The evolution of pathology: From Jurassic Park to Avatar

Professor Carol-Ann Benn explains how the connecting of two worlds, the old Jurassic Park world and the new and much more exciting Avatar world of understanding cancer cells, has revolutionised the ability to treat breast cancers.

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By understanding how cancer cells differ from normal cells, scientists can develop treatment strategies. This information can help us understand what is going on inside your body when you have a cancer and acquire insight into what information gained from these cells can help the oncologists treat the cancer. This is a bit like looking at fossils of dinosaurs then dinosaur DNA, and by understanding all the information ensuring the beasts stay in Jurassic Park.

What does cancer look like?

If we’re seeing it as tiny cells, can someone making the diagnosis get it wrong? When something is this minute, this is like digging through the dirt and declaring, “It’s a Velociraptor.” This is an important concept that I’m often asked, and an old-fashion reason why surgeons like to cut out cancers to make a diagnosis (kind of like shooting the animal to identify it). We don’t support this today.  

In the Jurassic surgical era, surgeons would needle lumps in their consulting rooms (this is why they are dinosaurs). The pathologists (who were scientific toddlers at the time) when they received a splat of cells mixed often with blood cells (often could not determine what it was) needed to assess features of these cells to identify them. This is much like me spotting in the bush a blur, shape, colour. Nope, just a rock.

To identify the predator, it must look different. Cancer cells can be variable and not uniform to the cells of the organ they originate from. Larger or smaller; the shape of both the cell and the cells brain (nucleus) are dissimilar to the cells of the organ they arise from.  

Strides in pathology

Thanks to the invention of the microscope in the late 1500s by the Janssen father and son duo, it didn’t take long for the already clever scientists to realise the key to understanding cancer was to analyse the cell (this was already being proposed in the late 1800s). The smart pathologists became the key to understanding.

This is why back then the field of pathology was developed. Pathology comes from a Greek word pathologia meaning the study of emotions and well-being. Trying to think of pathologists I know historically as the types to study emotions and well-being reminds me a bit of a movie character of a psychologist studying a person on a couch and asking them to get in touch with their inner self so as to solve their problems. This was much like the pathology and treatment approach to cancer centuries ago.

It took till the early 19^th century for the advent of a pathology examination of surgical breast specimens (macroscopy) in theatre. Macroscopy is the examination of the specimen and then the development of microscopy (what one sees down the microscope). Maybe this is why the Jurassic Park mentality of cutting out cancers to diagnose them still exists with some surgeons. Hopefully with more public awareness this concept will die like the dinosaurs.

Ways to detect cancer

Although doctors use many ways to detect and diagnose these little cells that are trying to trick your body, from blood and urine tests looking for biochemical abnormalities (high or low levels of certain substances), abnormal results don’t necessary mean that you have cancer. 

Imaging tests are like the word says: ways of looking at different parts of the body. These vary from ultrasound scans and X-rays to CT-, MRI-, PET scans and bone scans. Different scans are used in different circumstances. A scan can suspect something, but the issue is you need tissue to confirm who this baddie is; this means a biopsy. 

Biopsy

A biopsy is a small sample of tissue that is examined under a microscope. It’s mostly done under radiology-guidance and the tissue is then sent for sampling.Best practice is to get confirmation on imaging before considering any biopsy. This is the high-res photograph by the five-star bush photographer. The award-winning way to make the diagnosis of a breast cancer and best international practice is the one sweet shot: an image-guided percutaneous core needle biopsy. 

This might be a stereotactic (under mammogram-guidance) or sonar-guided core biopsy, but image-guidance ensures the abnormality has been well-visualised (like sighting a target), resulting in an accurate tissue sample. 

When biopsies are done free-hand in a doctor’s room, this is like putting on a blindfold and poking the needle where you think the concerning area is. The bush analogy is putting your hand or head in that hole. Who knows what lives there but it’s not a very clever way to find out. Not only is this blind man’s bluff but swelling and hematomas will make further assessment more difficult. Blind biopsies, done in a doctor’s room or in the laboratory, can result in a report being labelled inconclusive resulting in unnecessary surgery.

Histopathology

So, we realise that to determine what type of cancer it is, whether it’s invasive or non-invasive, the cells need to be studied within the structure of the tissue. This is the term histopathology. This is necessary to tell if the cancer is invasive (infiltrating) or whether it’s an in-situ growth (cancer hasn’t spread beyond the basement membrane which is like the walls of the room in which the cancer cells are living) of the ductal cells. Remember a biopsy from a lymph node or gland needs the pathologist to tell us if the cancer is a lymphoma (arising from the lymph node) or a secondary cancer from elsewhere.

A closer look at the cancer cell

The answers are in understanding the future connections between pathos and science. From Jurassic Park to Avatar; the modern-day pathologist is less. Let’s get in touch with the feeling of the cancer; a detailed analyse of the psychopath and its behaviour. 

