During this time, the biological behavior of the pre-malignant cells slowly changes from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits of a pre-malignant lesion are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation. The most severe cases of dysplasia are referred to as carcinoma in situ. In Latin, the term in situ means "in place"; carcinoma in situ refers to an uncontrolled growth of dysplastic cells that remains in its original location and has not shown invasion into other tissues. Carcinoma in situ may develop into an invasive malignancy and is usually removed surgically when detected. Clonal evolution Just as a population of animals undergoes evolution, an unchecked population of cells also can undergo "evolution". This undesirable process is called somatic evolution, and is how cancer arises and becomes more malignant over time. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. However, once cancer begins, cancer cells undergo a process of natural selection: the few cells with new genetic changes that enhance their survival or reproduction multiply faster, and soon come to dominate the growing tumor as cells with less favorable genetic change are out-competed. This is the same mechanism by which pathogenic species such as MRSA can become antibiotic-resistant and by which HIV can become drug-resistant), and by which plant diseases and insects can become pesticide-resistant. This evolution explains why a cancer relapse often involves cells that have acquired cancer-drug resistance or resistance to radiotherapy). Biological properties of cancer cells In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows: Acquisition of self-sufficiency in growth signals, leading to unchecked growth. Loss of sensitivity to anti-growth signals, also leading to unchecked growth. Loss of capacity for apoptosis, allowing growth despite genetic errors and external anti-growth signals. Loss of capacity for senescence, leading to limitless replicative