Soft Tissue Sarcomas
BASIC SCIENCE QUESTIONS
1. Which of the following embryonic cell type is the most common origin of sarcomas?
Sarcomas are a heterogeneous group of tumors that arise predominantly from the embryonic mesoderm, but can also originate, as does the peripheral nervous system, from the ectoderm. (See Schwartz 9th ed., p 1284.)
2. Which of the following is an expected molecular event in an older patient with a sarcoma?
A. Point mutation of an oncogene
B. Translocation causing overexpression of an autocrine growth factor
C. Oncogenic fusion transcription factor
D. None of the above
Molecular genetics, cytogenetics, and expression profiling have been used to investigate sarcomas resulting in their classification into two main groups: those with defined diagnostic molecular events and those with variable histological and genetic changes. In general, the group of sarcoma patients with defined molecular events have been found to be younger with a defined histology suggesting a clear line of differentiation. The defined molecular events include point mutations, a translocation causing over-expression of an autocrine grow factor, or oncogenic fusion transcription factor. In contrast, sarcomas without currently identifiable genetic changes or expression profile signatures tend to occur in older patients exhibiting pleomorphoic cytology and p53 dysfunction. (See Schwartz 9thed., p 1285.)
3. Which of the following mechanisms is felt to play the most significant role in the development of sarcomas?
A. Activation of cancer suppressor genes
B. Chromosomal translocation with activation of oncogenes
C. Gene fusion with expression of oncoproteins
D. Germ line mutation with suppression of oncogenes
Cytogenetic analysis of soft tissue tumors has identified distinct chromosomal translocations that seem to encode for oncogenes associated with certain sarcoma histologic subtypes. These specific genetic changes result in the in-frame fusion of genes and fused product codes for the expression of onco-proteins functioning as transcriptional activators or repressors. The best characterized gene rearrangements are found in Ewing’s sarcoma (EWS–FLI-1 fusion), clear-cell sarcoma (EWS–ATF1 fusion), myxoid liposarcoma (TLS–CHOP fusion), alveolar rhabdomyosarcoma (PAX3–FHKRfusion), desmoplastic small round-cell tumor (EWS–WT1 fusion), and synovial sarcoma (SSX–SYT fusion). It has been estimated that in aggregate, fusion gene-related sarcomas may account for up to 30% of all sarcomas. The oncogenic potential of many of these genes has been demonstrated in vitro and in vivo. These fusion genes provide not only specific diagnostic markers but encode chimeric proteins, both of which may be potential therapeutic targets. (See Schwartz 9th ed., p 1285.)
1. Which of the following is the most common soft tissue sarcoma in adults?
C. Synovial sarcoma
D. Malignant fibrous histiocytoma
The most common histologic types of soft tissue sarcoma in adults (excluding Kaposi’s sarcoma) are malignant fibrous histiocytoma (28%), leiomyosarcoma (12%), liposarcoma (15%), synovial sarcoma (10%), and malignant peripheral nerve sheath tumors (6%). (See Schwartz 9th ed., p 1284, and Table 36-1.)
TABLE 36-1 Relative frequency of histologic subtypes of soft tissue sarcoma
2. Which of the following is the most common soft tissue sarcoma in children?
Associated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site that has striated muscle. These tumors generally present as a painless enlarging mass; about 24% in the genitourinary system, 20% in the extremities, 20% in the head and neck, 16% in the parameningeal region, and 22% in miscellaneous other sites. Regional lymphatic spread of tumor occurs frequently in extremity tumors and in paratesticular tumors. About 15 to 20% of cases have metastasis at presentation, most commonly (40 to 50%) involving the lungs, followed by bone marrow and bone. However, all patients are considered to have micrometastatic disease at presentation which is the rationale for universal chemotherapy. (See Schwartz 9th ed., p 1299.)
3. Malignant fibrous histiocytoma is most likely to metastasize to which of the following organs?
D. Lymph node
The dominant pattern of metastasis (of sarcomas) is hematogenous, primarily to the lungs. Lymph node metastases are rare (5%) except for a few histologic subtypes such as epithelioid sarcoma, rhabdomyosarcoma, clear-cell sarcoma, synovial sarcoma, malignant fibrous histiocytoma, and angiosarcoma. (See Schwartz 9th ed., p 1284.)
