Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal

Abstract

Cancer evolution is a step-wise non-linear process that may start early in life or later in adulthood, and includes pre-malignant (indolent) and malignant phases. Early somatic changes may not be detectable or are found by chance in apparently healthy individuals. The same lesions may be detected in pre-malignant clonal conditions. In some patients, these lesions may never become relevant clinically whereas in others, they act together with additional pro-oncogenic hits and thereby contribute to the formation of an overt malignancy. Although some pre-malignant stages of a malignancy have been characterized, no global system to define and to classify these conditions is available. To discuss open issues related to pre-malignant phases of neoplastic disorders, a working conference was organized in Vienna in August 2015. The outcomes of this conference are summarized herein and include a basic proposal for a nomenclature and classification of pre-malignant conditions. This proposal should assist in the communication among patients, physicians and scientists, which is critical as genome-sequencing will soon be offered widely for early cancer-detection.

Keywords: Cancer; Clonal evolution; Neoplastic stem cells; Pre-malignant states.

Fig. 1

Model of cancer evolution an initial transforming event (Initial Event) converts a normal stem/progenitor cell into a somatically mutated clonal stem cell. In case the stem cell can survive and retains self-renewal capacity, it has become a neoplastic premalignant stem cell (Early Lesions). Usually, these cells are slowly cycling cells or dormant cells and contain passenger mutations. After several years or decades, the resulting clone has acquired first driver lesions and expands and may have replaced some or most of the polyclonal cells in the normal organ (First Driver Lesions). At that time, neoplastic cells and normal cells are often indistinguishable by morphology or in functional terms. In a next step, one or more sub-clones acquire additional driver-lesions (Additional Lesions). Depending on the type of lesion and the type of preformed clones and their passenger signature, the resulting new subclones may either expand immediately, or may again reside in a slowly cycling or even dormant stage. In these patients, the driver mutation may or may not be detectable depending on the size of the affected sub-clones. However, as soon as additional driver lesions have been acquired, the resulting sub-clones can finally expand and replace the normal organ (Complex Multi-Lesion Patterns). In many cases, the created neoplasm may still behave as an indolent driver-positive neoplasms for some time. However, unless treated, many of these conditions will finally progress to an aggressive malignancy.