Diagnostic certainty in pancreatic cancer

J Clm Epidemiol Vol. 49, No. 5, pp. 601-603, 1966 Published 1996 Elsevier Science Inc.

08954356196/$00.00

ELSEVIER

LETTERS TO THE EDITORS Diagnostic Certainty

in Pancreatic Cancer

Porta and colleagues [l] investigated the degree of diagnostic certainty of cancer of the exocrine pancreas in two hospitals in the Barcelona area of Spain. They found that only 52% of 140 cases identified for study had a high probability of having pancreatic cancer based on a diagnostic certainty classification developed for their study. Porta et (11.(11 also observed no temporal change in the degree of diagnostic certainty during the lo-year study period from 1980 to 1990. On the basis of a different diagnostic certainty classification, Lyon et al. [2] found that about 68% of the 125 cases in a case-control study in Utah had a high probability of having pancreatic cancer. Both studies suggested that difficulties in diagnosing pancreatic cancer may be a source of significant misclassification of disease status in case-control studies of pancreatic cancer. This bias may, in fact, lead to dilution of the odds ratios estimated in such studies. In a population-based, case-control study of pancreatic cancer conducted in three areas of the United States [3], in-depth medical chart reviews by a physician-epidemiologist and a surgeon specializing in pancreatic cancer indicated that 94.5% of the 1196 identified cases aged 30 to 79 years were considered “likely” to have had pancreatic cancer. The diagnosis was classified as “likely” if at least one of the following criteria was satisfied: (1) a pancreatic mass was known by radiographic visualization or surgery, with a compatible histological diagnosis; (2) a pancreatic mass was known by surgery and, although a biopsy specimen was not obtained, it appeared to be malignant due to either visible hepatic metastasis or local extension; or (3) a pancreatic mass was known by radiographic visualization, although a biopsy specimen was not obtained, and there were supporting clinical signs, symptoms, and course (e.g., rapid death).

TABLE 1. Incident pancreatic SEER Prowam. 1974-1991

cancer

cases by method

The case series from this study was fractionated according to both degree of diagnostic certainty and whether the diagnosis was microscopically confirmed. We estimated odds ratios for cigarette smoking, the most consistent risk factor for pancreatic cancer. After adjustment for potential confounders (i.e., age at diagnosis, race, sex, geographic area, alcohol drinking, gallbladder disease, and income), the odds ratio for “ever smoker” was 1.8 (confidence interval [CI] = 1.4-2.4) for microscopically confirmed cases considered “likely” to have had pancreatic cancer, 1.3 (CI = 0.6-2.8) for nonmicroscopically confirmed cases considered “likely” to have had pancreatic cancer, and 1.0 (CI = 0.4-2.4) for casesconsidered “unlikely” to have had pancreatic cancer. Odds ratios were similar for subjects younger than age 65 years at diagnosis/interview and for those age 65 years or older. Assuming that smoking is indeed a risk factor for pancreatic cancer, these findings suggest that when the case series includes only “likely” patients with microscopic confirmation, the degree of diagnostic certainty is higher and misclassification of disease status is less. When the case series includes “likely” patients without microscopic confirmation, the degree of diagnostic certainty is lower, misclassification of disease status increases, and the odds ratio is biased toward the null. Thus, it appears that restriction of the case series to “likely” cases with microscopic confirmation will generate the most precise estimates of risk. It is interesting to note that, on the basis of data from the U.S. Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute from 1974 to 1991 [4], the percentage of pancreatic cancer patients with microscopic confirmation of the diagnosis remained remarkably constant, ranging from 73 to 76%, despite dramatic changes in the techniques used to diagnose pancreatic cancer (Table 1). The percentage of patients diagnosed

of diagnosis

and time period Time

Method

of diaenostic

confirmation

1974-1976

1977-1979

1980-1982

for ail races and sexes combined,

U.S.

period 1983-1985

1989-1991

7035

7022

5696

5937

6339

73

74

76

75

76

75

71 1 1

72 1 0

71 4 0

67 8 0

63 I3 0

58 17 0

27

27

23

24

24

25

12 6 5

11

9 10

:

2

6 12 3

5 14 2

4 14 3

Not ascertained (%)

4

4

2

3

3

4

‘Histological confirmation of resected tissue from either Abbreviation: NOS, not otherwise specified.

the pancreas or a metastatic

Total number of cases Microscopically confirmed (%) Positive histology” Positive exfoliated cytology Microscopically confirmed, NOS Nonmicroscopically

confirmed (%)

Direct observation at surgery Radiographic visualization Nonmicroscopically confirmed, NOS

ate.

6967

1986-1988

602

Letters to the Editors

by histological confirmation (resected tissue from either the pancreas or a metastatic site) decreased from 71 to 58% during this time period. This decline was accompanied by an increase from 1 to 17% in the percentage of patients diagnosed by cytological confirmation, reflecting the increasing use of computerized tomography (CT)-guided skinny needle biopsy of the pancreas since about 1980. The percentage of patients diagnosed by direct observation of the pancreas at surgical exploration without microscopic confirmation dropped from 12 to 4% during the same time period, while the percent diagnosed by radiographic visualization without microscopic confirmation increased from 6 to 14%. The effect of these changes on the degree of accuracy of diagnosis of pancreatic cancer is unknown. Changes in diagnostic techniques also appear to have had little impact on the overall incidence of pancreatic cancer, which remained stable at 9-10 per 100,000 person-years during the last two decades [4]. SEER data also indicate that the proportion of cases with microscopic confirmation decreases with age at diagnosis from 94% at ages 30-49 years, 89% at ages 50-69 years, 76% at ages 70-79 years, to 46% for those 80 years of age or older, based on data from 1989 to 1991. By restricting subject eligibility for case-control studies of pancreatic cancer to patients under age 80 years, the proportion with microscopic confirmation may be as high as 84% (percent microscopically confirmed for ages 30-79 years), which is likely to improve the accuracy of diagnosis in the case series under study. In summary, the inclusion of only microscopically confirmed cases, as well as restriction of study subjects to those under age 80 years, should lead to more valid and informative epidemiological studies of pancreatic cancer by decreasing misclassification of disease status. DEBRA

