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Surgery_Schwartz. of the retroperitoneum developed a solitary lung metastasis 6 years after surgical resection.Brunicardi_Ch36_p1567-p1598.indd 158101/03/19 6:38 PM 1582SPECIFIC CONSIDERATIONSPART IIpatients with limited disease experience stabilization of disease with multidisciplinary treatment, which often includes surgery and radiation therapy in addition to chemotherapy. Several factors predict better outcome for patients with recurrent metastatic sarcoma undergoing chemotherapy, including good performance status, previous response to chemotherapy, younger age, absence of hepatic metastases, low-grade tumor, and long disease-free interval.165 Isolated liver metastases, if stable over several months, may be amenable to resection,166 radiofrequency ablation,167 or chemoembolization.168As data accumulate regarding the sensitivity of sarcoma subtypes to particular chemotherapies, it is critical that histologydriven treatment approaches be used. New therapies are also being identified based on the


Surgery_Schwartz

Surgery_Schwartz. regarding the sensitivity of sarcoma subtypes to particular chemotherapies, it is critical that histologydriven treatment approaches be used. New therapies are also being identified based on the unique molecular signatures of sarcomas.128Palliative Radiation Therapy. Definitive radiation therapy can be considered when no acceptable surgical option is avail-able (e.g., in patients with significant medical comorbidities). In this setting, radiation doses greater than 63 Gy yielded superior tumor control, but doses greater than 68 Gy resulted in increased rates of major complications.169SPECIAL CLINICAL SITUATIONSMyxoid LiposarcomaMyxoid liposarcomas belong to the group of soft tissue sarco-mas with lipomatous differentiation. However, myxoid liposar-comas differ from the other liposarcoma subtypes with respect to morphology (i.e., myxoid stroma and lipomatous differen-tiation) and clinical behavior. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower


Surgery_Schwartz

Surgery_Schwartz. subtypes with respect to morphology (i.e., myxoid stroma and lipomatous differen-tiation) and clinical behavior. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower extremity and can metastasize to other soft tissue locations, including the retroperitoneum and extremities.170,171 For this reason, CT of the chest, abdomen, and pelvis is recommended for adequate stag-ing and surveillance of myxoid liposarcoma.Retroperitoneal SarcomaMost retroperitoneal tumors are malignant, and about one-third are soft tissue sarcomas. Also to be considered in the differen-tial diagnosis of a retroperitoneal tumor are primary germ cell tumors, lymphoma, and metastatic testicular cancer. Approxi-mately 1000 new cases of retroperitoneal sarcoma are diagnosed annually in the United States, and these tumors account for 10% to 15% of all adult tissue sarcomas. Approximately two-thirds of retroperitoneal sarcomas are high grade (either grade 2 or 3), and liposarcoma and


Surgery_Schwartz

Surgery_Schwartz. the United States, and these tumors account for 10% to 15% of all adult tissue sarcomas. Approximately two-thirds of retroperitoneal sarcomas are high grade (either grade 2 or 3), and liposarcoma and leiomyosarcoma are the most common histologies.Retroperitoneal sarcomas generally present as large masses: 70% are larger than 10 cm at diagnosis.172 They typi-cally do not produce symptoms until they grow large enough to compress or invade contiguous structures, although pain, early satiety, and obstructive gastrointestinal symptoms may occur early in the disease course in some patients. Evaluation of a patient with a retroperitoneal mass begins with an accurate his-tory that should exclude signs and symptoms associated with lymphoma (e.g., fever and night sweats). A complete physical examination, with particular attention to all nodal basins and with a testicular examination in men, is critically important. Laboratory assessment can be helpful; elevated lactate dehy-drogenase levels may


Surgery_Schwartz

Surgery_Schwartz. with particular attention to all nodal basins and with a testicular examination in men, is critically important. Laboratory assessment can be helpful; elevated lactate dehy-drogenase levels may suggest lymphoma, and elevated β-human chorionic gonadotropin levels or α-fetoprotein levels may indi-cate a germ cell tumor.Figure 36-9. A 50-year-old man with a large right dedifferentiated liposarcoma. Note the atypical fat surrounding the right kidney and displacing the viscera to the left hemiabdomen and the large dedifferentiated mineralized solid nodule lateral to the right kidney.Although the general principles of evaluation and man-agement for retroperitoneal sarcomas are similar to those for extremity sarcomas, there are some differences. Contrast-enhanced CT of the abdomen and pelvis is used to define the extent of the tumor and its relationship to surrounding struc-tures, particularly vascular structures, for surgical planning; contrast-enhanced CT can also often distinguish between


Surgery_Schwartz

Surgery_Schwartz. to define the extent of the tumor and its relationship to surrounding struc-tures, particularly vascular structures, for surgical planning; contrast-enhanced CT can also often distinguish between well-differentiated and dedifferentiated liposarcoma. CT imaging is also done to evaluate the liver for the evidence of metastases, the peritoneal cavity for evidence of discontiguous disease, and the kidneys for assessment of function. Angiography or mag-netic resonance arteriography/venography can also be used to delineate vascular anatomy when involvement of critical vascu-lar structures is suspected. Thoracic CT should be performed to evaluate for potential lung metastases because 11% of patients with retroperitoneal sarcoma present with synchronous meta-static disease. CT-guided core needle biopsy is appropriate to provide a tissue diagnosis; however, well-differentiated liposar-coma may be diagnosed with CT imaging alone, and negative biopsy findings should not delay operative


Surgery_Schwartz

Surgery_Schwartz. needle biopsy is appropriate to provide a tissue diagnosis; however, well-differentiated liposar-coma may be diagnosed with CT imaging alone, and negative biopsy findings should not delay operative intervention.Complete surgical resection is the most effective treatment for primary or recurrent retroperitoneal sarcoma (Fig. 36-9). En bloc resection often necessitates sacrificing contiguous struc-tures such as the colon, kidney, spleen, pancreas, psoas muscle, small bowel, inferior vena cava, and aorta.173 In a review of 25 patients who underwent resection of retroperitoneal sarcoma with major blood vessel involvement in a 16-year time span, postoperative morbidity and mortality rates were 36% and 4%, respectively. Vessel patency rates were greater than 88% with a median follow-up time of 19.3 months.83,174 Local control and survival rates were favorable in patients with tumor-free resec-tion margins. The authors concluded that vascular resection is the treatment of choice in sarcomas


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Surgery_Schwartz. 19.3 months.83,174 Local control and survival rates were favorable in patients with tumor-free resec-tion margins. The authors concluded that vascular resection is the treatment of choice in sarcomas that involve major blood vessels in the retroperitoneum.83 Similar considerations were made by other groups reporting specifically on inferior vena cava resection in the context of multivisceral resection for ret-roperitoneal sarcoma and on surgical morbidity after extended surgical resection of retroperitoneal sarcoma. Extended proce-dures, including also vessels, are feasible and safe if carried out in experienced centers. While the goal of sarcoma resection is Brunicardi_Ch36_p1567-p1598.indd 158201/03/19 6:38 PM 1583SOFT TISSUE SARCOMASCHAPTER 36wide excision, this is unlikely to be achievable in most patients with retroperitoneal sarcomas. Surgery is considered marginal in most cases, even when macroscopically complete, but every attempt should be made to minimize this


Surgery_Schwartz

Surgery_Schwartz. to be achievable in most patients with retroperitoneal sarcomas. Surgery is considered marginal in most cases, even when macroscopically complete, but every attempt should be made to minimize this marginality by liberally resecting surrounding organs when involved. The extension of surgery should then take into consideration a trade-off between expected morbidity and benefit and should be best carried out at high-volume centers, where technical skills and knowledge of the natural history of this very rare disease can be found.In an analysis of 500 patients with retroperitoneal soft tissue sarcoma treated at Memorial Sloan-Kettering Cancer Center, the median survival time was 103 months for those who underwent complete resection versus 18 months for those who underwent incomplete resection or observation without resection.172 In general, surgical resection should not be offered unless radiographic evidence indicates the potential for complete resection; however, palliative surgical


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Surgery_Schwartz. or observation without resection.172 In general, surgical resection should not be offered unless radiographic evidence indicates the potential for complete resection; however, palliative surgical resection may be considered to reduce symptoms of intestinal obstruction, pain, or bleeding.175 In particular, in patients with atypical lipomatous tumors, an aggressive surgical approach including incomplete resection or debulking is justified to palliate symptoms and may provide a potential survival benefit.176 Such an approach is not justified for dedifferentiated liposarcomas or other high-grade retroperitoneal sarcomas because these tumors have high rates of distant metastasis and local recurrence.Adjuvant Therapy. Most studies have failed to show a sur-vival benefit from adjuvant chemotherapy for retroperitoneal sarcoma.177-179 Because of the high rates of local recurrence, radiation therapy has been proposed for treating microscopic residual disease as an adjunct to surgical resection.


