Introduction
Upper gastrointestinal (UGI) cancers (of the oesophagus and stomach) characteristically
present at a late stage in the Western world. This contributes to the poor overall
5-year survival rates of patients with UGI cancer, which are 13 % for those with oesophageal
cancer and 17 % for those with gastric cancer [1]. However, when UGI cancers are diagnosed at an early stage, 5-year survival rates
can be as high as 80 % [2].
Patients who undergo a colonoscopy procedure that does not diagnose colorectal cancer
are at a low risk of between 0.5 % and 6 % for the subsequent development of colorectal
cancer within 3 years [2]
[3]. Whereas awareness of the importance of adenomatous polyps to the subsequent development
of colorectal cancer is universal, awareness of the endoscopic appearance of premalignant
lesions and early cancers in the oesophagus and stomach appears to be much less widespread
among endoscopists in the Western world. It would be expected, therefore, that patients
are undergoing UGI endoscopic procedures that fail to diagnose UGI cancers in the
years before the UGI cancers are finally diagnosed, and that crucial opportunities
to diagnose these cancers at an earlier and more treatable stage are being missed.
We have undertaken a meta-analysis of studies of how frequently UGI endoscopy fails
to diagnose cancer in patients in whom UGI cancer is subsequently diagnosed, so as
to quantify how commonly these missed diagnoses occur and examine potential risk factors
for missed diagnoses.
Methods
MEDLINE (U.S. National Library of Medicine, 1966 – 2009) was searched to extract all
studies that included the key words missed cancer, missed upper gastrointestinal cancer, missed oesophageal cancer, and missed gastric cancer. Only studies of adults (age older than 18 years) and studies in English were included.
Studies were included in the meta-analysis if they investigated retrospectively either
of the following: (1) whether patients with UGI cancer had undergone an endoscopic
procedure before the diagnosis that failed to diagnose the cancer or (2) whether patients
who had undergone endoscopy without being given a diagnosis of UGI cancer were subsequently
given a diagnosis of UGI cancer.
Abstracts were reviewed, and studies that met the above criteria were examined in
detail. Reference lists were hand-searched for additional studies. Abstracts presented
at national and international meetings (British Society of Gastroenterology, Digestive
Disease Week, United European Gastroenterology Week) in the past 5 years were also
searched. Studies were ultimately included in the meta-analysis based on agreement
by the two investigators.
Missed cancers were defined as cancers in subjects who had undergone an endoscopic
procedure that did not diagnose UGI cancer in the 3 years before they were given a
diagnosis of UGI cancer.
Random effects meta-analysis was performed to obtain a pooled endoscopic missed UGI
cancer rate, and I
2 values were computed to assess heterogeneity. Comprehensive Meta-Analysis Version
2, Biostat, Englewood, New Jersey (2005), was used for analysis. Forest plots were
created to allow studies and their 95 % confidence intervals to be compared. Publication
bias was assessed with a funnel plot and the classic fail safe N test.
Results
The MEDLINE search yielded 22 studies, 8 of which met the inclusion criteria [4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]. Two abstracts that fulfilled the inclusion criteria were also included [12]
[13]. These 10 studies included 3,787 subjects, among whom 487 (12.9 %) had undergone
an endoscopic procedure that missed UGI cancer in the 3 years before diagnosis ([Table 1]). Of these UGI cancers, 49 (10.1 %) were oesophageal cancers and 414 (85 %) were
gastric cancers ([Table 2]). Four duodenal cancers were also included in one study [9], and in another study, published as an abstract, 20 UGI cancers were not subdivided
into oesophageal and gastric cancers [13]. Six of the studies examined only the rate of missed gastric cancer at endoscopy
[4]
[7]
[8]
[9]
[10]
[11].
Table 1
Summary of studies included in the meta-analysis.
|
First author
|
Year published
|
Study period
|
Region
|
Sample size
(total number of cancers)
|
|
Hosokawa [4]
|
1998
|
1984 – 1989
|
Japan
|
770
|
|
Amin [5]
|
2002
|
1994 – 1999
|
UK
|
129
|
|
Suvakovic [6]
|
1997
|
1989 – 1994
|
UK
|
81
|
|
Yalamarthi [7]
|
2004
|
1996 – 2001
|
UK
|
305
|
|
Voutilainen [8]
|
2005
|
1994 – 2001
|
Finland
|
284
|
|
Hosokawa [11]
|
2007
|
1990 – 1995
|
Japan
|
730
|
|
Raftopoulos [9]
|
2010
|
1990 – 2004
|
Australia
|
822
|
|
Milestone [12]
|
2007
|
2000 – 2006
|
UK
|
248
|
|
Vradelis [10]
|
2011
|
2005 – 2008
|
UK
|
74
|
|
Vesey [13]
|
2013
|
2002 – 2009
|
UK
|
344
|
Table 2
Summary of the total number of upper gastrointestinal cancers and subjects undergoing
endoscopy in the previous 3 years that failed to diagnose the cancer in each study.
