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Gastrointestinal Stromal Tumors

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

March 2001.     Review Article.

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Gastrointestinal Stromal Tumors are uncommon mesenchimal tumors that arise in the wall of the gastrointestinal tract.
They account for approximately 0,1% to 3% of all gastrointestinal neoplasms, with about 150 new cases per year diagnosed in the United States.
The term GIST first used by Mazur and Clark in 1983 includes a heterogeneous group of nonepithelial neoplasms with spindle or epithelioid cells, which display a range of differentiation (Crosby).
It is difficult to determine microscopically the exact origin of these tumors. They have a complicated histogenesis and moreover it is not easy to assign a benign or malignant classification; for these reasons the non-specific term Gastrointestinal Stromal Tumor, GIST has been coined (Pidhorecky ).
Immunohistochemistry and electron microscopy introduced the new evidence that GISTs may have myogenic features (smooth muscle GISTs), neural attributes (gastrointestinal anatomic nerve tumor), or characteristic of both muscle and nerve (mixed GISTs), or may lack differentiation (GISTs not otherwise specified).
The Cajal cell, an intestinal pacemaker cell, has been proposed the cellular origin of GISTs, having both cell markers in common. It has characteristics of both smooth muscle and neural differentiation on ultrastructural esamination ( DeMatteo).

The authors don't take care of specifing the histologic subtypes because at the present it is not clear whether a clinical difference exists between the subtypes of GISTs. Furthermore no histologic grading system has been established for this group of tumors ( Mudan ).

Grossly GISTs are smooth gray - white tumors which arise within the muscolaris propria of the GI tract. They are well circumscribed and containe a pseudocapsule. They may grow in an endophytic fashion compromising bowel lumen patency or may exhibit an exophytic or dumbbell growth pattern. In GISTs with an endophytic component the submucosal mass may have an overlying mucosal necrosis and ulceration.
At a intraoperative appearance it is possible to distinguish a mass attached to the stomach or the bowel wall projecting into the abdominal cavity, displacing other organs. Malignant GISTs are characterized by the invasion of adjacent structures and by the presence of multiple nodules in the surrounding tissue , or evident metastatic disease (Pidhorecky).

The mean age of patients is 58.5 years (range 22-79 years). (Yao).

The risk factors and etiology of GISTs remain undetermined (Pidhorecky).

Because of the nonspecific symptoms, a delayed diagnosis is generally associated with Gastrointestinal Stromal Tumors, with a mean duration of symptoms before presentation of 6 months.
The most frequent clinical manifestations are gastrointestinal bleeding, a palpable mass and mild abdominal pain in order of frequency.
Over 5% of patients has more than 1 complaint or physical findings.
There isn't a correlation of these symptoms with prognosis (Yao ).

The most frequent diagnostic test is CT; it can demonstrate a mass lesion , the contigous organ invasion and distant metastases.
CT (in particular spiral CT scan with thin cuts ) is the most sensitive test for the detection and staging of a primary gastrointestinal sarcoma, in respect to other imaging tests (upper gastrointestinal contrast study, abdominal ultrasound scanning, angiography).
Endoscopic ultrasound would be helpful to assess pancreatic involvement, whether mucosal ulceration is due to sarcoma or due to a non stromal tumor, and to assess involvement in the lower gastrointestinal tract.
Patients with upper gastrointestinal bleeding are submitted to upper endoscopy (Yao ).

The most common anatomic locations are the stomach (53%), the small intestine (33%), rectum (5%), esophagus (5%) and colon (4%).
The location of the tumor is not considered a significant prognostic factor (Yao ).

Preoperative percutaneous biopsy carries the theoretical risk of peritoneal seeding or tumor rupture. It is indicated only for clearly unresectable disease or when treatment would be altered , as would be the case if the mass proved to be a lymphoma or germ cell tumor.
Only highly experienced pathologists are likely to provide a diagnosis with a intraoperative frozen section. (DeMatteo ).