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Surgery_Schwartz. for retroperitoneal sarcoma.177-179 Because of the high rates of local recurrence, radiation therapy has been proposed for treating microscopic residual disease as an adjunct to surgical resection. However, the optimal technique and timing of radiation therapy have not been established, and the potential benefits of radiation therapy must be weighed against the increased risk of treatment-related toxic effects.Radiation treatment of retroperitoneal sarcomas is com-plex because tumors are usually large, which necessitates large treatment fields close to radiosensitive structures (e.g., bowel). Several techniques have been used, including preoperative and postoperative external-beam radiation therapy, intraoperative radiation therapy, and brachytherapy.180 Preoperative radiation therapy is feasible and well tolerated. Toxic effects may be less severe with preoperative radiation therapy given that the tumor borders are definable, the tumor displaces radiosensitive viscera away from the


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Surgery_Schwartz. feasible and well tolerated. Toxic effects may be less severe with preoperative radiation therapy given that the tumor borders are definable, the tumor displaces radiosensitive viscera away from the treatment field, and effective doses of radiation may be lower preoperatively.181Several studies have shown favorable local control rates for intermediateand high-grade retroperitoneal sarcoma treated with preoperative radiation therapy and complete resection.180 However, most studies have failed to show a survival benefit.182 This situation prompted the initiation of a multicenter, ran-domized trial sponsored by the American College of Surgeons Oncology Group (ACOSOG) comparing surgery to surgery with preoperative radiation (ACOSOG Z9031). Unfortunately, the study was closed prematurely in 2006 because of low patient accrual. A similar study is now ongoing in Europe, sponsored by the Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC.Current recommendations for radiation therapy for


Surgery_Schwartz

Surgery_Schwartz. because of low patient accrual. A similar study is now ongoing in Europe, sponsored by the Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC.Current recommendations for radiation therapy for patients with retroperitoneal sarcoma at high volumes centers are based on disease characteristics at presentation.183 For high-risk patients, defined as those with large, high-grade tumors or recurrent low-grade tumors, preoperative radiation therapy to a total dose of 50 Gy followed by surgical resection is considered. Postoperative radiation is discouraged unless the resected tumor bed is clearly away from dose-limiting structures.Treatment of Recurrence. Retroperitoneal sarcomas recur more often than extremity and trunk wall ones. Retroperito-neal leiomyosarcomas, in addition to recurring locally in the tumor bed and metastasizing to the lungs, frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). Resection of


Surgery_Schwartz

Surgery_Schwartz. in the tumor bed and metastasizing to the lungs, frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). Resection of recurrent retroperitoneal sarcoma is similar to resection of recurrent extremity sarcoma. However, the likelihood that a recurrent retroperitoneal sarcoma will be resectable declines precipitously with each recurrence. In a large series of patients treated at Memorial Sloan-Kettering Cancer Center, the authors were able to resect recurrent tumors in 57% of patients with a first recurrence but only 20% of patients with a second recur-rence and 10% of patients with a third recurrence.68 In up to 25% of patients, well-differentiated retroperitoneal liposarcoma recurs in a poorly differentiated form or recurs with areas of dedifferentiation. Dedifferentiated retroperitoneal liposarcoma is more aggressive than its well-differentiated precursor and has a greater propensity for distant


Surgery_Schwartz

Surgery_Schwartz. form or recurs with areas of dedifferentiation. Dedifferentiated retroperitoneal liposarcoma is more aggressive than its well-differentiated precursor and has a greater propensity for distant metastasis.Gastrointestinal SarcomaPatients with gastrointestinal sarcoma most often present with nonspecific gastrointestinal symptoms that are determined by the site of the primary tumor. In a series from Memorial Sloan-Kettering Cancer Center, early satiety and dyspepsia were noted in patients with tumors of the upper gastrointestinal tract, whereas tenesmus and changes in bowel habits were common in patients with tumors of the lower gastrointestinal tract.184 In a series of 80 patients with various smooth-muscle tumors of the gastrointestinal tract, Chou and colleagues185 identified the most common presenting symptoms and signs as gastrointes-tinal bleeding (44%), abdominal mass (38%), and abdominal pain (21%).Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often


Surgery_Schwartz

Surgery_Schwartz. presenting symptoms and signs as gastrointes-tinal bleeding (44%), abdominal mass (38%), and abdominal pain (21%).Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often difficult. Radiologic assessment, includ-ing CT of the abdomen or pelvis, is sometimes useful to deter-mine the anatomic location, size, and extent of disease. Patients with localized disease frequently present with a large intra-abdominal mass. However, there is no radiographic evidence of regional lymph node metastases, which would be typical of an adenocarcinoma of similar size and anatomic location. In patients with advanced gastrointestinal sarcoma, CT may dem-onstrate disseminated intra-abdominal masses with or without concomitant ascites and invasion of tissue planes.Endoscopy (esophagoduodenoscopy or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and


Surgery_Schwartz

Surgery_Schwartz. or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and biopsy are important diagnostic tests used to distinguish gastrointestinal sarcoma from adenocarcinoma of the stomach. Endoscopic biopsy of these tumors is preferred over CT-guided biopsy if feasible. This distinction is clinically significant because the extent of resection (local excision versus gastrectomy) and the role of regional lymphadenectomy differ for these two condi-tions. For gastrointestinal sarcomas, lymphatic spread is not the primary route of metastasis; consequently, lymphadenectomy is not routinely performed as part of resection. The general rec-ommendation for gastrointestinal sarcoma, based on published data and the primary pattern of distant (vs. local) failure, is to Brunicardi_Ch36_p1567-p1598.indd 158301/03/19 6:38 PM 1584SPECIFIC CONSIDERATIONSPART IIresect the tumor


Surgery_Schwartz

Surgery_Schwartz. based on published data and the primary pattern of distant (vs. local) failure, is to Brunicardi_Ch36_p1567-p1598.indd 158301/03/19 6:38 PM 1584SPECIFIC CONSIDERATIONSPART IIresect the tumor with a 2to 4-cm margin of normal tissue. However, some cases may be technically challenging because of the tumor’s anatomic location or size. For example, for gastric tumors located near the gastroesophageal junction, achieving adequate surgical margins may not be possible without a total or proximal subtotal gastrectomy. This recommendation is much different when considering resection of gastrointestinal stromal tumors (GIST) where a gross margin negative resection is rec-ommended are rarely is a total gastrectomy required. Similarly, large leiomyosarcomas arising from the stomach with invasion of adjacent organs should be resected together with the adjacent involved viscera en bloc.For sarcomas of the small or large intestine, segmental bowel resection is the standard treatment. For sarcomas


Surgery_Schwartz

Surgery_Schwartz. adjacent organs should be resected together with the adjacent involved viscera en bloc.For sarcomas of the small or large intestine, segmental bowel resection is the standard treatment. For sarcomas of the jejunum, ileum, and colon, the tumor is excised en bloc with the involved segment of intestine and its mesentery; radical mesenteric lymphadenectomy is not attempted. For sarcomas originating in the rectum, the tumor resection technique is based on the anatomic location and size of the tumor. For small, low rectal lesions, clear margins may be achievable with a transanal excision. Large or locally invasive lesions may require more extensive operations for complete tumor extirpation.186,187Breast SarcomaSarcomas of the breast are rare tumors, accounting for less than 1% of all breast malignancies and less than 5% of all soft tissue sarcomas. A variety of histologic subtypes have been reported within the breast, including angiosarcoma, stromal sarcoma, fibrosarcoma, and malignant


