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Gastrointestinal Stromal Tumors: updating.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

August 2002.     Review Article.

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To the first updating
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Ronald P. DeMatteo ( Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York ) in an educational review ( ASO 2002 ) riaffirms that gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract.
Currently, it is believed to originate from an intestinal pacemaker cell called the interstitial cell of Cajal.
GIST may develop anywhere along the gastrointestinal tract, but most often it arises in the stomach and, less commonly, in the intestine. Occasionally, GIST develops outside the gastrointestinal tract in the mesentery, omentum, or retroperitoneum.
Only within the last 5 to 10 years has GIST been distinguished from visceral leiomyosarcoma, which has a similar appearance by light microscopy. GIST had also been designated variably as leiomyoblastoma, plexosarcoma, gastrointestinal autonomic tumor, or gastrointestinal pacemaker cell tumor ( 1, 2 ).

The diagnosis of GIST has been facilitated considerably by the widespread application of Kit (CD117) immunohistochemistry, which is nearly always positive in GIST. There is also a greater general awareness of this distinct pathologic entity because there is now an effective treatment for it ( 1, 3 ).

GIST represents a spectrum of tumors that range from benign to highly malignant. Predicting the clinical behavior of a particular GIST is imprecise. In general, the malignant potential of GIST depends primarily on tumor size, mitotic activity, and anatomical origin. However, there are no widely accepted criteria for what constitutes a malignant GIST. Consequently, many pathologists will classify GIST only as low risk or high risk of being malignant. It is generally agreed that almost all tumors <1 cm in size are benign. Conversely, tumors >5 to 10 cm are usually malignant, as are tumors with >2 to 5 mitoses per 10 high-power microscopic fields. Tumors from the small intestine often behave more aggressively than tumors from the stomach. However, most GISTs fall into a "gray zone," and, therefore, the ultimate determination of malignancy depends on the development of tumor recurrence or metastasis ( 1, 4 ).

The principal treatment of a patient with a primary GIST is complete surgical resection. The tumor is often fragile, especially if it is large or there is extensive intratumoral hemorrhage or necrosis. Therefore, preoperative biopsy is used selectively to avoid the risk of rupture, bleeding, or tumor extravasation. Meticulous surgical technique is necessary to avoid intraoperative tumor rupture, which is associated with a poor prognosis.
The importance of negative microscopic margins on the resected organ is dubious when there is a massive (e.g., 15-cm) GIST that is free to shed cells throughout the abdomen. Lymphadenectomy is not performed routinely in patients with GIST because lymph node metastases are rare ( 1, 5 ).

Tumor size is an independent prognostic factor of survival on multivariate analysis. Patients with tumors larger than 10 cm had a relative risk of 2.5 (95% confidence interval, 1.2-5.5) and only a 20% actuarial 5-year survival.
In addition to tumor size, mitotic rate, location, and tumor rupture, a variety of other prognostic factors have been identified, including aneuploidy, proliferative index, and percentage S-phase fraction ( 1, 4, 5, 6 ).

After resection of the primary tumor, most patients still subsequently develop recurrent GIST. In some cases, tumor rupture can account for the recurrence, particularly if it occurs in the peritoneum. However, in most patients, recurrence develops after what seemed to be a curative resection.
The median time to recurrence is approximately 1.5 to 2 years. The first site of recurrence in GIST is typically within the abdomen and involves the peritoneum, the liver, or both.
Unfortunately, once patients develop recurrent disease, their chance of cure with conventional therapy is extremely low (i.e., <10%) ( 1, 6 ).

Conventional chemotherapeutic agents, including doxorubicin and ifosfamide, have only minimal activity in patients with metastatic GIST.
Overall, there is no obvious or standard drug regimen to use for patients with metastatic GIST ( 1, 7, 8, 9 ).

Surgical resection may be beneficial in some patients with GIST who develop peritoneal recurrence.
Unfortunately, resection of recurrent peritoneal GIST is seldom curative, even when all gross tumor is removed. To improve the results of surgery, Berthet et al. championed the strategy of cytoreduction and intraperitoneal chemotherapy for peritoneal recurrence of GIST and other intra-abdominal malignancies.
Eilber et al. at the University of California-Los Angeles studied adjuvant intraperitoneal mitoxantrone after the resection or debulking of recurrent peritoneal GIST.
Intraperitoneal mitoxantrone for recurrent GIST is currently being examined at MSKCC, although the first dose is being administered during surgery to promote broader peritoneal distribution of the drug. However, it is now indicated only for patients whose tumor is resistant to STI571 ( 1, 10, 11, 12 ).