The reason for this is that the modern management of a breast cancer is based on an understanding of the individual characteristics of that cancer cell (tumour). These characteristics define the likely behaviour of the tumour and aid in understanding the likely therapeutic response to treatment. The tumour at a microscopic and molecular level as reported on the pathology report is the starting point for the successful management of the individual patient and tumour.

Three main snapshots

Pathology information is divided into three main snapshot events: 

Making the diagnosis

Remember that small core of tissue examined down the microscope. Once this is confirmed that the creature is cancer, there are two important categories of information needed.

Prognostic factors

The microscopic and molecular characteristics of a tumour that will determine the likely behaviour of the tumour, specifically a measurement of the cancer’s ability to recur or metastasise and cause death. This is done by looking at special behaviour characteristics that are found on the cancer cells (the clothes of oestrogen and progesterone receptors; HER2 receptor; and division rate of the cells (KI); as well as many more).

Predictive factors

The microscopic and molecular features of a tumour that will determine the likely response to certain drugs, specifically predicting a response to the drug if used to treat the cancer.

There is some overlap and interplay between these two categories. The real avatar assessments are the pathologists today start analysing the tumour genomics, how truly “tree of life” is this. 

Now by understanding the genes in the cancer cell, assessed by the clever pathologists, the oncologists can be aided as to what drugs can be used for what cancers. Gene sequencing of cancers will become more and more relevant to what drugs, when and how for managing cancers. Remember genomics of the cancer cell is different from your genetics.

Jargon busting pathology terms

Fine needle aspiration (FNA) 

That rare dinosaur, not quite extinct but seldom seen. FNA cytology aspirates cells from a breast lesion onto a glass slide with cytofixative (similar to Pap smear). The slide is stained so that the cells can be detected and evaluated by microscopy. FNA looks at the cellularity, the size and shape of the nuclei of the cells, and the degree of cohesion (stickiness) of the cells. Whilst FNA can differentiate between cancer cells and non-cancer cells, thus aiding diagnosis of breast carcinoma, these naked cancer cells don’t give a full dataset of information required for management; useful “clothing” information isn’t accurate. 

Matching the cards between FNA; clinical presentation and radiological is essential. A cancer shouldn’t be treated based on an FNA, the devil is in the histopath detail. 

Histopathology/Histology (clothes the cancer is wearing)

How we get a cancer dressed is by taking the biopsy and final resection specimens fixing them in formalin and processing through various chemicals (histo-chemical stains) that allow preservation of the tissue, cutting sections, staining them and looking down the microscope. Histo-chemical stains use different chemical dyes that are attached to certain substances in the cancer cell. For example, one stain attaches to the mucous in cancer cells thus giving the pink red colour. 

Histology allows the appreciation of the architecture of the tissue (how it looks) as well as the cytological features of cells (what the little cancer peeps look like). Histology is the gold standard of tissue diagnosis and is performed by a histopathologist. The preservation of the tissue allows for many other tests to be performed on the tissue, including staining with antibodies to determine types and expression of cells. 

Immunohistochemistry (IHC) 

This is the use of antibodies on tissue sections to diagnose cancers (which organ are they from, prognostic and predictive response to therapy). Basically, our bodies make antibodies that recognise antigens on germs and help protect us against infections (this is a bit like how a vaccine works). 

The antibodies used in IHC stains are different in that they are made in the lab to recognise antigens that are linked to cancers. In breast carcinoma, IHC is used routinely to determine the oestrogen (ER), progesterone (PR) and HER2 neu (HER2) receptor status on the tumour cells in a biopsy specimen. This was the start of the new era; pathology sci-fi. On our way to understanding a world that is and what shouldn’t be part of our world. 

There are hundreds of IHC tests that can be used to help identify cells. Some are quite specific in that they react and are seen with one type of cancer; others can be found on many. So, the pathologist keeps on applying these IHC stains to find out more and more information about where the cancer’s home is (where it started). This is because you can have melanomas in the breast; lymphomas in the breast; squamous cell cancers. I have even seen ovarian cancers in the breast.

In situ hybridisation (ISH) 

This is the process of labelling a specific gene in the nucleus with a DNA probe. In breast carcinoma, ISH is used to quantify the gene copy number of HER2 and determine whether the tumour will respond to trastuzumab as well as other medication now. 

Different methods are used for the detection of the DNA probe on the gene, hence the various names that include fluorescence in situ hybridisation (FISH), silver-enhanced in situ hybridisation (SISH) or chromogenic in situ hybridisation (CISH). ISH is performed on biopsy specimens.

Complex job

A pathologist’s job is very complex today as the tissue needs to be prepared for studying. And this is a detailed complex procedure to ensure maximum information can be tweezed from the tissue, cells and cell genetics.

So, our fabulous pathologists are the behind the scene avatars that connect the clinicians and the patient together by accessing both worlds; our world, the old Jurassic Park world and the new and much more exciting Avatar world of understanding cancer cells from both what they look like to the minute detail of their naughty DNA and thus has revolutionised our ability to treat breast cancers. They are the true medical heroes in our fight for domination over this scourge.