4. Which of the following is a risk factor for developing a sarcoma?
A. Hypaque (isotonic contrast)
C. Chronic lymphedema
D. Dental radiographs
In 1948, Stewart and Treves first described the association between chronic lymphedema after axillary dissection and subsequent lymphangiosarcoma. Lymphangiosarcoma has also been reported as occurring after filarial infections and in the lower extremities of patients with congenital or heritable lymphedema.
External radiation therapy is a rare but well-established risk factor for soft tissue sarcoma. An eightfold to 50-fold increase in the incidence of sarcomas has been reported among patients treated for cancer of the breast, cervix, ovary, testes, and lymphatic system. Dental radiographs would not expose the patient to enough radiation to increase the risk of sarcoma.
Thorotrast, which is a contrast material, has been implicated in carcinogenesis of sarcomas. There is no increased risk with exposure to Hypaque.
Although patients with sarcomas often report a history of trauma, no causal relationship has been established. More often, a minor injury calls attention to a preexisting tumor that may be accentuated by edema or hematoma. (See Schwartz 9th ed., p 1285.)
5. Which of the following syndromes is associated with an increased risk of developing a sarcoma?
A. Familial adenomatous polyposis
B. Ehlers-Danlos syndrome
C. Down syndrome
D. Turner syndrome
Sarcomas occur more commonly within several hereditary cancer syndromes including retinoblastoma, Li-Fraumeni syndrome, neurofibromatosis type I, and familial adenomatous polyposis. Germline mutations have been identified as causal in only a limited number of these disorders. Developments in the field of molecular biology have led to a better understanding of some of the basic cellular processes governed by oncogenes and tumor suppressor genes. (See Schwartz 9th ed., p 1285.)
6. Abdominal metastases are most likely to occur from which of the following tumors?
A. Synovial sarcoma
D. Myxoid liposarcoma
Computed tomography of the abdomen and pelvis should be done when histologic assessment of an extremity sarcoma reveals a myxoid liposarcoma, because this subtype is known to metastasize to the abdomen. (See Schwartz 9th ed., p 1286.)
7. The most appropriate initial method to biopsy a suspected 4-cm sarcoma of the lower leg is
A. Core needle biopsy
B. Suction biopsy
C. Incisional biopsy
D. Excisional biopsy
Core needle biopsy is a safe, accurate, and economical procedure for diagnosing sarcomas. The tissue sample obtained from a core needle biopsy is usually sufficient for several diagnostic tests such as electron microscopy, cytogenetic analysis, and flow cytometry. The reported complication rate for core needle biopsy is less than 1%.
Fine-needle aspiration is an acceptable method of diagnosing most soft tissue sarcomas, particularly when the results correlate closely with clinical and imaging findings. However, fine-needle aspiration biopsy is indicated for primary diagnosis of soft tissue sarcomas only at centers where cytopathologists have experience with these types of tumors. Incisional biopsy and excisional biopsy may change the outcome for patients by complicating staging. They are not considered the best initial diagnostic method for sarcomas >3 cm in diameter. (See Schwartz 9th ed., p 1287.)
8. In which of the following would an excisional biopsy of a suspected sarcoma be acceptable?
A. 2-cm superficial flank mass
B. 1.5-cm lesion of the dorsum of the hand
C. 2-cm lesion over the calcaneus
D. 4-cm superficial thigh mass
Excisional biopsy can be performed for easily accessible (superficial) extremity or truncal lesions smaller than 3 cm. Excisional biopsy should not be done for lesions involving the hands and feet, because definitive re-excision may not be possible after the biopsy. Excisional biopsy results have a 30 to 40% rate of recurrence when margins are positive or uncertain. Excisional biopsies rarely provide any benefit over other biopsy techniques and may cause postoperative complications that could ultimately delay definitive therapy. (See Schwartz 9th ed., p 1287.)