Surgery_Schwartz

Surgery_Schwartz. malignancies and less than 5% of all soft tissue sarcomas. A variety of histologic subtypes have been reported within the breast, including angiosarcoma, stromal sarcoma, fibrosarcoma, and malignant fibrous histiocytoma.Angiosarcoma of the breast accounts for about 50% of all sarcomas of the breast and has increasingly been associated with radiation therapy for treatment of primary breast cancer.10 The period between radiation therapy and diagnosis of radiation-associated breast sarcoma has been reported to range from 3 to 20 years, with an incidence of 0.3% at 10 years and 0.5% at 15 years.188 In a retrospective study of 55 patients with angiosarcoma of the breast, patients with radiation-associated angiosarcoma were on average 30 years older and were less likely to present with distant metastases than radiation-naive patients. Clinically, radiation-associated angiosarcoma of the breast may occur in the irradiated chest wall after mastectomy or in the irradiated breast following


Surgery_Schwartz

Surgery_Schwartz. metastases than radiation-naive patients. Clinically, radiation-associated angiosarcoma of the breast may occur in the irradiated chest wall after mastectomy or in the irradiated breast following segmental resection. The findings at presentation of a patient with cutaneous angiosarcoma often include an expanding erythematous patch, red papular eruptions, bluish-black lesions, or bruise-like discoloration overlying an area of induration. Mammography is often nonspecific, and diagnosis requires punch or incisional biopsy.Cystosarcoma phyllodes are generally not considered to be sarcomas because these tumors are thought to originate from hormonally responsive stromal cells of the breast and are usu-ally benign. In patients with these tumors, infiltrating tumor margins, severe stromal overgrowth, atypia, and cellularity have all been identified as risk factors for metastases.189As with sarcomas at other anatomic sites, histopathologic grade and tumor size are important prognostic factors


Surgery_Schwartz

Surgery_Schwartz. atypia, and cellularity have all been identified as risk factors for metastases.189As with sarcomas at other anatomic sites, histopathologic grade and tumor size are important prognostic factors for sarco-mas of the breast. The likelihood of local recurrence increases as tumor size increases; tumors smaller than 5 cm are associated with better overall survival. Local and distant recurrences are more common in patients with high-grade lesions. Complete excision with negative margins is the primary therapy. Simple mastectomy confers no additional benefit if complete excision can be accomplished by segmental mastectomy. Because of low rates of regional lymphatic spread, axillary dissection is not rou-tinely indicated. Neoadjuvant chemotherapy or radiation ther-apy may be considered for patients with large, high-risk tumors.Uterine SarcomaSarcomas account for less than 5% of uterine malignancies. Uterine sarcomas have been classified into four histologic sub-groups: uterine


Surgery_Schwartz

Surgery_Schwartz. for patients with large, high-risk tumors.Uterine SarcomaSarcomas account for less than 5% of uterine malignancies. Uterine sarcomas have been classified into four histologic sub-groups: uterine leiomyosarcoma, endometrial stromal sarcoma, malignant mixed Müllerian tumor (carcinosarcoma), and undif-ferentiated endometrial sarcoma. Five-year overall survival rates for patients with uterine sarcoma are 30% to 50%.190 Total abdominal hysterectomy (TAH) is recommended for localized disease. Bilateral salpingo-oophorectomy is mandatory only in endometrial stromal sarcoma. Because uterine sarcomas are rare, the benefits of adjuvant therapy (e.g., chemotherapy, hor-monal therapy) have not been adequately evaluated. Pelvic post-operative irradiation has been studied instead in a randomized fashion. The results of such study have been reported, showing no benefit in survival in favor of radiation therapy.191Uterine leiomyosarcomas are smooth-muscle tumors and account for 35% to 40% of uterine


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Surgery_Schwartz. The results of such study have been reported, showing no benefit in survival in favor of radiation therapy.191Uterine leiomyosarcomas are smooth-muscle tumors and account for 35% to 40% of uterine sarcomas. Leiomyosarcoma can affect women in their twenties, although it is more com-monly diagnosed between 50 and 60 years of age. Standard treatment is TAH with or without ovarian preservation depend-ing on the patient’s wishes and menopausal status. Lymph node metastasis is present in less than 5% of patients at diagnosis, and lymphadenectomy is not recommended. Adjuvant pelvic radia-tion therapy can be considered for selected high-risk patients. Adjuvant chemotherapy is controversial. Gemcitabine plus docetaxel has been noted to be well tolerated and highly active, with a response rate of 53% in patients with unresectable uter-ine leiomyosarcoma.130 Doxorubicin and trabectedin have also demonstrated activity when used as firstor second-line therapy.Endometrial stromal sarcomas account


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Surgery_Schwartz. 53% in patients with unresectable uter-ine leiomyosarcoma.130 Doxorubicin and trabectedin have also demonstrated activity when used as firstor second-line therapy.Endometrial stromal sarcomas account for approximately 7% to 10% of uterine sarcomas. Mitotic count is used to clas-sify endometrial stromal sarcomas as low grade (<10 mito-ses per 10 high-power fields) or high-grade (>10 mitoses per 10 high-power fields). In general, low-grade tumors demon-strate an indolent clinical course, while high-grade tumors are more aggressive with a poorer prognosis. Unlike other uterine sarcomas subtypes, endometrial stromal sarcomas express pro-gesterone receptors and have been found to be responsive to hormonal manipulation as an adjuvant therapy or for treatment of recurrent disease.192,193 Surgical treatment for these tumors includes TAH and bilateral salpingo-oophorectomy in premeno-pausal women; postoperative hormone replacement therapy is contraindicated.194 Recurrent or advanced disease


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Surgery_Schwartz. treatment for these tumors includes TAH and bilateral salpingo-oophorectomy in premeno-pausal women; postoperative hormone replacement therapy is contraindicated.194 Recurrent or advanced disease may respond to antiestrogen therapy. Tamoxifen is not recommended because it may be proestrogenic in this setting.Malignant mixed müllerian tumor accounts for 50% of uterine sarcomas and arises predominantly in postmenopausal women. This tumor is regarded as epithelial and is treated not with agents typically used to treat sarcoma but with agents used to treat ovarian and endometrial cancers.Undifferentiated endometrial sarcoma is an aggressive malignancy that does not express estrogen or progesterone receptors. It is associated with a poor prognosis even in patients presenting with localized disease. TAH with or without pres-ervation of the ovaries is recommended; postoperative pelvic radiation therapy may also be administered. Systemic agents for other soft tissue sarcomas are used for


Surgery_Schwartz

Surgery_Schwartz. disease. TAH with or without pres-ervation of the ovaries is recommended; postoperative pelvic radiation therapy may also be administered. Systemic agents for other soft tissue sarcomas are used for recurrent and/or meta-static disease.Brunicardi_Ch36_p1567-p1598.indd 158401/03/19 6:38 PM 1585SOFT TISSUE SARCOMASCHAPTER 36GASTROINTESTINAL STROMAL TUMORSGISTs, which account for the majority of gastrointestinal sar-comas, have distinctive molecular features that have been char-acterized over the last decade. These tumors share phenotypic similarities with the intestinal pacemaker cells known as the interstitial cells of Cajal195; interstitial cells of Cajal and GIST cells express the hematopoietic progenitor cell marker CD34 and the growth factor receptor c-Kit.196 Expression of the c-Kit gene protein product, CD117, has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated to be 6 to 15 cases per million


Surgery_Schwartz

Surgery_Schwartz. the c-Kit gene protein product, CD117, has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated to be 6 to 15 cases per million individuals per year.197-199 Until recently, systemic treat-ment for patients with unresectable or metastatic GIST was of little benefit because these tumors were resistant to conventional chemotherapy. Since the recognition that KIT activation occurs in most GISTs, KIT inhibition has emerged as an adjunct to sur-gery in select patients with resectable disease and as a primary treatment modality for patients with stage IV disease.Approximately 80% of GISTs have a mutation in the gene encoding the KIT receptor tyrosine kinase, and 5% to 10% have a mutation in the gene encoding the related PDGFRA recep-tor tyrosine kinase; such mutations result in the expression of mutant proteins with constitutive tyrosine kinase activity.1 The remaining GISTs do not have a detectable mutation, but lack of


