most tumors originate in the metaphysis of long bones, the region of highest growth velocity. Tender, bony masses in the distal femur, proximal tibia, and proximal humerus account for 85% of cases. Nearly always high grade.
c. Features of low-grade osteogenic sarcoma. Rare; central lesions can occur.
d. Features of osteogenic sarcoma of the jaw. Affects patients between the ages of 20 and 40 years; men are more commonly affected; frequently detected during dental examinations. These tumors often have a cartilaginous component. High- and low-grade varieties are treated with hemimaxillectomy or hemimandibulectomy and reconstruction. Local control can often be a major problem if less than radical surgery is performed.
e. Features of telangiectatic osteogenic sarcoma. Affects younger patients; a purely lytic tumor that can be confused with an aneurysmal bone cyst. Highly malignant; metastasizes early.
f. Features of multifocal sclerosing osteogenic sarcoma. Rare; affects children <10 years of age. Develops multiple simultaneous primary sites in metaphyses; rapidly metastasizes to lung and soft tissues.
g. Features of periosteal osteogenic sarcoma. Rare. Affects patients between the ages of 15 and 25 years; arises on external bone surface growing into the overlying soft tissues as an enlarging painless mass with minimal involvement of medullary canal. Histologically confused with chondrosarcomas. More than 50% metastasize (also see Section II.D.9).
9. Parosteal (juxtacortical) sarcoma
a. Tissue of origin (incidence). Bone surface (<2%)
b. Features. A distinct clinical entity (see Section II.D.8.g). Onset from 20 to 30 years of age. Characteristic exophytic lesion that is often on the posterior aspect of the distal femur or medial aspect of the proximal humerus. Presents as a fixed painless mass. Usually low grade with an indolent course; rarely involves medullary canal. Infrequently metastasizes; the 5-year survival rate is 80%.
10. Sarcomas of bone associated with other conditions
a. Paget disease of the bone. Affects patients >60 years of age; the risk for sarcoma is 1,000-fold greater than in the general population at this age. Sarcomatous transformation occurs in 0.7% of patients with Paget disease and accounts for 5% to 14% of osteogenic sarcomas. The histologic form varies among reported series but is usually osteogenic sarcoma, MFH, or fibrosarcoma; chondrosarcoma, giant cell tumor, and other forms occur infrequently. Tends to affect the pelvis and proximal femur; frequently presents as pathologic fracture of the femur. Highly malignant.
b. After high-dose RT. Sarcoma develops within the irradiated field (bone or adjacent soft tissue structures) about 10 years after treatment. Highly malignant.
c. Familial or bilateral retinoblastoma. A tumor-suppressor gene (RB) has been identified on the 13q chromosome in some patients with retinoblastoma. Patients who have a 13q deletion are at increased risk for later development of osteogenic sarcoma, not only in the irradiated field but also in long bones distant from irradiated sites about 10 to 20 years later. Highly malignant.
III. DIAGNOSIS
A. Symptoms and signs are summarized in Sections II.C and D. Patients with STS typically present with a painless, progressive swelling in an extremity; all such swellings are suspect for malignancy. Head and neck sarcomas manifest as proptosis, masses, or neurologic abnormalities. Retroperitoneal sarcomas present with back pain, lower extremity edema, and abdominal masses. Bone sarcomas usually result in visible enlargement of bone and pathologic fractures.
B. Biopsy. An accurate biopsy diagnosis is essential. Computed tomography (CT) or ultrasound-guided biopsies are increasingly employed at initial diagnosis and in the evaluation of possible recurrences. An open biopsy is still performed when the results of CT-guided biopsies are equivocal.
C. Radiographic studies
1. Plain radiographs of soft tissues may demonstrate bone involvement. Stippled calcification may be present within the mass. Patients with painful or enlarged bones should have radiographic study of these areas. The following findings are helpful for making the diagnosis of osteogenic sarcoma:
a. An osteoblastic appearance is often seen in osteosarcoma.
b. Periosteal reaction with elevated periosteum forming a triangle (Codman triangle) with bone cortex. Any periosteal elevation in an apparent bone lesion is an indication for biopsy.
c. Sunray-like spiculation of bones
d. Onion-skin appearance (a common finding in Ewing sarcoma)
2. CT scans are most useful for evaluating retroperitoneal or head and neck regions. CT scanning of the extremities appears to be effective in delineating the extent of the tumor.
3. Magnetic resonance imaging (MRI) is comparable to CT scans in defining the relation of the tumor to neurovascular and skeletal structures, but MRI might be better for predicting resectability.
4. Arteriography may be useful in certain cases to plan surgical resection.
5. Radionuclide scans. Bone scan is performed in patients with bone sarcomas to search for multifocal disease. PET scanning is useful both for determining sites of disease and for assessing response to therapy.
