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Short Communication |
Departments of Health Research and Policy [A. S., J. P.], Pathology [T. A. L.], and Medicine [J. P.], Stanford University School of Medicine, Stanford, California 94305, and Department of Pathology [B. P.] and Division of Research [L. A. H.], Kaiser Foundation Research Institute, Oakland, California 94611
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Abstract |
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coefficient was 0.59 (95% confidence
interval, 0.44–0.73). Concordance for tumor grade was 87%, with a
coefficient of 0.72 (95% confidence interval, 0.57–0.87). Both
observed concordance and coefficient for histological type and
tumor grade were similar across three calendar periods of study.
Interobserver agreement was virtually identical between tumors with
biopsy specimens only and those with surgical specimens. Although the
level of disagreement for histological type observed in this study is
comparable with that in other studies, the resulting misclassification
would lead to the reduction in observed differences in prevalence and
odds ratio estimates between two histological types. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Investigators have examined risk factors and molecular changes that might be differentially associated with various histological types. In such investigations, consistent and reliable classification of tumors is essential. As a part of our molecular epidemiological study of stomach cancer, we examined the concordance between two pathologists in assessment of Laurén classification and tumor grade. We also assessed the effects of misclassification in histological typing on the observed differences in prevalence and OR3 estimates between intestinal-type and diffuse-type tumors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first screened pathology reports and H&E-stained slides to confirm the eligibility of subjects. The following tumors were excluded from this study: adenocarcinoma of the gastroesophageal junction; gastric neoplasia other than adenocarcinoma; metastatic tumor to the stomach from another organ; and metastatic cancer of gastric origin without concomitant histological material from primary tumor in the stomach. The present analysis includes 95 cases of gastric adenocarcinoma, and tumor specimens of these cases were reviewed by two study pathologists before August 1999.
Histological Review of Tumor Specimens.
H&E-stained slides from endoscopic biopsies and gastrectomies were
obtained from pathology departments and a storage facility of the
KPMCP. Biopsy specimens alone were available for 42 of 95 (44%)
subjects. For each subject, one pathologist reviewed all of the
available slides (mean = 4.7 slides/subject, including slides that
did not contain tumor) and selected slides containing most
representative tumor sections. The selected slides (mean = 1.8
slides/subject) were forwarded to the second pathologist. The two
pathologists, each of whom was blinded to the other’s assessment,
recorded their assessment for histological type and grade of tumor on
an evaluation form. For each tumor, pathologists were instructed to
identify a type [intestinal type (tubular, papillary, or mucinous
carcinoma or not otherwise specified), diffuse type (signet cell
carcinoma or not otherwise specified), or other (undifferentiated or
borderline)] and indicate the degree of differentiation (well,
moderately, or poorly differentiated; Ref. 5
).
Initial review of the 95 tumors was conducted between November 1997 and July 1999. The pathologists held joint review sessions in July 1998 and April 1999 to resolve disagreements between their assessments. Data analyzed in this study came from the initial assessments made by each pathologist before these joint reviews.
Assessment of Interobserver Agreement.
Responses of the two pathologists regarding histological type were
considered as concordant if their responses both fell on one of the
three categories (i.e., intestinal type, diffuse type, or
other). Observed concordance was calculated as a percentage of tumors
with concordant responses (i.e., tumors that fell on the
diagonal cells in a 3 x 3 table, such as Table 1
). coefficient, a measure of interobserver agreement, and its 95%
CI were calculated (6)
. Agreement of tumor grade
assessment was examined similarly, using three categories (well,
moderately, and poorly differentiated).
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Assessment of the Effects of Misclassification.
We assessed how misclassification of tumors with respect to
histological type would affect the observed differences between
intestinal-type and diffuse-type tumors, using two examples:
(a) prevalence of tumors stained with a p53 antibody by IHC;
and (b) OR for cancer risk associated with H.
pylori infection. We assumed that a certain percentage (10% or
15%) of intestinal-type tumors was misclassified as diffuse type and
that the same percentage of diffuse-type tumors was misclassified as
intestinal type, independent of p53 IHC and H. pylori
status (i.e., nondifferential misclassification). The two
percentages used in the examples were chosen to represent the level of
disagreement between pathologists observed in this study. For the
purpose of these illustrations, we assumed, although it is unrealistic,
that there was no measurement error in p53 IHC and H. pylori
status.
For the example of p53 IHC, we assumed that the true prevalence of p53-positive tumors was 60% in intestinal-type tumors and 30% in diffuse-type tumors (reasonable estimates based on work by A. S.4 ). We estimated the difference between the two percentages observed in a study including 200 gastric tumors (100 intestinal-type and 100 diffuse-type tumors) when a specified level of misclassification occurred.
For the example of H. pylori and gastric cancer risk, we assumed that the true ORs were 5.0 for intestinal-type tumors and 10.0 for diffuse-type tumors. Assuming that 60% of control subjects were H. pylori positive, these ORs are translated into the H. pylori prevalence of 88% and 94% in subjects with intestinal-type and diffuse-type tumors, respectively. We estimated observed ORs for intestinal-type and diffuse-type tumors if the tumors were misclassified at a specified level, in a hypothetical case-control study with 200 cases (100 intestinal-type and 100 diffuse-type tumors) and 200 controls.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The coefficient was 0.59 (95% CI, 0.44–0.73).
The observed concordance for the three calendar periods was 79%, 79%,
and 69%, with coefficients of 0.62 (95% CI, 0.37–0.87), 0.62
(95% CI, 0.43–0.82), and 0.40 (95% CI, -0.01 to 0.81). The level of
agreement was almost identical, regardless of whether only biopsy
specimens were available (concordance, 77%; , 0.58) or surgical
specimens were available (concordance, 79%; , 0.61).