Surgery_Schwartz

Surgery_Schwartz. recep-tor tyrosine kinase; such mutations result in the expression of mutant proteins with constitutive tyrosine kinase activity.1 The remaining GISTs do not have a detectable mutation, but lack of a mutation does not preclude a diagnosis of GIST if the tumor is morphologically typical of GIST. The presence and type of KIT (exon 11 or exon 9) or PDGFRA (exon 18) muta-tion has been found to predict tumor response to imatinib. In a phase 2 trial, patients with KIT exon 11 mutations had bet-ter response rates (83.5% vs. 47.8%) and survival than those with KIT exon 9 mutations or those without KIT or PDGFRA mutation.200 These findings have subsequently been confirmed in two additional phase 3 trials conducted by the EORTC– Italian Sarcoma Group–Australasian Gastrointestinal Trials Group (EORTC-62005).201,202The most common locations for GISTs are the stomach (60%) and small intestine (30%), but GISTs can arise anywhere along the gastrointestinal tract.203 Gastric GISTs have been shown to


Surgery_Schwartz

Surgery_Schwartz. most common locations for GISTs are the stomach (60%) and small intestine (30%), but GISTs can arise anywhere along the gastrointestinal tract.203 Gastric GISTs have been shown to be associated with a more favorable prognosis than GISTs at other sites.204 GISTs are most commonly diagnosed by upper endoscopy and/or CT of the abdomen as an incidental finding in an asymptomatic patient or in a patient being evalu-ated for symptoms of early satiety, abdominal pain, or gastroin-testinal bleeding. GIST most frequently metastasizes to the liver and/or abdominal cavity.Radiologic AssessmentStandard imaging techniques apply for GIST as for other intraabdominal sarcomas. In general, oral and IV contrast enhanced spiral CT is the staging modality of choice for GIST. CT scan of the abdomen and pelvis allows for assessment of the primary lesion and the presence or absence of intraabdomi-nal disseminated disease or metastatic disease to the liver (the two most common locations for distant


Surgery_Schwartz

Surgery_Schwartz. pelvis allows for assessment of the primary lesion and the presence or absence of intraabdomi-nal disseminated disease or metastatic disease to the liver (the two most common locations for distant metastasis of GIST). FDG-PET has been reported to be useful for preoperative stag-ing of GISTs because it may reveal early metastases and estab-lish baseline metabolic activity and may be considered in select patients where equivocal findings are identified on CT or in the setting of following metabolic response to therapy. PET has been shown to be highly sensitive in detecting early response to imatinib treatment and in predicting long-term response in patients with metastatic GIST. If PET is to be used for moni-toring response to therapy, baseline PET should be performed before initiation of treatment. Useful and effective CT-based criteria by Choi et al for detection of GIST and for predicting prognosis of GIST have also been proposed and may be used readily without incurring the cost and


Surgery_Schwartz

Surgery_Schwartz. Useful and effective CT-based criteria by Choi et al for detection of GIST and for predicting prognosis of GIST have also been proposed and may be used readily without incurring the cost and radiation exposure of PET/CT.205Management of Localized DiseaseComplete surgical resection with negative margins is the rec-ommended treatment for localized GISTs. Extended anatomic resection, wide margins, and lymphadenectomy are not required; therefore, total gastrectomy for gastric primaries is rarely required even with the largest of lesions. Resection of even locally advanced tumors is associated with improved survival.206 The 5-year survival rate for all patients with GISTs ranges from 20% to 44%, and the 5-year survival rate for patients with com-pletely excised early-stage tumors is up to 75%.206 An analysis of 200 patients by DeMatteo and colleagues found a disease-specific survival rate of 54% for patients with grossly complete resection of primary GIST, and the median survival duration


Surgery_Schwartz

Surgery_Schwartz. An analysis of 200 patients by DeMatteo and colleagues found a disease-specific survival rate of 54% for patients with grossly complete resection of primary GIST, and the median survival duration for patients with metastatic disease was only 20 months.58As for other soft tissue sarcomas, tumor size has con-sistently been identified as an important prognostic factor for GIST. Mitotic activity has also been identified as an important prognostic factor and is generally categorized as fewer than 5, 5 to 10, or more than 10 mitoses per high-power field. The National Institutes of Health207 and the Armed Forces Insti-tute of Pathology203 have proposed prognostic criteria for risk stratification of surgically treated, localized primary GIST. Both groups take into account tumor size and mitotic count; the Armed Forces Institute of Pathology also includes tumor site as a prognostic variable. Accurate risk stratification is essential for selecting patients most likely to benefit from adjuvant


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Surgery_Schwartz. count; the Armed Forces Institute of Pathology also includes tumor site as a prognostic variable. Accurate risk stratification is essential for selecting patients most likely to benefit from adjuvant treatment.Management of Locally Advanced or Metastatic DiseaseTreatment with imatinib mesylate (Gleevec, ST1571), a selec-tive inhibitor of the KIT protein tyrosine kinase, has resulted in impressive clinical responses in a large percentage of patients with unresectable or metastatic GISTs. On the basis of the initial results in a single patient with metastatic GIST, the EORTC Soft Tissue and Bone Sarcoma Group initiated a phase 1 study to test the safety and efficacy of imatinib.208 In that study, 53% of patients with GISTs had confirmed partial responses; investiga-tors concluded that imatinib is safe and effective against this disease.208 A multicenter, international trial of imatinib for GIST was begun in July 2000 at four treatment centers: Dana-Farber Cancer Institute, Oregon Health


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Surgery_Schwartz. is safe and effective against this disease.208 A multicenter, international trial of imatinib for GIST was begun in July 2000 at four treatment centers: Dana-Farber Cancer Institute, Oregon Health Sciences University, Fox Chase Cancer Center, and University Hospital of Helsinki, Finland.209 A total of 147 patients with unresectable or metastatic GISTs were randomized to 400 or 600 mg of imatinib daily for up to 24 months. Objective response was demonstrated in 79 patients (54%); all had partial responses, and there was no significant difference in response rate between imatinib doses.210 Fourteen percent of patients experienced disease progression. The toxic-ity profile was acceptable; the predominant effects were gastro-intestinal effects (diarrhea, nausea), periorbital edema, muscle cramps, and fatigue. However, 21% of patients experienced serious (grade 3 or 4) adverse events, including gastrointestinal bleeding in 5% of patients, most likely related to the rapid tumor response of


Surgery_Schwartz

Surgery_Schwartz. and fatigue. However, 21% of patients experienced serious (grade 3 or 4) adverse events, including gastrointestinal bleeding in 5% of patients, most likely related to the rapid tumor response of mural lesions.Brunicardi_Ch36_p1567-p1598.indd 158501/03/19 6:38 PM 1586SPECIFIC CONSIDERATIONSPART IIA phase 3 randomized Intergroup trial was simultaneously performed to assess the clinical activity of imatinib at two dose levels for patients with unresectable or metastatic GIST express-ing the c-Kit tyrosine kinase.211 From December 15, 2000, to September 1, 2001, 746 patients were accrued and randomized to low-dose (400 mg/d) or high-dose (800 mg/d) imatinib. The primary endpoint of the trial was survival. Preliminary toxicity data from 325 patients revealed a 23% incidence of grade 3 or 4 adverse events, including nausea and vomiting, gastrointestinal bleeding, abdominal pain, edema, fatigue, and rash.In February 2002, the FDA approved imatinib for treat-ment of GIST based on the


