Prof Carol-Ann Benn explains why pathologists are like psychiatrists when they use the DSM assessment to analyse what the cancer is and what it is capable of.
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First, understanding the terminology of the DSM assessment and getting in touch with my pathos (pathology diagnosis feelings) is needed.
D – Definitions
S – Stage
M – Metastatic disease
What could these baddies be?
The clever pathologist analyses the cancer and labels it (all baddies need to be classified and boxed), and although we have four basic boxes, some may be outliers as not quite behaving as the rest in that box. Sometimes we don’t get the analysis right and occasionally a psychopath needs re-evaluation. Not everyone is whom they seem on the outside and that is why we mine the cancer’s brain and torture it by genetic profiling. This can provide a more detailed way of determining how to treat cancers.
Cancer psychology terms
Malignant: Means evil intention; virulent and wants to spread outside the little house structure it has arisen from.
In situ carcinoma: This is a pre-malignant process (sleeping cancer) that is often associated with or may precede the progression to invasive carcinoma. Kind of like a delinquent teenager acting out and requiring time on the couch but really may only need minor therapy in terms of medication and maybe surgery.
In situ carcinoma occurs within the ducts (duct carcinoma in situ (DCIS)) and in the lobules (lobular carcinoma in situ (LCIS) or lobular neoplasia). This is considered a risk lesion or precursor lesion (tsotsi in the breast).
Invasive carcinoma: This term means the tumour shows growth of malignant cells out the ducts and into the breast tissue. In other words, it’s outside the prison cell in the yard. An invasive carcinoma carries a risk of accessing the vascular system (main roads near the prison), resulting in spread elsewhere.
If the cancer is in the glands or lymph nodes, this is like being caught by the security. All invasive cancers have an ability to spread this is why they usually require systemic therapy (whole body therapy) in the form of oncology drugs, which may include cytotoxic, target therapy or hormonal blockage or a combination, in addition to local therapy.
What is the histological subtype (personality)?
Today all breast cancers are named no special type (NST), although they have different personalities once you clothe them. There are four different subtypes of breast cancers and once you test the cells for receptors, you can then divide breast cancer into the four different psychology families: triple-negative, HER2-positive, luminal B and luminal A. Duct carcinoma is the more common cancer and is a form of adenocarcinoma (carcinoma of glandular type epithelium). The precursor of duct carcinoma is understood to be DCIS.
Lobular carcinoma is a form of adenocarcinoma arising from the lobular epithelium (lactational unit), and if rarely has LCIS around; this isn’t necessary the same problem child as DCIS. It’s really a bit of a passive aggressive precancer, kind of like a teenager acting out. Most are passive but some aren’t. Lobular carcinoma is almost uniformly low grade (but there are delinquents in this family, and like all invasive cancers has the ability to metastasise). Lobular cancers have a characteristic growth pattern: the loss of a cell adhesion molecule (E-cadherin) in the tumour cells causes the cells to be single file. Immunohistochemistry (IHC) for E-cadherin is therefore often used to confirm the diagnosis. PS – most are E-cadherin negative.
Other oddities in the cancer variants family
Metaplastic/sarcomatoid carcinoma of the breast is when a high-grade derivative of a duct carcinoma starts losing all features of a carcinoma, displaying soft tissue differentiation and looks like a sarcoma. This is an example of a narsistic psychopath and requires detailed on-the-couch understanding of its genetic profile before starting treatment. As they may behave like sarcomas and breast cancers in fact they are all about themselves and can thus be difficult to treat. Again remember this is all part of one community and however weird they may look on the outside, we treat on how their heart looks. So, lets get a closer look of who is lying on the psychiatric couch and how we can aid the diagnosis.
