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10.1245/s10434-006-9228-0
Annals of Surgical Oncology 14:526-532 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Surgical Management After Neoadjuvant Imatinib Therapy in Gastrointestinal Stromal Tumours (GISTs) with Respect to Imatinib Resistance Caused by Secondary KIT Mutations

Florian Haller1, Sven Detken2, Hans-Jürgen Schulten1, Nicole Happel3, Bastian Gunawan1, Jens Kuhlgatz4 and László Füzesi1

1 Department of Pathology, Georg August University, Robert-Koch-Str. 40, 37099 Göttingen, Germany
2 Department of Oncology, Albert Schweitzer Hospital, Northeim, Germany
3 Institute for Biochemistry and Molecular Cell Biology, Georg August University, Göttingen, Germany
4 Department of General and Visceral Surgery, Albert Schweitzer Hospital, Northeim, Germany

Correspondence: Address correspondence and reprint requests to: Florian Haller, MD; E-mail: florian.haller{at}med.uni-goettingen.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENT AND METHODS
 DISCUSSION
 REFERENCES
 
Background: In metastasized GISTs, resistance to imatinib after initial tumour response has been associated with observation of secondary mutations in the activation loop of KIT. The aim of the current study was to evaluate the tumour response and observance of secondary KIT mutations in a case of GIST undergoing neoadjuvant imatinib therapy.

Methods: We report on a case of an initially unresectable gastric GIST with curative resection after 10 months of neoadjuvant imatinib therapy. Mutation analysis of KIT was performed on a pretherapeutic biopsy specimen, as well as on the resected tumour specimen.

Results: The pretherapeutic biopsy revealed cKit positive tumour cells with mutation of KIT exon 11 Del 560–576. The remaining tumour mass after neoadjuvant imatinib therapy almost exclusively consisted of hypocellular myxohyalinale stroma with rare microfoci of cKit positive tumour cells. Laser microdissection of several tumour microfoci revealed two additional point mutations located in the activation loop of KIT exon 17, C809G and N822Y, each observed separately in a distinct microfocus. Neither of these two point mutations has been reported in a GIST so far.

Conclusions: Neoadjuvant imatinib therapy successfully reduces tumour size in GISTs. Since resistance relevant secondary mutations of the activation loop of KIT may be observed after neoadjuvant imatinib therapy, the time elapse with preoperative imatinib therapy should be chosen as short as curative tumour resection or function sparing surgery can be carried out. The determination of the optimal time point for surgery is therefore a critical event and will be discussed.

Key Words: Gastrointestinal stromal tumour • GIST • Imatinib • KIT • Secondary resistance • Neoadjuvant therapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENT AND METHODS
 DISCUSSION
 REFERENCES
 
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, and are thought to arise from the interstitial cells of Cajal.1,2 Central to the tumouri-genesis in GISTs are oncogenic mutations in the proto-oncogene tyrosine protein kinase kit (KIT) or the platelet-derived growth factor receptor a (PDGFRA), both belonging to the subclass III family of receptor tyrosine kinases.3,4 The receptor tyrosine protein kinase inhibitor STI571 or imatinib (Gleevec, Novartis, Switzerland) effectively blocks autophosphorylation of oncogenic KIT, thus inhibiting ligand-independent intracellular signal transduction.5,6 After a first report describing highly effective tumour mass reduction in a metastasized GIST under imatinib treatment,5 imatinib therapy is now standard in metastasized/advanced GISTs and dramatically improves progression-free survival and overall survival.7 As complete surgical resection is the most important cure in primary GISTs,8 neoadjuvant imatinib therapy is confined only to patients with unresectable tumours, or tumours where a reduction in size may enable function sparing surgery.9 Criteria for the assessment of response to neoadjuvant therapy, and the optimal time point for surgery are not well defined to date.

We herein report a case of a large gastric GIST, for which resectability could be achieved after successful neoadjuvant imatinib therapy, and review the neo-adjuvant cases reported in the literature.


