Audit of a series of 40 gastrointestinal stromal tumour cases

EJSO 32 (2006) 1125e1129

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Audit of a series of 40 gastrointestinal stromal tumour cases S. Hinz a,*, U. Pauser b, J.H. Egberts a, C. Schafmayer a, J. Tepel a, F. Fa¨ndrich a a

Clinic of General Surgery and Thoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, 24105 Kiel, Germany b Institute of Pathology, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, 24105 Kiel, Germany Accepted 31 May 2006 Available online 20 July 2006

Abstract Aims: To analyze prognostic factors influencing survival and tumour recurrence after resection of gastrointestinal stromal tumours. Methods: Forty patients who underwent surgery for a GIST at our institution were reviewed. Patients were classified on the basis of tumour size, mitotic rate and CD117 positivity. The overall survival and disease free survival were calculated using KaplaneMeier method considering the extent of surgery comparing local tumour excisions with segmental organ resections. Results: Tumours were localized in the oesophagus, stomach, duodenum, small bowel and large bowel and rectum. Sixty-five percent of the patients had an intermediate or high risk GIST according to tumour size and mitotic count. In 26/40 patients tumour resection was performed using segmental organ resection, in all other patients local tumour excision was carried out. The mean overall survival was 73 months. Disease free survival was significantly better after local tumour excision compared to segmental organ resection (73 months versus 53 months; p ¼ 0.05). Large tumour size ( p ¼ 0.07) and high mitotic count ( p ¼ 0.14) were negative prognostic factors for disease free survival, although statistical significance was not reached yet. Conclusion: Primary surgery remains the cornerstone in the treatment of primary and recurrent GIST. Risk adapted surgery is the most important factor to avoid early tumour recurrence. In case of small tumour size segmental organ resections can be avoided favouring local tumour excisions with a low risk of tumour recurrence. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Gastrointestinal stromal tumours; GIST; Prognostic factors; Surgery; Adjuvant therapy

Introduction Gastrointestinal stromal tumours (GIST) are the most frequent mesenchymal tumours of the gastrointestinal tract. Until recently GIST were classified as leiomyosarcomas, leiomyoblastomas, schwannomas or leiomyomas. Since immunohistochemistry staining for c-kit (CD117) GIST can be distinguished from other smooth muscle tumours, although a small entity of c-kit negative GIST exists.1 The oncogenic development of GIST involves the activating mutation of the c-kit gene and the homologous PDGFRa gene, which leads to ligand independent activation of receptor tyrosine kinase c-kit or exclusively PDGFRa, resulting in increased cell survival and proliferation.2 Mutations involving the c-kit and PDGFRa proto-oncogene are linked with a decreased survival and more frequent tumour relapse.3,4 Specifically, mutations involving exon 11 of c-kit have * Corresponding author. Tel.: þ49 431 597 4581; fax: þ49 431 597 1939. E-mail address: [email protected] (S. Hinz). 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.05.018

a worse prognosis but have initially a good response to treatment with Imatinib. Tumours with mutations involving the kinase region have a low response to Imatinib. Until recently standard chemotherapy for soft tissue sarcomas with doxorubicin and ifosfamide was applied to advanced GIST and showed only poor results.5 Since the development of Imatinib, a selective inhibitor of tyrosine kinase c-kit/PDGFRa, a very effective treatment option for metastatic GIST exists.6,7 Currently clinical trials are being conducted to analyze the value of Imatinib as adjuvant treatment option after complete resection of intermediate and high risk GIST (EORTC 62024, ACOSOG, and SSGXVIII/AIO). Tumour resection is the standard therapy in localized GIST.8 Most important factor to avoid tumour recurrence is the complete resection of the tumour as en bloc removal of the tumour and if necessary with adjacent organs.9 As lymph node metastases in primary tumour stage are rarely found, systematic lymph node dissection is not necessary. To treat large tumours multivisceral surgery is necessary.

S. Hinz et al. / EJSO 32 (2006) 1125e1129

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tumours were not included. To define the risk of the aggressive behaviour in GISTs we applied risk categories as suggested by Fletcher et al.10 (very low, low, intermediate and high risk). Tumour prognosis was classified according to tumour size and number of mitoses per 50 high-power fields (HPF). The prognostic value of number of mitosis, type of resection, tumour size, sex and gender and primary tumour site were analyzed concerning their prognostic value.

To assign the risk of a malignant behaviour of the GIST tumour size and mitotic count are the accepted factors to classify GIST as very low, low, intermediate or high risk.10 The aim of this study was to report the outcome of our series of 40 tumours. Methods Patients

Statistics

From 1992 to 2004 all hospital charts of patients with a GIST were reviewed. Of 46 patients, 40 with primary or secondary surgery (recurrent disease) for a GIST were included. Six patients with local endoscopic treatment of very small gastric GIST were excluded from the study.

