ARTICLE
Auteur(s) : Geneviève
Monges1, Ségolène Bisot-Locard2,
Jean-Yves Blay3, Anne-Marie Bouvier4, Marisol
Urbieta2, Jean-Michel Coindre5, Jean-Yves
Scoazec6
1Institut Paoli-Calmettes, 232, boulevardd
Sainte-Marguerite, 13309 Marseille, France
2Novartis Pharma, 92506 Rueil-Malmaison, France
3Centre Léon-Bérard, Université Claude-Bernard, 69373
Lyon Cedex 08, France
4Inserm U866, Registre des cancers digestifs, Dijon,
F-21079 France
5Institut Bergonié, 229, Cours de l’Argonne, 33076
Bordeaux, France
6Hospices civils de Lyon, Hôpital Édouard-Herriot,
Service d’anatomie pathologique, 69437 Lyon cedex 03, France
Article reçu le 21 Juillet 2009, accepté le 8 Decembre 2009
Introduction
Gastrointestinal stromal tumors (GISTs) are the most common
mesenchymal neoplasms of the gastrointestinal tract (GI tract). The
true annual incidence of these tumors is not well known because
GISTs have only recently been recognized as a separate entity, both
morphologically and immunophenotypically, from smooth-muscle
neoplasm (leiomyoma, leiomyosarcoma) and gastrointestinal
peripheral nerve-sheath tumor (schwannoma).
Since 2000, when a new marker, the KIT protein (CD 117), was
discovered, GISTs have been defined as a specific, KIT-expressing
and KIT-signaling driven mesenchymal tumor of the GI tract.
GISTs usually occur in adults (median age 55–60 years) and
rarely in young people (<1%) throughout the gastrointestinal
tract: 60% in stomach, 35% in the small intestine, and less than 5%
in the rectum, esophagus, omentum, and mesentery; most GISTs in the
latter two sites are metastatic [1-6].
There was no effective medical therapy prior to 2000, and the
chemotherapy response rate was under 5% for all tested cytotoxic
agents. Recent identification of the tyrosine kinase inhibitor,
Imatinib mesylate (STI-571, Glivec/Gleevec; Novartis), has markedly
changed the outcome and treatment options for patients with
nonresectable or metastatic disease [7].
All GISTs are considered with a malignant potential. GISTs are
therefore classified GISTs as either low or high risk of relapse
[8]. The risk can be evaluated according to factors such as the
tumor’s size and mitotic activity/index, and site of the primary
tumor [9, 10].
Only very limited epidemiological data concerning GISTs are
available, particularly in France.
GISTs are rare tumors, whose estimated incidence may be close to
1.5 new cases per 100, 000 persons per year in France [5,
6].
In France, regional cancer registries have been put in place
over the last several years. These registries provide precise,
reliable epidemiologic information, as well as allow an assessment
of diagnostic and therapeutic practices and their impact on the
survival rates of all people living with cancer. The objective of a
registry is to enable the most exhaustive possible data collection,
but these registries only track cancerous tumors, and for this
reason, a proportion of GISTs are not recorded in the
registries.
Two approaches were possible to determine the incidence of GISTs
in France over a one-year period. We could either analyze the
information already collected in the various cancer registries or
conduct our own epidemiological study. We chose to perform an
epidemiological study because a lot of GISTs are not included in a
register focused on malignant tumors.
This epidemiological study focused on the annual incidence of
the GISTs in France, as well as the description of distribution of
patients according to age group, gender, circumstances of the
diagnosis, characteristic of the tumor, and prognosis.