6. CT of the thorax is necessary for all patients with sarcoma to detect lung metastases, which may be resected after the primary tumor is managed. An “old calcified granuloma” is an untenable radiologic diagnosis in a young person with sarcoma.
7. Serum alkaline phosphatase levels are elevated in 60% of patients with osteogenic sarcoma and rarely in other bone sarcomas. When elevated at the time of diagnosis, this result is an important tumor marker to evaluate response to therapy.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. Tumor grade is the single most important prognostic factor in sarcomas and is incorporated into the G-TNM staging system.
1. Grade (G). All rhabdomyosarcomas, Ewing sarcomas, and synovial sarcomas are high grade. Three systems used for grading sarcomas and their relationships are as follows:
2. TNM staging classification for sarcomas is shown in Table 17.1.
Table 17.1 TNM Staging of Sarcomasa
aAdapted from the AJCC Cancer Staging Manual. 7th ed. Springer; 2010.
B. Prognostic factors
1. Histologic grade (the degree of differentiation, the amount of necrosis, and the number of mitoses per high-power microscopic field) is the single most important prognostic factor, especially for STS. The shortcoming of this system is less-than-ideal reproducibility.
2. Local recurrence predisposes to further recurrences. The absence of clear surgical margins, with or without postoperative RT, increases the rate of local recurrence in patients with STS but does not affect survival. The development of distant metastases after local recurrence may be either directly related to the recurrence or only a reflection of the more aggressive tumor biology.
3. Site of disease. Half of deaths in patients with STS occur in the 8% of patients with retroperitoneal lesions.
4. Tumor-suppressor gene p53 is located on the short arm of chromosome 17. Nuclear accumulation of p53 protein appears to be a marker of tumor aggressiveness and may be a useful prognostic factor for STS.
C. Stage groupings and survival for STS are shown in Tables 17.2 and 17.3. The rate of progression for GIST (Table 17.3) depends both on the stage and the site of the primary tumor.
Table 17.2 Stage Grouping and Survival for Soft Tissue Sarcomas
Table 17.3 Anatomic Stage/Prognostic Groups for GIST
aGastric GIST includes stomach and omentum.
bIntestinal GIST includes small intestine, esophagus, colorectum, mesentery, and peritoneum.
cGastric GIST stage I includes stage IA (T1,2 N0 M0 LMR) and IB (T3 N0 M0 LMR).
MR, mitotic rate; LMR = low MR (≤5/50 high power fields, low grade), HMR = high MR (>5/50 high power fields, high grade).
Adapted from the AJCC Cancer Staging Manual. 7th ed. Springer, 2010; Miettinen M, et al in Selected Reading.
D. Long-term survival. About 80% of all STSs that recur do so within 2 years. Patients with osteogenic sarcoma who survive 3 years without evidence of disease appear to be cured.
V. PREVENTION AND EARLY DETECTION
The physician must suspect and biopsy all soft tissue masses, de novo bony abnormalities, and periosteal elevations with an apparent bone lesion.
VI. MANAGEMENT OF BONE SARCOMAS
A. Surgery. Treatment of osteogenic sarcomas results in a 65% to 80% 10-year, disease-free survival. Relapse after 3 years of disease-free survival is unusual.
1. Limb-salvage surgery is now the standard treatment for most patients with osteogenic sarcomas of the extremities, where nearly 90% of these tumors originate. The historical fear of “skip metastases” (within the same bone of involvement) has proved excessive; the occurrence rate of skip metastases appears to be <10%. Only occasionally do patients require amputation. The widespread, successful use of limb-salvage therapy has been made possible by the following advances:
a. Significant progress in the development of modern prostheses that are available immediately after surgery. For example, young children who would have had unacceptable leg-length discrepancy with limb-salvage procedures can now be given a prosthesis that can be lengthened as the patient grows (expandable prosthesis).
b. The use of preoperative (neoadjuvant) chemotherapy
(1) Preoperative chemotherapy can result in enough tumor shrinkage to permit the use of prosthesis for limb-sparing surgery.
(2) Preoperative chemotherapy provides an in vivo drug trial to determine the drug sensitivity of an individual tumor and to customize postoperative chemotherapy regimens. Patients who have an excellent response to preoperative chemotherapy (>95% necrosis) have the most favorable long-term prognosis.
2. Amputation provides definitive surgical treatment in patients in whom a limb-sparing resection is not a prudent option. The procedures include hip disarticulation, hemipelvectomy, and forequarter resection. Although these procedures were once used for technically difficult resections and proximal tumors, most sarcomas of the shoulder girdle or knee can now be resected rather than amputated.
B. Adjuvant RT is usually not utilized for osteogenic sarcomas of the extremities. Tumors of the jaw, facial bones, and axial skeleton require combined RT and limited surgery.