   PATIENT AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENT AND METHODS
DISCUSSION
 REFERENCES
 
Case Report
A 66-year-old female patient initially presented with gastric pain and dysphagia. A large gastric submucosal tumour was detected by gastroscopy, and biopsy specimen revealed the diagnosis of a cKit positive spindle-cell GIST (Fig. 1CGo). The biopsy specimen was too small to be evaluated for mitotic count in 50 high power fields (HPFs), but the proliferation rate as immunohistochemically assessed by Mib1 staining was 10%. Computed tomography (CT) scan of the abdomen demonstrated a GIST potentially arisen from the gastric wall with a size of 17 cm x 17 cm x 12 cm (total tumour volume: 3468 cm3). According to the large tumour size and the intimate relation to adjacent liver and spleen (Fig. 1AGo), neoadjuvant imatinib therapy with a daily dose of 400 mg was chosen. Apart from frequent nausea, edema of the face, and elevated liver enzymes, the patient reported no severe therapy side effects. CT scan was performed at 4, 6, 8, and 10 months of therapy to evaluate operability. Under therapy with imatinib, the maximal tumour diameter continuously shrunk on a linear scale to a size of 5.9 cm x 5.9 cm x 4.6 cm after 8 months (35% of initial maximal tumour diameter), whilst the total tumour volume exponentially shrunk to 160 cm3 (5% of initial total tumour volume). The initially unclear demarcation of the tumour to the liver disappeared (Fig. 1BGo). After 10 months of neoadjuvant therapy, a steady state in tumour shrinkage was observed (Fig. 2Go), thus partial gastrectomy according to Merendino with interposition of a jejunal segment was performed. Splenectomy was also performed due to an intraoperative detectable close relation of the residual tumour to the spleen (Fig. 1DGo). Tumour resection was complete, and 8 months after surgery, the patient has no signs of tumour recurrence. Grossly, the operation specimen revealed a whitish residual tumour mass with a diameter of 7.5 cm x 5.5 cm x 4.5 cm (total tumour volume: 185 cm3). Histologically, the tumour consisted almost exclusively of hypocellular, myxohyalinale stroma (Fig. 1EGo), with macrophages, lymphocytes, and focal necroses. Only in <1% of the residual tumour mass, rare cKit positive microfoci no larger than 0.3 cm in diameter of spindled tumour cells were present (Fig. 1FGo). The mitotic count/50 HPFs could not be evaluated due to the small size of these microfoci, but the proliferation rate ranged from 1 to 10%.


Figure 1
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  		FIG. 1. Comparison of pre- and post-imatinib CT scan and tumour tissue in a gastric GIST undergoing neoadjuvant imatinib therapy: A CT scan before imatinib therapy revealed a 17 cm in diameter sized tumour (*) potentially arisen from the gastric wall ({blacktriangleup}) with intimate relation to the liver and spleen ({downarrow}); B CT scan after 10 months of neoadjuvant imatinib therapy demonstrates a 5.9 cm in diameter sized residual tumour (*); C biopsy specimen before neoadjuvant imatinib treatment showing the spindle-cell shaped tumour cells, H&E 200x ; D gross specimen after neoadjuvant imatinib therapy demonstrating partial gastrectomy ({blacktriangleup}) with adjacent whitish residual tumour mass (*) in close proximity to the spleen ({downarrow}); E representative section of the tumour mass after imatinib therapy showing hypocellular my-xohyaline stroma, H&E 400x; F microfocus of cKit positive tumour cells with secondary KIT C809G mutation (cKit, 1:400 dilution, code no. A4502, DakoCytomation, visualization of the primary antibody was performed using the Dako ChemMate Detection Kit, DakoCytomation, with NeoFuchsin as Chromogen 100x).

 

Figure 2
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  		FIG. 2. Comparison of the relative reduction of maximal tumour diameter under neoadjuvant imatinib therapy from eight GISTs reported in the literature and the current case. In three cases including the current case ({diamond}), a stagnancy in tumour shrinkage was observed after 6, 10 and 12 months of neoadjuvant imatinib therapy.

 
Mutation Analysis
The tissue sections of formalin-fixed and paraffin-embedded tumour material of five distinct microfoci were subjected to contact-free laser microdissection (PALM, Microlaser Technologies, Bernried, Germany). The dissected tissue fragments were analysed for mutation of KIT exon 9, 11, 13, 17, and PDGFRA exon 12 and 18 as described previously.10 The initial biopsy specimen revealed solely a deletion of codons 560–576 of KIT exon 11. The microdissected tissue from all five distinct microfoci revealed the identical KIT Del 560–576. In tumour microfoci 1 and 3, there was a further point mutation in KIT exon 17, leading to substitution of cysteine to glycine at codon 809 (C809G) in the activation loop of KIT. Microfocus 5 had another secondary point mutation in KIT exon 17, leading to substitution of asparagine to tyrosine at codon 822 (N822Y) within the activation loop of KIT. Microfoci 2 and 4 had no further secondary mutations.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENT AND METHODS
 DISCUSSION
REFERENCES
 
