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Soft tissue sarcoma, a heterogeneous collection of rare tumors derived from mesenchymal tissue, results in significant mortality. These tumors are found throughout the human body, with nearly one third arising in the retroperitoneal and intra-abdominal regions. Recent advances in molecular diagnostics have led to the revelation that more than 90% of intra-abdominal sarcomas are a specific histological variant known as gastrointestinal stromal tumors (GISTs). The overexpression of the KIT protein on the surface of these tumors linked them to the interstitial cell of Cajal, and it is now generally accepted that GISTs arise from either these mesenchymal cells or their progenitor stem cells. On the other hand, a plethora of histological variants of sarcoma are found within the retroperitoneum. Despite this histological variation, retroperitoneal and intra-abdominal sarcomas tend to display a high propensity for recurrence, either locally or distant. This tendency for recurrent disease despite surgical resection results in poor long-term prognosis for patients diagnosed with these 2 classes of tumors. The development of molecular therapy targeting the intracellular cascade responsible for GIST tumorigenesis has resulted in improvement in overall survival for patients with metastatic disease, yet, as is the case with retroperitoneal sarcoma (RPS), GIST remains a surgical disease since resection offers the primary hope for complete disease cure.

As a result of the large proportion of mobile soft tissue and the relative depth of the retroperitoneal and abdominal cavities, these indolent growing sarcomas can achieve impressive sizes before diagnosis. As a testament to this slow growth pattern, a significant percentage of RPS and GIST patients are asymptomatic when their tumors are discovered incidentally during radiographic testing or physical examination. When symptoms are present, they are typically chronic in nature and consist of vague abdominal pain, distention, and discomfort. The mass effect of these tumors can eventually compress retroperitoneal and intraperitoneal structures resulting most frequently in neurologic and gastrointestinal symptoms. The gastrointestinal symptoms of nausea, emesis, and bowel pattern changes appear more commonly in GIST patients because these tumors arise within the muscular wall of the gastrointestinal tract. Retroperitoneal sarcomas frequently compress local spinal nerve roots and venous structures, resulting in lower extremity neuralgia, paresthesias, and occasionally, venous congestion and edema. Additionally, both tumors may manifest with either acute or chronic gastrointestinal bleeding secondarily to local invasion or chronic compression of vascular structures resulting in visceral venous congestion and mucosal ulceration. This finding is more frequently seen in GIST patients. GIST and RPS result in a wide spectrum of vague signs and symptoms, and as a result, should be considered in patients with chronic, nonspecific abdominal complaints.

The clinical evaluation of a patient suspected of having an intra-abdominal or retroperitoneal tumor is similar. As is the case with any newly seen patient, a thorough history and physical examination is mandatory to assess the extent of disease. An understanding of the duration and degree of symptoms can suggest specific organ involvement and thereby aid in preoperative planning. A majority of patients undergo thorough radiographic imaging before surgical evaluation, and as a result, typically present with a known intra-abdominal or retroperitoneal mass. These patients should be approached with a differential diagnosis in mind. Nowhere is this approach more critical than in a patient with a retroperitoneal mass, because, in addition to soft tissue sarcomas, lymphomas and germ cell tumors are frequently found in this region. As a result, the history and physical examination should be tailored to assess for signs and symptoms of all of these diagnoses. This distinction is relevant because all 3 of these entities are treated differently: sarcomas with complete resection, lymphomas with primary chemotherapy, and germ cell tumors commonly with radical retroperitoneal lymphadenectomy and/or chemotherapy. Gastrointestinal adenocarcinomas can complicate the clinical diagnosis of GIST; yet on imaging these epithelial tumors frequently lack an exophytic component which is characteristic of GIST.

The radiographic evaluation of patients with suspected GIST or RPS should consist of abdominal and chest imaging to determine the resectability of primary disease and assess for peritoneal, hepatic, and pulmonary metastases. The necessity of a preoperative tissue diagnosis is highly debated in both GIST and RPS. If, after a complete evaluation, there is substantial clinical and radiographic suspicion for a disease process other than GIST or RPS, then tissue sampling is justified. In the case of GIST, endoscopy, when feasible, affords an opportunity for tumor visualization and biopsy. Additionally, endoscopic ultrasound can evaluate submucosal masses and its associated fine needle aspiration has been shown to be a reliable method of tissue sampling in patients with lesions suspicious for GIST. Because it preserves microscopic tumor architecture and does not jeopardize the chance at complete gross resection, CT-guided core needle biopsy is the preferred method for biopsy of a retroperitoneal mass. If a patient presents with lesions suspicious for metastases, then a tissue diagnosis is necessary to guide therapy. Due to the highly vascular and cystic nature of these sarcomas, there is a real risk of hemorrhage and peritoneal seeding with any method of tissue sampling. As a result, the decision for a preoperative biopsy should be a true decision and not part of a routine diagnostic protocol.