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Surgery_Schwartz. or 4 adverse events, including nausea and vomiting, gastrointestinal bleeding, abdominal pain, edema, fatigue, and rash.In February 2002, the FDA approved imatinib for treat-ment of GIST based on the results of these promising clinical trials. Both the Intergroup trial mentioned in the preceding paragraph and a separate phase 3 trial compared the efficacy of low-dose (400 mg/d) and high-dose (800 mg/d) imatinib in patients with metastatic or unresectable GISTs.212,213 Both stud-ies showed equivalent response rates and overall survival for the two doses but increased toxicity for the 800-mg/d dose. Current recommendations include consideration of dose escalation to 800 mg/d for patients who experience disease progression at a dose of 400 mg/d and for patients with advanced GIST and KIT exon 9 mutations.1,214The optimal duration of imatinib treatment, the duration of benefit from imatinib, and the long-term toxicity of imatinib have not been established. When feasible, imatinib should


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Surgery_Schwartz. 9 mutations.1,214The optimal duration of imatinib treatment, the duration of benefit from imatinib, and the long-term toxicity of imatinib have not been established. When feasible, imatinib should be continued in the absence of disease progression. A random-ized trial reported worse median progression-free survival in patients who stopped imatinib after 1 year than in patients who continued beyond 1 year (progression-free survival of 6 months vs. 18 months).215 Less than 4% of patients with GISTs have experienced serious adverse events with imatinib. Mild gastrointestinal toxicity is the most frequently reported adverse event, but gastrointestinal tract hemorrhage, presum-ably from rapid tumor necrosis, has also been reported. Thus, all patients with GISTs treated on clinical protocols should be evaluated and followed by a team of medical professionals that includes a surgeon.Many patients with GIST develop resistance to imatinib. Primary resistance is defined as clinical progression


Surgery_Schwartz

Surgery_Schwartz. be evaluated and followed by a team of medical professionals that includes a surgeon.Many patients with GIST develop resistance to imatinib. Primary resistance is defined as clinical progression that devel-ops during the first 6 months of treatment and is most commonly seen in patients with KIT exon 9 mutation, PDGFRA exon 18 mutation, or no mutations.216 Secondary resistance is defined as progression that develops more than 6 months after the start of treatment in a patient with an initial response.217 Imatinib resis-tance should be managed by either dose escalation or transition to treatment with sunitinib.1In 2006, sunitinib malate (SU11248, Sutent, Pfizer) emerged as an alternative systemic treatment for patients unable to tolerate imatinib and patients with imatinib-refractory GIST. Sunitinib is a tyrosine kinase inhibitor that targets multiple kinases, including the vascular endothelial growth factor receptors, PDGFRA, KIT, and FLT3. Sunitinib has both antiangiogenic and


Surgery_Schwartz

Surgery_Schwartz. GIST. Sunitinib is a tyrosine kinase inhibitor that targets multiple kinases, including the vascular endothelial growth factor receptors, PDGFRA, KIT, and FLT3. Sunitinib has both antiangiogenic and antiproliferative activity. In a phase 3, randomized, placebo-controlled trial, sunitinib was associated with a significant improvement in median time to progression (27.3 weeks vs. 6.4 weeks with placebo) in patients with imatinib-resistant GIST.135 In addition, sunitinib therapy was well tolerated; diarrhea, fatigue, and nausea were the most common adverse effects. Sunitinib has also been associated with hand-foot skin reaction, hypertension, cardiotoxicity, and hypothyroidism.218-220 In 2006, sunitinib was approved by the FDA for treatment of patients with resistance or intolerance to imatinib.The third FDA-approved drug recently made available for treatment of patients with imatiniband sunitinib-resistant GIST is regorafenib. Regorafenib is a structurally unique inhibitor of multiple


Surgery_Schwartz

Surgery_Schwartz. third FDA-approved drug recently made available for treatment of patients with imatiniband sunitinib-resistant GIST is regorafenib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and PDGFR, with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, a multicenter, single-stage phase 2 trial examined regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.221 Thirty-four patients were enrolled from February to December 2010 and given regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Clinical benefit was noted in 79% of patients with a median progression-free survival of 10 months. This trial was then followed by a phase 3, international, placebo-controlled, randomized trial of regorafenib for metastatic GIST after failure of imatinib and sunitinib.222 Patients with


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Surgery_Schwartz. 10 months. This trial was then followed by a phase 3, international, placebo-controlled, randomized trial of regorafenib for metastatic GIST after failure of imatinib and sunitinib.222 Patients with progres-sion of disease on the placebo arm were crossed to the treatment arm of the study. Patients treated with regorafenib had a median progression-free survival of 4.8 months compared to 0.9 months on the placebo arm. Other tyrosine kinase inhibitors have dem-onstrated modest activity against GIST and target more than one family of protein kinases.223 Among these are sorafenib, dasatinib, and nilotinib for the treatment of imatinib-resistant GIST, and these are now generally reserved for therapy after progression with regorafenib.222Multidisciplinary TreatmentAlthough imatinib has improved survival of patients with advanced GIST, most patients with advanced GIST are not cured with imatinib. Some patients develop secondary resistance to imatinib with one or more sites of disease


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Surgery_Schwartz. survival of patients with advanced GIST, most patients with advanced GIST are not cured with imatinib. Some patients develop secondary resistance to imatinib with one or more sites of disease progression after 6 months of clinical response (Fig. 36-10A [before imatinib], Fig. 36-10B [after imatinib]). The mechanisms of imatinib resistance are currently being investigated. Surgery has been shown to be beneficial for selected patients with isolated disease progression during imatinib therapy.224-227 Surgical resection of residual metastatic disease responding to imatinib-sensitive GIST has also been shown to result in progression-free survival in 70% to 96% of patients with imatinibor sunitinib-sensitive GISTs.226-228 The optimal timing of surgery in relation to ima-tinib therapy for patients with metastatic disease remains to be determined. It is not possible to compare outcomes for patients treated with kinase inhibitors alone and patients treated with kinase inhibitors plus surgical


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Surgery_Schwartz. with metastatic disease remains to be determined. It is not possible to compare outcomes for patients treated with kinase inhibitors alone and patients treated with kinase inhibitors plus surgical resection outside the context of randomized trials given the heterogeneity of patients and biases associated with selection of patients for surgical resection.Postoperative ImatinibGiven the promising results of imatinib therapy for metastatic and locally advanced GIST, the next step was to study the efficacy of imatinib as adjuvant (postoperative) treatment in patients with surgically resectable disease, particularly those at high risk for recurrence because of large tumor size or high mitotic count. The ACOSOG first evaluated the efficacy of 1 year of postoperative imatinib in a single-arm phase 2 trial with 106 patients with high-risk GIST and compared the results with historical controls. Adjuvant treatment with imatinib for GIST patients was then examined in two key trials. In the


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Surgery_Schwartz. phase 2 trial with 106 patients with high-risk GIST and compared the results with historical controls. Adjuvant treatment with imatinib for GIST patients was then examined in two key trials. In the ACOSOG randomized, double-blind, phase 3 Z9001 study,230 treatment with 12 months of imatinib was compared with placebo, fol-lowing complete resection of a primary GIST smaller than 3 cm. Primary and secondary endpoints were recurrence-free survival Brunicardi_Ch36_p1567-p1598.indd 158601/03/19 6:38 PM 1587SOFT TISSUE SARCOMASCHAPTER 36ABFigure 36-10. A 57-year-old man with a history of a pelvic gastrointestinal stromal tumor involving the small bowel mesen-tery treated preoperatively with 6 months of imatinib (Gleevec). A. Before imatinib. B. After imatinib.(RFS) and overall survival (OS), respectively. Results showed a significant benefit in RFS, but not OS, with 12 months of imatinib. Based on these results, imatinib for the adjuvant treat-ment of adult patients following resection


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Surgery_Schwartz. respectively. Results showed a significant benefit in RFS, but not OS, with 12 months of imatinib. Based on these results, imatinib for the adjuvant treat-ment of adult patients following resection of KIT-positive GIST was approved by the FDA in 2008 and by the European Medical Agency (EMA) in 2009.A more recent study conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbe-itsgemeinschaft Internistische Onkologie (AIO; SSGXVIII/AIO trial) compared 12 versus 36 months of adjuvant imatinib 400 mg/d in patients with GIST at high risk of recurrence (defined as a GIST tumor diameter >10 cm, or mitotic count >10 per 50 high-powered fields, or tumor diameter >5 cm and mitotic count >5 per 50 high-power fields, or tumor rupture).231 Results showed that both RFS and OS significantly improved with 36 months of imatinib: the 5-year RFS rates for patients receiving 36 versus 12 months of imatinib were 65.6% versus 47.9%, respectively, and the 5-year OS rates were 92%


