Central nervous system disorders

VI./2.3.: Issues of tumor malignancy

VI./2.3.1.: Definition

Malignant are those tumors which without effective treatment, by ourselves, lead to the patient’s death directly, or indirectly, due to their biological behavior.

VI./2.3.2.: Malignancy, progression, propagation

This inaccurate definition – from various aspects – explains why malignant tumors show so variable characteristics. In a universal, oncological sense, metastatizing is closely related to malignancy, since it is one of the most important signs of malignancy, and vica versa, malignancy is a conditio sine qua non - a condition without which it would never occur - for metastatizing.

(The oncological sense of metastatisation has been emphasized, because this term is used by the pathology of inflammatory diseases too, especially when describing metastatic abscesses. However, this latter is a completely different process, it has only formal relation to the oncological metastatisation, that is, when septic emboli are torn off from an inflammatory node and through traveling by the blood stream end up forming new abscessi in different, distant places.) However, even this association, that is known as one of the corner-stone of oncology, cannot be automatically applied. Primary brain tumors, for example, typically never give extracranial metastasis, still, there is no doubt about their malignancy, which lies in their agressive tendeny to recidivate.

The „visible” time during which the tumor actually causes death can be different. Majority of those tumors that are lethal in short term (within a few months-years from the time they were noticed) are mainly undifferentiated or poorly differentiated (high grade tumors [depending on the tissue type, GrIII., or GrIV.]) Biologically agressive behavior and the level of differentiation are inversely proportional, undifferentiated tumors usually grow fast and spread around the body (propagation) easily. (Tumor progression [decreasing level of differentiation] and propagation [spreading of the tumor] are two different aspects of a tumor!) Highly differentiated tumors usually show slower progression and propagation.

It is not rare that these kind of tumors become lethal only over years. This is explained by the clonal selection, that is when an agressive clon of undifferentiated cells, which is capable of metastatizing takes over the dominancy within the tumor. However, the accumulation of genetic lesions that are necessary for this process may take even years. The level of differentiation is directly proportional to the degree of which tumor cells show functional and characteristic similarities to the tissue they originate from. If the similarity is significant, we say it is a well differentiated tumor and when the tumor deviates from the features of the mother-tissue, it is called poorly differentiated tumor. Either the lesions, or on the other hand, the preservation of the genetic substance responsible for creating the features of the cells, are in the background of all this. At the end of this line stands the complete loss of cellular characteristics, that is called histological anaplasia.

VI./2.3.3.: Malignancy and the death of the host

It is also variable how the tumors cause the death of the host:

• - Some tumors are lethal bacause of their space-occupying characteristic (for example: primary brain tumors);

• - A non-tumor related complication of the presence of a tumor can also be lethal, for example:

  • - central lung cancer >> bronchoconstriction >> lack of air, superimposed infection, pneumonia of the area behind;

  • - lymphomatoid mediastinal enlargement of the lymphnodes >> v. cava superior syndrome;

  • - esophageal cancer >> esophageal stricture due to cancer (strictura oesophagi propter tumorem) >> general bodily exhaustion due to under-nutrition (inanitio),

  • - esophageal cancer >> tracheaesophageal fistula >> aspiration pneumonia,

  • - esophageal cancer >> aortoesophageal fistula due to cancer >> exsanguination;

• - bioactive products of tumor cell metabolism may cause paraneoplastic syndrome (e.g.: certain rhabdomyosarcomas may paraneoplastically produce insulin-like hormone >> hypoglycemic coma);
  

• - in case of extensive tumors (large primary tumor with multiple, generalized metastases), the tumor mass is a burden to the body, and leads to final destruction (so called cachexia tumorosa) through the metabolites of the tumor cells.

VI./2.3.4.: Characteristics of malignant tumors

Characteristics that are more or less typical in all malignant tumors have been defined in the past decade as follows: (i) the presence of continuous signalization that stimulates proliferation; (ii) limitation of tumor suppressing effects; (iii) avoiding the immune-mediated destruction; (iv) ability of both local invasion and long distant metastatization; (v) substantial effect of the micro-environment of the tumor and the biophysical features of the tumor cells on the survival and invasion of malignant cells; (vi) unlimited mitotic capacity (so called replicative immortality); (vii) angiogenetic ability; (viii) avoidance of programmed cell death (apoptosis); (ix) deregulation of the energy-state of the cell (suspension of the normal regulation).