Data were analyzed using SPSS for Windows. Disease free survival and overall survival were calculated using KaplaneMeier method. Univariate analysis was performed using Log rank test, all p values < 0.05 were considered as statistically significant.

Definition of surgical approach In all cases the resection margins were histologically examined intraoperatively. The extent of tumour resection was classified as ‘‘local excision’’ on the one hand (e.g. wedge resection) and ‘‘segmental organ resection’’ (e.g. partial or complete gastrectomy and segmental small bowel resection) on the other hand.

Results Patients Forty patients with a GIST treated at our institution were included in the study. The median age was 64 years (36e90 years). From the 40 patients were 18 males and 22 females. Among these, 37 patients had first time surgery for a GIST at our institution and three patients were treated at our institution for recurrent GIST after initial tumour resection at a secondary hospital. In six patients an upper GI-bleeding (reflecting 25% of all patients with a GIST localized in the stomach) and in two patients a lower GI-bleeding was the leading symptom. Detailed tumour localizations are shown in Table 1.

Evaluated parameters Follow-up data were obtained either via the outpatient department or by contacting the general practitioner. For all patients tumour localization, tumour size, mitotic count (per 50 HPF) and c-kit immunohistochemistry were recorded. Positive c-kit (CD117) immunohistochemistry was used to declare a tumour as GIST. c-kit negative Table 1 Tumour characteristics Oesophagus (n ¼ 1)

Stomach (n ¼ 24)

Duodenum (n ¼ 5)

Small bowel (n ¼ 6)

Rectum (n ¼ 1)

Other (n ¼ 3)

Total (n ¼ 40)

Tumour size >5 cm <5 cm

1 e

15 9

2 3

3 3

e 1

1 2

22 18

Mitotic count >5 mitoses/50 HPF <5 mitoses/50 HPF

1 e

9 15

2 3

3 3

e 1

3 0

18 22

Fletcher classification Very low risk Low risk Intermediate risk High risk

e e 1 e

4 5 3 12

e 1 2 2

1 2 e 3

e 1 e e

e e 1 2

5 9 7 19

e 1

10 14

e 5

1 5

1 e

2 1

14 26

1/1

5/14

3/5

0/5

e

e

9/26

e 1

5 19

2 3

3 3

e 1

1 2

11 29

Type of resection Local excision Segmental organ resection With multivisceral resection Recurrent disease Disease free

S. Hinz et al. / EJSO 32 (2006) 1125e1129

Tumour characteristics Applying the established risk categories of GIST, five patients had very low risk, nine had low risk, six patients had intermediate and 20 patients had high risk of a malignant behaviour of the GIST. This reflects that the majority of the patients had an intermediate or high risk of an aggressive behaviour of their GIST. Regarding tumour size 18/40 of all tumours were smaller and 22/40 larger than 5 cm. The median tumour size was 7.3 cm. Tumour characteristics are shown in detail in Table 1. Surgical procedures The surgical procedures carried out in this study varied from local excision of the tumour to complex multivisceral surgery. The type of surgery was grouped in local excision and segmental organ resection as described in detail in ‘‘Methods’’. In 26/40 patients tumour resection was performed using segmental organ resection, whereas in 14/40 cases local excision of the tumour was carried out. GIST in the stomach could be treated in 10/24 cases by local excision and in 14/24 cases with segmental organ resection (eight patients with partial gastrectomy and six patients with total gastrectomy). In 2/24 patients local excision of the gastric GIST had to be extended to total gastrectomy, due to infiltrated resection margins. In five cases with gastric GIST multivisceral surgery was necessary to achieve an R0 (histologically tumour free) resection (for overview see Table 1). Only one patient with a gastric GIST was treated with a local excision using laparoscopic techniques. All the surgical procedures are summarized in Table 2. Complete tumour resection (R0 resection) was achieved in 35/40 patients, whereas 3/40 patients had incomplete tumour resection (R2 resection) and 2/40 patients had histological residual tumour cells (R1). In six patients GIST were coincidental findings during operations for other malignancies

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and not the primary cause for surgery. The three patients who were treated at our institution for recurrent disease underwent liver segmentectomy (n ¼ 1), left hemihepatectomy (n ¼ 1) and resection of local recurrent disease (n ¼ 2). Complications Post-operative complications were observed in 10/40 patients. There was no early post-operative mortality (until day 7) but 3/40 patients died in hospital: one patient developed liver failure due to portal vein thrombosis after left hemihepatectomy and two patients died due to sepsis following anastomosis leakage. In five cases dehiscence of anastomosis was observed. The high rate of anastomosis dehiscence might be influenced to locally large tumour size and high number of multivisceral resections. Survival and tumour recurrence The mean overall survival (OS) was 73 months with a median follow-up of 41 months (2e109 months). During follow-up 13 patients died, 10 due to tumour progression, which results in an overall tumour specific survival of 75% within the follow-up period. Ten out of 40 patients developed recurrent disease after a median disease free survival (DFS) of 84 months (Fig. 1). Among the 10 patients who developed recurrent disease five underwent secondary surgery, resulting in an R0 resection in two cases and R2 resection in three cases. Both patients with R0 resection developed a secondary recurrence and underwent tertiary surgery with consequent R2 resection. In four cases of recurrent disease and R2 resection adjuvant treatment

