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Gastrointestinal stromal tumours (GIST) – 17 years experience from Mid Trent Region (United Kingdom)
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EJSO 34 (2008) 445e449
www.ejso.com
Gastrointestinal stromal tumours (GIST) e 17 years experience from Mid Trent Region (United Kingdom) I. Ahmed, N.T. Welch, S.L. Parsons* Department of General and Upper GI Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK Accepted 8 January 2007 Available online 21 February 2007
Abstract Objectives: To report our experience with gastrointestinal stromal tumours (GISTs). Methods: Retrospective data were collected from January 1987 to December 2003. Clinical and histological data were analysed to identify recurrence patterns and factors predicting survival. The tumours were studied with respect to size, number of mitosis and cell type. Results: One hundred and eighty-five patients were identified with GIST with the age range of 18e93 years (mean 64.4 years) with a mean follow up of 6.7 years. Eighty out of 185 patients were in the low group, 38/185 in intermediate risk and 67/185 were in the high risk group. Eighty-three percent of the patients underwent surgical resection. Ten percent of the patients in the intermediate group and 25% of the patients in high risk group developed recurrence. Mortality was 5% and 37% in intermediate and high risk groups, respectively. There was no tumour related mortality or recurrence in the low risk group. Conclusions: It is important to identify the patients in low and high risk groups. Patients in intermediate and high risk groups require complete resection (R0) and follow up with CT scans. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: GIST; Gastrointestinal stromal tumour; CD117; Resection margins; Recurrence
Introduction In 1940 Stout et al. described ‘‘stromal tumours’’ arising from the gastrointestinal (GI) tract smooth muscle as leiomyoma, leiomyosarcoma, leiomyoblastoma and bizarre leiomyoma. With the use of electron microscope (1970s) and immunohistochemistry (1980s), it was realized that large number of these tumours lacked features of smooth muscles and expressed antigens related to neural crest cells. The term ‘‘stromal tumours’’ was first used in 1983 and 1984.1,2 Later with the identification of immunopositivity to CD34 and then to CD117 (c-kit protein), the diagnosis has become standardized.3,4 Certain interstitial cells of Cajal (ICCs) have been proposed to be the cells of origin of GIST.5,6 GISTs represent 1% of all primary GI tumours and are the commonest of GI tumours of mesenchymal origin.7 * Corresponding author. Department of Upper GI Surgery, Nottingham University Hospitals, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Tel.: þ44 (0) 115 969 1169, þ44 (0) 07976643472 (mobile); fax: þ44 (0) 115 962 77 64. E-mail address: [email protected] (S.L. Parsons). 0748-7983/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2007.01.006
The aggregate prevalence of GIST is difficult to estimate as it comprises both patients currently accurately diagnosed and those previously misdiagnosed. Using yearly incidence and survival data, total world wide prevalence of 20,000e50,000 cases can be estimated.8 High mitotic index and larger tumour size remain the two most reliable predictors of increasing risk of malignancy.9 GIST tumours can now be treated with chemotherapy with Imatinib (GlivecÒ) with patient 5-year survival after surgical resection ranging from 48% to 80%.10e13 Aims of the study Aims of this study were to report recurrence and survival data of GIST in the Trent Region with correlation to high/intermediate and low risk groups as suggested by Fletcher,9 to report the incidence of GISTs by anatomical site, to see whether the anatomical site correlated with risk classification and to report the influence of resection margin on recurrence and survival of these patients.
