Precancerous Phase

In the precancerous phase, the disease is not clinically apparent. Yet this phase has been recognized as pathogenic in experimental carcinogenesis and its characteristic changes also have been identified in human subjects. Morphological changes—abnormalities in size and form—can be observed in the chromosomes. These changes are not identified as related to cancer in human subjects except where multiple centers of cancerization are found (as in the stomach, for instance). (Note 1) These chromosomal abnormalities can be considered to be precancerous lesions, since experimental carcinogenesis has indicated that these changes precede the appearance of cancerous cells. In terms of hierarchic organization, then, the precancerous phase can be considered to be limited to the subnuclear levels.

Noninvasive Phase

In the noninvasive phase, also known as "cancer in situ," abnormal intra epithelial cells are present. The abnormality involves two changes. One, morphological, affects the nucleus; the other affects arrangement of the cells in the epithelium. The abnormal changes in the nucleus in this phase have been widely studied in exfoliative cytology. (Note 2)

Abnormality in this phase appears to be limited entirely to the nucleus. The cells continue to have an almost normally differentiated cytoplasm, a fact which originally led to the description of this phase as "cancer of differentiated cells." Besides the nuclear changes, cells in this phase show, histologically, an anarchic arrangement different from the regular disposition which is one of the basic characteristic of the epithelium. Since the regular relationship between the cells forming epithelium can be attributed to dipolarity, the anarchic disposition seen in this phase of cancer can be ascribed to loss of cellular dipolarity.

Cancer in situ, in terms of hierarchic organization, would appear to involve the level of the nuclei, and the noninvasiveness, characteristic of this phase, persists as long as the "cancerous" abnormality remains limited to this level, that is, as long as the cytoplasm of cells remains apparently unaffected.

Invasive Phase

This phase is characterized by irregular proliferation of cells and penetration into neighboring tissues. To the anarchic arrangements noted in the noninvasive phase, now has been added exaggerated growth. And the change of a noninvasive cancer into an invasive one can be considered to result solely from the addition of the new factor of abnormal growth. The invading cells will persist only if, concurrently, there is a loss of the defense mechanism of the invaded tissues, as will be seen later.

Studies of invading cells have revealed, in this phase, an anomaly no longer limited to the nucleus but now encompassing the cytoplasm as well. Exfoliative cytology has shown an abnormal and rapidly disintegrating cytoplasm and this has served as an important diagnostic criterion. From the point of view of organization, it can be said that, with the participation of the cytoplasm, the disease has progressed from the nuclear to the cellular level.

Painful Phase

Pain is the principal clinical manifestation characterizing the next phase of the disease. As we shall explain in greater detail later, pain arises from changes in the pH of the intercellular fluid that bathes sensorial nerve endings. For the moment, we can remark that biochemical changes now occur outside the cells, and, with the participation of interstitial formations, the disease has progressed to the tissular level.

Preterminal And Terminal Phases

In the next stage, the preterminal, biochemical changes affect the function of various organs which may or may not in themselves contain cancerous cells. While some changes in function may be seen even before this preterminal phase, now, there is manifest impairment. And, while the invasion of an organ by cancerous masses is a factor precipitating the functional changes, invasion is not indispensable. Abnormal biochemical changes leading to serious functional impairments are seen in organs entirely exempt from tumor masses.

With further progress of cancer, metabolic functions that are sys temically important become abnormal. Later, we will analyze in detail these changes which affect the whole organism profoundly. For the moment we want only to note that, with these changes cancer passes from the clinically preterminal to the terminal phase.

In the light of this systematization, cancer then appears to progress clinically in organized fashion as it passes from the relatively innocuous nuclear noninvasive cancer in situ to a lethal systemic disease, the progress being marked by the successive participation of different hierarchic levels of the organization. Table I sums this up.

Table I

Organizational

Level

Physiopathological Changes

Clinical Phase

Subnuclear

Gene and chromosome anomalies

Precancerous

Nuclear

Nuclear anomalies and atypical

Noninvasive cancer

cellular arrangements

Cellular

Atypical growth

Invasive cancer

Tissular

Local pH changes

Painful cancer

Organic

Organic metabolic changes

Preterminal cancer

Systemic

Systemic metabolic changes

Terminal cancer

By extrapolation, a similar progressive participation of hierarchic entities can be conceived of below morphologically recognizable levels. This would permit us, as a working hypothesis, to attribute the pathogenesis of cancer to abnormalities in nucleo proteins or, even lower in the scale, to abnormalities in histones or alkaline amino acids. (Note 3)

This concept—of progressive participation of successive hierarchic levels in cancer—contrasts sharply with the view generally held today which places the entire burden of anomaly on the cancerous cell itself. The classical concept has led to the currently prevailing all or nothing approach in which therapeutic attempts are directed to the cancerous cells as the only avenue for controlling the disease at any moment of its evolution. Under our hierarchic concept, therapeutic possibilities can be extended beyond the cancerous cell.

These considerations raise the question of the relative importance of the multiple changes which occur in cancer. Subnuclear and nuclear changes are of relatively little importance as long as there is no progress of disease beyond these levels. Corroboration for this can be found in the great number of cases in which cancer in situ cells are noted in an organ, yet clinical cancer does not follow. In our concept, the changes which occur at levels above the nuclear are critical in the evolution of the disease and, as such, are the important pathogenic factors. On the other hand, as we shall see later, changes at higher levels similar to those encountered in cancer may occur independently of cancer, and without a sequence of changes at lower levels. It is only when changes at higher levels appear in proper sequence, affecting already abnormal entities of the lower levels, that clinical cancer results and the malignancy moves relentiessly from the noninvasive cancer in situ to the terminal phase.

This concept, then, focuses attention on all changes occurring at different hierarchic levels of the organization rather than on those in the cell alone. It emphasizes the importance of the relative independence which exists between the different hierarchic levels, an independence which governs their participation in the complex condition which is cancer.

From the therapeutic standpoint, then, it seems logical to suppose that, if the progressive participation of successive levels can be interrupted, many if not all of the noxious manifestations and the course of cancer can be favorably influenced. In view of this, it has been essential, first, to obtain more information about the cancer manifestations which are added as the disease takes its hierarchically progressive course and about the mechanisms that account for these manifestations.