Prognostic factors affecting survival after surgical resection of gastrointestinal stromal tumours: a two-unit experience over 10 years
© Chiappa et al; licensee BioMed Central Ltd. 2006
Received: 26 April 2006
Accepted: 09 October 2006
Published: 09 October 2006
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal (GI) tract which has only been recently described based on their specific immunohistochemistry and the presence of particular KIT-related mutations which potentially make them targets for tyrosine kinase inhibition.
Sixty-one patients (29 M; 32 F, median age 60 years; range: 23–86 years) between June 1994 and March 2005, were analyzed from two allied institutions. Patient, tumour, and treatment variables were analyzed to identify factors affecting survival.
Of the 61 patients, 55 (90%) underwent complete surgical resection of macroscopic disease. The 5-year overall survival (OS) rate in the 61 patients was 88% and the 5-year disease-free survival (DFS) in the 55 cases completely resected was 75%. Univariate analysis revealed that R0 resection was strongly associated with a better OSrate (p < 0.0001). Likewise, univariate analysis also showed high mitotic count of > 10 mitoses/per 50 HPF was a significant variable in worse prognosis for OS (≤ 10 mitoses/per 50 HPF 95% 5-year OS vs. > 10 mitoses/per 50 HPF 74% 5-year OS, respectively; p = 0.013). On subsequent multivariate analysis, only high mitotic count remained as a significant negative prognostic variable for OS (p = 0.029). Among patients resected for cure, there were 8 recurrences during follow-up. The mean time to recurrence was 21 ± 10 months (range: 4–36 months). Univariate analysis revealed that mitotic count of > 10 mitoses per 50 high power fields, intratumoural necrosis, and pathological tumour size (> 10 cm in maximal diameter) significantly correlated with DFS (p = 0.006, 0.002 and 0.02, respectively), with tumour necrosis and high mitotic count remaining as independent predictive variables affecting prognosis on subsequent multivariate analysis.
Most GISTs are resectable with survival principally dependent upon mitotic count and completeness of resection. Future metabolic and genetic analyses will define the role of and resistance to induction or postoperative adjuvant targeted kinase inhibition therapy.
Gastrointestinal stromal tumors (GISTs) are uncommon tumours which have relatively recently been separated from conventional leiomyomas, leiomyoblastomas, and leiomyosarcomas, based on their specific immunohistochemistry, presumed aetiopathogenesis, molecular biology and differential outcome [1, 2]. There is still controversy over their histogenetic origin with immunohistochemical and ultrastructural resemblance to the interstitial cells of Cajal [3, 4] as well as from cells which are smooth muscle cell precursors responsible for generation of the slow-wave pacemaker activity of the gut musculature . The designation of these tumours has largely been based on the immunohistochemical expression of c-KIT (CD 117; stem cell factor [6, 7], and CD 34) , with a relative lack of desmin and S-100 immunoreactivity, although recently, a subset of KIT-negative GISTs has been recognised with the morphological features of classical stromal tumours but retaining PKC-theta expression . More recently, cytogenetic and comparative genomic hybridisation (CGH) studies have shown characteristic chromosomal patterns in GISTs which have distinguished them from other gastrointestinal mesenchymal tumours,  and where most GISTs demonstrate specific DNA copy number changes which correlate with their clinical behaviour and which differentiate benign from malignant cases .
Considerable debate still exists concerning the biological behaviour of GISTs, centering largely around the tumour site, tumour size, the presence of intra-tumoural necrosis, and mitotic count [12–14]. Based on this recent data, our study assesses the surgical outcome of unselected GISTs referred to two allied institutions over a 10 year period and analyses the factors affecting prognosis after resection with curative intent.
Patients and methods
Using our hospital databases, we collected the records of patients with a histopathologic diagnosis of primary leiomyoma, leiomyoblastoma, leiomyosarcoma, gastrointestinal sarcoma, and stromal cell tumour of the GI tract from the period including 1994 to October 2004. Each of the patients had undergone surgical resection of their tumour. We recorded the patients' age, gender, presenting clinical symptoms, tumour site, maximal tumour diameter after resection, duration of surgery, surgical procedure, extent of surgical resection, the presence and date of local recurrence or distant metastasis, and the clinical outcome until last follow-up, including date of death where appropriate. There was no strict follow-up protocol in either institution, although follow-up included physical examination, chest X-ray, thoracoabdominal and pelvic computerised tomography (CT) scan, endoluminal ultrasonography, and GI endoscopy, where appropriate. The median follow-up of all patients was 35 months (range 2–140 months). Those tumours deemed to have histologically free resection margins were included as cases where surgery was performed with curative intent and were referred to as complete (R0) resections. After the surgical treatment, patients were followed regularly using clinical assessment on a 3 monthly basis with abdominopelvic CT and/or ultrasound annually, where appropriate.