446
I. Ahmed et al. / EJSO 34 (2008) 445e449
Materials and methods The study was conducted in two teaching hospitals (Nottingham City Hospital and Queens Medical Centre, Nottingham, UK). The data were collected from January 1987 until December 2003 (17 years). Prospectively collected histopathology database was used to identify patients with a possible diagnosis of GIST. We used the keywords leiomyoma, cellular leiomyoma, leiomyosarcoma, myoblastoma, sarcoma, schwannoma, GANT (Giant Autonomic Nerve Tumour) and GIST for the initial search. Total of 303 records were obtained. Histopathology specimen and slides were re-examined to identify possible GIST tumours. Tumours with the old classification were re-stained using the CD117 (provided by Novartis). All the newly classified tumours were stratified into risk groups based on size of the tumour and number of mitotic count/50 HPF (Fletcher classification). Resection margins were classified as R0eR2 according to the Union International Contra Cancrum system. Recurrence was defined as the appearance of macroscopic tumour at the site of original resection. A metastasis was defined as the appearance of tumour distant to the site of resection (liver, lymph nodes or peritoneal cavity). Clinical and histological data were analysed to identify recurrence patterns and factors predicting survival. The tumours were evaluated with respect to size, number of mitosis/50 HPF and cell type. The medical records were reviewed for clinical correlation. Resection margins and their influence on the risk of recurrence were studied. Complete macroscopic and microscopic resection was considered as R0 resection. If the tumour was completely removed macroscopically but there was evidence of involved resection margins in histopathology report, it was considered as R1 resection. Residual tumour left behind at the original operation was considered as R2 resection. Recurrence was defined as documented appearance (clinical or radiological) of tumour after R0 or R1 resection. As macroscopic tumour was left after R2 resection this group was not looked at while analysing the recurrence data. As most of the patients previously diagnosed as having smooth muscle tumours were discharged from the clinics, the follow up data were completed by contacting general practitioners (GPs) and individual patients by telephone. Patients who were lost to follow up were excluded from the study. In the event of death, details and cause of death were obtained from hospital records, GPs and national database. All the results were recorded in a database (Microsoft Access XP) and analysed. Results Two hundred and twenty-five patients were identified with GIST tumours over a period of 204 months in the
Mid Trent. The annual incidence was calculated as 13.2 per million population. Histology was available for all the patients. Fifty-two out of 225 tumours were initially classified as GIST while the old classification was used in 173/ 225 patients. One hundred and fifty-seven tumours were re-classified using immunohistochemistry (CD117 staining). Thirty-one patients were lost to follow up and these were excluded from the study. On completion of the study, complete histopathological, clinical and follow up data were available for 185/225 patients. Eighty patients were in the low risk group, 38 were in the intermediate risk group and 67 were in the high risk group. Age range of all the patients was 18e93 years (mean 64.4 years). There was slight female pre-dominance (male: female 87:98). Tumour size ranged from 10e4500 mm (mean 67 mm, median 32 mm). Immunohistochemistry of these tumours showed that 183/185 tumours were positive for CD117 and 144/185 positive for CD34. There were various modes of presentation of these tumours. Majority of the patients (94/185) presented with either upper or lower GI bleeding. Thirty-four out of 185 presented with abdominal pain. Twenty-three out of 185 tumours were incidental finding and nine out of 185 presented with intestinal obstruction. Not all the patients underwent pre-operative biopsy. Only 53/185 had a biopsy before the surgical procedure. Fourteen out of 53 pre-operative biopsies showed musoca only and an operation was carried out on 10/14 of these patients based on clinical suspension. One hundred and fifty-three out of 185 of the patients underwent surgical resection. The remaining 32/185 were not operated on due to reasons like patient co-morbidity, metastatic disease or locally advanced disease. Local excision of tumour was carried out in 91/153 and resection of the involved organ was carried out in 62/153 patients. Tumour location The majority of the tumours (96/185) were found in the stomach. Remaining tumour distribution was 16/185 in the oesophagus, 11/185 in the duodenum, 19/185 in the small bowel (jejunum/ileum), 24/185 in the colon, 7/185 in the rectum and 11/185 were found in extra gastrointestinal sites (Table 1). Resection margins Seventy-nine out of 153 patients had documented R0 resection (45 low risk, 19 intermediate risk and 15 high risk). None of the low or intermediate risk patients in this group had further recurrence. Eleven out of 153 of the patients had R1 resection. Out of these patients who received an R1 resection, four were in
I. Ahmed et al. / EJSO 34 (2008) 445e449
447
Table 1 Distribution (%) of GISTs by site and their relative risk categories
Table 3 Recurrence and deaths in our series
Organs involved
Total cases Low risk (%) Intermediate (%) High risk (%) (n ¼ 185) (n ¼ 80) (n ¼ 38) (n ¼ 67)
Risk group
Total
Recurrence
Tumour related deaths
Oesophagus Stomach Duodenum Small bowel Appendix Colon Rectum Extra GI
16 96 11 19 1 24 7 11
Low risk Intermediate risk High risk
80 38 67
0 4 17
0 2 25
100 42.7 36.4 36.8 100 33.3 42.8 0
0 27 18.2 15.7 0 16.6 14.4 18.2
0 30.3 45.5 47.4 0 50 42.8 81.8