As in all tumors, clinical, operative, and tumor-specific predictors of outcome have been identified for patients diagnosed with GIST or RPS. In both of these tumors, the presence of metastatic or locally advanced, unresectable disease at presentation is associated with poor prognosis. Additionally, in patients who undergo attempted resection, an incomplete gross resection has been shown repeatedly to correlate with significantly decreased overall survival. Furthermore, in patients with RPS, overall survival after incomplete gross resection is no different than after biopsy alone, confirming that there is generally no therapeutic role for surgical debulking in the asymptomatic patient and that complete gross resection should be extensively pursued. Tumor rupture during GIST resection is predictive of poor outcome because this can result in rapid progression to disseminated peritoneal disease. In GIST and RPS, high mitotic activity correlates with decreased disease-free survival and overall survival. Large tumor size and small intestinal location in GISTs are negative predictors of outcome, whereas in RPS, large size has inconsistently been shown to correlate with poor prognosis in univariate analysis. Because the molecular pathogenesis of GISTs is well understood, certain activating mutations have been discovered which have prognostic relevance in predicting overall outcome and response to molecular-targeted therapy.

Gastrointestinal stromal tumors are unique soft tissue tumors because a molecular marker highly specific to their constituent cells has been found. This marker, CD117 or KIT, not only identified their specific mesenchymal cell lineage but also pinpointed the intracellular cascade responsible for their tumorigenesis. Additionally, this discovery focused the search for chemotherapeutic agents to this single receptor cascade. Subsequently, imatinib, a small-molecule inhibitor of KIT tyrosine kinase activity, became the first FDA approved molecular-targeting agent for cancer treatment.

As expected, imatinib has drastically affected the overall outcome of patients with GISTs. Currently, imatinib has been approved for use as first-line therapy in patients with unresectable or metastatic GISTs. For patients with clinically and radiographically resectable disease, surgical intervention with complete gross resection is recommended. The goal of surgery is the complete removal of all tumors with microscopically negative margins. To achieve this goal, en bloc resection of involved organs and intra-abdominal structures is not uncommon and should be considered preoperatively. Wide local resection and routine lymphadenectomy are not indicated since these procedures have not been shown to afford any clinical benefit. Imatinib is utilized as neoadjuvant therapy in patients with marginally resectable and unresectable tumors, and in patients in which the necessary resection would result in unacceptable morbidity. In this role, frequent surveillance is required to monitor for response and possible resectability.

Since nearly 50% of GISTs recur within 5 years, the adjuvant role of imatinib has been studied extensively in the clinical setting. Two American College of Surgeons Oncology Group (ACOSOG) trials have demonstrated significant improvement in disease-free survival in patients receiving adjuvant imatinib and have shown a survival advantage compared with historical controls. Consequently, imatinib is frequently used as adjuvant therapy in patients at high risk of recurrence although the exact duration of therapy is currently unknown. In nearly 80% of patients with metastatic or recurrent disease, imatinib has shown either disease stabilization or improvement resulting in an improvement in median survival. Despite this success, a majority of patients benefiting from imatinib therapy develop resistance to the drug and eventually show focal or diffuse disease progression. A second tyrosine kinase inhibitor, sunitinib, has shown promise in countering disease progression in these patients, and as a result, has been approved for this specific use.

Unfortunately, the treatment of RPS has not evolved with the same successes as seen in the treatment of GIST. The most significant advancement in patient overall survival came with the understanding of the importance of complete resection of all gross tumor at the initial operation. With an aggressive operative approach, 5-year overall survival has increased from 30% to 40% to nearly 70% over the last 25 years. En bloc partial organ resection is required in more than one half of patients to achieve complete resection. Despite complete gross resection, it is estimated that 70% of patients will develop local recurrence resulting in significant mortality. In this circumstance, aggressive re-resection should be pursued after evaluation of comorbidities and the likelihood of complete gross resection. Despite extensive efforts, chemotherapeutic agents have demonstrated no clinical benefit in the treatment of RPS. On the contrary, radiation therapy may provide some element of local control, yet this comes at the expense of multiple therapy-associated complications. The intra-abdominal organs, and more specifically small bowel, are sensitive to radiation therapy at “sarcoma-cidal” doses. Series using radiation at doses less than the therapeutic extremity sarcoma level have reported high rates of gastrointestinal fistulas, stricture-causing obstructions, and neuropathies. Consequently, multiple different means of delivering different doses of radiation have been extensively studied. Currently, preoperative external beam radiation therapy appears to provide the highest local control rate with the least amount of associated complications.

Despite the advances in radiation therapy for RPS and the development of molecular-targeted therapy for GIST, these neoplastic processes continue to display high levels of recurrence resulting in significant morbidity and mortality. Long-term overall survival is primarily achieved in those patients who undergo aggressive complete tumor resection and those who have low grade tumors. Because many of these tumors will recur locally, it is important for surgeons to appreciate the balance between cancer cure and functional preservation in these patients. Prior to offering the “next operation,” the oncological surgeon must understand the existing comorbidities and the extent of symptoms, as well as the development of new therapeutic modalities in order to appropriately maximize quality of life and survival.