Until now, few case reports with neoadjuvant imatinib treatment of primary GISTs have been reported (Table 1Go).11–17 Five gastric and one intestinal GISTs were admitted to neoadjuvant therapy because of size dependent primary unresectability (mean initial maximal tumour diameter 20 ± 8.2 cm), whilst in three rectal GISTs abdominoperineal resection of the rectum with colostomy was declined by the patient (mean initial maximal tumour diameter 8.2 ± 2.6 cm). In all but one case where 800 mg/day was used, a constant dose of 400 mg/day imatinib was applied. The mean maximal tumour diameter after neoadjuvant therapy was 10.8 ± 5.3 cm in the gastric and intestinal GISTs, and 2.9 ± 1.1 cm in the rectal GISTs, respectively. The therapy duration notedly varied from 1.5 to 12 months, and enabled complete tumour resection in all cases. Function sparing surgery with preservation of the anal sphincter was possible in all three rectal cases. In the current case, the relative reduction of maximal tumour diameter was linear, whilst the relative reduction of total tumour volume was exponential. Thus, the latter was more sensitive to disclose initial tumour response, whilst the first was more sensitive for the detection of a steady state in tumour shrinkage. After 10 months of neoadjuvant therapy, the tumour ceased to shrink, indicating that the maximum effect of imatinib therapy had been achieved. By then, the tumour was regarded resectable, and curative resection could be performed successfully. A stagnancy in tumour shrinkage was also observed in two other cases after 6 and 12 months (Fig. 2Go). Stagnation of tumour shrinkage represents a critical marker for the reevaluation of resectability and consideration of surgical intervention, apart from clearcut signs of resistance to imatinib therapy such as formation of nodules or tumour growth.


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  		TABLE 1. Review of neoadjuvant imatinib treatment in primary GISTs
 
Neoadjuvant imatinib therapy of primarily inoperable GISTs commonly results in "downsizing" (Fig. 1A–CGo) and enables curative surgical resection11–14 or function sparing surgery.15–17 Although imatinib therapy has dramatically improved progression-free and overall-survival in patients with metastasized/advanced GISTs,7 a complete pathologic remission is rarely achieved.18–21 Thus, surgical intervention should always be considered in neoadjuvant treated GISTs,8 preferably when the maximum effect of imatinib therapy has been achieved. In our case, multiple tumour microfoci of no more than 0.3 cm with secondary KIT mutations were the only remainder after 10 months of therapy (Fig. 1D–FGo). On the other hand, these microfoci can represent the earliest morphologically detectable correlates of imatinib resistance through clonal expansion of tumour cells. Resistance to imatinib after initial response through expansion of therapy-resistant and potentially pretherapeutic existent clones with secondary mutations has also initially been described in chronic myeloid leukemia,22 but is now also recognized in metastasized GISTs.23–26 Most secondary mutations affect codons 820–823 of KIT exon 17, which codes for the activation loop of KIT.27 As the corresponding amino acids are located directly at the imatinib binding site, a reduced binding of imatinib as a consequence of conformation change or reduced hydrogen bonds is very likely. Other secondary mutations affecting codons 815–816 of KIT exon 17, codon 654 of KIT exon 13, or codon 670 of KIT exon 14 have been reported as well.19,25,26,28,29 In our case, subsequent mutation analysis of laser microdissected tumour cells from biopsy specimen and distinct tumour microfoci revealed an initial KIT exon 11 Del 560–576 in the tumour biopsy obtained before treatment, and all analysed foci within the resected tumour. Furthermore, we found two novel secondary point mutations, KIT C809G and KIT N822Y, in distinct tumour microfoci after 10 months of imatinib treatment, which apparently were resistant to imatinib therapy. Neither of these two point mutations has been reported in a GIST so far.

As the mutations status corresponds with the grade of initial imatinib response, in that GISTs with mutation of KIT exon 11 typically show a better response compared to wildtype GISTs or GISTs with PDGFRA mutation D842V,30 a pretherapeutical mutation analysis from biopsy specimen may facilitate the decision for neoadjuvant imatinib treatment. With a rapidly ever increasing number of therapeutic agents like SU11248, AMG706, PKC412 or dasatinib emerging into clinical trials, mutation analysis can contribute to predict the optimal choice between these agents in each individual GIST. In the near future, an initial combination of two or more agents may be expected to overcome the currently imminent problem of imatinib resistance caused by secondary mutations.26


   ACKNOWLEDGMENTS
 
We thank Christina Enders, Kristina Hänecke and Stefanie Schwager for excellent technical assistance.

Received for publication August 1, 2006. Accepted for publication August 3, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENT AND METHODS
 DISCUSSION
 REFERENCES
 

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