the intermediate risk category with two out of four patients developing recurrence. All the five patients in the R1 resection group who were in the high risk category developed recurrence. Fifteen out of 153 patients had an R2 resection as the resection could not be completed due to extensive disease. No further recurrence data were collected for this group. In 48/153 resections there was no comment on the resection margin in the histopathology report (Table 2). The patients having biopsy and no further surgery were not included for analysis. Follow up Mean follow up of the patients was 6.8 years (6 monthse15 years) with a median of 4.2 years. Four out of 38 patients in the intermediate risk group and 17/67 patients in the high risk group developed recurrence. None of the 80 patients in the low risk group developed recurrence (Table 3). Interval of development of recurrence was 4e24 months (median 9 months). Eighty-seven patients have died since the diagnosis of the tumour. Sixty patients died of a cause not directly related to the tumour. The disease specific mortality was 14.5% with 27/185 patients dying as a result of the disease (Figs. 1 and 2) There was no recurrence or death in the low risk group. Two out of 27 deaths were in the intermediate risk group. Twenty-five out of 27 deaths were in the high risk group (Table 3) Discussion GISTs are uncommon mesenchymal tumours of gastrointestinal tract. Recent retrospective studies using Table 2 Resection margins (Union International Contra la Cancrum system) Margins
Total (n ¼ 185)
Low (n ¼ 80)
Intermediate (n ¼ 38)
High (n ¼ 67)
R0 R1 R2 Not commented Biopsy only
79 11 15 48 32
45 2 0 28 5
19 4 5 10 0
15 5 10 10 27
diagnostic markers on historical specimens have identified that GISTs still remain under-diagnosed.14 A few case series are available but the number of cases in all these series remains small. Only a few series have reported cases in three figures up to 200 cases.11,15e18 The only large study comes from Miettinen and colleagues analysing 1869 cases originally classified as smooth muscle tumours of the stomach and found that 1765 (94%) of these were GISTs.19 They concluded that the outcome was strongly dependent on tumour size and mitotic activity. The strengths of our study compared to other similar series include the number of cases, re-classification of the historic specimen and completeness of follow up. Our series remains one of the largest studies combining histological data with the clinical presentation and long term follow up. Looking at the tumour behaviour according to the risk groups correlates well with the long term outcome of these patients with no recurrence or deaths identified in the low risk group. Intermediate risk group still remains a grey area regarding further follow up and management as we have identified two patients with recurrence in that group. This group should be included in the regular follow up. The high risk group had the highest rate of recurrence and mortality. The suggested and potentially curative treatment remains surgical with a wide local excision margin of the entire tumour to achieve microscopic clearance. Our study has looked into the recurrence patterns and highlighted that incomplete resection remains the main factor. If the lesion is operable (considering tumour and patient factors) it should be completely resected and sent for analysis. Needle biopsy should be avoided in these cases due to the risk of tumour seeding. Surgery should aim at complete removal of tumour and preservation of function without compromising the completeness of the resection. Early re-excision should be considered in case of incomplete resection if the patient is fit to undergo revisional surgery as these patients have a high risk for recurrence. Complete resection (R0) is also recommended by other authors.20 Unresectable or metastatic lesions can be biopsied (EUS guided) to prove the diagnosis and imatinib can be used according to current NICE guidelines.21 It is clear from the available data that it is important to clearly identify patients into risk groups as it will determine the overall prognosis and need for regular and long term follow up. Intermediate and high risk tumours have significant risk of recurrence and tumour related deaths hence the need to stay under regular surveillance.
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Survival Data:Survival proportions
105 100 95 90
Percent survival
85 80 75 70 65 60 55 50 High risk Intermediate risk Low risk
45 40 35
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220
Time in months Figure 1. KaplaneMeier survival curve of the patients who died due to GIST (excluding other causes of death).
There have been recent guidelines regarding the investigation, treatment and follow up of GISTs.22 A UK guidelines document in October 2004 suggests that the management of GISTs should be undertaken by a multidisciplinary team (MDT) with experience in this disease. Pathological review of all cases should be made by a pathologist experienced in this tumour type. Surgery is the principal treatment for GISTs and suitability for resection should be explored by an appropriate sub-specialist surgeon. Fletcher’s criteria are simple to follow and we suggest follow up of patients should be based on classification according to the risk groups based on these criteria).
Further data analysis is required concentrating on site specific GISTs to determine whether the site influences prognosis. In our study it is difficult to make a firm judgement due to small number of GISTs in individual organs. A national or multi-centre data collection will help answer this question. The role of neo-adjuvant and adjuvant therapies in GISTs is also not clear. Observation is the current standard of care after resection of a primary tumour.23 At present there is no evidence that adjuvant chemotherapy or radiotherapy reduces recurrence rates.24 A trial of the use of Imatinib (Glivec) in the adjuvant setting is being planned for intermediate and high risk tumours and we await the
Recurrence Data
105 100 95
Percent survival
90 85 80 75 70 65 High risk Intermediate risk Low risk
60 55
0
10 20
30 40 50
60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220
Time in months Figure 2. KaplaneMeier recurrence for the patients who developed clinical recurrence following resection of GIST.