The grade is an attempt to measure the likely aggressiveness. This is a basic pathology assessment. Grade is divided into three criteria that are all analysed by looking down the microscope. Intuitively, a carcinoma that is less well-differentiated is growing faster, resemblance to the benign epithelium (clothes normal tissue wears) is less and it’s therefore more likely to behave aggressively. This is certainly the case with breast carcinoma and a standard grading system which applies to breast cancer assesses the following parameters:
The term adenocarcinomas means derived from glandular structures in the breast. The greater the percentage of the carcinoma that forms glands, the better the differentiation and the less aggressive the tumour. In other words, the more the cancer tries to look like the structure it’s derived from, the less aggressive it is. It’s putting more time and effort into fitting in. The less it tries to look like the tissue it’s derived from, the more it’s giving the whole world and the organ from which is has arisen the universal V sign; this would be for its potential victory. But our multi-disciplinary meeting (MDM) A team is smarter.
This is the cell brain. The larger and more variable looking, the more aggressive or malignant the cells tend to be. This means the more egg head (the more odd), the more the cancer is likely to be proudly beating to its own drum. But, our clever pathology psychiatrist gets this and will confer with the oncologist as to what medication can subdue this baddie.
Basically means pregnant cells. The number of dividing cells can be determined by assessing the mitotic index, visualised as cells in the dividing phase of the cell cycle, quantitated as the number of mitoses per ten high power fields. The more mitotic figures present, the faster growing the tumour is and the more aggressive it may be.
The grading system described above is known as the Nottingham Prognostic Index or Bloom-Richardson-Elston Index. It’s a good background skeleton to understanding breast cancer. Carcinomas are scored in each of these three categories on a scale of 1 to 3, where 1 is less aggressive and 3 is more aggressive. The three scores are added, and the tumour graded as follows:
|Total Grading Score||Grade of carcinoma|
But, it’s not all about the grade. So, what else do we need to check when we look at cancer cells down the microscope?
What is the receptor status?
Steroid hormone receptors
Normal breast tissue responds to hormones in a physiological way during the menstrual cycle, pregnancy and lactation. These hormones include oestrogen and progesterone, with receptors, oestrogen receptor (ER) and progesterone receptor (PR), in the cells that bind the hormones. In the same way that normal breast epithelium responds to these hormones and is stimulated, so too are breast carcinoma cells driven by the proliferative response to oestrogen and progesterone. The following is important to understand: this doesn’t mean that the hormones are causing the cancer. The levels of ER and PR in a breast cancer cell are a measure of the degree of differentiation of the tumour; high expression of ER and
PR are indicative of a more differentiated tumour. There are therefore two components to the receptor status in the carcinoma. The first is the prognostic (how well it can potentially behave) effect; carcinomas that retain ER and PR are trying to resemble normal breast tissue and may tend to be less aggressive. Not that simple and this is why we check the cells genetics, those pesky behaviour traits that aren’t reflected when you look at the clothes the cancer is wearing.
In addition, there is a predictive effect; tumours that show ER expression may be therapeutically targeted with ER blockade therapies, an example is tamoxifen (which isn’t a hormone blocker). Carcinomas with dual ER and PR expression may show an even better response to steroid hormone blockade medication.
ER and PR are assessed with a score on IHC by the pathologist, integrating the percentage of the tumour that is positive for the receptor (proportion, scale of 1-5) and the intensity of the staining (intensity, scale 1-3). The proportion and intensity scores are added to a total out of eight, called the Allred score. A score of 3 and above is regarded as positive from a therapeutic point of view, with a possible score of 8.
HER2 over expression (HER2/neu)
Breast epithelial cells, like most cells in the body, have cell surface receptors that respond to hormonal stimulation from the outside and feed into signaling pathways in the cell. This is really a form of cell communication. It follows that abnormalities of these receptors that result in increased activity can cause abnormal growth of the cell, leading to carcinoma growing and helping the malignant cells to grow faster than normal cells and spread.
HER2 is one of these receptors and is affected in 15 to 20% of invasive breast carcinomas. Evaluating HER2 status is therefore an essential part of the pathological investigation of the cancer, and similar to steroid hormone receptors, has dual significance.
