Chapter 18

Neoplasia is an abnormality of cell growth and multiplication characterized by the following features: (1) excessive cellular proliferation that typically but not invariably produces an abnormal mass, or tumor; (2) uncoordinated growth occurring without any apparent purpose; and (3) persistence of excessive cell proliferation and growth even after the inciting stimulus that evoked the change has been removed—ie, neoplasia is an irreversible process.

At a molecular level, neoplasia is a disorder of growth regulatory genes (proto-oncogenes and tumor suppressor genes). It develops in a multistep fashion, such that different neoplasms, even of the same histologic type, may show different genetic changes.

Several hypotheses have been advanced to explain neoplasia, many of them reflecting or in response to advances in the basic sciences current at the time. For example, hypotheses of the viral cause of neoplasia coincided with the demonstration of transmission of certain animal neoplasms by ultrafiltrable agents (Rous sarcoma, 1908; Shope papilloma, 1933; Bittner milk factor, 1935). Immunologic hypotheses came to the fore after experiments involving tumor transplantation in animals (Ehrlich, 1908; immune surveillance, Burnet, 1950s). Deoxyribonucleic acid (DNA) mutations as a cause of neoplasia were proposed after the discovery of DNA structure and function (Watson and Crick, 1950s). Several of these hypotheses have enjoyed a phase of respectability, followed by a period of discreditation and then reemergence in modified form.

Two general types of origins have been proposed for neoplasms.

### Monoclonal Origin

According to the concept of monoclonal origin, the initial neoplastic change affects a single cell, which then multiplies and gives rise to the neoplasm. The monoclonal origin of neoplasms has been clearly shown in neoplasms of B lymphocytes (B-cell lymphomas and plasma-cell myelomas) that produce immunoglobulin and in some other tumor types by isoenzyme studies (Figure 18-1).

###### Figure 18–1.

Methods of characterization of cell populations as monoclonal or polyclonal. A: Immunoglobulin light and heavy chain distribution in a B lymphocyte population. B:Glucose-6-phosphate dehydrogenase (G6PD) isoenzyme studies may be used in some female patients. G6PD isoenzyme inheritance is X-linked. In heterozygous females, one X chromosome codes for the A isoenzyme and the other for the B isoenzyme. Because one X chromosome is randomly inactivated in the adult cell, an adult cell will contain only one of the isoenzymes. A polyclonal population will be composed of cells containing both isoenzymes in approximately equal amounts, whereas a monoclonal population will be composed of cells that express only one isoenzyme.

Note that as a neoplasm progresses, further subclones may evolve from the initial clone as a result of additional ongoing genetic changes (multiple hits; see below).

### Field Origin

A carcinogenic agent acting on a large number of similar cells may produce a field of potentially neoplastic cells. Neoplasms may then arise ...

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