|
First author
|
Missed cancers (OGD within 3 years before diagnosis)
|
Oesophageal cancers
|
Gastric cancers
|
Duodenal cancers
|
Total cancers
|
Prevalence of missed cancers (%)
|
|
Hosokawa [4]
|
111
|
NA
|
111
|
NA
|
770
|
14.4
|
|
Amin [5]
|
18
|
NA
|
18
|
NA
|
129
|
14.0
|
|
Suvakovic [6]
|
11
|
NA
|
11
|
NA
|
81
|
13.6
|
|
Yalamarthi [7]
|
30
|
16
|
14
|
NA
|
305
|
9.8
|
|
Voutilainen [8]
|
13
|
NA
|
13
|
NA
|
284
|
4.6
|
|
Hosokawa [11]
|
188
|
NA
|
188
|
NA
|
730
|
25.8
|
|
Raftopoulos [9]
|
55
|
16
|
35
|
4
|
822
|
6.7
|
|
Milestone [12]
|
25
|
17
|
8
|
NA
|
248
|
10.1
|
|
Vradelis [10]
|
16
|
NA
|
16
|
NA
|
74
|
21.6
|
|
Vesey [13]
|
20
|
Not provided
|
Not provided
|
NA
|
344
|
5.8
|
Abbreviation: OGD, oesophagogastroduodenoscopy.
Data on the total number of endoscopic procedures performed during the study period
were available for eight studies [4]
[6]
[9]
[11]
[12]
[13]. A total of 181,662 procedures in these eight studies were associated with 456 missed
cancers, with an overall UGI cancer prevalence of 2.1 % and a missed cancer prevalence
of 0.25 %. In these studies, UGI cancer was diagnosed at 1 in every 48 endoscopies,
and UGI cancer was missed at 1 in every 398 endoscopies.
The mean age of subjects with UGI cancer missed at endoscopy in three studies was
70 (range, 66 – 72) years [7]
[8]
[9]. Missed cancer appeared more common in male (79 %) than in female (21 %) patients
in one study, but this difference was not statistically significant (chi-square test,
P = 0.29) [9].
Heterogeneity
Marked heterogeneity was observed between studies: I
2 = 94.4 %, P < 0.001 for endoscopy missing cancers up to 3 years before diagnosis and I
2 = 83.2 %, P < 0.001 for endoscopy missing cancers within 1 year before diagnosis. Therefore,
a random effects meta-analysis was performed.
Rate of upper gastrointestinal cancers missed at endoscopy
Within 3 years before a diagnosis of UGI cancer, 487 subjects had undergone an endoscopic
procedure that failed to diagnose their oesophagogastric or duodenal cancer. On random
effects meta-analysis, the pooled miss rate of UGI cancer within 3 years before diagnosis
was 11.3 % (7.5 % – 16.6 %; [Fig. 1]).
Fig. 1 Forest plot of subjects undergoing endoscopy that failed to diagnose upper gastrointestinal
cancer within 3 years before the diagnosis.
One hundred forty-three (29 %) subjects had undergone an endoscopic procedure that
failed to diagnose their cancers within 1 year before diagnosis. Of these, 33 (23 %)
were oesophageal cancers, 96 (67 %) were gastric cancers, and 3 (2 %) were duodenal
cancers. No data were available on the site of cancer in 11 (8 %). On random effects
meta-analysis, the pooled miss rate of UGI cancer within 1 year before diagnosis was
6.4 % (4.3 % – 9.5 %; [Fig. 2]).
Fig. 2 Forest plot of subjects undergoing endoscopy that failed to diagnose upper gastrointestinal
cancer within 1 year before the diagnosis.
Three hundred forty-four (71 %) subjects had undergone an endoscopic procedure that
failed to diagnose their cancers between 1 and 3 years before diagnosis. Of these,
31 (9 %) were oesophageal cancers, 303 (88 %) were gastric cancers, and 1 (0.2 %)
was a duodenal cancer. No data were available on the site of cancer in 9 cases (2.6 %).
