A 33-year-old man presents for evaluation of swelling in his right thigh. He first noticed the swelling 8 to 10 weeks ago and attributed it to injuries incurred during long-distance running. The patient has no known medical problems. He is physically fit and runs approximately 3 to 5 miles daily. On examination, he is found to have a 6- × 5-cm, firm, nontender mass in the anterior portion of the right thigh. There are no skin or motor/sensory changes in the right leg and no lymphadenopathy in the right groin. A radiograph of the thigh reveals no bony abnormalities.
What is the most likely diagnosis?
How would you confirm the diagnosis?
What is the best therapy?
ANSWERS TO CASE 20: Sarcoma (Soft Tissue)
Summary: A 33-year-old man presents with a large, nontender, soft tissue tumor that is highly suggestive of an extremity sarcoma.
• Most likely diagnosis: Soft tissue sarcoma (STS) should be highly suspected.
• Confirmation of diagnosis: A core-needle biopsy of the mass should be obtained for tissue diagnosis.
• Best therapy: Surgical excision is the mainstay of therapy. Multimodality therapy, including radiation and chemotherapy delivered either preoperatively or postoperatively, may be indicated for selected high-grade, large STSs.
1. Know the presentation of extremity, truncal, and retroperitoneal sarcomas and the importance of obtaining tissue for early diagnosis and treatment.
2. Learn the treatment options and outcome for patients with sarcomas.
3. Learn the genetic conditions and risk factors associated with sarcoma development.
4. Learn the management of gastrointestinal stromal tumor (GIST).
The initial approach in this patient should include biopsy of the mass for pathologic diagnosis. The biopsy can be performed using a core-needle biopsy or by open incision if a needle biopsy fails to obtain adequate tissue. Excisional biopsy should never be attempted with lesions suspected to be STSs because of the difficulty in achieving adequate resection margins, which would compromise the definitive care of the patient. Young (aged <30 years), healthy, active individuals with extremity STSs are frequently misdiagnosed as having a hematoma or a bruised muscle because sarcomas are infrequently encountered by physicians in most medical practices. Therefore, it is imperative to consider STS whenever an unexplained soft tissue mass or swelling is identified in an individual of any age. Certain clinical features in this case should further raise a suspicion of STS, including the size of the lesion (6 ë 5 cm), the absence of a specific event to account for a hematoma of this size, the firmness of the mass, and the absence of surrounding skin changes to suggest an inflammatory or infectious process. As a rule, most patients with STS present without any regional lymphadenopathy or systemic symptoms such as weight loss, night sweats, or cachexia. STS may manifest occasionally as local pain, erythema, or tenderness over the mass and can be easily misdiagnosed as a soft tissue abscess; these symptoms are caused by rapid tumor growth leading to partial necrosis of the STS.
APPROACH TO: Sarcomas
SARCOMA: One of a group of tumors usually arising from connective tissue, and are characterized as extremity, truncal, or retroperitoneal.
LI-FRAUMENI SYNDROME (LFS): A cancer predisposition syndrome associated with soft tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. Individuals with LFS are at increased risk for developing multiple primary cancers. LFS is diagnosed in individuals meeting established clinical criteria. More than 50% of individuals diagnosed clinically have an identifiable TP53 gene.
TNM STAGING FOR SOFT TISSUE SARCOMAS:
Sarcomas can be categorized as extremity, superficial truncal, and visceral/retroperitoneal. Diagnostic delays associated with extremity STSs are not uncommon, in part because of the failure of the patient to seek treatment and because of misdiagnoses by physicians. The typical presentation is that of a new area of swelling in the arm or leg frequently thought to be a hematoma or bruised muscle and often noticed after trivial trauma to the area. It is important to note that trauma is not the cause of STS but rather the event that brings attention to the mass itself. The differential diagnosis for a soft tissue mass includes benign lipoma, which is much more common; however, STS should be suspected in any patient with a new fixed mass, a mass that is increasing in size, or a mass bigger than 5 cm in diameter.
Approximately 50% of STSs are found in the extremities, but the distribution can involve any site. Sarcomas arise from mesodermal tissue and can exist as one of many pathologic subtypes (eg, liposarcoma, fibrosarcoma, leiomyosarcoma, and malignant fibrohistiocytoma). The diagnosis of STS begins with development of a high index of suspicion based on the history and physical examination, followed by either a core-needle or a fine-needle biopsy for diagnosis. Patients with tumors of large size or high grade (highly mitotic) based on histologic study are at increased risk for pulmonary metastasis. These individuals should undergo CT imaging of the lung. Staging of an extremity STS is based on size, grade, and superficial versus deep location. Table 20–1 outlines favorable and unfavorable characteristics of extremity and superficial trunk STSs. All sarcomas with either lymph node or distant metastasis are considered stage IV. Lymph node metastasis is rare in STS; however, when it occurs, patient survival is similar to that for individuals with distant metastasis. Distant metastasis occurs most commonly in the lungs. Disease-specific survival (DSS) for patients with extremity STS varies depending on the site, histology, grade, and size. Basically, patients with low-grade tumors smaller than 5 cm have greater than 90% 5-year DSS, whereas those with high-grade tumors bigger than 5 cm have approximately a 50% 5-year DSS. Patients with stage IV STSs have a 10% to 15% 5-year DSS. Nevertheless, when pulmonary metastases are amenable to complete resection, the 5-year DSS may be as high as 35%.