Concordance of Tumor Grade
Responses on tumor grade were available for 91 tumors. Poorly
differentiated tumors were the most common (67% and 66% by two
pathologists, respectively). Overall agreement for tumor grade was
87%, with a coefficient of 0.72 (95% CI, 0.57–0.87; Table 2
). The observed concordance for the three calendar periods was 93%,
83%, and 88%, with coefficients of 0.85 (95% CI, 0.64–1.00),
0.64 (95% CI, 0.42–0.86), and 0.73 (95% CI, 0.37–1.00).
Interobserver agreement was virtually identical between cases with
biopsy specimens only (concordance, 88%; , 0.70) and those with
surgical specimens (concordance, 86%; , 0.72).
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A), the number of p53 IHC-positive tumors in 100 "nominal"
intestinal-type tumors is 90 x 0.6 + 10 x 0.3 = 57.
Similarly, 33 of 100 tumors classified as diffuse type are p53 IHC
positive. Consequently, the difference in prevalence of p53 IHC tumors
between the two types is 57% - 33% = 24%, which is smaller than the
true difference of 30%. Similarly, if 15% of tumors are
misclassified, the difference in p53 IHC positivity between
intestinal-type and diffuse-type tumors is 21%.
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, whereas
the observed OR for diffuse-type tumors decreases from 10.0 to 8.9,
resulting in a smaller ratio of the two ORs (1.6 rather than 2). If the
misclassification occurs in 15% of tumors, the ORs for intestinal-type
and diffuse-type tumors are even closer to each other. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Histological classification of cancers, as is the case with all measurements, is prone to error. Histological typing and grading are inherently subjective because they depend on a pathologist’s judgement in the absence of objective "gold standard" measures. Pathologists would be more likely to disagree for tumors with overlapping histological patterns, which consist of as high as 15% of all gastric cancers (1 , 8) . Given the absence of a "gold standard," examining the level of agreement between two or more pathologists is a feasible alternative to estimate the reliability of histological data.
Our study showed an overall agreement for Laurén classification
between two pathologists in 77% of the 92 gastric adenocarcinomas; a
coefficient of 0.59 is considered as "fair to good" agreement
(6)
. Both observed concordance and coefficient for
histological type were consistent across the three calendar periods and
regardless of whether surgical specimens of tumor were available in
addition to biopsy specimens. The level of agreement was higher
for tumor grade, which was somewhat surprising to us because we had
expected that determination of tumor grade would be more subjective and
thus more variable between pathologists. For example, in a study of 17
gastric cancers reviewed by 14 pathologists (8)
, agreement
with accepted reference pathology was higher for Laurén
classification (89%) than for tumor grade (63%).
Other studies also examined the reliability of histological typing and
grading for gastric cancers. Palli et al. (9)
observed agreement among six pathologists in 70–80% of the 100
gastric cancers reviewed for histological classification. Agreement
between repeat readings with an up to 3-year interval by the same
pathologist was also high (95%) (Ref. 9
). In a study by
Hansson et al. (10)
, one pathologist repeated a
review of gastric cancer specimens after a 2-year interval. Overall
agreement and coefficient, respectively, for Laurén
classification was 79% and 0.63 for 67 resection materials and 83%
and 0.70 for 88 biopsy materials. These results are comparable with our
findings.
Distinct pathways of carcinogenesis for the two histological types of Laurén were suggested by more frequent observations of precancerous lesions in gastric mucosa adjacent to intestinal-type tumors (2 , 3) . Subsequently, many studies examined risk factors (e.g., H. pylori infection) (Ref. 11 ) and molecular markers (e.g., p53 abnormalities4 ) for intestinal-type and diffuse-type tumors separately. Lack of reliability in histological assessment in these investigations would lead to misclassification of tumors, potentially resulting in inconclusive or erroneous findings. In our study, two pathologists disagreed on histological type for 24% of tumors; i.e., an average of 12% of tumors classified as intestinal type by one pathologist was classified as diffuse type by the other pathologist, and vice versa. As our hypothetical examples show, this level of misclassification would result in reduced differences in prevalence and OR estimates between histological types, such that those differences might be discounted. It would be difficult to assess the degree and direction of bias for actual studies, in which additional measurement error occurs in other variables, and histological misclassification might not be independent of other marker measurements.
Extrapolation of our findings to other settings may be limited due to
some aspects of study design. First, a second pathologist reviewed only
a subset of slides that a first pathologist considered as most
representative, which may have resulted in overestimated
coefficients. Second, the joint review by two pathologists may
have influenced subsequent typing of tumors, although we observed no
increase in concordance over the calendar periods.
In conclusion, we observed reasonably good agreement between pathologists for Laurén classification and grade of gastric cancers. A central review of pathology material and resolution of disagreements between pathologists will be practical alternatives to improve the reliability of histological data in epidemiological studies.
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Acknowledgments |
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Footnotes |
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1 Supported in part by American Cancer Society
Institutional Research Grant 32-36 and NIH Grants R01CA73011 and
R35CA49761. 
2 To whom requests for reprints should be
addressed, at Department of Health Research and Policy, Stanford
University School of Medicine, HRP-Redwood Building, Room T211,
Stanford, CA 94305-5405. Phone: (650) 723-6879; Fax: (650) 725-6951;
E-mail: ashibata{at}stanford.edu
3 The abbreviations used are: CI, confidence
interval; IHC, immunohistochemistry; KPMCP, Kaiser Permanente Medical
Care Program; MPHC, multiphasic health checkup; OR, odds ratio.
4 A. Shibata. Immunohistochemical analysis of p53
tumor suppressor in stomach cancer, manuscript in preparation.
Received 6/ 6/00; revised 11/ 2/00; accepted 11/ 4/00.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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