Learning from Case Reports

Abstract

Epidemiologic studies on exocrine pancreatic cancer show a large heterogeneity in diagnostic criteria applied to define “caseness.” Reanalyses conducted after review of diagnostic information have yielded substantially different results than those based on more crude classifications of disease. During a multicenter prospective study on mutations in the K-ras gene in pancreatic and biliary diseases, hospital diagnoses from 602 patients were reviewed by a panel of experts. There were two main motivations to do so: a generic interest for the quality of the diagnostic data, and the anticipation that a firm diagnosis could be needed to assess whether patients whose tumors did not harbor the mutation were true negatives or false negatives. In addition, the review of diagnoses was helpful to minimize tissue misclassification, and it had a high educational value for clinicians and epidemiologists. This article illustrates why and how this was so through a brief presentation of the 10 most significant cases. With respect to selection and classification of subjects, the main issues that studies on pancreatic cancer need to address are the differential diagnosis of exocrine pancreatic cancer and pancreatitis, the differential diagnosis of exocrine pancreatic cancer and other abdominal tumors, and the use of survival as a hallmark of pancreatic cancer. In epidemiologic studies of pancreatic cancer, it is warranted that a panel of experts centrally reviews all the existing diagnostic evidence (cytohistological and other) of all patients, regardless of whether they have cytohistological confirmation and of their hospital discharge diagnosis.

Introduction

Few issues seem to reflect more dramatically the “schism” between clinical medicine and epidemiology [1] than misclassification of disease. Epidemiologic and statistical approaches have largely worked on the basis that misclassification is nondifferential 2, 3. This assumption is often difficult to substantiate, but the alternative—that diagnoses frequently depend on clinical, sociodemographic, and environmental factors—is hard to treat on a purely quantitative basis: It requires to apply clinical knowledge to individual cases.

By contrast, a large body of medical knowledge has emanated from the intensive study of individual patients 4, 5, 6. The case study has long been and continues to be at the heart of clinical knowledge 7, 8.

Exocrine pancreatic cancer is one of the tumor types presenting more diagnostic difficulties, and epidemiologic studies show a large heterogeneity in diagnostic criteria used to define “caseness” 2, 9, 10, 11. In analytical studies, sensitivity is generally sacrificed for the sake of specificity. Whereas this strategy probably has more advantages than drawbacks, it cannot obscure what we and others 9, 10 deem an excessive simplicity of some epidemiologic approaches to diagnostic certainty. Studies on the clinical value of putative diagnostic tests will recruit patients with a suspected diagnosis, and this methodologic requirement will further underscore the need for an independent review of diagnoses. Molecular epidemiologic studies will have to face even more diagnosis-related questions.

We conducted a multicenter prospective study on the role of mutations in codon 12 of the K-ras gene and other genetic alterations in the diagnosis, prognosis, and etiology of pancreatic and biliary diseases, the PANKRAS II study 12, 13, 14. Hospital diagnoses were reviewed by a panel of experts on the basis of all clinical and pathologic (cytohistological) information available. Originally, there were two main motivations to do so: a generic concern for the quality of the diagnostic data, and the anticipation that a firm diagnosis could be needed to assess whether patients with the wild-type genotype (i.e., without the mutation) were true negatives or false negatives. But the review of diagnoses proved to be even more useful than expected. First, it was instrumental in minimizing tissue misclassification (the erroneous classification of the anatomic origin and pathologic characteristics of tissue samples). Second, it unveiled many theoretical and substantive issues that subsequent analyses could tackle. And third, it had a high educational value, both for clinicians and for epidemiologists. This article illustrates the reasons why this was so through a brief presentation of the 10 most significant cases.