Firstly, HER2 positive carcinomas tend as a group to be more aggressive, having a prognostic significance. So, because HER2 can be targeted therapeutically, a therapeutic agent can seek out the malignant cells and kill them. Trastuzumab therapy was the first drug.
In a class of antibodies that are now available for treating a HER2-positive carcinoma; a positive HER2 status can also direct the choice of chemotherapy should it be needed. The mechanism of increased HER2 activity in these cancer cells is the amplification of gene copy number in the nucleus. The normal cell has two copies of the gene and in HER2-positive cancers this number may rise to multiples of 10. It follows that with increased gene dosage, there are more copies of the receptor in the cell and amplification of the proliferative signal, thus encouraging the cell to grow.
HER2 is evaluated by IHC in the tumour cells and is given a semi-quantitative score on a scale of 0 to 3. ISH (genetic confirmation) is employed for equivocal cases and for confirmation of positive cases when required for release of HER2 therapy.
|0 or 1||Negative||No further action required for HER2 evaluation, negative in therapeutic decision-making.|
|2||Equivocal||HER2 status requires genetic evaluation by ISH and will emerge as positive or negative.|
|3||Positive||If targeted therapy is being considered, confirmation of gene amplification may be required for therapy.|
There are now many drugs available, so what was once considered a real psychopath can be killed with many target therapies.
Other features seen on your path report
Vascular invasion and lymphatic infiltration
Malignant cells inherently want to gain access to the systemic system (body) to send seedlings (baby cancer cells out to nest) and may do this through vascular spread. They do this by accessing the lymphatic vascular channels and blood vessels.
Vascular invasion refers to either lymphatic vessels or blood vessels and there is no distinction from prognostic (outcome) point of view. Identifying vascular invasion on the histological evaluation was used previously to identify an adverse prognostic significance by identifying tumours that have progressed to grow outside of the stromal environment in which they arose.
Note to all, malignant cells can gain access to the vascular system early in the cancer progression and the absence of vascular invasion on histology doesn’t exclude the potential of cancer cell spread.
Conversely, even though malignant cells may gain access to the systemic circulation, the process of metastatic growth is a complex one, dependent on the site of seeding and the properties of the tumour cell that seeds; only a small fraction of cells that spread from the primary site actually form metastatic deposits.
This is the shoes the cancer is wearing and is an important psychiatric safe-code. The growth rate of the tumour is measured by counting cell divisions or mitoses.
It’s now possible to evaluate proliferative rate using IHC, specifically Ki-67, which is a cellular marker of proliferation and is only present in cells that are actively cycling or proliferating. Ki-67 may therefore be used to add resolution to the grading of a tumour. The index is reported as a percentage of cells positive for proliferation (less than 15% is regarded as a low score).
The real DSM assessment of cancer cells
Today the pathologist psychiatrists are understanding the real DSM of cancer cells. They use many markers to provide clarity of how the cancer cells are behaving and how to treat them. Not all cancer cells can be placed in the right DSM box with the above battery of tests, sometimes you may hear of other tests being performed on cancer cells.
Pathologists look at the cytogenetics of cancer cells; they look at chromosomal changes in the cancer cells and at molecular genetic testing of cancers. The term PCR you would have heard around COVID testing; this is a very sensitive test to look at specific DNA sequences found in some cancers. Pathologists have lead the fight in our ability to test for COVID and cancer. To get even more sci-fi, we can use gene expression microarrays and doctors now use DNA sequencing to help predict which drugs work best for your cancer.
So, whether your cancer thinks it’s a psychopath but really is a delinquent or a true nasty in training, detecting and looking at them early in a MDM discussion (not an operation) allows for the ability of the A team of oncology psycho-analysis to take place and ensure what is required to lock up this baddie in C-max or to just give mere community service.
MEET THE EXPERT – Prof Carol-Ann Benn
Prof Carol-Ann Benn heads up an internationally accredited, multi-disciplinary breast cancer centre at Netcare Milpark Hospital. She lectures at Wits University and, in 2002, established the Breast Health Foundation.