9. Which of the following has a low risk of metastasis?
A. Clear-cell sarcoma
C. Dermatosarcoma protuberans
Tumors with limited metastatic potential include desmoid, atypical lipomatous tumor (also called well-differentiated liposarcoma), dermatofibrosarcoma protuberans, and hemangiopericytoma. Tumors with an intermediate risk of metastatic spread usually have a large myxoid component and include myxoid liposarcoma and extraskeletal chondrosarcoma. Among the highly aggressive tumors that have substantial metastatic potential are angiosarcoma, clear-cell sarcoma, pleomorphic and dedifferentiated liposarcoma, leiomyosarcoma, rhabdomyosarcoma, and synovial sarcoma. (See Schwartz 9th ed., p 1287.)
10. Which of the following is the most important determinant of prognosis for a patient with a sarcoma?
A. Depth of invasion
B. Cell type
C. Histologic grade
D. Tumor size
Histologic grade remains the most important prognostic factor for patients with sarcomas. For an accurate determination of tumor grade, an adequate tissue sample must be appropriately fixed, stained, and reviewed by an experienced sarcoma pathologist. The features that define grade are cellularity, differentiation, pleomorphism, necrosis, and the number of mitoses. Tumor grade has been shown to predict the development of metastases and overall survival. The metastatic potentials have been estimated at 5 to 10% for low-grade lesions, 25 to 30% for intermediate-grade lesions, and 50 to 60% for high-grade tumors. (See Schwartz 9th ed., p 1288.)
11. Which of the following is appropriate treatment following wide local excision of a 4-cm leiomyoma of the calf with negative margins and no metastases?
A. Radiation therapy
B. Systemic chemotherapy
C. Isolated limb perfusion of chemotherapy
D. Radiation therapy and chemotherapy
Small (5 cm) primary tumors with no evidence of distant metastatic disease are managed with local therapy consisting of surgery, alone or in combination with radiation therapy, when wide pathologic margins are limited because of anatomic constraints. (See Schwartz 9th ed., p 1289, and Fig. 36-1.)
FIG. 36-1. Treatment algorithm of extremity soft tissue sarcoma. CT = computed tomography; CXR = chest x-ray; MRI = magnetic resonance imaging; US = ultrasound.
12. Which of the following sarcomas is most responsive to chemotherapy?
D. Synovial sarcoma
As a group, sarcomas include histologic subtypes that are responsive to cytotoxic chemotherapy and subtypes that are universally resistant to current agents. A spectrum of chemosensitivity has been demonstrated for various histologic subtypes. In particular, synovial sarcoma and fibrosarcoma have been noted to be highly sensitive to chemotherapy. Liposarcoma and myxofibrosarcoma as having intermediate sensitivity to chemotherapy; and gastrointestinal stromal tumors and chondrosarcoma as being highly resistant to chemotherapy. (See Schwartz 9th ed., p 1293.)
13. The most common presenting symptom of a retroperitoneal sarcoma is
A. A large abdominal mass
B. Ureteral obstruction
C. Rectal obstruction
D. Lower extremity swelling from venous congestion
In contrast to extremity sarcomas, many retroperitoneal sarcomas present as large tumor masses abutting or involving vital structures, making margin-free resection difficult. As a result, locoregional recurrence is common (72% at 5 years) and prognosis for patients with retroperitoneal sarcoma is poor with 5-year survival estimated at 36 to 58%. (See Schwartz 9th ed., p 1295.)
14. The most appropriate surgical treatment for a 2-cm leiomyosarcoma of the greater curvature of the stomach is
A. Local resection with 3-cm margin of normal tissue
B. Subtotal gastrectomy
C. Total gastrectomy
D. Total gastrectomy and lymphadenectomy
Lymphatic spread is not the primary route of metastasis for gastrointestinal sarcomas. Consequently, lymphadenectomy is not routinely performed as part of resection. Based on published data and the primary pattern of distant (versus local) failure, the general recommendation is to perform a margin-negative resection with a 2- to 4-cm margin of normal tissue. (See Schwartz 9th ed., p 1297.)
15. Which of the following is used in the treatment of gastrointestinal stromal tumors?
Until recently, systemic treatment options for patient with unresectable or metastatic GIST were of little therapeutic benefit. Treatment with imatinib (Gleevec, ST1571), a selective c-Kit inhibitor, has resulted in impressive clinical responses in a large percentage of patients with unresectable or metastatic GISTs. (See Schwartz 9th ed., p 1298.)