Surgery_Schwartz

Surgery_Schwartz. significantly improved with 36 months of imatinib: the 5-year RFS rates for patients receiving 36 versus 12 months of imatinib were 65.6% versus 47.9%, respectively, and the 5-year OS rates were 92% versus 81.7%, respectively.The NCCN and the European Society of Medical Oncol-ogy now recommend that imatinib be considered for patients at intermediate or high risk of recurrence after resection and that at least 36 months of adjuvant imatinib be considered for patients at high risk of recurrence.232 Further, both the FDA and EMA updated the label, extending the duration of adjuvant therapy to at least 36 months in patients at high risk of recurrence.Whether longer treatment durations may be of further benefit is still an open question that will be addressed by future studies. However, paralleling what is commonly done in the metastatic setting, many investigators believe that even adju-vant imatinib should become a chronic therapy. While moving toward more prolonged adjuvant treatment


Surgery_Schwartz

Surgery_Schwartz. what is commonly done in the metastatic setting, many investigators believe that even adju-vant imatinib should become a chronic therapy. While moving toward more prolonged adjuvant treatment durations, it is all the more essential to identify the appropriate patients to treat to avoid the burden of adverse events or increased financial liabil-ity for patients who will not derive therapeutic benefit from imatinib. Risk stratification based on patients’ risk of recur-rence is a key component to optimizing adjuvant treatment. The most practical stratification scheme to use for making a decision for adjuvant therapy is the modified National Insti-tutes of Health consensus criteria.233 High-risk GIST patients, whose tumor harbors a sensitive genotype, should be treated by adjuvant imatinib because they have a poor prognosis. On the contrary, neither low-risk nor intermediate-risk GIST patients need adjuvant therapy, even if their tumor carries a sensitive genotype. In fact, evidence has


Surgery_Schwartz

Surgery_Schwartz. they have a poor prognosis. On the contrary, neither low-risk nor intermediate-risk GIST patients need adjuvant therapy, even if their tumor carries a sensitive genotype. In fact, evidence has been provided that the out-come of these patients with intermediateor low-risk GIST is good. When using other risk stratification schemes, such as the Armed Forces Institute of Pathology table, Memorial Sloan-Kettering Cancer Center nomogram, or the heat map,204,234,235 there is a consensus to treat all patients having 30% or higher risk of recurrence, if their tumor carries a sensitive genotype. There is also a consensus not to treat patients having 10% or less risk of recurrence, even if their tumor carries a sensitive genotype. All patients having a risk between 10% and 30% should be evaluated on a case-by-case basis, and advantages/disadvantages of treatment should be made clear and discussed with the patient. Whenever a decision for adjuvant therapy is made, treatment duration of at least


Surgery_Schwartz

Surgery_Schwartz. a case-by-case basis, and advantages/disadvantages of treatment should be made clear and discussed with the patient. Whenever a decision for adjuvant therapy is made, treatment duration of at least 36 months should be con-sidered independently from the risk.Beside the risk of recurrence, the other important factor to consider is the tumor genotype. In other words, as found in both the metastatic and adjuvant settings, GIST tumors with KIT exon 11 and PDGFRA non-D842V mutations are sensitive to imatinib. Patients with these mutations are suitable for adjuvant imatinib if the risk determined by stratification tools is signifi-cant. Patients with KIT exon 9 mutations should also be treated; a higher dose (800 mg/d) may be more appropriate but remains to be studied clinically. Patients with PDGFRA D842V–mutated tumors should not be treated with adjuvant imatinib, nor should patients with KIT and PDGFRA wild-type tumors associated with neurofibromatosis type 1 or the pediatric


Surgery_Schwartz

Surgery_Schwartz. with PDGFRA D842V–mutated tumors should not be treated with adjuvant imatinib, nor should patients with KIT and PDGFRA wild-type tumors associated with neurofibromatosis type 1 or the pediatric GIST/Carney-Stratakis syndromes, whatever the risk. Patients with sporadic wild-type GIST could be treated on an individual basis.Preoperative ImatinibPatients with marginally resectable GIST or at significant risk for operative morbidity should be considered for preoperative imatinib with close monitoring. Since the optimal duration of preoperative therapy is unknown, imatinib should be continued until maximal response is achieved or until there is evidence of progression.236 Preoperative imatinib can be stopped imme-diately before surgery and resumed when oral medications are restarted.Brunicardi_Ch36_p1567-p1598.indd 158701/03/19 6:38 PM 1588SPECIFIC CONSIDERATIONSPART IIPreoperative imatinib in patients with primary GIST or resectable metastatic GIST has been evaluated in the context of


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Surgery_Schwartz. 158701/03/19 6:38 PM 1588SPECIFIC CONSIDERATIONSPART IIPreoperative imatinib in patients with primary GIST or resectable metastatic GIST has been evaluated in the context of two randomized phase 2 studies. The Radiation Treatment Oncology Group (RTOG 0132/ACRIN 6665) evaluated the efficacy of preoperative imatinib (600 mg/d) for 8 to 10 weeks before surgery and 24 months after surgery in patients with primary (n = 30) or potentially resectable recurrent or metastatic (n = 22) tumors.237 Primarily stable disease was noted during imatinib treatment, and the 2-year progression-free survival rates were 83% for primary GIST and 77% for recurrent or metastatic GIST. In another study, 19 patients undergoing surgical resection at a single institution were randomized to preoperative imatinib (600 mg/d) for 3, 5, or 7 days followed by surgical resection and postoperative imatinib for 24 months. The response rate assessed using FDG-PET was 69%, and the median disease-free survival time


Surgery_Schwartz

Surgery_Schwartz. (600 mg/d) for 3, 5, or 7 days followed by surgical resection and postoperative imatinib for 24 months. The response rate assessed using FDG-PET was 69%, and the median disease-free survival time following treatment with surgery and imatinib was 46 months.238 Similar results were observed in a prospective series of patients treated at a major institution.239All of these studies show that neoadjuvant treatment is feasible, but to maximize the benefit of preoperative therapy, the following factors need to be considered. First, the patient should in principle have a favorable mutational status; other-wise, the treatment would be in vain, allowing the tumor to con-tinue growing. Fortunately, the majority of GISTs will respond, but it should not be forgotten that, especially in gastric loca-tion, the amount of insensitive mutations in the localized setting is less uncommon than what has been previously reported.240 However, we do not absolutely need to know the mutational status in


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Surgery_Schwartz. loca-tion, the amount of insensitive mutations in the localized setting is less uncommon than what has been previously reported.240 However, we do not absolutely need to know the mutational status in advance, but we should be aware that mutation is an issue. Alternatively, if mutation status is not determined prior to treatment, we may also check response very early, either by CT, PET, or contrast-enhanced ultrasound. If a radiographic response is detected within a month, then the mutation status is likely favorable, and the treatment could be continued with-out necessarily pursuing mutation testing. If not, then mutation status should be investigated before continuing the treatment.Second, the resectability of the tumor and the extent of resection necessary should be considered. Other than presenta-tions of clearly inoperable tumors (which are usually treated with imatinib upfront) or symptomatic tumors requiring urgent intervention (hemorrhage, perforation, etc), there are few


Surgery_Schwartz

Surgery_Schwartz. than presenta-tions of clearly inoperable tumors (which are usually treated with imatinib upfront) or symptomatic tumors requiring urgent intervention (hemorrhage, perforation, etc), there are few rea-sons today to perform extended procedures (i.e., multivisceral resections or formal organ resections) without first attempting preoperative therapy. For instance, patients with large GISTs who may require a long midline incision for resection may benefit from neoadjuvant imatinib to downstage the operation, potentially converting an open laparotomy approach to a laparo-scopic one. Another typical circumstance in which neoadjuvant therapy may be beneficial is in patients with GISTs arising in the esophagus, gastroesophageal junction, duodenum, or distal rectum. Preoperative treatment may shrink the tumor and allow a more conservative local excision. In general, such patients would normally undergo postoperative adjuvant treatment as well because of the expected recurrence risk. The chance