1,0

Procedures

n

Resection stomach Local excision Partial gastrectomy Total gastrectomy Small bowel resection Partial liver resection Oesophageal resection Whipple procedure Rectal wall excision Splenectomy Left resection of pancreas

24 10 8 6 8 2 1 1 1 4 2

Resection margins R0 resection R1 resection R2 resection

35 2 3

disease free survival

,8

Table 2 Surgical procedures

,6

,4

,2

all patients segmental organ resection local excision

0,0 0

24

48

72

96

120

months Figure 1. Analysis of the extent of surgical resection as prognostic factor influencing the disease free survival.

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with Imatinib was administered resulting in a stable disease in one case, partial remission in two cases and full remission in one case (mean time of treatment, 24 months). Tumour size > 5 cm and mitotic count > 5 mitoses/50 HPF were prognostic factors of a poor outcome for DFS although they did not reach statistical significance yet. The mean DFS of tumours > 5 cm is 47 months and 87 months in tumours < 5 cm ( p ¼ 0.07). Concerning the mitotic rate the DFS of tumours with <5 mitoses/50 HPF was 77 months and 50 months in tumours with >5 mitoses/50 HPF ( p ¼ 0.14). The mean DFS after segmental organ resection was 53 months, whereas in patients with a local excision of the tumour the mean DFS reached 73 months ( p ¼ 0.05) (Fig. 1). After local excision of the tumour we found no patient with tumour recurrence, in contrast to this 10/24 of the patients with segmental organ resection developed recurrent disease after a mean of 56 months. Using the Chi-quadrat test we could show that the development of a recurrence depends on tumour size > 5 cm ( p ¼ 0.002), mitotic count > 5 mitoses/50 HPF ( p ¼ 0.007) and tumour resection using segmental organ resection ( p ¼ 0.015). All other parameters analyzed (age, sex, and primary tumour site) showed no prognostic value for the development of a recurrent disease. Discussion Despite the great success of Imatinib in the treatment of metastatic GIST, primary surgery remains the cornerstone in the treatment of localized and resectable GIST. Recurrent disease is still a great problem most notably due to secondary resistance against Imatinib11 and arise new problems in the treatment of advanced GIST. Therefore primary risk adapted surgery is the most important factor to avoid an early tumour recurrence and it is important to identify patients who may be candidates to receive an adjuvant treatment after complete tumour resection. Large tumour size and high mitotic count negatively influence DFS Our results show that large tumour size (>5 cm) and high mitotic count (>5 mitoses/50 HPF) were predictive for a reduced DFS, although due to low case numbers statistical significance was not reached yet. These results were expected as these criteria are already accepted to define the risk of malignancy of GIST10 and were confirmed in a large series of patients.12 The type of surgery with local excision on the one hand and segmental organ resection on the other hand did influence the DFS. Patients with a segmental organ resection developed more recurrences than patients who underwent only local tumour excision. This is largely a result of tumour size, as small tumours can easily be treated by local excision and only large tumours needed a segmental organ resection for complete resection. In four cases segmental organ resection was

performed despite small tumour size and low mitotic rate (one patient with a tumour of the duodenum near the papilla vateri, two patients with a tumour in the small bowel, one patient with a GIST in the stomach coincidentally with an adenocarcinoma). In our hands no patient with local excision developed a recurrent disease. This supports the ESMO guidelines for the treatment of GIST, which recommend local excisions of small tumours as adequate surgery as far as tumour free resection margins are achieved.13 In other hands more local recurrences are seen in patients with local excision versus segmental organ resection and Aparicio et al. recommend to avoid local excision of GIST even in small tumours14 which disagrees with our results. The treatment of a recurrent GIST with secondary surgery alone has a high risk of tumour recurrence even in cases with R0 resection. Currently two adjuvant therapy trials are conducted in Europe to evaluate the benefit of Imatinib in those GIST patients who have a substantial risk of relapse after complete surgery. Furthermore, the administration of Imatinib in patients with advanced GIST preoperatively to avoid multivisceral surgery is still an individual decision as data from a controlled trial are still missing. Conclusion Summarizing our results with the influence of tumour size and mitotic count on the DFS, which is reflected by a high rate of recurrences after segmental organ resection and not after local tumour excision, we support the concept that all patients with high risk GIST or patients with segmental organ resection need to be assessed for adjuvant treatment with Imatinib.

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