Table 20–1 • CHARACTERISTICS OF EXTREMITY SOFT TISSUE SARCOMAS
The treatment of extremity STSs has evolved substantially over the past several decades. Previously, amputation was the standard of care. A landmark prospective randomized study by the National Cancer Institute comparing limb-sparing surgery with radiation to amputation, however, found no survival benefits in performing amputations. The current standard treatment is wide local excision, with all efforts made to obtain negative microscopic margins. Complete resection of a muscle compartment results in greater functional loss and is generally unnecessary. Complete resection with a 2-cm gross margin is reasonable to ensure negative microscopic margins. Patients with superficial, low-grade, and small sarcomas rarely experience a recurrence or die of the disease, but the risk of local recurrence increases with the stage. Radiation therapy should be considered for stage II and stage III disease to reduce local recurrence. Generally, brachytherapy (radioactive catheters placed directly in the tumor resection bed) is given for high-grade tumors, and external beam therapy is given for larger, low-grade, and more deeply located tumors. Because brachytherapy catheters are placed intraoperatively, a tissue diagnosis should be obtained by core biopsy preoperatively whenever such therapy is considered.
Local recurrence of STS takes place despite resection with grossly clear margins. For this reason, every attempt should be made to obtain negative microscopic margins during the initial resection. With large tumors in deep locations, MRI or CT imaging performed preoperatively can help more clearly define the tumor’s relationship to major structures. Patients with tumors encasing bone, major vessels, or nerves may be more appropriately treated with preoperative (neoadjuvant) chemoradiation to shrink the tumor to allow for limb-sparing surgery.
The role of adjuvant chemotherapy in patients following the complete resection of extremity sarcoma is controversial. While the individual clinical trials have not demonstrated any survival advantage with treatment, two meta-analyses have reported survival advantages for patients receiving certain chemotherapy regimens. The marginal benefits of systemic chemotherapy must be considered along with the toxicity and potential harm associated with administration of these chemotherapeutic regimens.
Recommendations for follow-up after surgical resection currently are not standardized. A reasonable practice is to follow patients with a low risk for recurrence biyearly with a physical examination and yearly with a chest radiograph. Patients at high risk for recurrence are usually examined every 3 months, with chest radiographs obtained every 3 to 6 months indefinitely.
Sarcomas arising from retroperitoneal structures tend to remain asymptomatic until they reach a large size. Most patients have late presentations, commonly with tumor involvement of contiguous structures. Patients with high-grade and/or incompletely resected primary tumors have a substantial recurrence risk. Unlike high-risk extremity STS, more likely to result in death because of recurrence at a distant site, retroperitoneal sarcomas are much more likely to recur locally and cause death as a result of local involvement. Lewis and colleagues evaluated 231 patients following the resection of retroperitoneal sarcomas and found 2- and 5-year survivals of 80% and 60%, respectively. Complete resection is best achieved during the initial surgery, and the probability of complete resection is reduced with each subsequent operative attempt. Distant metastasis from retroperitoneal sarcoma, which infrequently occurs, often involves the liver and lungs. Postoperative follow-up for retroperitoneal sarcoma is not clearly defined. CT scans performed at 6-month intervals may be considered reasonable.
Genetic and Environmental Predisposition to Sarcomas
Both physical and genetic factors can predispose to the development of sarcomas. Physical factors include prior radiation, lymphedema, and chemical exposure (including prior chemotherapy). Table 20–2 lists the genetic predisposing factors. Patients with neurofibromatosis are prone to develop sarcomas arising from nerve structures, as well as paragangliomas and pheochromocytomas. The development of retinoblastoma in patients with the LFS (an autosomal dominant disorder with predisposition to the early onset of many types of cancers) has been genetically linked to mutations in Rb-1 and p53 genes, respectively. Whereas patients with the LFS have an increased risk for several cancers, those with retinoblastoma are prone to develop osteosarcomas. Patients with familial polyposis coli have an increased risk of developing desmoid tumors, which are generally considered benign tumors with a predilection for local recurrence following excision.