I. Ahmed et al. / EJSO 34 (2008) 445e449
results with interest. Imatinib remains the only available effective therapy for unresectable and/or metastatic GISTs25 and is recommended by NICE.21 Clinical trials of imatinib for treatment of GIST led to early registration in 2002, with a recommended initial dose of 400 mg daily.25e27 Conclusions Over the last 10 years, GISTs have been found to be c-kit and CD34 positive and this has led to their re-classification from a heterogeneous group of rare tumours to a single group of tumours. We have shown that their behaviour can be accurately predicted from their risk classification and whether they have been completely resected. With the development of Imatinib (Glivec), which has been shown to be a safe and effective treatment of recurrent or metastatic GISTs, follow up of intermediate and high risk GISTs has become mandatory. Conversely low risk GISTs can safely be discharged from long term follow up. Conflict of interest CD117 was provided by Novartis for back testing of all the historical samples. Acknowledgement We would like to acknowledge the histopathology departments in Queens Medical Centre and City Hospital Nottingham for allowing us to use their data in preparation for this paper. References 1. Mazur MT, Clark HB. Gastric stromal tumors: reappraisal of histogenesis. Am J Surg Pathol 1983;7:507–19. 2. Schaldenbrand JD, Appleman HD. Solitary solid stromal tumors in gastrointestinal tumors in Von Recklinghausen’s disease with minimal smooth muscle differentiation. Hum Pathol 1984;15:229–32. 3. Miettinen M, Virolainen M, Sarlomo-Rikala M. Gastrointestinal stromal tumors: value of CD34 in their identification and separation from true leiomyomas and schwannomas. Am J Surg Pathol 1995; 19:207–16. 4. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577–80. 5. Kindblom L-G, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cells (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of interstitial cells of Cajal. Am J Pathol 1998;152:1259–69. 6. Sircar K, Hewlett BR, Huizinga JD, Chorneyko K, Berezin I, Riddell RH. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol 1999;23(4):377–89. 7. Nishida T, Hirota S. Biological and clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol 2000;15:1293–301.
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8. Novartis Pharma AG. Basel, Switzerland; 2002. 9. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33:459–65. 10. Rossi CR, Mocellin S, Mencarelli R, et al. Gastrointestinal stromal tumours: from a surgical to a molecular approach. Int J Cancer 2003;107(2):171–6. 11. Dematteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumours: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231:51–8. 12. Demetri G. Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571). Eur J Cancer 2002;38:S52–9. 13. Langer C, Gunawan B, Schuler P, Huber W, Fuzesi L, Becker H. Prognostic factors influencing surgical management and outcome of gastrointestinal stromal tumours. Br J Surg 2003;90:332–9. 14. Koch S, Besuch P. Gastrointestinal stromal tumours e retrospective classification of mesenchymal tumours of the gastrointestinal tract. DGHO 2003. http://www.cancerimprovement.nhs.uk/%5Cdocuments %5Cupper_gi%5Cpathways%5CGIST_Mngmnt7.pdf. 15. Urbanczyk K, Limon J, Korobowicz E, et al. Gastrointestinal stromal tumours. A multicenter experience. Pol J Pathol 2005;56(2):51–61. 16. Wong NA, Young R, Malcomson RD, et al. Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach. : Histopathology 2003;43(2):118–26. 17. Fujimoto Y, Nakanishi Y, Yoshimura K, Shimoda T. Clinicopathologic study of primary malignant gastrointestinal tumour of the stomach, with special reference to prognostic factors: analysis of results in 140 surgically resected patients. Gastric cancer 2003;6(1):39–48. 18. Orosz Z, Tornoczky T, Sapi Z. Gastrointestinal stromal tumours: a clinicopathologic and immunohistochemical study of 136 cases. Pathol Obcol Res 2005;11(1):11–21. 19. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumours of the stomach: a clinicopathological, immunohistochemical and molecular genetic study of 1765 cases with long term follow-up. Am J Surg Pathol 2005;29(1):52–68. 20. Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumours. Br J Surg 2003;90:1178–86. 21. TA086 Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. Technology Appraisal 86. National Institute for Clinical Excellence; October 2004.. 22. Judons I, Leahy M, Whelan J, et al. A guideline for the management of gastrointestinal stromal tumour (GIST). Sarcoma 2002;6:83–7. 23. DeMatteo RP, Heinrich MC, El-Rifai WM. Clinical management of gastrointestinal stromal tumours: before and after STI-571. Human Pathology 2002;33:466–77. 24. Lehnert T. Gastrointestinal sarcoma (GIST) e a review of surgical management. Ann Chir Gynaecol 1998;87:297–305. 25. Demetri GD, von Mehren M, Blanke CD. Efficacy and safety of imatinib mesylate in advanced gastrointestinal tumours. N Engl J Med 2002;347(7):472–80. 26. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3. 27. Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003;39:2006–11.