Surgery_Schwartz

Surgery_Schwartz. the tumor and allow a more conservative local excision. In general, such patients would normally undergo postoperative adjuvant treatment as well because of the expected recurrence risk. The chance of obtaining a response is high, and the benefit for tumor shrink-age obvious, so this approach should always be discussed with patients affected by bulky and/or poorly located disease (esoph-agus, gastroesophageal junction, duodenum, distal rectum) as well as for those who would be candidates for an adjuvant treat-ment anyway.Third, in the studies mentioned earlier, patients underwent surgery after a limited treatment duration (3 months at best). It is now well known that the preoperative treatment may result in sustained tumor shrinkage if given for a longer duration. Sur-gical resection may then be performed between 6 and 12 months or sooner if treatment effect plateaus. This allows for optimal tumor shrinkage, or at least shrinkage to the point where there is no further benefit to be


Surgery_Schwartz

Surgery_Schwartz. then be performed between 6 and 12 months or sooner if treatment effect plateaus. This allows for optimal tumor shrinkage, or at least shrinkage to the point where there is no further benefit to be gained by further neoadjuvant therapy without the risk of developing secondary resistance.DESMOIDSDesmoid tumors are not low-grade sarcomas but can be locally aggressive, although they do not metastasize. Approximately half of these tumors arise in the extremities; the remaining lesions are located on the trunk or in the retroperitoneum. Abdominal wall desmoids are associated with pregnancy and are thought to be the result of hormonal influence. Although usually sporadic, desmoids may occur in association with famil-ial adenomatous polyposis, a presentation that is referred to as Gardner’s syndrome and is linked to germline mutations in the APC gene. Sporadic cases of desmoid fibromatosis are com-monly linked to mutations in CTNNB1, the gene for β-catenin.The primary therapy for desmoid


Surgery_Schwartz

Surgery_Schwartz. and is linked to germline mutations in the APC gene. Sporadic cases of desmoid fibromatosis are com-monly linked to mutations in CTNNB1, the gene for β-catenin.The primary therapy for desmoid tumors has long been considered surgical resection with wide local excision to achieve negative margins. However, local recurrence occurs in up to one-third of patients independently of the quality of surgical margins.241-243 Up to two-thirds of the patients operated on with positive margins do not recur. This is why there is growing evidence that the primary approach could be more conservative. Function-sparing operations should be the goal, even if a positive margin is left on a critical structure. Moreover, some authors advocate the possibility to observe patients at presentation, limiting surgery to those who progress or fail medical therapies. It has in fact been reported that by this approach, up to 50% of patients skip surgical resection.244,245 Radiation therapy may be effective in


Surgery_Schwartz

Surgery_Schwartz. to those who progress or fail medical therapies. It has in fact been reported that by this approach, up to 50% of patients skip surgical resection.244,245 Radiation therapy may be effective in patients with unresectable tumors or as adjuvant therapy following surgery for recurrent disease, although long-term side effects and the risk of radiation-induced sarcoma should always be considered. When used, a dose of 50 to 54 Gy is usually recommended. Systemic treatment is another option when surgery is not indicated. Hormonal therapies such as tamoxifen have been reported to be beneficial, as have nonsteroidal anti-inflammatory drugs, which are known to affect the β-catenin signaling pathways. Chemotherapy is also effective, although usually reserved for patients with tumor-associated symptoms who have not responded to other interventions. Combinations of methotrexate and vinblastine have been shown to have activity, as have single-agent pegylated liposomal doxorubicin246 and


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Surgery_Schwartz. symptoms who have not responded to other interventions. Combinations of methotrexate and vinblastine have been shown to have activity, as have single-agent pegylated liposomal doxorubicin246 and sorafenib.247 Imatinib has also been studied with unconvincing results.248-250DERMATOFIBROSARCOMA PROTUBERANSDermatofibrosarcoma protuberans is a rare low-grade sarcoma arising in the dermis that rarely metastasizes but is locally aggressive. The overall annual incidence has been estimated at 4.2 cases per million individuals,251 and the incidence is higher among blacks than whites (6.5 vs. 3.9 per million per year). Approximately 40% of cases arise on the trunk, and most of the remaining tumors are distributed between the head and neck and the extremities. Dermatofibrosarcoma protuberans presents as a nodular, cutaneous mass that grows slowly and persistently. Satellite lesions may be found in patients with larger tumors. Brunicardi_Ch36_p1567-p1598.indd 158801/03/19 6:38 PM 1589SOFT


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Surgery_Schwartz. as a nodular, cutaneous mass that grows slowly and persistently. Satellite lesions may be found in patients with larger tumors. Brunicardi_Ch36_p1567-p1598.indd 158801/03/19 6:38 PM 1589SOFT TISSUE SARCOMASCHAPTER 36Standard treatment is wide local excision, which generally results in local recurrence rates of less than 10%.252 Although local recurrence rates as high as 30% to 50% have been reported in population-based series, the associated 5-year survival rate is greater than 99%.251Dermatofibrosarcoma protuberans arises from a specific chromosomal translocation involving chromosomes 17 and 22, in which the collagen 1 α 1 gene is fused to the gene for PDGF β-chain (PDGFB).253 The resultant deregulated expression of PDGFB leads to continuous activation of the PDGFR protein tyrosine kinase, which promotes tumor cell growth. The identification of this chromosomal translocation in more than 90% of cases of dermatofibrosarcoma protuberans has led to the development of targeted


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Surgery_Schwartz. kinase, which promotes tumor cell growth. The identification of this chromosomal translocation in more than 90% of cases of dermatofibrosarcoma protuberans has led to the development of targeted therapy. Inhibiting PDGFR with imatinib has been shown to induce clinical and radiologic improvement in patients with unresectable dermatofibrosarcoma protuberans.21 These data have resulted in the approval by the FDA of imatinib for treatment of patients with locally advanced dermatofibrosarcoma protuberans.PEDIATRIC SARCOMASSoft tissue sarcomas in children are relatively rare, accounting for 7% to 8% of all pediatric cancers and totaling approximately 600 new cases per year.254 Pediatric sarcomas have traditionally been divided into two groups: rhabdomyosarcoma and nonrhab-domyosarcoma soft tissue sarcomas.RhabdomyosarcomaAssociated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site comprised of


Surgery_Schwartz

Surgery_Schwartz. tissue sarcomas.RhabdomyosarcomaAssociated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site comprised of striated muscle. Patients with these tumors generally present with a painless enlarging mass; about 24% of tumors are located in the geni-tourinary system, 20% in the extremities, 20% in the head and neck, 16% in the parameningeal region, and 22% in other sites.255Rhabdomyosarcoma is a small round cell tumor that dem-onstrates muscle differentiation upon light microscopy and immunohistochemical analysis. Two primary histologic sub-types account for 90% of cases: embryonal (70%) and alveolar (20%). Alveolar rhabdomyosarcoma is associated with cytoge-netic translocation [t(2:13)(q35:q14)] in 85% to 90% of cases and [t(1:13)(p36:q14)] in 10% of cases.256 These translocations affect biologic activity at the levels of protein function and gene expression, thereby affecting the control of cell


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Surgery_Schwartz. to 90% of cases and [t(1:13)(p36:q14)] in 10% of cases.256 These translocations affect biologic activity at the levels of protein function and gene expression, thereby affecting the control of cell growth, apopto-sis, differentiation, and motility and ultimately contributing to tumorigenic behavior.256 Whereas alveolar rhabdomyosarcomas often have translocations, most embryonal rhabdomyosarcomas have an allelic loss at chromosome 11p15.5 that is thought to inactivate a tumor suppressor gene.256,257 Both of these dis-tinct molecular subtypes of rhabdomyosarcoma are thought to have similar alterations in downstream targets such as the p53 and Rb pathways.256 Further insight into these genetic altera-tions may lead to a better understanding of the pathogenesis of rhabdomyosarcoma and provide novel targets for therapeutic approaches.Extent of disease is the strongest predictor of long-term outcome. Several staging systems for rhabdomyosarcoma are available. The Intergroup Rhabdomyosarcoma