Materials and Methods
The study involving pathologists was conducted in France over
one-year period, extending from 1 December 2004 to
30 November 2005. All pathologists (1205) from
349 institutions including private and public were contacted
by letter. The list of the pathologists was established from the
Cogedim files, which is updated daily and included
1205 pathologists at the start of the study. One pathologist
per institute was required, and a total of 330 institutions
showed interest in participating in the study. Among them,
136 institutions actually enrolled patients in the study. Data
were captured on paper files or electronically online via a
dedicated site managed by an independent company. The diagnosis and
prognosis criteria published in the literature were noted for every
patient enrolled [2, 9, 11]. Patients were identified with the
first letters of both first name and surnames; the gender and the
date of birth were recorded to easily identify patients enrolled
twice and remove them from the database. The patients received an
information letter about the study in compliance with the
recommendations of the French Data Protection Authority (CNIL).
Cases were identified as an incident or prevalent recurrence.
GISTs were categorized according to their localizations, their
specific morphology, and their characterization according to
immunohistochemical staining with anti-CD117. The size of the tumor
and its mitotic rate per 50 high power fields were determined,
and these criteria were used for the risk assessment of GISTs
according to Fletcher et al. [9, 12].
Diagnosis was also based on the KI67 or Mib 1 value,
where available, and the results of the other immunohistochemical
staining procedures performed for CD 34, α smooth-muscle actin,
desmin, caldesmon, and S100. Finally, the pathologists had to state
whether it was a GIST CD117 positive or it was probably a GIST
CD117 negative. Those cases correspond to spindle-cell tumor
CD117 negative and also to CD 34 α smooth-muscle actin,
desmin, caldesmon, and S100 negative. For the localized forms,
pathologists had to classify them using the four-grade system
proposed by Fletcher [9], in addition with a fifth class for
already metastatic tumors. This registry (data) has been checked
and compared to the results given by pathologists (size and mitotic
index).
Statistical analyses were descriptive; the quantitative
variables were presented as the mean, standard deviation and
extreme values, and the qualitative variables as the absolute
frequency and percentage per modality. The groups were compared
using a Student t-test or the chi-square method, depending on the
variable type.
Results
One hundred thirty-six centers actually enrolled patients:
123 centers enrolled 1 to 9 patients,
11 centers included between 10 and 20 patients, and
2 centers enrolled 33 and 43 patients, respectively.
In total, 591 cases were included in the study after
duplicate cases were removed; this does not take into account the
91 cases diagnosed by pathologists from the Paris public
hospital system (Assistance Publique Hôpitaux de Paris AP-HP), who
did not obtain permission to submit their data.
Doubles were eliminated (37 in total): 33 were due to
a double report from two laboratories after rereading for advice,
2 cases for which the laboratory performed the analysis twice
(one from a biopsy and the other from a surgical specimen), and
2 real doubles.
The 591 cases eligible for inclusion consisted of
535 incident cases and 56 prevalent recurrent cases.
Globally, 183 (31.1%) cases were recruited by private
institutions and 408 cases (68.9%) by the Public Hospital
System (Hôpitaux Universitaires, Hôpitaux Généraux et Centres de
Luttes Contre le Cancer [CLLC]). Private institutions recruited
168 (31.4%) of the incident cases and 16 (28.6%) of the
prevalent recurrent cases, and Public Hospital System recruited
367 (68.6%) of the incident cases and 40 (71.4%) of the
prevalent recurrent cases. The estimation of the incidence was
calculated on the basis of the census of the French population in
2005, which gave 62.9 million inhabitants in metropolitan
France, leading to an estimated incidence of GIST in France of
8.5–10 (including the cases of Paris AP-HP) cases per million
inhabitants in 2005 with 95%CI [1.3;15] and [2.2;17.7],
respectively.
The main results presented here concern only the incidence cases
because data concerning prevalent recurrent cases are less
informative given that few cases (n = 56) were included.
Population characteristic
In the population of the 535 incident cases, 490 (91.6%)
had localized disease and 45 (8.4%) had metastatic spreading
at initial diagnosis. The mean age was 65.2 years,
65.1 for the localized forms and 66.8 for patients with
metastasis. The male/female ratio showed a female predominance for
localized forms (51.4 vs 48.6%), but the trend was opposite
for metastatic patients (26.7 vs 73.3%). This difference was
statistically significant (P = 0.0005). Details of these results
are provided in Table 1.
