Why is cancer diagnosed by pathologists?

Why is cancer diagnosed by histology?  Many of you can still recall that the diagnosis of COVID-19 infection was made using either an antibody test or a PCR test. Although the scientific field believes that cancer is a genetic disease, its diagnosis is based on light microscopic observation of its histology. Not the blood test, CT, MRI scanning, endoscopy or colonoscopy observation. Importantly, no PCR test or DNA sequencing for cancer diagnosis.

From 100 years ago to now, cancer has been diagnosed by pathologists, who look at specimens under a light microscope. They cannot diagnose COVID-19 infection because the virus cannot be seen under a light microscope. They cannot diagnose diabetes because they cannot see insulin or glucose under a light microscope. These diseases are diagnosed by other means that make invisible factors, such as viruses, proteins, and metabolites, visible in colours or numbers using detectors.   

Interestingly, in this sense, cancer is something directly visible under a light microscope. Therefore, pathologists can make decisions for diagnosis.

Please do not misunderstand here. The COVID virus is invisible, but the respiratory damage is visible. Pathologists can tell if a patient had a respiratory problem or not. However, they cannot determine whether the damage is caused by COVID-19 or another virus.

An interesting question is, when pathologists diagnose cancer, are they seeing the cancer itself or the damage caused by cancer?

Rudolph Virchow, a pathologist in the 19^th century, described cancer as a wound that does not heal. Disorganized tissue structures are signs of inflammation. Again, they are visible under a light microscope. In addition, pathologists use nuclear anomaly, cellular morphology and the nuclear/cytoplasmic ratio. All of them are visible. Are these visible histological changes cancer itself or associated damages?

Our understanding of cancer has been advanced. We now have biomarkers for the primary cancer screening and remission monitoring. Subtype characterization using gene panels to identify the most effective available drugs is also available. However, in diagnosis, none of them goes beyond the histological observation under a light microscope. We must take this reality seriously. Perhaps what we see under a light microscope is not the associated damages, but cancer itself.

Before the emergence of modern science with Galileo, any proof of statements was based solely on demonstration and testimony. No concept of evidence or probability. For example, Galileo demonstrated that a heavy object and a light object fall at the same speed, contradicting the common belief that the heavy one falls faster, as proposed by Aristotle.  Demonstration is a direct visualization of a statement. Testimony is a statement of one’s own experience. 

On the other hand, evidence is the recognition of associations. Evidence is not the demonstration of a statement. Evidence is visible objects and events associated with the statement. Because of visible objects and events, it is possible to have multiple pieces of evidence for one statement. However, none of them is a demonstration.

Because evidence is always associations, there is a possibility that it is not associated.

Galileo observed the Moon’s landscape, Jupiter’s moons, Venus’ phases and the Sun’s blackspots. All of them were direct observations using his telescope. He could have demonstrated his observations by letting others look through it, but no one tried that. His observations led him to realize Copernicus's statement of the concept of the solar system, heliocentrism. Now, his observation became the evidence supporting Copernicus’s statement, but not the demonstration. After all, no one has ever directly observed the solar system, but we believe it based on visible evidence.  As the devil’s advocate, there is clear evidence to believe that the Sun is moving around the Earth because the Sun rise every morning.

I want you to think about whether it is evidence or a demonstration of what pathologists can see under a light microscope. What are the associations with cancer, and what is actual cancer? Modern technologies have allowed us to visualize something previously invisible (i.e. PCR in the COVID case), but for cancer, we still use the histological observation under a light microscope. All data derived from modern technology does not take over cancer diagnosis but remains for refining subclasses.  Isn’t this interesting?

Then, what pathologists are looking for and recognizing? First, disorganized tissue structures. Under normal conditions, each tissue has a unique pattern of cell allocation and cell morphology. In cancer, its order (i.e. pattern) is disrupted. Inflammation is the key player in disrupting the order. Although inflammation is not directly visualized, disorganized tissue structures are associated with inflammation. Disorganized tissue structures are evidence of inflammation.

In a healthy individual, inflammation is not sustained. This means that disorganized tissue structures can be restored to an orderly tissue structure. Think of a scratch. But how and why is the order restored? Perhaps we should start by explaining how the order is established in the body. The order within a tissue is established in development and matures during adolescence. However, the order is not a permanently fixed property. I would like you to think about the roads in Montreal. Frequent digging and fixing with a temporary break in between. After digging, it is back to the usable road. Each digging project should have a specific intention, such as fixing an old drain or installing electric cables. Once the purpose is accomplished, the road will be restored.

In a tissue, the paved road is ECMs. During development, a road is built from no road to one that gradually develops from muddy to gravelled to paved. Inflammation initiates the digging/disruption of a paved road. When the inflammation is cleared, the road will be reconstructed. ECMs have different degrees of maturity and stability, like muddy, gravelled and paved. ECMs in an embryo are immature and easily remodelable, while in an adult, ECMs are mature and stable. That is why our body shape is consistent every day, with almost no change in size and shape. 