C. Chemotherapy
1. Preoperative (neoadjuvant) chemotherapy provides a response rate of 60% to 85% with combination regimens, including high-dose methotrexate (HDMTX) with leucovorin rescue. Response to preoperative chemotherapy is the single most important prognostic variable in predicting relapse-free survival.
2. Adjuvant chemotherapy is standard practice in the management of all patients with osteogenic sarcoma. Prospective, randomized, controlled studies demonstrated improvement in relapse-free survival for patients treated adjuvantly with chemotherapy compared with those treated with surgery alone (17% vs. 65% to 85% at 2 years). A steep dose–response curve has been repeatedly observed for chemotherapy of sarcomas: the higher the dose, the higher the response rate. Combination chemotherapy incorporating high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin has produced the best responses. Some regimens reserve ifosfamide for poor responders to methotrexate, doxorubicin, and cisplatin. Recent reports have shown acceptable response rates for regimens without methotrexate. As the cure rates for chemotherapy have plateaued with the currently available drugs, new approaches are necessary for progress to occur against this disease.
D. Treatment of other bone sarcomas. Cryosurgery—using liquid nitrogen after curettage of a tumor cavity—can decrease local recurrence for aggressive benign bone tumors and low-grade sarcomas.
1. Chondrosarcoma. Complete surgical excision with limb-sparing procedures where applicable. Adjuvant RT or chemotherapy is not helpful but may be tried in cases of dedifferentiated chondrosarcoma.
2. MFH of bone. Radical surgical resection. Because of the poor prognosis, adjuvant chemotherapy is justified, but its efficacy has not been proved.
3. Fibrosarcoma of bone. Surgery alone
4. Chordoma. The first surgical procedure has the best chance for cure. Inadequate surgery results in local recurrence and ultimate death. RT is also used adjuvantly with disappointing results. Heavy-particle irradiation appears promising for improving local control. Recent studies have shown activity for tyrosine kinase inhibitors such as sunitinib.
5. Ewing sarcoma is discussed in Chapter 18, “Ewing Sarcoma.”
6. Giant cell tumor of bone. Surgical removal cures 90% of these tumors when benign. Amputation is reserved for massive recurrence or malignant transformation. RANK ligand inhibition with agents such as denosumab has shown activity against this entity.
VII. MANAGEMENT OF STS
A. Surgery. Wide, adequate surgical resection with pathologically proven clear margins is the most effective therapeutic approach. Soft-part resection can be accomplished without amputation in at least 80% of patients.
1. Extent of resection. Surgical exploration of the tumor demonstrates apparent encapsulation; this is actually a pseudocapsule. Local recurrences develop in 80% of patients treated only by enucleation of the pseudocapsule. The surgeon must remove the localized sarcoma within a complete envelope of normal tissue; normal structures must be sacrificed if necessary to encompass the tumor. The biopsy site, skin, and most of the subcutaneous tissue, fibrous tissue, and (often) the adjacent muscle group should be included in the resection.
2. Regional lymph node dissection. Node dissection is not done routinely for soft tissue or bone sarcomas and is only performed if nodal involvement is suspected clinically.
3. Amputation of painful extremities. Removal of a painful, functionless extremity that is the site of an eroding, necrotic tumor may be palliative, even in patients with metastatic disease. Surgery may be attempted after chemotherapy and RT have failed to control progressive disease.
4. Resection of pulmonary metastasis is a reasonable measure in selected patients with resectable pulmonary metastasis and no other evidence of disease (see Chapter 29, Section II). The best results of this approach are observed in patients with sarcomas or germ cell tumors, as compared with patients with carcinomas or melanomas.
B. RT is administered to the tumor bed before or after surgery (depending on the treatment center) for high-grade or large STSs to improve local control rates.
1. Microscopically positive surgical margins increase the risk for local failure. The presence of microscopically positive surgical margins or the occurrence of local failure, however, does not affect overall survival. Adjuvant RT may be most important when achieving clear margins would require amputation or significant functional compromise of the extremity.
2. For lesions distal to the elbow or knee, postoperative RT raised the ability rate to perform limb-salvage surgery to 95% and reduced the local recurrence rate to 10%. These results were the same as if radical amputation or muscle group excision were performed.
3. Palliation. RT can provide palliation to sites of painful bony disease or to sites of unresectable local soft tissue disease.
C. Treatment of STS for specific presentations
1. Grade 1 and small grade 2 lesions are treated with surgery alone; the relapse rate is <10% with surgery alone. Adjuvant RT is not required.
2. Grade 2 lesions that are proximal and large are treated with surgery and postoperative RT.
3. Grade 3 or 4 lesions. RT is advisable before or after surgery.
4. Head and neck STS. Appropriate therapy is not defined. Wide surgical excision and RT before or after surgery is advisable.
5. Childhood rhabdomyosarcoma is treated intensively with chemotherapy, RT, and surgery (see Chapter 18, “Rhabdomyosarcoma”).