However, for localized forms, we observed no difference between
tumors of low risk and high risk according to sex. For men, we
observed 74.9% of tumors of low risk and 25.1% of tumors with high
risk, and for women 70.1% of tumors of low risk and 23.2% of tumors
with high risk (P = 0.74).
Table 1 Population characteristics.
|
Incident cases
|
Localized N: 490
|
Already metastatic N: 45
|
Total N: 535
|
|
Age Mean ± SD [Min; Max]
|
65.0 ± 13.4 [16; 93]
|
66.8 ± 11.4 [47; 87]
|
65.2 ± 13.2 [16; 93]
|
|
Gender Male/Female N (%) [CI 95%]
|
227(46.3%)/263(53.7%) [41.9; 50.7]/[49.3; 58.1]
|
33(73.3%)/12(26.7%)* [60.4; 86.3]/[13.8; 39.6]
|
260(48.6%)/275 (51.4%) [44.4; 52.8]/[47.2; 55.6]
|
Clinical presentation
Circumstances of discovery were fortuitous for one-third of
localized forms. Discovery for most of the already metastatic forms
was principally through symptoms and signs. A gastric site
(67.1%) was most common for the localized forms while the site was
predominantly undefined for metastatic patients. Site
identification was impossible because either the tumor involved
several organs or multiple lesions were detected, and it was
unclear which was the first affected organ; details of these
results are provided in Table 2.
Table 2 GISTs presentation.
|
Incident cases
|
Localized N: 490
|
Already metastatic N: 45
|
Total N: 535
|
|
Circumstances of discovery N (%)
|
|
|
|
|
[CI 95%]
|
|
|
|
|
Fortuitous
|
158 (32.2%)
|
5 (11.1%)
|
163 (30.5%)
|
|
[28.1; 36.4]
|
[2.3; 23.3]
|
[26.9; 34.7]
|
|
Symptomatic
|
220 (44.9%)
|
29 (64.5%)
|
249 (46.5%)
|
|
[40.5; 49.3]
|
[60.7; 88.0]
|
[42.8; 51.3]
|
|
Not specified
|
112 (22.8%)
|
11 (24.5%)
|
123 (23.0%)
|
|
[18.8; 26.1]
|
[11.9; 37.1]
|
[18.1; 25.1]
|
|
Tumor Site N (%)
|
|
|
|
|
[CI 95%]
|
|
|
|
|
Esophagus
|
4 (0.8%)
|
0
|
4(0.7%)
|
|
[0.1; 1.6]
|
|
[0.1; 1.5]
|
|
Stomach
|
329 (67.1%)
|
12 (26.7%)
|
341 (63.7%)
|
|
[63.0; 71.3]
|
[16.3; 45.3]
|
[60.4; 68.5]
|
|
Small bowel
|
107 (21.8%)
|
11 (24.4%)
|
118 (22.1%)
|
|
[18.1; 25.5]
|
[11.9; 36.9]
|
[18.6; 26.6]
|
|
Colon/Rectum
|
16 (3.3%)
|
1 (2.2%)
|
17 (3.2%)
|
|
[1,4; 4,3]
|
|
[1,3; 4,2]
|
|
Mesentery
|
28 (5.7%)
|
7 (15.6%)
|
35 (6.5%)
|
|
[3.7; 7.8]
|
[5.9; 30.0]
|
[4.5; 8.2]
|
|
Not defined
|
6 (1.2%)
|
14 (31.1%)
|
20 (3.7%)
|
|
[0.2; 2.2]
|
[17.6; 44.6]
|
[2.1; 5.3]
|
GIST diagnosis
GISTs were diagnosed on standard histological examination and on
the basis of cKIT (CD117) positivity. Among the 535 GIST
cases, 95.3% were c-KIT positive and 3.7% cKIT negative. For these
cases, both histological appearance and tumor site argued in favor
of this diagnosis, and tumor immunophenotype did not comply with
the diagnosis of leiomyoma or schwannoma (α smooth actin, desmin,
caldesmon, S100 protein negative). These cases were considered
cKIT-negative GISTs.
