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Gastrointestinal Stromal Tumors: updating.

Romeo Giuli MD, Giacomo Nastri MD, residents.
School of General and Emergency Surgery.
University of Siena.   Italy.

June 2001.     Review Article.

To Previous Article about GIST
To the second updating
To the third updating

Recent articles underline the prognostic importance of tumor grade in gastrointestinal stromal tumors, the management of peritoneal and hepatic recurrences, and the discovery of a new amazing medicine: Gleevec.

Yao (Northwestern University Medical School, Chicago) affirms that in patients with complete resections (complete resection is the main prognostic variable in this study), tumor grade is the most important prognostic factor, and despite complete resection patients with high grade tumors remain at risk for recurrence.
Nevertheless the criteria used to grade tumors have not been established. Most pathologists use a combination of cellularity, mitotic count, differentiation, and atypia as criteria to determine grade (Yao).

JP Pierie (Harvard Medical School) stresses that gastrointestinal stromal tumors are known for a wide variability in clinical behaviour and for difficulty in determining malignancy and prognosis.
Complete gross surgical resection is at the moment the only means of cure for GIST.
Tumor grade is the second major factor that has an effect on survival and on recurrence. The author proposes to simplify the classification for tumor grade to high (formerly high or intermediate) and low grade tumors only. The cutoff point in this classification would be 1 mitosis per 10 HPF (low grade) vs more than 1 mitosis per 10 HPF (high grade).
A consequence of this grading system is that GIST are to be considered malignant tumors on a scale from low to high grade, and it eliminates the confusion created by the older terminology of "benign" and "malignant" GIST, or "leiomyoma" vs "leiomyosarcoma".

If the tumor is larger than 5 cm and/or the subsequent histologic features demonstrate a high grade the patient is at very high risk for recurrence and subsequent mortality. These are patients in critical need of new adjuvant modalities, such as intraperitoneal chemotherapy.
With the frequency of late recurrences, follow up beyond the usual 5 year period is essential (Pierie).

Kwon (Hanyang University Medical School) in a study about gastric stromal tumors indicates that mitotic count and tumor size are major discriminants predictive of biologic behaviour.
MCs has a close correlation with tumor size.
The author categorizes tumors as malignant GISTs when MC is >5/50 high power fields (HPF) and the size >5 cm or as benign GISTs when the MC is < 5/50 HPF and the size is <5 cm. In his experience none of the benign tumors recurred or metastasized.
Substantially the patients are divided into two group: those with a benign tumor and those with a malignant tumor, affirming that there is a statistically significant survival difference (Kwon).

Another study that reproposes the distinction between benign and malignant tumors is that of DC Rice et al. (Mayo Clinic) who presents the surgical experience over a 20 year period in the treatment of duodenal leiomyomas.
They are the most common benign tumor of the upper gastrointestinal tract, according to Rice's opinion.
But the author specifies that all resected specimens underwent frozen section and permanent histopathologic analysis
Experienced pathologists should be able, in most cases, to differentiate between benign and malignant tumors that are fully excised. Factors such as tumor invasion, cytologic features and size are crucial to the decision making in the frozen section laboratory (Rice).

BM Clary (Memorial Sloan Kettering Cancer Center) citing previous studies affirms that survival in patients with GISTs depends most heavily on the presentation status and the ability to achieve a complete resection. Tumor size appears to be less important, although significant, whereas gender and the site of tumor origin are less important.

Recurrence following a complete resection is common and involves both local (52%) and distant sites (67%). Only one third of patients has recurrence following complete resection that is local only in extent. Hepatic metastasis are the predominant site of distant metastasis and are a component of 63% of first site recurrence following resection.

Carefully selected patients with resectable, locally recurrent or metastatic disease also may benefit from surgical resection, particularly in patients with a long disease free interval (>12 months).
Moreover regional forms of investigational therapy that addresses intrabdominal sites of recurrence may be appropriate (Clary).

