Do pathologists play dice? Uncertainty and early histopathological diagnosis of common malignancies

According to Kassirer and Kopelman, a gold standard in medicine is a ‘relatively irrefutable standard that constitutes recognized and accepted evidence that a certain disease exists’. Throughout the 20th century, the pathological diagnosis has served well as a gold standard for both establishing the presence of, and classifying, human tumours. At an individual case level, the pathological diagnosis plays a pivotal role in the patient’s and physician’s choice of therapy for neoplastic disease. At a societal level, pathological diagnoses determine the apparent frequency of malignancy, guide public policy decisions about the allocation of health care and research funding, and supply data to decide whether massive screening programmes are effective or ineffective. Confounding factors such as the underlying complexity of biological systems and the variation in pathologists’ skills have resulted in some diagnoses that either falsely predict behaviour characteristic of malignant disease or falsely predict behaviour characteristic of benign lesions. However, it has been apparent to both pathologists and non-pathologists that histopathological techniques are remarkably successful at identifying patients who either are or are not at greatly increased risk for near or intermediate-term morbidity or mortality from neoplasia. The pioneer surgical pathologists who were responsible for laying the groundwork for the specialty’s success in tumour evaluation adopted a benign/ malignant paradigm. This paradigm appropriately met the expectations of doctors and patients, in large part because it was congruent with the available therapeutic options. For example, a large breast mass might be cancer or fat necrosis, and the therapeutic options were major surgery or no further treatment. Occasionally, pathologists encountered examples of lesions that appeared to be early steps in the development of carcinoma. Some of these lesions resembled advanced cancers in every way except for size and the absence of metastatic disease at diagnosis, while other lesions had only a few histopathological features in common with traditional cancers. Because pathologists had experienced such remarkable success in the evaluation of advanced neoplastic disease, it was to be expected that they could apply their proven techniques and their benign/malignant paradigm to the diagnostic labelling of these early lesions. Furthermore, pathologists were under considerable pressure from patients and medical colleagues to classify these lesions as either benign or malignant, and the answer ‘in between’ or ‘I don’t know’ was met only with the demand to show the case to someone who did know. Thus, acknowledgement of uncertainty was confused with incompetence, and, conversely, exuding confidence when evaluating equivocal lesions was held to be an important diagnostic skill. The purpose this critical review is to examine the modern role of histopathologists in the evaluation of lesions that have traditionally been labelled as carcinoma, but are often unassociated with clinical manifestation of malignancy. This topic involves the complex interaction between deeply held diagnostic beliefs, and a changing external environment that includes both increasingly sensitive screening programmes and a harsh legal system that is particularly intolerant of ‘missed cancer’.