EJSO 34 (2008) 445e449
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Gastrointestinal stromal tumours (GIST) e 17 years experience from Mid Trent Region (United Kingdom) I. Ahmed, N.T. Welch, S.L. Parsons* Department of General and Upper GI Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK Accepted 8 January 2007 Available online 21 February 2007
Abstract Objectives: To report our experience with gastrointestinal stromal tumours (GISTs). Methods: Retrospective data were collected from January 1987 to December 2003. Clinical and histological data were analysed to identify recurrence patterns and factors predicting survival. The tumours were studied with respect to size, number of mitosis and cell type. Results: One hundred and eighty-five patients were identified with GIST with the age range of 18e93 years (mean 64.4 years) with a mean follow up of 6.7 years. Eighty out of 185 patients were in the low group, 38/185 in intermediate risk and 67/185 were in the high risk group. Eighty-three percent of the patients underwent surgical resection. Ten percent of the patients in the intermediate group and 25% of the patients in high risk group developed recurrence. Mortality was 5% and 37% in intermediate and high risk groups, respectively. There was no tumour related mortality or recurrence in the low risk group. Conclusions: It is important to identify the patients in low and high risk groups. Patients in intermediate and high risk groups require complete resection (R0) and follow up with CT scans. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: GIST; Gastrointestinal stromal tumour; CD117; Resection margins; Recurrence
Introduction In 1940 Stout et al. described ‘‘stromal tumours’’ arising from the gastrointestinal (GI) tract smooth muscle as leiomyoma, leiomyosarcoma, leiomyoblastoma and bizarre leiomyoma. With the use of electron microscope (1970s) and immunohistochemistry (1980s), it was realized that large number of these tumours lacked features of smooth muscles and expressed antigens related to neural crest cells. The term ‘‘stromal tumours’’ was first used in 1983 and 1984.1,2 Later with the identification of immunopositivity to CD34 and then to CD117 (c-kit protein), the diagnosis has become standardized.3,4 Certain interstitial cells of Cajal (ICCs) have been proposed to be the cells of origin of GIST.5,6 GISTs represent 1% of all primary GI tumours and are the commonest of GI tumours of mesenchymal origin.7 * Corresponding author. Department of Upper GI Surgery, Nottingham University Hospitals, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Tel.: þ44 (0) 115 969 1169, þ44 (0) 07976643472 (mobile); fax: þ44 (0) 115 962 77 64. E-mail address: [email protected] (S.L. Parsons). 0748-7983/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2007.01.006
The aggregate prevalence of GIST is difficult to estimate as it comprises both patients currently accurately diagnosed and those previously misdiagnosed. Using yearly incidence and survival data, total world wide prevalence of 20,000e50,000 cases can be estimated.8 High mitotic index and larger tumour size remain the two most reliable predictors of increasing risk of malignancy.9 GIST tumours can now be treated with chemotherapy with Imatinib (GlivecÒ) with patient 5-year survival after surgical resection ranging from 48% to 80%.10e13 Aims of the study Aims of this study were to report recurrence and survival data of GIST in the Trent Region with correlation to high/intermediate and low risk groups as suggested by Fletcher,9 to report the incidence of GISTs by anatomical site, to see whether the anatomical site correlated with risk classification and to report the influence of resection margin on recurrence and survival of these patients.