Tumor characteristics
The size of the tumor ranged from 2 to 5 cm in 36.5% of
the cases represented, and 39.4% of cases had a mitotic index
ranging from >1 to ≤5 included. Pathologists
classified the GISTs according to the consensus criteria [9],
almost 50% were considered to be at high risk for malignant
behavior (Table 3).
The risk assessment was detailed according to the localization
of the tumor and the combination of two categories regrouping very
low risk and low risk cases on the one hand and intermediate risk,
high risk, and already metastatic cases on the other; details of
these results are provided in Tables 4 and
5, according to Fletcher classification, and in Table 6, according to Miettinen classification.
No difference in terms of prognosis factors (localization,
mitotic index, Ki67 value, and localized form versus already
metastatic cases) was found between the KIT positive and KIT
negative GISTs.
Table 3 Tumors Characteristics: Localized Incident
cases, already metastatic forms not mentioned.
|
Tumor Size ≤2 cm >2 cm ≤ 5 cm
>5 cm ≤ 10 cm >10 cm Not known/not
evaluated*
|
N (%) [CI 95%] 76 (15.5%) [12.3; 18.8] 179 (36.5%) [32.3;
40.9] 125 (25.5%) [21.7; 29.4] 69 (14.1%) [11.0; 17.2] 41 (8.4%)
[5.8; 10.6]
|
|
Mitotic index ≤1 >1 ≤5 >5 Not known/not evaluated*
|
N (%) 138 (28.2%) [24.2; 32.2] 193 (39.4%) [35.1; 43.8] 107
(21.8%) [18.2; 25.6] 52 (10.6%) [7.7; 13.1]
|
|
Prognosis evaluation Very low risk Low risk Intermediate
risk High risk Already metastatic Not known/not evaluated*
|
N (%) 72 (13.5%) [12.4; 18.9] 125 (23.4%) [23.0; 31.0] 113
(21.1%) [20.5; 28.3] 113 (21.1%) [20.5; 28.3] 45 (8.4%) [6; 10.8]
67 (12.5%) [9.7;15.3]
|
|
Regrouped prognostic evaluation Low risk** Very high risk
Not known/not evaluated*
|
197 (36.9%) [32.8; 41.0] 271 (50.6%) [46.4; 54.8] 67 (12.5%) [9.7;
15.3]
|
Table 4 Localized forms (N: 490). Incident cases risk
according to Fletcher classification, as function of site. Number
of case (%) and 95% CI.
|
Stomach (N: 329)
|
Small bowel (N: 107)
|
Colon/rectum (N: 16)
|
Mesentery (N: 28)
|
Esophagus (N: 4)
|
Not defined (N: 6)
|
|
Very low risk N: 72 (15%)
|
58 (18%) [13.8; 22.2]
|
10 (9%) [3.6; 14.4]
|
2 (12%)
|
1 (3.5%)
|
1 (25%)
|
0
|
|
Low risk N:125 (25%)
|
96 (29%) [24.1; 33.9]
|
25 (23.5%) [15.5; 31.5]
|
2 (12%)
|
1 (3.5%)
|
0
|
1 (16.5%)
|
|
Intermediate risk N:113 (23%)
|
74 (22,5%) [18; 27]
|
30 (28%) [19.6; 36.5]
|
3 (19%)
|
5 (18%) [3.8; 32.2]
|
1 (25%)
|
0
|
|
High risk N:108 (22%)
|
57 (17%) [12.9; 21.1]
|
25 (23.5%) [15.5; 31.5]
|
6 (38%) [14.2; 62.8]
|
15 (53.5%) [35.0; 72.0]
|
1 (25%)
|
4 (67%)
|
|
Not evaluable N:72 (15%)
|
44 (13,5%) [9.8; 17.2]
|
17 (16%) [9.1; 22.8]
|
3 (19%)
|
6 (21.5%) [6.3; 36.7]
|
1 (25%)
|
1 (16.5%)
|
Table 5 Localized and already metastatic forms (N:
535). Incident cases risk according to Fletcher classification, as
function of site. Number of case (%) and 95% CI.