T. SILVERMAN,

MARK

SCHIFFMAN,

AND SUSAN

DEVESA

National Cancer Institute Bethesda, Maryland

References Porta M. Malats N. Pifiol IL. Rifa 1. Andreu M, Real FX. Diagnostic certainty and potential for misclassification in exocrine pancreatic cancer. J Clin Eiidemiol 1994; 47: 1069-1079. Lvon IL. Robison LM. Moser R. Ir. Uncertaintv in the diagnosis of h&&&ally confirmed pancreatic ;ancer cases. int J Epidemyol 1989; 18: 305-308. Silverman DT, Dunn JA, Hoover RN, Schiffman M, Lillemoe KD, Schoenberg JB, Brown LM, Greenberg RS, Hayes RB, Swanson GM, Wacholder S, Schwartz AC, Liff JM, Pottem LM. Cigarette smoking and pancreas cancer: A case-control studv based on direct interviews. I NatiCancer Inst 1994; 86: 1510-1516. Ries LAG. Miller BA. Hankev BF. Kosarv CL. Harras A. Edwards BK (eds.). SEER Cancer Statistics’Review, 1973-1491: Tables and Graphs. NIH Publ. No. 94-2789. National Cancer Institute, Bethesda, Mary land, 1994. _.

I

SSDI 0895-4356(95)00508-2

RESPONSE We appreciate the interest of Silverman et al. in our study [l], and are particularly interested in the data reported in their letter. The differences they found in risk estimates for smoking across strata of diagnostic certainty are remarkably in line with the results of the reanalysis conducted by Garabrant et ul. for exposure to DDT and related compounds [2,3]. We think both analyses teach us that epidemiological studies ought to pay closer attention to the meth-

ods and strategies actually used in every geographic area and clinical setting to achieve a differential diagnosis of exocrine pancreatic cancer (EPC). They also show that a simple classification of diagnostic basis may suffice to make relevant findings come to light. Then why are analyses that stratify by diagnostic certainty (or related variables) so scarce in EPC epidemiology? An example of research where such an approach seems fully justified is the SEARCH program, a set of case-control studies conducted under the auspices of the International Agency for Research on Cancer (IARC) [4]; in such a program the proportion of histologically verified EPC cases was sometimes as low as 68% (even 43%). The figures are well within the range usual in epidemiological studies of EPC-which brings us to our second point. What is the true diagnosis of cases without cytohistological confirmation or deemed less “likely”? In our view, that group is composed of (1) subjects who did have EPC, (2) subjects with any of the other cancers EPC is likely to be mistaken for, and even (3) subjects with other benign pancreatic and peripancreatic diseases. In view of the findings of Silverman et al., this explanation is scientifically coherent only to the extent that such pathologies are not tobacco related. In our view it is correct to assume that smoking is indeed a risk factor for EPC; naturally, this does not entail that all true cases of EPC must smoke, that is, that smoking is a necessary cause of EPC. Thus, smoking could be a risk factor for the spectrum of cases who had cytohistological confirmation but not for the rest of cases. The latter may have risen from cohorts of subjects with low or null exposure to tobacco, or with other more powerful, yet unidentified contributory causes of EPC. The reasoning could similarly be applied to the study by Garabrant et ul. [3]. With growing interest in possible precursor lesions of EPC and in the genetic alterations of benign pancreatic disorders 151, it may be that we should keep in mind the possibility that some “unlikely” EPC cases have some of the less usual histological forms of pancreatic cancer, or suffer from diseases whose relationship with it is not yet established. Excluding this part of the spectrum of pancreatic pathology could thwart our capacity to discover new environmental exposures that cause pancreatic cancer, new genetic and clinical precursors of the disease, and the mechanisms through which they interact. How comfortable should we feel excluding patients without cytohistological confirmation and above 80 years of age? Patients without confirmation represent one fourth of the total number of EPC cases in the SEER program [6]; in other U.S. areas and demographic groups, the figure may be 60% or higher [7]. Of course, the proportion of cases without cytohistological confirmation is even greater in some areas of other countries [7], including Spain [7,8]. Again, few clinicians would be surprised by these figures [l]. In the United States, where the median age at diagnosis of EPC is estimated to be 71 years [9], a significant proportion of cases are diagnosed after the age of 80 years (e.g., about 28% of white females) (see Ref. [7], pp. 303-305). In Europe, about 30% of male cases are 75 years of age or older; the corresponding figure for women is over 40% [lo]. As Silverman et al. point out, cytohistological confirmation decreases markedly with age; actually, in the United States and elsewhere, it also varies by gender, race, and geographic area [7], but a formal analysis is lacking. If the magnitude of the differences in confirmation rates was to be found significant and to vary over time, some aspects of the descriptive epidemiology of EPC (incidence, mortality, and distribution of stage at diagnosis) may need revision [l 11. Whereas the percentage of EPC patients with confirmation remained constant in the SEER program