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Illustrative Case Series

Postoperative Management of GIST

December 1, 2012
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By William B. Ershler, MD

A 61-year-old nuclear engineer with a past history of hypertension was admitted through the emergency department because of persistent lower abdominal pain. Clinical picture and imaging studies initially pointed to pelvic abscess. Computerized tomography (CT) had revealed a large (14 x 14 x 14 cm) fluid collection most consistent with that diagnosis. He was treated with antibiotics including Flagyl, vancomycin, and Zosyn and underwent percutaneous drainage. Repeat CT (post drainage) demonstrated residual fluid and an adjacent solid mass. Subsequently, he underwent a CT-guided biopsy revealing a spindle cell tumor strongly positive for CD117 and negative for CD34, S100, CD68, and pancytokeratin. The findings were more consistent with gastrointestinal stromal tumor (GIST). The patient was readmitted and underwent surgical resection at which time a 12 cm tumor was removed intact. Histologic evaluation once again revealed a high-grade spindle-cell tumor with a high mitotic index (12 mitoses per 50 high power fields) and extensive necrosis.

The postoperative course was marked by gradually diminishing abdominal pain and was otherwise uneventful. Two weeks after discharge he was seen in the office for discussion regarding adjuvant therapy.

His prior medical history was significant only for hypertension, which was controlled with metoprolol 25 mg daily.

On physical exam he appeared thin and somewhat pale. His blood pressure was 120/70 and pulse was 84 and regular. The abdominal exam revealed the surgical site to be well healed with slight tenderness but no palpable mass. CBC and chemistries revealed a mild microcytic anemia but without other abnormalities.

Future management recommendations were solicited.

Discussion

GISTs are mesenchymal in origin, most commonly arise from the stomach or small intestine, and frequently have demonstrable mutation in the KIT (approximately 75%) and/or PDGFRA (approximately 10%) gene.1,2 Complete surgical excision offers the best chance for cure, yet up to 50% of patients relapse within 5 years.3,4 For patients with advanced disease, imatinib has proved to be effective in reducing tumor burden, but eventually disease progression occurs.5,6

Predictive models have been developed to assess risk for disease recurrence after primary GIST resection.7,8 Risk factors include mitotic index and tumor size. The commonly used NIH Consensus Criteria for high risk include the presence of one of the following: 1) tumor diameter greater than 10 cm, 2) mitototic count greater than 10 per 50 high power fields (hpf), 3) tumor diameter greater than 5 cm AND mitototic count greater than 5/ 50 hpf, or 4) tumor rupture before or during surgery.7,8

For patients at high risk for recurrence, there have been two large trials that support the role for adjuvant imatinib by demonstrating both improved relapse-free and overall survival.9,10 From these and other supporting data, a recent panel of experts concluded that adjuvant imatinib should be considered the standard treatment in all patients with significant risk of recurrence following resection of primary GISTs.11 What remains to be answered is the length of therapy. Although 1 year of treatment had been common practice, the Scandinavian Sarcoma Group SSGXVIII trial10 clearly demonstrated that 3 years of treatment of 400 mg of imatinib per day for high-risk GIST was superior to 1 year in terms of both relapse-free and overall survival, and the FDA has now recommended the extended treatment for such patients.

Accordingly, as the patient presented above met criteria for high-risk for recurrence (based on both size and mitotic index), a minimum of 3 years of imatinib therapy would be recommended. The question would be whether the drug should be discontinued after 3 years if he remains relapse free. Inasmuch as the specific mutations that drive this neoplastic proliferation are directly inhibited by imatinib, it would be tempting to continue indefinitely. On the other hand, it is notable that patients who present with metastatic disease are known to become imatinib-resistant over time. Hopefully, additional research will address whether there is an advantage to continue patients indefinitely on imatinib or stop at a defined time, such as 3 years.

References

1. Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 2006; 130:1466-1478.

2. Rubin BP, et al. Gastrointestinal stromal tumour. Lancet 2007; 369:1731-1741.

3. DeMatteo RP, et al. Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231:51-58.

4. Nilsson B, et al. Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era — a population-based study in western Sweden. Cancer 2005; 103:821-829.

5. Blanke CD, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26:620-625.

6. Verweij J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004; 364:1127-1134.

7. Gold JS, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: A retrospective analysis. Lancet Oncol 2009; 10:1045-1052.

8. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008; 39:1411-1419.

9. Dematteo RP, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial. Lancet 2009; 373:1097-1104.

10. Joensuu H, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: A randomized trial. JAMA 2012; 307:1265-1272.

11. Reichardt P, et al. Adjuvant therapy in primary GIST: State-of-the-art. Ann Oncol 2012; 23:2776-2781.