The tumour samples from all 61 patients were evaluated for various markers by using immunohistochemistry with commercially available antibodies against CD 117-KIT, (1:50, Santa Cruz Biotech, CA USA) S-100 protein, (1:40, Novocastra Labs, USA) Desmin, (1:50, DAKO, Glostrup, Denmark) and Smooth-muscle Actin (1:200, DAKO, Glostrup, Denmark) with qualitative assessment of immunoreactivity in accordance with the manufacturers' instructions. Cases were classified according to risk and their potential for aggressive clinical behaviour based on the NIH consensus statement of 2001 for GISTs,  where tumour size < 2 cm and mitotic count < 5/50 high power fields (HPF) was graded as very low risk, tumour size between 2 and 5 cm and a mitotic count < 5/50 HPF was considered low risk, tumours < 5 cm with a mitotic count between 5/50 HPF and 10/50 HPF or tumours between 5 and 10 cm with a mitotic count less than 5/50 HPF were deemed as intermediate risk and tumours > 10 cm and/or those tumours with a mitotic count > 10/50 HPF and tumours > 5 cm with a mitotic count > 5/50 HPF were classified as high risk.
Statistical analysis was performed with SPSS 12.0 software (Chicago, IL, USA). The Student's t test was used to compare continuous variables with the χ2 test being utilized for dichotomous variables. Overall survival was calculated from the day of diagnosis until death or the last day of a patient's visit to the outpatient clinic. The disease-free survival was calculated from the first diagnosis until tumour recurrence or distant metastases were found. Kaplan-Meier analysis with a Mantel-Haenszel log-rank test was used to compare overall and recurrence-free survival  with the proportional hazards method being used to evaluate significant prognostic factors . All p values < 0.05 are reported.
Of the resected cases, there were 29 males and 32 females with an overall median age 60 years (range 23–86 years). All tissue samples were proven to be CD-117 positive on immunohistochemical staining. Tumours were located in the stomach in 41 cases (67%), the small bowel in 14 (23%), the colon in 4 (5%) the rectum in 1 (2%), and the duodenum in 2 cases (3%). Three of the 61 patients (5%) presented with synchronous hepatic metastases. The most frequent presenting symptoms included gastrointestinal tract bleeding and abdominal pain in 11 cases (18%) and abdominal fullness and/or discomfort in 7 patients (11%). Twenty patients (33%) had anaemia on presentation with 15 patients (26%) having a palpable abdominal mass on clinical examination. Six patients (10%) were asymptomatic and were referred for incidental GISTs after routine physical examination and investigation.
Surgical procedures performed in 61 patients affected by gastrointestinal stromal tumours.
Wedge gastric resection*
Small bowel resection
Clinico-pathological variables of 61 gastrointestinal stromal tumours patients according to number of mitoses per 50 HPF(≤ or > 10)*
Mitoses ≤ 10/50 per HPF
Mitoses > 10/50 per HPF
Surgical resection type
≤ 10 cm
> 10 cm
The 5-year disease-free survival in the 55 patients completely resected was 75% (Figure 2). Among those patients resected for cure, 8 patients developed tumour recurrence after a mean of 21 ± 10 months (range: 4–36 months) follow-up. The liver was the most frequent site of tumour relapse (n = 6; 75% of the recurrences) and in the 8 patients, survival after recurrence was 30% at 3 years. Patients designated as NIH class 4 had a 5-year disease-free survival rate of 65% compared with 94% for all other groups combined (p = 0.03). On univariate analysis, a higher number of mitoses (i.e. > 10 per 50 HPF) correlated with worse disease free-survival in those resected for cure (87% for < 10 mitoses/per 50 HPF vs. 57% for > 10 mitoses/per 50 HPF respectively, p = 0.006), as did tumour size (tumours < 10 cm in maximal diameter had an 86% disease-free survival at 5 years compared with only 63% for those tumours > 10 cm in size; p = 0.02). The presence of tumour necrosis was also significantly associated with a worse disease-free survival on univariate analysis (51% vs. 91% 5-year disease-free survival with or without tumour necrosis respectively; p = 0.002). On multivariate analysis of these three significant factors detected on univariate analysis, only tumour necrosis and the number of mitoses (> 10 mitoses/per 50 HPF) proved to be significant independent predictive variable affecting disease-free survival (HR = 11.226; CI 2.199–57.315: p = 0.004 and HR = 8.054; CI 1.842–35.205: p = 0.006, respectively).