446
I. Ahmed et al. / EJSO 34 (2008) 445e449
Materials and methods The study was conducted in two teaching hospitals (Nottingham City Hospital and Queens Medical Centre, Nottingham, UK). The data were collected from January 1987 until December 2003 (17 years). Prospectively collected histopathology database was used to identify patients with a possible diagnosis of GIST. We used the keywords leiomyoma, cellular leiomyoma, leiomyosarcoma, myoblastoma, sarcoma, schwannoma, GANT (Giant Autonomic Nerve Tumour) and GIST for the initial search. Total of 303 records were obtained. Histopathology specimen and slides were re-examined to identify possible GIST tumours. Tumours with the old classification were re-stained using the CD117 (provided by Novartis). All the newly classified tumours were stratified into risk groups based on size of the tumour and number of mitotic count/50 HPF (Fletcher classification). Resection margins were classified as R0eR2 according to the Union International Contra Cancrum system. Recurrence was defined as the appearance of macroscopic tumour at the site of original resection. A metastasis was defined as the appearance of tumour distant to the site of resection (liver, lymph nodes or peritoneal cavity). Clinical and histological data were analysed to identify recurrence patterns and factors predicting survival. The tumours were evaluated with respect to size, number of mitosis/50 HPF and cell type. The medical records were reviewed for clinical correlation. Resection margins and their influence on the risk of recurrence were studied. Complete macroscopic and microscopic resection was considered as R0 resection. If the tumour was completely removed macroscopically but there was evidence of involved resection margins in histopathology report, it was considered as R1 resection. Residual tumour left behind at the original operation was considered as R2 resection. Recurrence was defined as documented appearance (clinical or radiological) of tumour after R0 or R1 resection. As macroscopic tumour was left after R2 resection this group was not looked at while analysing the recurrence data. As most of the patients previously diagnosed as having smooth muscle tumours were discharged from the clinics, the follow up data were completed by contacting general practitioners (GPs) and individual patients by telephone. Patients who were lost to follow up were excluded from the study. In the event of death, details and cause of death were obtained from hospital records, GPs and national database. All the results were recorded in a database (Microsoft Access XP) and analysed. Results Two hundred and twenty-five patients were identified with GIST tumours over a period of 204 months in the
Mid Trent. The annual incidence was calculated as 13.2 per million population. Histology was available for all the patients. Fifty-two out of 225 tumours were initially classified as GIST while the old classification was used in 173/ 225 patients. One hundred and fifty-seven tumours were re-classified using immunohistochemistry (CD117 staining). Thirty-one patients were lost to follow up and these were excluded from the study. On completion of the study, complete histopathological, clinical and follow up data were available for 185/225 patients. Eighty patients were in the low risk group, 38 were in the intermediate risk group and 67 were in the high risk group. Age range of all the patients was 18e93 years (mean 64.4 years). There was slight female pre-dominance (male: female 87:98). Tumour size ranged from 10e4500 mm (mean 67 mm, median 32 mm). Immunohistochemistry of these tumours showed that 183/185 tumours were positive for CD117 and 144/185 positive for CD34. There were various modes of presentation of these tumours. Majority of the patients (94/185) presented with either upper or lower GI bleeding. Thirty-four out of 185 presented with abdominal pain. Twenty-three out of 185 tumours were incidental finding and nine out of 185 presented with intestinal obstruction. Not all the patients underwent pre-operative biopsy. Only 53/185 had a biopsy before the surgical procedure. Fourteen out of 53 pre-operative biopsies showed musoca only and an operation was carried out on 10/14 of these patients based on clinical suspension. One hundred and fifty-three out of 185 of the patients underwent surgical resection. The remaining 32/185 were not operated on due to reasons like patient co-morbidity, metastatic disease or locally advanced disease. Local excision of tumour was carried out in 91/153 and resection of the involved organ was carried out in 62/153 patients. Tumour location The majority of the tumours (96/185) were found in the stomach. Remaining tumour distribution was 16/185 in the oesophagus, 11/185 in the duodenum, 19/185 in the small bowel (jejunum/ileum), 24/185 in the colon, 7/185 in the rectum and 11/185 were found in extra gastrointestinal sites (Table 1). Resection margins Seventy-nine out of 153 patients had documented R0 resection (45 low risk, 19 intermediate risk and 15 high risk). None of the low or intermediate risk patients in this group had further recurrence. Eleven out of 153 of the patients had R1 resection. Out of these patients who received an R1 resection, four were in
I. Ahmed et al. / EJSO 34 (2008) 445e449
447
Table 1 Distribution (%) of GISTs by site and their relative risk categories
Table 3 Recurrence and deaths in our series
Organs involved
Total cases Low risk (%) Intermediate (%) High risk (%) (n ¼ 185) (n ¼ 80) (n ¼ 38) (n ¼ 67)
Risk group
Total
Recurrence
Tumour related deaths