Until more effective adjuvant therapy becomes available , the treatment of GISTs remains primarly surgical.
Every effort should be made to achieve complete resection of all gross disease , sometimes necessitating the removal of adjacent organs.
Incomplete resection should be performed only for the palliation of symptoms due to bleeding , pain, or mass effect. It is defined complete resection the excision of all gross disease , regardless of microscopic margins. ( DeMatteo ).
It is essential to avoid tumor spillage or tumor rupture in the abdomen. They have been associated with an increased risk of peritoneal recurrence (Pidhorecky).
Systematic limph node dissection is not thought to be necessary for surgical management of gastric leiomyosarcoma . Although laparoscopic wedge resection is not indicated for tumors at inappropriate locations, such as the cardia or pylorus or large tumors resulting in postoperative stenosis, this procedure is appropriate for tumors located in others parts of the posterior and anterior wall of the stomach ( Yoshida ).
For small bowel stromal tumors Crosby reccomends an attempt at preoperative diagnosis, careful surgical planning and an effort to achieve complete gross resection in patients with malignant small intestinal GISTs even in the presence of local invasion.
He finds no correlation between tumor grade and clinical behaviour in the 50 patients study. Even patients with histologically benign lesions and no detectable mitotic figures can develop metastases and die of disease ( Crosby).

Yao , with some difference, does not advocate extended lymphadenectomy for gastric lesions. He advocates to remove the perigastric nodes and omentum. For small bowel lesions it is recommendable to remove the adjacent mesentery; for colon and rectal lesions the mesocolon or the mesorectum ( Yao).

The overall survival rate for all patients has been 35% at 5 years.
Patients with complete resection had a 54% 5 year survival rate . Patients who could not undergo complete resection had a median survival of only 12 months; median survival was 19 months in those with metastases and 12 months in those with local recurrence.
In the entire population male sex, tumor size >5cm and incomplete resection have been significant predictors of survival on multivariate analysis. In the patients without metastases and who underwent complete gross resection size has been an important predictor of survival on both univariate and multivariate analysis. Tumor size >10cm has been the most significant factor.
The status of the microscopic margin of resection does not affect survival . Many of this tumors are exophytic and protrude into the abdominal cavity , therefore the microscopic margin of resection may not be as important as whether the tumor sheds cells directly into the peritoneal cavity ( DeMatteo).

Recurrence of GIST is usual and one report find only 10% of patients to be free of disease after long term follow up.
Recurrence of the disease after resection is predominantly intraabdominal and involves the original tumor site, peritoneum and liver. In the patients with primary disease who underwent complete resection the liver was involved in 63% of patients who had recurrence; this was the only site of the disease in 44% of recurrences. Extrabdominal metastases are much less common ( 15%).
The status of microscopic margins of resection does not predict recurrence. (DeMatteo).
In multivariate analysis of postrecurrence survival, the length of the disease free interval between the initial operation and recurrence is the only significant determinant of survival .
The outcome for patients who achieve a CR of the recurrence is statistically the same for those who have incomplete resections. Despite macroscopic and microscopic clearance , local recurrence seems to be predictive of the emergence of further local disease and progression to distant disease.
Those patients with isolated liver metastases show a trend toward better survival (PRSv of 34 months compared with 12 months for all others- postrecurrence survival , the time from diagnosis of the recurrence to tumor related death or the last follow up) however all of the patients who presented with the liver as the sole site of initial recurrence failed again by disease within the liver.
Except for patients with a long disease free interval second surgery should be restricted to symptom control.
The follow up of patients with curatively resected primary gastrointestinal sarcoma is a combination of clinical and appropriate imaging directed to the early identification of a small group of patients in whom failure is confined to the liver and in whom the potential for liver resection exists. (Mudan ).

There is currently no strong data to support the use of chemotherapy, other than in a controlled trial.
Intraperitoneal chemotherapy after cytoreductive surgery for abdominal sarcomatosis has been investigated by Karakousis et al. and Sugarbaker, with reported 5 year survival rates of 7% and 12% respectively.
A prospective study evaluating the role of intraperitoneal mitoxantrone after complete resection of abdominal sarcomas was recently published by Eilber et al.This approach had little effect on survival, as the rate of liver metastases was unaffected. However it did significantly affect the rate of peritoneal recurrence and thus may be of benefit to those patients with peritoneal-only disease.
Some authors have prompted the use of intraoperative radiotherapy in GISTs because it permits to deliver a meaningful amounts of radiation (Pidhorecky).
Photodynamic therapy (PDT) combining photosensitizer drug, oxygen and laser light has been designed to evaluate the effectiveness of surgical debulking and PDT in carcinomatosis and sarcomatosis (Hendren).


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