Most patients with liver metastases from GIST have multiple, diffuse tumors and are therefore inoperable. In a recent analysis of 131 patients with liver metastases from GIST or intestinal leiomyosarcoma (not all archival specimens could be tested for Kit) treated at MSKCC, hepatic resection of all gross disease was possible in 34 (26%) patients. There were no perioperative deaths after resection. The 1- and 3-year survival rates were 90% and 58%, respectively. On multivariate analysis, survival was predicted by the time interval between the resection of the primary tumor and the development of a liver metastasis. In fact, all five patients who took at least 2 years to develop liver metastases survived more than 4 years after hepatic resection. Others have had similar results. Nevertheless, as is the case after resection of peritoneal recurrence, nearly all patients' disease subsequently recurs after hepatectomy, with the liver being the most common site of relapse ( 1, 13, 14 ).
Hepatic artery embolization (HAE) is an effective palliative therapy for patients with liver metastases from GIST because the tumors tend to be hypervascular and derive most of their blood supply from the hepatic artery. The value of adding a chemotherapeutic agent to the injection of particles is controversial. The chemotherapy may enable prolonged drug delivery and enhance the effects of arterial occlusion. However, because chemotherapeutic agents are ineffective against GIST when given systemically, they may only increase the toxicity of HAE. Indeed, comparable results can be achieved with particles alone. HAE may be used to treat patients with liver metastases who have pain or discomfort. It is also the first line of therapy in patients with acute hemorrhage from a liver metastasis. However, in most patients, HAE is used to reduce the size of the liver metastases. Although it may produce a dramatic reduction in tumor burden, there is no conclusive evidence that it actually prolongs survival ( 1, 15 ).

External beam radiation is generally not indicated in patients with metastatic GIST because of the diffuse distribution of recurrent disease that typically occurs within the liver or peritoneum. When radiation is used, it is strictly for palliation. It can reduce pain or discomfort associated with a liver metastasis or pelvic recurrence. Occasionally, it may also be used to control bleeding from a peritoneal recurrence that is causing gastrointestinal bleeding (1, 16 ).

In 1998, Hirota et al. reported that a mutation of c-kit was found in the tumors of five patients with GIST. Activating mutations in c-kit have also exist in germ cell tumors, myelofibrosis, chronic myelogenous leukemia (CML), and mastocytosis ( 1, 17, 18 ).
The reported prevalence of c-kit mutations in GIST has varied considerably. The discrepancy in prevalence may relate to different methods of detection and the type of tissue analyzed (paraffin-embedded vs. frozen tissue). GIST has also been shown to contain a variety of chromosomal abnormalities. ( 1, 19, 20, 21, 22, 23 ).
The presence of c-kit mutation has been reported to adversely affect survival in patients with GIST ( 1, 24 ).

The development of STI571 (Gleevec,TM imatinib mesylate; Novartis Pharmaceuticals, Basel, Switzerland) is a landmark achievement in cancer therapy. The application of STI571 to GIST was a direct result of (1) its selective inhibition of the Kit receptor tyrosine kinase, which is constitutively active in most GISTs; (2) its efficacy and minimal toxicity in patients with CML; (3) the parallels between the pathogenesis of GIST and CML; and (4) the lack of effective alternative treatments for metastatic GIST. Its use in GIST has been exceedingly rapid. Unlike traditional chemotherapeutic agents that are relatively nonspecific, STI571 is a specific inhibitor that acts on only a few tyrosine kinases ( 1, 25, 26 ).

STI571 has rapidly become the first-line treatment for patients with metastatic GIST. Nevertheless, conventional therapies, and surgery in particular, may actually now become more important in the treatment of metastatic GIST. Because complete responses have not been observed with STI571 therapy, patients with stable disease or partial responses should be considered for surgical resection or cytoreduction.
It is unknown when, and to what extent, resistance to STI571 will occur in STI571-responsive patients with GIST, but it is likely to emerge as it has in CML. Patients who do not respond initially to STI571 should be treated with the traditional palliative options for metastatic GIST that include chemotherapy, surgery with or without intraperitoneal chemotherapy, HAE, or radiation.
For patients with primary GIST, surgery remains the principle treatment but the results may be improved by neoadjuvant or adjuvant STI571. STI571 is being evaluated as an adjuvant therapy after complete resection of primary GIST because (1) the risk of recurrence after surgical resection alone is high, (2) conventional chemotherapy is ineffective in preventing or treating recurrent disease, and (3) STI571 has demonstrated considerable activity in metastatic GIST.
Because of the complexities of multimodality therapy, the treatment of patients with GIST now requires a multidisciplinary team that may include medical oncologists, general surgeons, surgical oncologists, hepatobiliary surgeons, molecular pathologists, surgical pathologists, and radiologists ( 1, 27, 28, 29, 30, 31, 32 ).

There are a number of unanswered questions regarding the use of STI571 in patients with GIST.
The first question is whether the type of c-kit mutation will predict the clinical response to STI571 therapy. There is preliminary evidence that it may.
Other critical issues are to determine the duration of response in patients with STI571-sensitive tumors and the mechanisms of STI571 resistance. Gene amplification and additional mutation have already been identified in the development of resistance to STI571 in CML.
All of these uncertainties should be answered by the current clinical trials and the correlative laboratory studies that accompany them.
Perhaps the ultimate question, though, will be how the paradigm of STI571 in CML and GIST will apply to other human malignancies. Because the pathogenesis of many common tumors seems to be more complex and involve multiple genetic aberrations, as opposed to what seems to be a single, dominant defect in GIST (and CML), other molecularly targeted agents may not demonstrate such dramatic activity as STI571. Nevertheless, the identification of critical pathways will enable the development of specific inhibitors in the ongoing colossal effort to uncover the true essence of neoplastic diseases and develop more effective therapies against them ( 1, 33, 34, 35, 36, 37, 38 ).


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