Oesophagus Stomach Duodenum Small bowel Appendix Colon Rectum Extra GI
16 96 11 19 1 24 7 11
Low risk Intermediate risk High risk
80 38 67
0 4 17
0 2 25
100 42.7 36.4 36.8 100 33.3 42.8 0
0 27 18.2 15.7 0 16.6 14.4 18.2
0 30.3 45.5 47.4 0 50 42.8 81.8
the intermediate risk category with two out of four patients developing recurrence. All the five patients in the R1 resection group who were in the high risk category developed recurrence. Fifteen out of 153 patients had an R2 resection as the resection could not be completed due to extensive disease. No further recurrence data were collected for this group. In 48/153 resections there was no comment on the resection margin in the histopathology report (Table 2). The patients having biopsy and no further surgery were not included for analysis. Follow up Mean follow up of the patients was 6.8 years (6 monthse15 years) with a median of 4.2 years. Four out of 38 patients in the intermediate risk group and 17/67 patients in the high risk group developed recurrence. None of the 80 patients in the low risk group developed recurrence (Table 3). Interval of development of recurrence was 4e24 months (median 9 months). Eighty-seven patients have died since the diagnosis of the tumour. Sixty patients died of a cause not directly related to the tumour. The disease specific mortality was 14.5% with 27/185 patients dying as a result of the disease (Figs. 1 and 2) There was no recurrence or death in the low risk group. Two out of 27 deaths were in the intermediate risk group. Twenty-five out of 27 deaths were in the high risk group (Table 3) Discussion GISTs are uncommon mesenchymal tumours of gastrointestinal tract. Recent retrospective studies using Table 2 Resection margins (Union International Contra la Cancrum system) Margins
Total (n ¼ 185)
Low (n ¼ 80)
Intermediate (n ¼ 38)
High (n ¼ 67)
R0 R1 R2 Not commented Biopsy only
79 11 15 48 32
45 2 0 28 5
19 4 5 10 0
15 5 10 10 27
diagnostic markers on historical specimens have identified that GISTs still remain under-diagnosed.14 A few case series are available but the number of cases in all these series remains small. Only a few series have reported cases in three figures up to 200 cases.11,15e18 The only large study comes from Miettinen and colleagues analysing 1869 cases originally classified as smooth muscle tumours of the stomach and found that 1765 (94%) of these were GISTs.19 They concluded that the outcome was strongly dependent on tumour size and mitotic activity. The strengths of our study compared to other similar series include the number of cases, re-classification of the historic specimen and completeness of follow up. Our series remains one of the largest studies combining histological data with the clinical presentation and long term follow up. Looking at the tumour behaviour according to the risk groups correlates well with the long term outcome of these patients with no recurrence or deaths identified in the low risk group. Intermediate risk group still remains a grey area regarding further follow up and management as we have identified two patients with recurrence in that group. This group should be included in the regular follow up. The high risk group had the highest rate of recurrence and mortality. The suggested and potentially curative treatment remains surgical with a wide local excision margin of the entire tumour to achieve microscopic clearance. Our study has looked into the recurrence patterns and highlighted that incomplete resection remains the main factor. If the lesion is operable (considering tumour and patient factors) it should be completely resected and sent for analysis. Needle biopsy should be avoided in these cases due to the risk of tumour seeding. Surgery should aim at complete removal of tumour and preservation of function without compromising the completeness of the resection. Early re-excision should be considered in case of incomplete resection if the patient is fit to undergo revisional surgery as these patients have a high risk for recurrence. Complete resection (R0) is also recommended by other authors.20 Unresectable or metastatic lesions can be biopsied (EUS guided) to prove the diagnosis and imatinib can be used according to current NICE guidelines.21 It is clear from the available data that it is important to clearly identify patients into risk groups as it will determine the overall prognosis and need for regular and long term follow up. Intermediate and high risk tumours have significant risk of recurrence and tumour related deaths hence the need to stay under regular surveillance.
I. Ahmed et al. / EJSO 34 (2008) 445e449
448
Survival Data:Survival proportions
105 100 95 90
Percent survival
85 80 75 70 65 60 55 50 High risk Intermediate risk Low risk
45 40 35
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220
Time in months Figure 1. KaplaneMeier survival curve of the patients who died due to GIST (excluding other causes of death).
There have been recent guidelines regarding the investigation, treatment and follow up of GISTs.22 A UK guidelines document in October 2004 suggests that the management of GISTs should be undertaken by a multidisciplinary team (MDT) with experience in this disease. Pathological review of all cases should be made by a pathologist experienced in this tumour type. Surgery is the principal treatment for GISTs and suitability for resection should be explored by an appropriate sub-specialist surgeon. Fletcher’s criteria are simple to follow and we suggest follow up of patients should be based on classification according to the risk groups based on these criteria).