On random effects meta-analysis, the pooled miss rate of UGI cancer between 1 and
3 years before diagnosis was 6.3 % (3.1 % – 12.4 %).
Site of Cancer
Of the 10 studies examined in this meta-analysis, 6 studies did not include oesophageal
cancers. In the 3 studies that included both oesophageal and gastric cancers, 51 %
of the missed cancers were gastric cancers and 44 % were oesophageal cancers (chi-square
test, p = 0.42) [7]
[9]
[12]. One study did not provide data on the breakdown of oesophageal and gastric cancers
[13].
Publication bias
Publication bias was examined by creating a funnel plot of the log transformed event
rates for the individual studies ([Fig. 3]). The plot shows that the majority of the studies are scattered around the point
estimate. The classic fail safe N test suggests an N value of 3,190 (for z = – 35.1, two-tailed P < 0.001), which makes publication bias unlikely because 3,190 “null” studies would
be needed for the combined two-tailed P-value to exceed 0.05, or 319 missing studies would be required for every observed
study to be nullified.
Fig. 3 Funnel plot of studies of the rate of endoscopy failing to diagnose upper gastrointestinal
cancer to assess for publication bias.
Discussion
A doubling time of 2 to 3 years for mucosal gastric cancer was originally suggested
by Fujita [14]. This figure has been used subsequently in studies to define intervals for “missed”
cancers, with the assumption that a cancer diagnosed within a year after a normal
UGI endoscopy would almost certainly have been present as a macroscopic lesion at
the time of the initial endoscopy and therefore had been missed. If one assumes that
the doubling time for mucosal cancers is 2 to 3 years, UGI cancers diagnosed within
2 to 3 years after a normal endoscopy may well have been associated with a mucosal
lesion at the time of endoscopy and are therefore regarded as “possibly missed.”
In this meta-analysis, failure to diagnose or missing a UGI cancer at endoscopy was
a relatively common event among patients with UGI cancer, occurring in 6.4 % within
1 year before diagnosis and 11.3 % up to 3 years before diagnosis. However, it is
important to recognize that this is a relatively uncommon event in all patients undergoing
endoscopy, occurring in 1 in every 398 endoscopic procedures.
Two series from the same unit in Japan reported high rates (14 % and 26 %) of missed
gastric cancer, diagnosed within 3 years after endoscopy that did not diagnose cancer
[4]
[11]. Male subjects and endoscopists with fewer than 10 years of experience were associated
with failure to detect gastric cancer at endoscopy. Neither series included oesophageal
cancer in its analysis.
A Scottish group subsequently reviewed 305 subjects (among 13,589 patients undergoing
endoscopy) with oesophageal and gastric cancer and found that 30 had undergone a minimum
of one endoscopic procedure during the preceding 3 years [7]. Surprisingly, 75 % of the patients with missed oesophageal cancers and 59 % of
those with missed gastric cancers had had alarm symptoms of dysphagia, anemia, haematemesis,
weight loss, or vomiting at the time of the endoscopy that missed the cancer. Detailed
analysis of individual cases revealed that 27 % of the missed UGI cancer cases were
due to pathologist error and the remaining 73 % due a variety of endoscopist errors,
including not detecting a lesion, detecting an abnormality but not taking a biopsy,
detecting an abnormality for which the biopsy was benign, taking an insufficient biopsy,
and inappropriate delays in follow-up. The same group recently reported their experience
of concentrating UGI endoscopy in the hands of two experienced individuals [13]. Between 2002 and 2009, these two endoscopists performed 16,503 procedures, and
there was a reduction from 7 % to 3.2 % in the percentage of UGI cancers missed at
endoscopy within 1 year before diagnosis. However, this reduction appeared to be due
to a reduction in pathology and follow-up errors, rather than improvement in endoscopy
performance.
More than 28,000 endoscopic procedures were examined at a single institution in Western
Australia, and of the 822 UGI cancers, 29 were missed cancers (endoscopy did not diagnose
cancer within 1 year before diagnosis) and 26 were possible missed cancers (endoscopy
did not diagnose cancer between 1 and 3 years before diagnosis) [9]. Again, alarm symptoms were associated with an increased risk for missing cancer
at endoscopy. In 69 % of the missed UGI cancer cases, an abnormality was described
at initial endoscopy that was at the same site as the subsequent malignancy. The authors
also noted that squamous cell carcinoma in the proximal esophagus seemed to be a commonly
missed lesion in their series.