Eilber (UCLA Medical Center) highlights again that aggressive surgical resection and intraperitoneal chemotherapy with mitoxantrone for recurrent GI stromal sarcomas is a non-toxic therapy that appears to have significantly lowered the rate of peritoneal recurrence and thus the morbidity of this disease.
Although this treatment have no effect on hepatic metastases or overall survival, there is a suggestion of a survival benefit in patients with disease limited to the peritoneum.
Moreover the author proposes a multicenter, randomized, prospective trial comparing surgical resection alone with surgical resection and intraperitoneal chemotherapy for primary GI stromal tumors. By treating the primary disease he hopes to interrupt the disease process at an earlier stage further decreasing the peritoneal recurrences and potentially preventing the hepatic spread of the disease before it occurs.

Hepatic failure remains a major problem severely limiting survival (Eilber).

The majority of patients with liver metastases have either bilobar disease or multifocal disease when staged accurately with sensitive tests like CT/MR angiogram or intraoperative ultrasound. Resection of liver metastases is therefore recommended only for patients who have shown an indolent biology and disease localized to a limited area of the liver that is deemed resectable.
For the subset of patients with shorter disease-free intervals suggesting more aggressive biology and therefore potentially systemic/disseminated nature of the disease, or patients with unresectable disease, experimental approaches or locoregional therapies are considered (for example with hepatic arterial chemoembolization).
Prognostic factors that are associated with improved survival after relapse are a disease- free interval of >18 months, recurrence limited to either peritoneal cavity or liver and complete resection of metastatic disease.
Patel (MD Anderson Cancer Center) specifies that the median interval to recurrence is 18 month and 60% of all recurrences occurs within 2 years from surgery.Patients who have either peritoneal or liver metastases or both can have lung metastases, subcutaneous metastatic nodules or bone metastases as late events (Patel).

A new technique for the treatment of sarcomatosis is proposed by Bauer et al ( PEN University).
Sarcomatosis has a poor prognosis, despite treatments such as repeated debulking and systemic chemotherapy, external beam radiation, and intraperitoneal chemotherapy.
The author affirms that debulking surgery with intraperitoneal PDT for sarcomatosis is feasible. Preliminary response data suggest prolonged relapse-free survival in some patients.
Photodinamic therapy is a treatment modality that combines a photosensitising agent, laser light of a specific wavelength to activate the sensitizer, and oxygen to kills cells (Bauer).

There is no standard chemotherapy for GI leimyosarcomas. Doxorubicin and ifosfamide, the two drugs that constitute standard systemic therapy for most other soft-tissue sarcomas, have very limited activity in GI leiomyosarcomas and therefore should not be used routinely (Patel).

But we report an interesting internet interview about a new amazing medicine Gleevec, a molecularly targeted therapy that has been found to work well on gastrointestinal stromal tumor . It sets a new paradigm for rational therapy of cancer. The interviewed Medical Doctor is George Demetri co-director of the sarcoma center at the Dana-Farber Cancer Institute, and a lead author on a study of Gleevec and GIST. He is also Editor of a beautiful web site: (see lectures).


KA Yao et al. Primary gastrointestinal sarcomas : analysis of prognostic factors and results of surgical management. Surgery 2000; 128:604-12.

JP Pierie et al. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg. 2001; 136: 383-389.

SJ Kwon et al. Surgery and prognostic factors for gastric stromal tumor. World J Surg. 25,290-295, 2001.

DC Rice et al. Surgical management of duodenal leiomyomas. Wold J Surg. 25, 562-566, 2001.

BM Clary et al. Gastrointestinal stromal tumors and leiomyosarcoma of the abdomen and retroperitoneum: a clinical comparison. Annals of Surgical Oncology, 8 (4): 290-299, 2001.

FC Eilber at al. Recurrent gastrointestinal stromal sarcomas. Surgical Oncology 9 (2000) 71-75.

S R Patel, R S Benjamin. Management of peritoneal and hepatic metastases from gastrointestinal stromal tumors. Surgical Oncology, 9 (2000) 67-70.

TW Bauer et al. Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis. Annals of Surgical Oncology, 8 (3): 254-259, 2001.

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