|
Stomach (N: 341)
|
Small bowel (N: 118)
|
Colon/rectum (N: 17)
|
Mesentery (N: 35)
|
Esophagus (N: 4)
|
Other Not specified (N: 20)
|
|
Low risk* N:197 (37%)
|
154 (45%) [39.7; 50.3]
|
35 (30%) [21.7; 38.3]
|
4 (23%) [3.0; 43]
|
2 (6%)
|
1 (25%)
|
1 (5%)
|
|
Malignant** N:266 (50%)
|
143 (42%) [36.8; 47.2]
|
66 (56%) [47.0; 65.0]
|
10 (59%) [35.6; 82.4]
|
27 (77%) [63.1; 90.9]
|
2 (50%)
|
18 (90%) [76.9; 100]
|
|
Not evaluable N:72 (13%)
|
44 (13%) [9.4;16.6]
|
17 (14%) [7.7;20.3]
|
3 (18%)
|
6 (17%) [4.6; 29.4]
|
1 (25%)
|
1 (5%)
|
Table 6 Localized forms (N: 490) Incident cases risk
according to Miettinen classification. Number of case (%) and 95%
CI.
|
Stomach (N: 329)
|
Small bowel (N: 92)
|
Duodénum (N: 15)
|
Rectum (N: 8)
|
Other Not specified*(N: 46)
|
|
Missing data
|
63
|
13
|
7
|
3
|
17
|
|
No risk
|
52 (19.5%) [14.8; 24.3]
|
10 (12.7%) [5.3; 19.9]
|
2 (25.0%)
|
1 (20.0%)
|
0 (0.0%)
|
|
Very low risk
|
108 (40.6%) [34.7; 46.5]
|
0 (0.0%)
|
0 (0.0%)
|
0 (0.0%)
|
0 (0.0%)
|
|
Low risk*
|
53 (19.9%) [15.1; 24.7]
|
21 (26.6%) [16.8; 36.3]
|
2 (25.0%)
|
0 (0.0%)
|
0 (0.0%)
|
|
Moderate risk
|
19 (7.1%) [4.0; 10.2]
|
24 (30.4%) [20.2; 40.5]
|
1 (12.5%)
|
0 (0.0%)
|
0 (0.0%)
|
|
High risk
|
34 (12.8%) [8.8; 16.8]
|
24 (30.4%) [20.2; 40.5]
|
3 (37.5%) [3.9; 71.0]
|
4 (80.0%) [44.9; 115.1]
|
0 (0.0%)
|
Discussion
This study shows that the reported annual incidence of GIST in
France is 8.5–10 cases per million inhabitants. This annual
incidence is in range with results reported in literature.
In the 1998 Finnish cancer registry database, Miettinen
et al. estimated the incidence of GISTs to be between
10 and 20 cases per million inhabitants [1, 13].
A retrospective study of all GI tumor samples in Sweden showed
that the annual incidence of GIST was 14.5 per million [14].
The incidence of GISTs was 13 per million in Italy,
12.7 in the Netherland, 11 in Iceland, and 10.9 in
Spain [14–18]. In the United States, a study based on cases of
GISTs reported to Surveillance, Epidemiology, and End Results
(SEER) cancer registries estimated a much lower incidence of
6.8 per million [19].