In a small series of 74 patients with a diagnosis of gastric cancer in Oxford in the
United Kingdom, taking fewer biopsy specimens at endoscopy was found to be associated
with an increased risk for missing UGI cancer [10]. Milestone et al reviewed data on oesophageal and gastric cancers from 2000 to 2006 at
a single center in the United Kingdom and reported that 25 of 248 patients had undergone
an endoscopic procedure within 3 years before diagnosis that failed to diagnose their
cancer [12]. Forty-seven percent of these missed lesions were in the same position as previously
documented endoscopic abnormalities.
There are several possible explanations for a “missed” upper GI cancer. These include
technical limitations in endoscopy technique and lesion recognition; inadequate supervision
of trainees; sampling error (too few or inaccurate biopsies); lack of patient tolerance
of the procedure or inadequate sedation, resulting in a poor or incomplete mucosal
assessment; inappropriate follow-up; and errors of histopathology interpretation.
The majority of the missed cancers included in this meta-analysis were gastric cancers.
The large surface area of the stomach may present particular challenges to complete
examination. The Japanese experience of gastric cancer emphasizes the importance of
meticulous UGI endoscopy. This entails preparation of the patient with a defoaming
agent combined with a mucolytic agent to improve visibility; careful, systematic inspection
of the stomach with adequate air insufflation to flatten the gastric folds; and extensive
photographic documentation (> 25 images) to ensure adequate views of all areas of
the stomach [15]. Clinical trials of defoaming and mucolytic agents have shown that the administration
of such agents does improve mucosal visualization [16].
In the studies that reported endoscopic findings, at least half of the patients with
a missed UGI cancer had an abnormality described at the site of the cancer that was
either not biopsied or biopsied insufficiently [9]
[12]. A greater number of biopsies taken at endoscopy correlates with the likelihood
of a “positive” diagnosis. Increasing the number of biopsies from two to six improved
the diagnostic yield for oesophageal cancer from 95.8 to 100 % [17]. An accuracy rate of up to 97 % for diagnosing gastric cancer was achieved when
at least five biopsy samples were taken [18].
The marked heterogeneity among the studies examined in this meta-analysis raises issues
about the justification of a meta-analytic approach. This is a particularly pertinent
issue when the definition of the clinical variable being examined is inconsistent
and the methodology of the studies varies, as is the case in a systematic review.
However, the studies examined in this meta-analysis have a uniform methodology and
a clear definition of “missed” cancer, and we believe that a meta-analytic approach
to these studies is therefore justified. Furthermore, given the degree of heterogeneity
among the studies, we feel that a random effects model was justified [19].
There are several limitations to our meta-analysis. The diagnosis of “missed” UGI
cancer was based on a retrospective review of the data, and although similar methodologies
were employed in the studies examined, not surprisingly, significantly heterogeneous
results were found given the variety of countries, variable endoscopic practices,
and differing incidence rates of UGI cancer. It was therefore not possible to characterize
further the various causes of missing UGI cancer at endoscopy, whether related to
the procedure, the organization of follow-up, or histopathology. One of the studies
included used a shorter time frame of 2 rather than 3 years before diagnosis to define
a case of missed UGI cancer, which may have slightly underestimated the number of
missed UGI cancers in this population [5]. Studies were not explicit in defining an appropriate follow-up interval, with the
exception of a study from Oxford that very generously allowed up to 6 months to be
an appropriate follow-up interval after an endoscopy that failed to diagnose cancer
[10]. The majority of subjects included in the meta-analysis had gastric cancer. Oesophageal
cancer appeared just as likely to be missed as gastric cancer, but this conclusion
is based on far fewer data. Additionally, data on age and sex were available from
only three studies and one study, respectively, thus limiting the interpretation of
the influence of age and sex on the prevalence of missed cancers.
In summary, 11.3 % of UGI cancers were missed at endoscopy during the 3 years before
diagnosis. Individual studies suggest that male gender, presentation with alarm symptoms,
endoscopists with less experience, pathology errors, failure to biopsy lesions adequately,
follow-up errors, and squamous cell carcinoma of the esophagus may all be important
factors in the failure to detect cancer at UGI endoscopy. Given the impact that an
endoscopic procedure that fails to diagnose cancer often has on patients, their relatives,
and their clinicians, studies to improve the quality of UGI endoscopy in the Western
world and continuing efforts to minimise histopathologic and follow-up errors are
needed.