Further data analysis is required concentrating on site specific GISTs to determine whether the site influences prognosis. In our study it is difficult to make a firm judgement due to small number of GISTs in individual organs. A national or multi-centre data collection will help answer this question. The role of neo-adjuvant and adjuvant therapies in GISTs is also not clear. Observation is the current standard of care after resection of a primary tumour.23 At present there is no evidence that adjuvant chemotherapy or radiotherapy reduces recurrence rates.24 A trial of the use of Imatinib (Glivec) in the adjuvant setting is being planned for intermediate and high risk tumours and we await the
Recurrence Data
105 100 95
Percent survival
90 85 80 75 70 65 High risk Intermediate risk Low risk
60 55
0
10 20
30 40 50
60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220
Time in months Figure 2. KaplaneMeier recurrence for the patients who developed clinical recurrence following resection of GIST.
I. Ahmed et al. / EJSO 34 (2008) 445e449
results with interest. Imatinib remains the only available effective therapy for unresectable and/or metastatic GISTs25 and is recommended by NICE.21 Clinical trials of imatinib for treatment of GIST led to early registration in 2002, with a recommended initial dose of 400 mg daily.25e27 Conclusions Over the last 10 years, GISTs have been found to be c-kit and CD34 positive and this has led to their re-classification from a heterogeneous group of rare tumours to a single group of tumours. We have shown that their behaviour can be accurately predicted from their risk classification and whether they have been completely resected. With the development of Imatinib (Glivec), which has been shown to be a safe and effective treatment of recurrent or metastatic GISTs, follow up of intermediate and high risk GISTs has become mandatory. Conversely low risk GISTs can safely be discharged from long term follow up. Conflict of interest CD117 was provided by Novartis for back testing of all the historical samples. Acknowledgement We would like to acknowledge the histopathology departments in Queens Medical Centre and City Hospital Nottingham for allowing us to use their data in preparation for this paper. References 1. Mazur MT, Clark HB. Gastric stromal tumors: reappraisal of histogenesis. Am J Surg Pathol 1983;7:507–19. 2. Schaldenbrand JD, Appleman HD. Solitary solid stromal tumors in gastrointestinal tumors in Von Recklinghausen’s disease with minimal smooth muscle differentiation. Hum Pathol 1984;15:229–32. 3. Miettinen M, Virolainen M, Sarlomo-Rikala M. Gastrointestinal stromal tumors: value of CD34 in their identification and separation from true leiomyomas and schwannomas. Am J Surg Pathol 1995; 19:207–16. 4. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577–80. 5. Kindblom L-G, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cells (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of interstitial cells of Cajal. Am J Pathol 1998;152:1259–69. 6. Sircar K, Hewlett BR, Huizinga JD, Chorneyko K, Berezin I, Riddell RH. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol 1999;23(4):377–89. 7. Nishida T, Hirota S. Biological and clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol 2000;15:1293–301.
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8. Novartis Pharma AG. Basel, Switzerland; 2002. 9. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33:459–65. 10. Rossi CR, Mocellin S, Mencarelli R, et al. Gastrointestinal stromal tumours: from a surgical to a molecular approach. Int J Cancer 2003;107(2):171–6. 11. Dematteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumours: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231:51–8. 12. Demetri G. Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571). Eur J Cancer 2002;38:S52–9. 13. Langer C, Gunawan B, Schuler P, Huber W, Fuzesi L, Becker H. Prognostic factors influencing surgical management and outcome of gastrointestinal stromal tumours. Br J Surg 2003;90:332–9. 14. Koch S, Besuch P. Gastrointestinal stromal tumours e retrospective classification of mesenchymal tumours of the gastrointestinal tract. DGHO 2003. http://www.cancerimprovement.nhs.uk/%5Cdocuments %5Cupper_gi%5Cpathways%5CGIST_Mngmnt7.pdf. 15. Urbanczyk K, Limon J, Korobowicz E, et al. Gastrointestinal stromal tumours. A multicenter experience. Pol J Pathol 2005;56(2):51–61. 16. Wong NA, Young R, Malcomson RD, et al. Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach. : Histopathology 2003;43(2):118–26. 17. Fujimoto Y, Nakanishi Y, Yoshimura K, Shimoda T. Clinicopathologic study of primary malignant gastrointestinal tumour of the stomach, with special reference to prognostic factors: analysis of results in 140 surgically resected patients. Gastric cancer 2003;6(1):39–48. 18. Orosz Z, Tornoczky T, Sapi Z. Gastrointestinal stromal tumours: a clinicopathologic and immunohistochemical study of 136 cases. Pathol Obcol Res 2005;11(1):11–21. 19. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumours of the stomach: a clinicopathological, immunohistochemical and molecular genetic study of 1765 cases with long term follow-up. Am J Surg Pathol 2005;29(1):52–68. 20. Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumours. Br J Surg 2003;90:1178–86. 21. TA086 Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. Technology Appraisal 86. National Institute for Clinical Excellence; October 2004.