6. Retroperitoneal STS (mostly leiomyosarcomas and liposarcomas) must be radically extirpated. Complete resection is possible in about 65% of patients and strongly predicts outcome. Median survival with complete resection is 80 months for low-grade STS and 20 months for high-grade disease. Median survival with incomplete resection for all STSs is only 24 months. The survival rate is not affected by tumor type or size.
7. GIST. Imatinib (Gleevec) has demonstrated activity in advanced GIST in up to 70% of cases with doses ranging from 400 to 800 mg/d. The durability of responses to imatinib is being evaluated. Sunitinib (Sutent) has demonstrated an improvement in time to progression and progression-free survival at a dose of 50 mg/d in those who have progressed after or were intolerant to imatinib.
Trials in the adjuvant setting have shown a decreased rate of recurrence with the use of imatinib for 1 year following complete surgical resection. Whether small tumors with low mitotic rates need treatment is not clear. Furthermore, some tumors, such as those with d842V mutations, appear to be resistant to imatinib.
8. Kaposi sarcoma
a. KS in AIDS. Highly active antiretroviral therapy (HAART) has markedly decreased the incidence of KS and is effective in the treatment of early KS. Management of KS in AIDS patients is discussed in Chapter 36, Section IV.G.
b. Classic KS. A topical treatment for cutaneous KS, 0.1% alitretinoin gel (Panretin), should be tried first for local control; however, local erythema and dermatitis may limit its use. Liquid nitrogen can be used for the destruction of localized nodular lesions. RT, including electron beams, is useful for local disease; KS is very radiosensitive. Chemotherapy is inconsistently effective; vinca alkaloids or liposomal doxorubicin (Doxil, 20 mg/m2 IV every 3 weeks) appear to be the most active agents.
D. Chemotherapy for STS. Currently used combination chemotherapy regimens for sarcoma are shown in Table 17.4.
1. Single agents. The response rates of STS to doxorubicin, ifosfamide, or dacarbazine used as single agents are 30%, 30%, and 15%, respectively. Other drugs have response rates of <15%. Intra-arterial administration is not superior to intravenous administration.
2. Adjuvant chemotherapy is standard practice in the management of rhabdomyosarcoma in children. Adjuvant chemotherapy for STS in adults with high-grade tumors remains controversial.
a. A meta-analysis of randomized trials of adjuvant doxorubicin for STS demonstrated a reduction in local and distant recurrence rates and a trend toward improved overall survival; this survival benefit was most clear for those with extremity sarcomas. Subsequent trials using the combination of ifosfamide with an anthracycline (either epirubicin or doxorubicin) showed an advantage in both disease-free survival and overall survival for those receiving chemotherapy. Additionally, preoperative treatment with both RT and chemotherapy that includes ifosfamide has shown higher rates of complete pathologic response at the time of surgery than prior preoperative regimens using either RT alone or RT with intravenous or intra-arterial doxorubicin.
b. At our institutions, patients with STS who are candidates for adjuvant chemotherapy typically are given two cycles of ifosfamide with mesna and one cycle of doxorubicin both before and after RT to the affected part. Dosages are shown in Table 17.4.
3. Combination chemotherapy regimens (e.g., CyVADic in Table 17.4) appear to provide no advantage over single agents for palliation or survival but are more toxic. Pulmonary and soft tissue metastases are more responsive than liver and bone metastases.
a. The combination of vincristine, actinomycin D, and cyclophosphamide (VAC) in children with rhabdomyosarcoma produces a response rate of 90% even with disseminated disease. Responses to these agents in other sarcomas are usually minimal and brief.
b. The combination of gemcitabine and docetaxel (dosage and schedule are shown in Table 17.4) has shown promising activity in advanced leiomyosarcomas.
c. Dose intensity probably correlates with response rates in the treatment of sarcomas. High-dose combinations of ifosfamide (with mesna uroprotection), doxorubicin, and dacarbazine (MAID regimen in Table 17.4) results in a higher response rate (45%) than single agents but at the expense of substantial myelosuppression. Ifosfamide as a single agent, when given in divided doses over several days at total doses of 10 to 14 g/m2, can produce responses in patients previously treated with ifosfamide at lower doses. Comparison studies of lower doses of ifosfamide (6 g/m2) versus higher doses ifosfamide (12 g/m2), both given with doxorubicin at 60 mg/m2, have not shown a clear benefit for the higher dose regimens in terms of either disease-free or overall survival at 1 year.
Table 17.4 Combination Chemotherapy Regimens for Sarcoma
CIV, continuous intravenous infusion; IV, intravenously
aGemcitabine dose reduced to 675 mg/m2 if patient received prior pelvic RT
bSupport with granulocyte colony-stimulating factor
cMaximum, 2 mg
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