VI./2.3.5.: Certain parts of the tumor expansion processes

Integrins (α6β4, αvβ3, αvβ5, α5β1), and chemokine-receptors (CXCR2, CXCR4) have fundamental role in the determination of cell motility and invasion characteristics. Motility and migration of cells with invasive features basically depend on:

1. (i) the dynamics of adhesion-deadhesion, which is the function of the molecular feature of the focal adhesion and the power of the adhesion;

2. (ii) the fluidity of the cell and its constituting parts, especially the nucleus, the restructuring capacity of the cytoskeleton, as well as „cell-stiffness” (rigidity, stiffness of the whole cell);

3. (iii) the interaction between the tumor cell and its environment (matrix) (digestion, meatbolisation, remodelling);

4. (iv) the force generation toward protrusion and contraction.

A shift in the balance of these features result in such fundamental cell-biological and morphological changes that are summarized as EMT (epithelial-mesenchymal transition); or MET ( mesenchymal-epithelial transformation). Besides the mesenchymal type of movement, amoboid movement, that is based on the cell-environment interactions (presence/abscence of „pulling forces” – tractions), plays also a fundamental role in the process of invasion and metastatizing. Currently, one focus of research is how tumor cells regulate the balance of the above four factors. To shed more light on how the micro-environment of the cell affects these processes is also important. Growth factors, cytokins, chemokines, the protein components of the matrix, the spatial structure, the concentration of the matrix components, mechanic features of the matrix (rigidity, hydrostatic pressure, etc.) are all playing important role in the latter interaction.

It is understandable that according to the classic metastatic cascade model, these factors are important not only in the escape of the metastatic cell, but also in the process of colonization (adhesion, extravasation, mesenchymal-epithelial transformation-MET) at the distant region (target-organ). In angiogenesis, the significance of the endothelial-mesenchymal transformation, next to the tumor cell-endothel connection, during the spreading through the blood stream and through the lymphoid system, is more and more obvious.

Matrix metallo-proteases (MMPs) and enzymes supporting the escape of the cells are dominant elements of the tumor cell – matrix interaction. Recently, the latter are called „sheddase” based on the word shedding. From these enzymes, ADAM-10 and ADAM-17 from the secretase family are known to cut NOTCH receptors, ephrins and E-cadherin, and they also induce the translocation of the nucleus, and the invasion of carcinoma cells, the latter by the induction of gene-expression.

From the cell-matrix adhesion receptors, integrins and focal adhesion molecules connected to them, like vinculin and FAK (focal adhesion kinase), have special significance. Integrins are thought to play role not only in influencing adhesion, but in other two important processes: (i) generating and transmitting contractile forces (ligand dependent outside-in regulation); and (ii) the „inside-out” regulation (integrin/growth factor interactions). The two-way signal transduction is determinant in the stimulation of integrin receptors and in the cytoskeleton remodelling.

VI./2.3.6.: The concept of malignancy from different viewpoints

It has to be noted, that malignancy cannot be conceptualized in one way only. Clinically, a tumor is malignant if it causes the death of the host, regardless to the level of cellular or histological differentiation. A good example for this is the highly differentiated (Gr. I.) meningeoma, which grows in the edge of the foramen magnum, and causes death by suppressing the brain stem.

Thus, it is understandable that in majority of the cases clinical progression refers to the enlargement of the tumor. However, biológical/pathological progression is the process during which genetic lesions accumulate (mutation-accumulation > biological progression), and at the same time, it also results in the development of subclones in the originally monoclonal tumor. This phenomenon might be interpreted as a bizarre, paradox form of Darwin’s natural selection. In this case, along the principal of the „survival of the fittest” takes place the process of encountering the nine, formerly mentioned malignancy features.

Numerous pathohistologic and pathocytologic signs of malignant behavior are known. Variance in size and form of cells and nuclei (anisonucleosis) , their enlargement (karyomegalia), increase in the chromatin of nuclei (hyperchromasia), increased basophilia of the cell; biased nucleus-cell body ratio toward the nuclei, increased mitotic activity with atypical mitotic forms, are parts of the cytopathologic signs.

Histopathology primarily examines the interaction between the tumor tissue and its environment: first of all, the tumor’s infiltrative invasion  to the tissues of the environment, into the vessels ([lymph-/haem-] angioinvasion), and the perineural or neural expansion. Occasionally, environmental infiltration is only a relative sign of malignancy (see the case of basalioma!), but angioinfiltration and neural infiltration are reliable signs, if they can be evaluated appropriately.