Macrophages are the best remodellers of ECMs. They can be a handyman for daily maintenance or a powerful worker in road construction. At the beginning of this essay, I mentioned that the disorganized tissue structure is a sign of inflammation. During the activation of inflammation, ECMs are remodelled, resulting in a disorganized tissue structure, similar to a paved road that has been dug up. In cancer diagnosis, pathologists primarily look for disorganized tissue structures. Although inflammation is not directly visible, the disorganization is visible under a microscope as evidence of inflammation.

After identification of disorganized tissue structures, pathologists examine the shape of individual nuclei and cells. I often refer to this as the evaluation of the ugliness of nuclear and cellular shapes. We can see the morphological changes that accompany cell division, which are rare in adult tissues. This will indicate the frequency of cell division —the degree of proliferation.

 In a healthy cell in a histological section, the nucleus is usually an oval shape with a smooth periphery. Each cell type has a consistent cytoplasm/nuclear ratio. The nucleus in a malignant cell is deformed and sometimes fragmented, occupying almost the entire cell volume. Looks ugly.  No consistent subcellular structure pattern within individual malignant cells.

What does this ugliness mean? Are these visible phenotypes the demonstration or the evidence of malignancy?

Does the ugliness represent mutations? I do not think so. The ugliness represents abnormality in chromosomal numbers and structures, which we cannot see directly. The ugliness also represents the breach of nuclear membrane integrity. In eukaryotic cells, DNA needs to be sequestered into the nucleus from the cytosol. Cytosolic DNA is only temporarily permitted during cell division.  Whatever the reason, when cytosolic DNA is present, it triggers inflammation as a misperception of viral infection. This inflammation has no pathogen involved; thus, no way to be cleared. The environment is sterile, but inflammation is initiated. 

This inflammation is initiated in a single cell due to the detection of cytosolic DNA. In contrast to extracellular pathogens, which can be cleared by macrophage phagocytosis, no other surrounding cell can eliminate the cause of inflammation. The only options are that the cell with misperception should be eliminated by self-claiming apoptosis or other immune cells, like T-cells. 

When self-claiming apoptosis is compromised, the last option is being killed by T-cells. However, giving a licence to kill one’s own cells to T-cells is tightly regulated. The slowness and ambiguity of the changing process from normal to malignant cells prevent this. After all, malignant cells are one’s own cells.

The point I want to clarify is that one’s own cells are very difficult to kill. A single cell initiates low-grade inflammation because of a misperception of viral infection caused by cytosolic DNA. This is a very private event. Should this cell be killed? I do not think so, unless it claims to die by apoptosis. This cell cannot be killed because of its own cell, when it does not die itself.  However, low-grade inflammation stimulates the surrounding local macrophages. They realize the inflammation, but nothing needs to be cleared by phagocytosis. The low-grade inflammation is too low to recruit circulating immune cells, as it involves only a single cell.  One cell becomes two, and then four.  This process is extremely slow compared to viral infection, which quickly infects hundreds and thousands of cells. Low-grade inflammation is compensated for, but persists. Small digging gradually becomes larger and larger. A wound is getting bigger without healing.

This histological alteration is something we can see.

Now, let's return to the first question I raised. Why can pathologists diagnose cancer?  

Because the histology is THE cancer, this is not evidence of or associated with cancer. I do not deny that the genetic mutations have a tight association with cancer; however, they are not the cancer itself. Furthermore, they are not the sole cause of cancer, although that is the case in animal cancer models. Importantly, mutations can be the downstream consequence of a chronic inflammatory environment. Entering the cell cycle in inflammatory stress environments causes errors in DNA replication and chromosomal segregation. Which comes first is a meaningless argument.

After all, tissue-level unstoppable circuitry interactions that control inflammation, cell cycle and ECM remodelling, are the cancer.  Disorganized tissue structure and disorganized subcellular structure are visible observations that represent the presence of active tissue-level perpetual circuits. In this sense, genetic mutations can be a starting point for the circuit, but inflammation can also be a trigger. Their relationship is not linear but circuitous, like a self-amplifying process. This circuitry momentum is almost impossible to shut off immediately. Acute shutting off causes overflow of momentum, which will continue the circuit. Slowing down the momentum and then depriving it would be another management strategy, rather than specifically eliminating one cell population. Complete elimination of one specific population is an impossible task because multiple intact endogenous circuits are involved as a system that deals with the misperception of cells. Cancer is not a disease of cells but a disease of tissues. The tissue is a village. Cancer is a village where bandits live together with non-bandit villagers, cooperatively. The villagers are not hostages nor manipulated. Since the bandits used to be villagers, for villagers, the bandits are still villagers. Villagers support each other. There is no way to eliminate bandits alone. They are fully integrated into the village's supportive and compensatory network. Surgery can take the whole village out; therefore, it has a chance for a cure. This bandit-villager network shows up in histology. Therefore, cancer is a disease that can be seen in histology under a light microscope.