Analysis of 61 cases of mixed-site GISTs in our study obtained from two tertiary referral centres over a 10-year period reveals that both overall survival and disease-free survival are affected by a high mitotic count in the tumour after resection with curative intent. The primary tumour sites noted in our study are similar to other previous reports [18, 19], with a similar demographic of presenting symptoms including gastrointestinal bleeding, abdominal pain and the presence of an abdominal mass [20–22]. CT and MRI are generally used for the preoperative imaging of GISTs [23–25]. However, there are no well-established, published guidelines to help surgeons determine the optimal manner in which to evaluate this intraabdominal, site-specific class of tumours. Although not reported in the results section of our current report, our limited use of endoluminal ultrasound has been unable to assist in the definition of malignant versus benign cases. Nevertheless, this has been as previously described , where tumour margin irregularity and heterogeneity with intratumoural degeneration and larger tumour size were more indicative of malignancy. No patient in our series underwent preoperative image-guided biopsy or aspiration cytology as has been advocated by some authors . Lastly, recent data shows a potential value for preoperative positron emission tomography (PET) in the prediction of malignant potential with a correlation between 18FDG uptake and mitotic count 
Others have shown that one of the principal prognostic factors determining cancer-specific outcome is tumour size, where tumours > 10 cm in maximal diameter have a relatively worse survival following surgical resection [2, 12, 18]. Our study was unable to substantiate an effect of tumour size except on univariate analysis of overall survival. This effect was not mantained on multivariate analysis, although larger patient numbers are probably required to determine a true effect of tumour size on cancer-specific outcomes. In this respect, GISTs, which exceed 5 cm in maximal diameter, have been previously shown to correlate with a worse prognosis independent of their primary location, [19, 29] where tumour diameter is part of most prognostic indices designed to govern treatment algorithms for patients deemed at high risk [2, 15, 30]. Equally, as in our study, most reports have shown high mitotic count to equate with a worse tumour-specific outcome [12, 31], although some recent studies have excluded this factor along with that of intratumoural necrosis from model analyses since they have not been proven to be independent prognostic markers of survival [12, 32]. Our study showed an effect of intratumoural necrosis on disease-free but not overall survival. Other studies have confirmed more objective immunohistochemical evaluation of cellular proliferation as correlating with an overall worse outcome using Ki 67 analysis,  proliferating cell nuclear antigen labelling index, cellular apoptotic marker (Bcl-2 and Bax) expression and overall tumour cellularity estimates [12, 33, 34].
T he clinicopathologic evaluation of GISTs is particularly difficult, since these tumours have only recently been characterized and since some previous studies have still grouped these tumours with spindle-cell and epithelial neoplasms, which may share similar histopathology, but which possess divergent outcomes. Attempts have been made to categorize these tumours by the establishment of an individualized immunophenotype based on neural and smooth muscle immunodifferentiation although up to one-quarter of these neoplasms cannot adequately be categorized on this basis . No patient in our series was treated primarily with the tyrosine kinase inhibitor Imatinib, which has been shown to be valuable in metastatic kit-positive GISTs [36, 37]. We have used this in our units only after proven disease recurrence. This issue is complex, since although most GISTs acquire a gain-of-function c-KIT mutation, many tumours ultimately demonstrate some resistance to targeted molecular therapy during treatment . It appears that c-KIT gene mutations are pivotal molecular events in the life of these tumours, adversely affecting their overall prognosis after surgery . Equally, there is controversy regarding the mechanisms of Imatinib resistance which are dependent upon missense mutations of the kinase domains of KIT and PDGFRA and there is no clear evidence at the present time that routine molecular analysis of GISTs to assess exon mutations alters management . Moreover, the follow-up protocol for resected GISTs has not been established although there are relatively specific changes detectable in tumours treated primarily with Imatinib on CT and MR imaging, including changes in tumour size, attenuation, enhancement, and vascularity [41, 42]
Our and other studies suggest that complete surgical resection (R0 resection) of GISTs as well as their initial size, mitotic activity, and the presence of intratumoural necrosis are potentially important variables associated with overall outcome, with the principal factor affecting overall survival being the mitotic count. These findings have been suggested in another very recently published report . In the era of Imatinib effectiveness, it is unclear what is the role of preoperative induction or postoperative adjuvant targeted therapy, as well as the place of surgery in partial Imatinib responsiveness or in isolated metastatic disease . In this light, at the present time, it may be that a clinico-pathological interpretation of the risk status of the tumour, as used in our study, is the most practical approach for such decision where complete surgical resection (R0 resection) is the key prognostic factor  and where high-risk GISTs surgery is supported by a selective approach towards induction or postoperative adjuvant molecular therapy [46, 47].
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