The true incidence of GISTs in France is probably even slightly
higher, including asymptomatic GISTs and small, clinically
insignificant GISTs, which were not biopsied or resected during the
time interval studied. The 91 cases registered by the AP-HP
pathologists couldn’t have been included in the calculation of the
incidence because there is no detail of incident cases and
prevalent recurrent cases. Besides, registration of the cases was
made on the basis of voluntary work and as such does not allow
considering that those reports are comprehensive. Another bias for
these results is the lack of central pathologic review and of
search for mutations, which was purposely agreed to avoid making
the research cumbersome, and to try to gain support from most
pathologists with as least constraints as possible.
The patient’s age range was 16 to 93 years, the median
being 65.2 years. This is higher than that shown in the
literature, as the median was 59 years for the large series of
Miettinen [20].
GISTs usually affect middle-aged and older patients; they are
rare before the age of 40 years and very rare in children. The
mean age of onset is identical for localized tumors and immediately
metastatic incident cases. But in some series, prognosis is age
dependent. GISTs below the fifth decade (<40 years) have
been stated to be more often malignant [5, 6].
In the study, there was a slight apparent female predominance
(51.4% female vs 48.6% male). In the Miettinen [20] study, there
was a male predominance (54.6% male), but this study contained a
male-dominated military and veterans subcohorts.
The SEER registry results showed identical results with 54% of
male, as well as a Norwegian study results, whereas in the Cancer
Registry of Northern Italy, the sex ratio was 1:1 [15, 19, 21]. It
is interesting to note there was a male predominance in malignant
GISTs (73.3% male vs 26.7% female), as shown in the population
survey based on SEER (54% male vs 46% female), whereas highly
malignant tumors were more than twice as common in men than in
women in Miettinen’s data [20, 21]. It is possible that there is a
true male predominance, especially among patients with high
malignant GISTs, or alternatively that male gender may be a risk
factor for relapse as for other sarcomas.
As expected, metastatic tumors are most frequently discovered
because of accompanying symptoms and signs. In terms of sites, as
in all series reported in the literature, stomach tumors were the
most common overall (63.7%), with secondary sites of predilection
being the small bowel followed by the mesentery; esophageal GISTs
were extremely rare, less than 1%. On the other hand, the
percentage of already metastatic forms was almost the same for the
stomach and small bowel, 26.7 and 24.4%, respectively, with
15.6% of mesenteric forms. Above all, this study found a relatively
high percentage of tumors whose point of origin was impossible to
locate.
The key immunohistochemical feature of GISTs is positivity for
the Kit (CD117) receptor tyrosine kinase, as observed in 95.3% of
cases; only 3.9% of tumors presenting all the features of GISTs
were Kit negative. Kit positivity is a major defining feature for
GIST, but it is no longer considered an absolute requirement. Kit
expression in GISTs is a consequence of mutation [10]. In a French
study focusing on the measurement and investigation of the
mechanisms of KIT activation in 80 KIT-positive GIST patients,
it was shown that KIT activation was detected in all GISTs, even in
the absence of KIT mutations [22].
According to the consensus criteria [9], our data showed 50%
high risk of relapse of tumors when the high risk, very high risk,
and already metastatic cases were taken into account. These results
are close to those published in the literature by Goettsch
et al. in the Netherlands [16], who reported a 45% malignancy
rate. Results reported in Italy [15] and in Spain [17] showed 50%
and 37%, respectively, of GISTs, which are considered to be at high
risk for malignant behavior, but they did not take into account the
intermediate risk tumors. A malignancy rate of 50% seems to be
realistic.
These data were based on enrolled cases. There was no central
pathological review. Globally, a large amount of pathologists
didn’t used CD117 antibody and send their cases to referent
pathologists for the final diagnose. So the major party of
immunohistochemistry was performed in public referent
institute.
This study provides for the first time an estimation of the
annual incidence of GISTs and a description of the characteristics
of these tumors in France based on pathology registration. The true
incidence may be comparable to what has been reported in recent
studies in other European countries.
Conflict of interest
none.
Acknowledgements. We acknowledge all pathologists for their
participation.
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