Cardinal manifestations of cancer
James F. Holland, MD, ScD (hc) 
Waun Ki Hong, MD, DMSc (Hon) 
Donald W. Kufe, MD 
Robert C. Bast Jr., MD 
William N. Hait, MD, PhD 
Raphael E. Pollock, MD, PhD, FACS 
Ralph R. Weichselbaum, MD
Overview
Cancer is asymptomatic at its initiation. Symptoms arise when a conduit is impaired, when cancer cells impinge on nerve fibers causing pain or dysfunction, when secretory products of the tumor cause systemic symptoms such as fever, weight loss, or fatigue, when ulceration and bleeding occur, or upon recognition of a mass. Indeed any symptom that lasts two weeks, even intermittently, could be a symptom of cancer, the great imitator. Cancer always belongs in the differential diagnosis.
Cancer is a singular word that embraces a vast diversity of diseases that can occur in any organ system throughout the animal kingdom. The unique characteristic of cancer is the proliferation of cells of a type different from, if ever so slightly, the normal complement of the organism. The proliferation of cancer cells may be rapid or slow, and the accumulation of cells may be massive or miniscule. The essence of the matter, however, is that aberrant cells, distinct from the ordinary evolution of cell types, appear and accumulate. Thus, a cancer differs from hypertrophy and hyperplasia, which involve normal cells.
A cancer cell does not obey the complex rules of architecture and function that govern the usual placement and behavior of cells within a tissue. The wondrous coexistence of cells and tissues of multiple types that make up the eye, the finger, or the kidney, for example, each with appropriate anatomic location with all connections intact to fulfill their appointed tasks, is part of the miracle we call life. The explanation for this marvelous organization is the field of continuing exploration seeking the messages and the exquisite controls that exist in multicellular organisms.
Cancer is distinguished from other abnormal cellular growths that lead to benign tumors in its characteristic independence from the restrictions present in normal tissues. Benign tumors expand and compress, but do not attack or invade adjacent tissues. Accumulated cancer cells make a tissue that ignores the anatomic barriers of adjacent cell membranes and basement membranes. Through chemical and mechanical means, the cancer cell insinuates itself between and into the space of the normal cells, killing them by chemical and physical means, the grand usurper. Even though the placenta in mammals shows this behavior, there is self-limitation in location and in survival of the placental invasion. Although leukocytes normally extravasate and permeate tissues, they do not share the other characteristics of cancer. The cancer cell is partially or absolutely insensitive to such normal constraints and may continue its invasiveness indefinitely.
Upon reaching a circulatory conduit, either lymphatic or capillary vessel, a process that may not be entirely haphazard, cancer cells often penetrate the wall as part of their invasive behavior. They then may be carried by the lymphatic or the venous circulation to remote sites where the possibility of adherence, extravasation, and colonization can occur, establishing metastases. In the absence of an intervening event, and given enough time, with few exceptions, the cancer process, as described, can lead to such anatomic or functional distortions that death ensues.
The cancer process does not start with a fully invasive cancer cell. A disorder in molecular instructions for protein synthesis is the common precursor lesion, nearly always because of qualitatively or quantitatively aberrant ribonucleic acid (RNA) messages transcribed from nuclear deoxyribonucleic acid (DNA). This occurs because of a mutation of the DNA, or because of overexpression of particular genes that encode proteins important as catalysts in pathways for stimulating growth, or because of under expression of genes whose coded proteins control and inhibit growth. Portions of genes may be lost, translocated, or amplified. Indeed, entire chromosomes may be deleted, replicated, or fused in abnormal ways. All such distortions of DNA can give rise to abnormal or unbalanced RNA messages, leading to qualitative or quantitative differences in proteins that result in disordered cellular function. Sometimes the functional abnormality is so extreme as to be lethal to the cell, initiating the suicidal mechanism of apoptosis. In other instances, the functional abnormality results in disease. Some of these diseases display the characteristics of cancer. Mutation, overexpression, and underexpression of genes can result from a wide spectrum of intrinsic and extrinsic causes, with various pathways that lead not to one final common pathway, but by several converging routes to cells with the phenotypic characteristics of cancer. When these cells are limited to an epithelial layer above the basement membrane, they are called carcinoma-in-situ or intraepithelial neoplasia. Similar changes probably occur, but are more difficult to recognize, in the mesenchymal tissues. Even cancer cells that do not penetrate the basement membrane, and thus lack one of the cardinal features of true cancer, represent a long series of antecedent molecular abnormalities that eventually lead to this optically recognizable cellular change. Furthermore, these evolving cancer cells are the common, if not the exclusive, precursor of invasive cancer.
In their initial stages, as proliferating cells accumulate, cancers are almost always asymptomatic. Cancers cause symptoms as they advance as a consequence of their mass, because they ulcerate on an epithelial surface, or because of change in function of the affected structure or organ. Nearly all the symptoms that can be caused by cancer can also be caused more commonly by noncancerous diseases. The astute clinician must include cancer in the differential diagnosis of virtually every symptom, albeit a benign disease may usually explain it. Doctors never diagnose diseases they do not think of. Cancers occur at any age. A longer life span provides greater opportunity for intrinsic organic events