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Surgery_Schwartz. novel targets for therapeutic approaches.Extent of disease is the strongest predictor of long-term outcome. Several staging systems for rhabdomyosarcoma are available. The Intergroup Rhabdomyosarcoma Study Group system is based on surgical-pathologic groupings. Multidis-ciplinary evaluation including pediatric oncologists, surgical subspecialists, and radiation oncologists is critical to plan the best treatment approach to maximize local tumor control while minimizing long-term treatment effects.Complete surgical resection is the treatment of choice for rhabdomyosarcoma when function and cosmesis can be preserved. Patients who are able to undergo a complete tumor resection with negative (group I) or microscopic surgical mar-gins (group II) are able to undergo less intensive systemic ther-apy and still have overall survival rates approaching 90%.258 At some anatomic sites, in particular the head and neck and genito-urinary system, surgery is often avoided because the associated


Surgery_Schwartz

Surgery_Schwartz. ther-apy and still have overall survival rates approaching 90%.258 At some anatomic sites, in particular the head and neck and genito-urinary system, surgery is often avoided because the associated morbidity would be substantial. Recent findings suggest that chemotherapy alone can adequately control many such tumors. In the second International Society of Paediatric Oncology study of rhabdomyosarcoma (MMT84), the choice of local treatment was based on response to initial chemotherapy such that radical surgery and radiation therapy were avoided in 66% of patients. Among the patients who subsequently developed local relapse, the 5-year overall survival rate after salvage therapy was 46%.258Unlike other soft tissue sarcomas, rhabdomyosarcomas have a high propensity for lymph node metastasis, with rates up to 20% to 30% for sites such as the extremities, parates-ticular nodes, and prostate. Lymph node sampling and, more recently, sentinel lymph node mapping have been used to evalu-ate


Surgery_Schwartz

Surgery_Schwartz. with rates up to 20% to 30% for sites such as the extremities, parates-ticular nodes, and prostate. Lymph node sampling and, more recently, sentinel lymph node mapping have been used to evalu-ate regional node status in children with rhabdomyosarcoma.About 15% to 20% of patients with rhabdomyosarcoma have distant metastasis at presentation, most commonly (40–50% of cases) to the lungs, followed by bone marrow and bone. However, all patients with rhabdomyosarcoma are assumed to have micrometastatic disease at presentation. Therefore, multia-gent chemotherapy is recommended for all patients with rhab-domyosarcoma. Combination regimens including vincristine, dactinomycin, and cyclophosphamide continue to be the basis of effective curative therapy.254 Although various combinations including doxorubicin, ifosfamide, cisplatin, and etoposide have been shown to be active against rhabdomyosarcoma, they have not improved outcomes.258,259 Radiation therapy is given to most patients with


Surgery_Schwartz

Surgery_Schwartz. doxorubicin, ifosfamide, cisplatin, and etoposide have been shown to be active against rhabdomyosarcoma, they have not improved outcomes.258,259 Radiation therapy is given to most patients with microscopic residual disease (group II) after resection.The prognosis for children with rhabdomyosarcomas is related to tumor site, surgical-pathologic grouping, and tumor histology. The 5-year disease-free survival rate for all patients has been reported to be 65%. Five-year disease-free survival rates for patients in groups I, II, III, and IV have been reported to be 84%, 74%, 62%, and 23%, respectively (see Table 36-3).260Nonrhabdomyosarcoma Soft Tissue SarcomasApproximately 60% of soft tissue sarcomas in children are nonrhabdomyosarcomas. These include numerous histologic subtypes, which are generally categorized into four groups: (a) fibrosarcoma, (b) Kaposi’s sarcoma, (c) other “specified” soft tissue sarcomas (e.g., synovial, angiosarcoma, hemangiopericy-toma, leiomyosarcoma,


Surgery_Schwartz

Surgery_Schwartz. are generally categorized into four groups: (a) fibrosarcoma, (b) Kaposi’s sarcoma, (c) other “specified” soft tissue sarcomas (e.g., synovial, angiosarcoma, hemangiopericy-toma, leiomyosarcoma, liposarcoma, and extraosseous Ewing’s sarcoma), and (d) “unspecified” soft tissue sarcoma.261 The most common subtypes are synovial sarcoma, MPNST, and fibro-sarcoma. No single histology accounts for more than 15% of all cases.As with adult tumors, the evaluation of the soft tissue mass begins with a history and physical examination followed by imaging, which usually includes MRI. A CT scan of the chest is important for evaluation of metastatic disease. A core needle biopsy is generally required to establish a diagnosis. Surgery remains the primary treatment of nonrhabdomyosarcoma, and Brunicardi_Ch36_p1567-p1598.indd 158901/03/19 6:38 PM 1590SPECIFIC CONSIDERATIONSPART IIlocal control of large, high-grade tumors is improved with radia-tion therapy. The prognostic factors for children with


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Surgery_Schwartz. 158901/03/19 6:38 PM 1590SPECIFIC CONSIDERATIONSPART IIlocal control of large, high-grade tumors is improved with radia-tion therapy. The prognostic factors for children with nonrhab-domyosarcoma are similar to those for adults, and the role of chemotherapy for high-risk tumors is unclear, as for adults.RESEARCH PERSPECTIVESAs the molecular alterations associated with various sar-coma subtypes are elucidated, many new potential targets for therapeutic intervention will be identified. A wide variety of DNA alterations have been observed in sarcomas that result in mutated genes encoding proteins ranging from transcription fac-tors to tyrosine kinases to cytokines. The challenge in identify-ing therapeutic targets in sarcoma is to identify those that are specifically important to cellular function. The ideal therapeutic target has been described as a single molecule that is critical for pathogenesis, is expressed and active, is involved in a single pathway amenable to blockade (i.e.,


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Surgery_Schwartz. function. The ideal therapeutic target has been described as a single molecule that is critical for pathogenesis, is expressed and active, is involved in a single pathway amenable to blockade (i.e., no alternative bypass path-ways exist), and is critical for sarcoma cell survival.25CONCLUSIONSSoft tissue sarcomas are a heterogeneous family of rare tumors, accounting for approximately 1% of malignancies in adults. The etiology in the vast majority of patients is sporadic, and the man-agement of such diverse tumors is complex. Diagnosis by light microscopy is inexact, but molecular diagnosis, although still in its infancy, holds great promise. The natural history of soft tissue sarcomas is well established. Approximately two-thirds of cases arise in the extremities, and the remaining one-third are distrib-uted between the retroperitoneum, trunk, abdomen, and head and neck. The management algorithm for soft tissue sarcomas is complex and depends on tumor stage, site, and histology. The


Surgery_Schwartz

Surgery_Schwartz. are distrib-uted between the retroperitoneum, trunk, abdomen, and head and neck. The management algorithm for soft tissue sarcomas is complex and depends on tumor stage, site, and histology. The most common site of metastasis is the lungs, and metastasis generally occurs within 3 years of diagnosis.Soft tissue sarcomas have unique molecular profiles that contribute to varying responses to systemic therapy. Doxorubicinbased regimens have been the mainstay of treatment for the past two decades; however, it is now clear that specific histologic subtypes have increased sensitivity to specific agents. For exam-ple, angiosarcomas are more sensitive to paclitaxel, while leio-myosarcoma is sensitive to gemcitabine and docetaxel. Progress in understanding of soft tissue sarcoma biology is crucial for the development of additional therapeutic targets. Drug engineering will enable molecular-based therapies to become increasingly incorporated into clinical trials and, with success, into standard


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Surgery_Schwartz. for the development of additional therapeutic targets. Drug engineering will enable molecular-based therapies to become increasingly incorporated into clinical trials and, with success, into standard treatment strategies for soft tissue sarco-mas in the near future.REFERENCESEntries highlighted in bright blue are key references. 1. Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)—update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2007;5(suppl 2):S1-S29; quiz S30. 2. Coindre JM, Terrier P, Guillou L, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91:1914-1926. 3. Gronchi A, Miceli R, Colombo C, et al. Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution. Ann Oncol.


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