Table 20–2 • GENETIC PREDISPOSITION ASSOCIATED WITH SARCOMAS
Gastrointestinal Stromal Tumor
Gastrointestinal stromal tumors (GISTs) are not true sarcomas; however, these tumors were at one time classified as sarcomas of the GI tract. GISTs the most common mesenchymal tumors of the gastrointestinal tract and they may appear histologically with spindle cell, epithelioid, or mesenchymal features. GISTs originate from the interstitial cells of Cajal within the GI tract. Approximately 95% of the GISTs have an overexpression of KIT protooncogene (CD117), which is associated with the increase in membrane tyrosine kinase receptor activities. GISTs typically are found in middle-age and older adults, with the majority of patients presenting with asymptomatic, incidentally identified masses. Some patients with GISTs present with acute GI bleeding as the result of spontaneous tumor necrosis. The stomach and small bowel are the most common sites associated with GISTs. GISTs that are small, with low mitotic activities, and amendable to complete resections should be treated initially with complete resections. A recently published randomized controlled trial examining the benefits of imatinib in the postsurgical adjuvant setting showed that patients with c kit–positive GISTs larger than 3 cm had a significantly improved 1-year recurrence-free survival after receiving adjuvant 400 mg imatinib (ACOSOG Z9001 Trial). Patients with initially unresectable GISTs can be treated with imatinib in the neoadjuvant setting. With this approach, some patients have had tumor regressions that have made subsequent surgical resections feasible following their initial courses of imatinib treatment.
Prognosis associated with GISTs is determined by tumor resectability, size, mitotic activities, and locations, where small bowel GISTs generally have worse prognoses than gastric GISTs.
20.1 A 35-year-old man notices a firm, nontender, 10-cm mass in his thigh after falling off a ladder. Which of the following is the most appropriate first step following a history and a physical examination?
A. Observation to see if it changes over the next month
B. Core-needle biopsy followed by a CT scan of the extremity
C. Immediate resection with wide margins
D. Ultrasonography of the mass
E. Incision and drainage of the hematoma
20.2 A 41-year-old woman underwent excision of what was thought to be a superficial lipoma of the upper extremity. Findings from pathology studies subsequently revealed a 6-cm high-grade sarcoma with positive histologic margins. Which of the following treatments is most appropriate?
A. Follow-up physical examination in 6 months
B. External beam radiation
D. Re-excision to obtain negative margins
E. Isolated limb perfusion therapy
20.3 A 28-year-old man is noted to have a leiomyosarcoma of the right leg. Upon investigation, he is noted to have metastatic involvement. Which of the following is the most likely site of metastasis?
A. Lymph nodes
20.4 A 54-year-old woman is seen in a follow-up after resection of a large retroperitoneal sarcoma. Which of the following locations is the most likely site of recurrence?
A. Peritoneal or retroperitoneal space.
D. Recurrence is unlikely following complete resection.
20.5 A 53-year-old man underwent small bowel resection for GIST of the small bowel. All gross disease was removed at the completion of the operation. The pathology revealed an 8-cm c kit–positive GIST with 15 mitotic figures per 50 high-power fields. What is the most appropriate next step?
A. Systemic chemotherapy with Adriamycin and cytoxan
B. Imatinib 400 mg daily for 1 year
C. Radiation therapy
D. Adriamycin + cytoxan + imatinib
20.1 B. This patient noted a large nontender mass of the thigh. The finding of a nontender mass is inconsistent with a soft tissue injury despite the history of a fall; therefore, a core biopsy is indicated.
20.2 D. Surgical resection to achieve negative margins is the best treatment in this case. If the margin status remains questionable following re-excision, adjuvant radiation therapy could be added to improve the success of local disease control. Isolated limb perfusion can involve isolated arterial infusion of chemotherapy drugs and/or cytokines, along with either normothermic or hyperthermic limb perfusion. Isolated limb perfusion is generally applied in patients to improve the success of limb-preserving treatments in high-risk patients with difficult tumor locations.
20.3 C. The lungs are the most common site of metastasis for extremity STS.
20.4 A. Local and regional recurrence is the most likely cause of treatment failure for retroperitoneal sarcomas.
20.5 B. The ACOSOG Z9001 trial is a large randomized controlled study that demonstrated that adjuvant therapy with 400 mg imatinib daily for 1 year improved disease-free survival in patients with high-risk GISTs larger than 3 cm in diameter. Cytotoxic chemotherapy and radiation therapy are not generally used for the treatment of GISTs.
Features of an extremity mass that are suggestive of sarcoma include the size of the lesion, the absence of a specific event to account for a hematoma, firmness of the mass, noticeable growth over weeks to months, and the absence of surrounding skin changes suggesting an inflammatory or infectious process.
The diagnosis of STS begins with a high suspicion based on the history and physical examination, followed by performance of a diagnostic core biopsy or fine-needle biopsy.
The current standard therapy for sarcomas is wide local excision with all efforts made to obtain negative microscopic margins, followed by radiation therapy in high-risk patients. Adjuvant chemotherapy may provide additional survival benefits for high-risk patients following complete resection, but risk-benefit of treatment must be considered.
Prior radiation or chemotherapy and genetic factors such as neurofibromatosis are risk factors for STS.
95% of GISTs express c kit or CD 117. GISTs with expression of c kit are responsive to imatinib.
Blay JY, von Mehren M, Blackstein ME. Perspective on updated treatment of guidelines for patients with gastrointestinal stromal tumors. Cancer. 2010:DOI:10.1002/cncr.25267.
Mendenhall WM, Indelicato DJ, Scarborough MT, et al. The management of soft tissue sarcomas. Am J Clin Oncol. 2009;32:436-442.
Pervaiz N, Colterjohn N, Farrokhyar, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113:573-581.
Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350:1647-1654.