In an earlier blogpost I wrote about how to understand the TNM Classification used in your medical records. Now I’ll familiarise you with other factors that are just as important in determining your treatment strategy and which are important to understand.
G or grading
Earlier, the phrase tumour differentiation grade was often used. Today, tumour grading is a broader concept, which reflects how much the tissues of the tumour differ from normal tissues of the respective organ. The grade also indicates how quickly the tumours can grow and spread. The characteristic sizes for grades can differ for different tumours. Depending on the detected abnormalities, tumour grading is divided into a number of levels from 1 to 4. G1 means that the tissues of the tumour are structurally similar to the healthy tissues. These are called well-differentiated tumours. These tumours usually grow and spread slowly and their prognosis in generally better. Yet, they also react poorly to chemotherapy, because only a proportionally small group of cells are in the process of actively dividing, which is why they respond better to drugs. G2 describes moderately differentiated tumours and G3 indicates poorly differentiated tumours, while G4 refers to undifferentiated tumours. The latter grow and spread more rapidly and offer a less-favourable prognosis, but they respond better to chemotherapy.
Pathologists use the Scarff-Bloom-Richardson grading system to characterise breast cancer. It takes into account mitotic activity, the shape and size of cell nuclei and the proportion of normal tubule formations. When evaluating prostate cancer the Gleason system is used where the most widespread and least widespread fragments are analysed separately according to a 5 point system: 1 indicates something very similar to healthy prostate tissue, while 5 is indicative of tissue that is pathologically different from the prostate. Both indicators are added together, so you’ll see notations such as 3+2 or 4+5. A Gleason score of 2 – 6 describes a well-differentiated tumour, a score of 7 a moderately differentiated tumour, while scores from 8 – 10 indicate poorly differentiated or undifferentiated tumours. The less differentiated the tumour is (G is larger), the more aggressive it is and the larger the risk that it will metastasise. Usually this means that additional systemic therapy will be required, because it’s possible that some cancer cells have already migrated from their original location.
R or resection margins
The capital letter R usually indicates whether or not cancer cells were discovered during the operation in the areas where the tissue was resected. Essentially this indicates if the tumour was removed within the boundaries of the healthy tissue. If no sign of the tumour is discovered in the resection margins then this is recorded as R0. This is also recorded as a negative result, clean margins or as resection margins are within the boundaries of healthy tissue. If the pathologist discovers cancer cells within the resection margins then this is classified as R1 or microscopic cancer cells at the resection margin. R2 means that remaining tumour tissues can still be seen with the naked eye. This can happen if, for example, the tumour is so close to a major blood vessels or nerves that its complete removal could be potentially hazardous to the patient. There are surgical guidelines in oncology, which indicate how far the surgeon should resect healthy tissue to best ensure clean margins. This can differ for different tumours. The further one resects into healthy tissue, the safer the result, but this isn’t always technically possible. In any event, cancer cells in the margins mean that either the operation must be repeated and the resection margins expanded or, if that isn’t possible, another course of local and/or systemic therapy will be necessary to reduce the risk of metastasis.
L or lymphatic system invasion
When examining a tumour sample under the microscope, a pathologist takes note of the lymphatic vessels and checks to see if any cancer cells or their emboli (groups of cells) are present inside. Lymphatic system invasion (LI or L) is a very significant factor in a prognosis. LI+ (plus sign) means that a pathologist has discovered the presence of cancer cells in the lymph vessels, while L- (minus sign) means that cancer cells were not found in the lymph vessels. Even if metastases have not been discovered in the regional lymph nodes (N0), a designation of LI+ still indicates an unfavourable prognosis and additional systemic (drug) therapy will be required.
V or vascular invasion
Not unlike the lymph vessels, pathologists also check the blood vessels. If cancer cells are discovered inside the lumen (the hollow interior) it is recorded as V+ or VI+. However, if cancer cells aren’t found in the blood vessels then this is classified as V- or VI-. The presence of cancer cells in the blood vessels indicates that tumour cells are in circulation and there is a large chance of metastasis. This is also a major factor in the prognosis, which could affect the treatment strategy. In this case, additional systemic drug therapy would most likely be prescribed.
PN or perineural invasion
Tumour cells often choose the path of least resistance to migrate to other parts of the body. One of these corridors is the space between a nerve and its outer sheath. Perineural invasion is found in patients with a variety of tumours. A positive lab result (PN+ or PNI+) can indicate a worse prognosis than a negative result (PN- or PNI-) and this discovery could make additional systemic therapy necessary.
Ki67 is a cellular marker for proliferation, which is closely connected to the intensity of cell division. The Ki67 protein can be found during all of the cycles of a cell, but aren’t found in cells that are in a so-called resting phase and aren’t currently dividing. Therefore, Ki67 is indicative of cell populations, which are actively dividing. This is important to understand, because cells that aren’t in the process of dividing don’t respond to chemotherapy or standard radiation therapy. If the Ki67 level is less than 10%, this is considered low. If the level is between 10 – 20% this is considered a borderline state, while levels over 20% are much higher and considered to be significant. It must also be noted that there currently is no consensus among scientists about the significance of this indicator and whether or not it should be a factor in creating a treatment strategy. However, the closer the level of Ki67 is to 100%, the greater the number of cells in the process of active division when they would best respond to chemotherapy.
ER/PR or estrogen/progesterone receptors
ER are cell proteins (some are in the nucleus, others in the cytoplasm) that, once activated by estrogen, regulate processes, which ensure cell division. This indicator is shown as a percentage (%) which illustrates the proportion of cells in which these receptors are found. Many laboratories only indicate ER levels, but some labs still indicate both ER and PR. Roughly 70 – 80% of breast cancer cells contain ER (ER+). Roughly 65% contain both ER and PR (ER+/PR+), which indicates that tumour growth is perhaps stimulated by both estrogen and progesterone. In rare cases, approximately 13% of cells contain ER, but no PR (ER+/PR-) and in exceedingly rare cases, roughly 2%, only PR (ER-/PR+) is discovered. Due to the rarity of these cases, it’s still not known what the optimal treatment strategy would be for these instances. In approximately one quarter (25%) of cases, neither ER, nor PR (ER-/PR-) are discovered in the tumour sample. These are referred to as receptor-negative tumours and in these cases hormone therapy isn’t prescribed. In any case, ER+ or PR+ indicate a tumour that is sensitive to hormones. A positive receptor result is recorded in different ways depending on the laboratory. However, if your medical records indicate that your tumour contains 0% ER and/or 0% PR, then it is considered to be receptor-negative and hormone therapy is rarely prescribed in these cases.
In receptor-positive cases (ER/PR), hormone therapy can slow the progress of the disease and hamper or prevent its recurrence. Today, hormone therapy uses a group of selective estrogen receptor modulating drugs, the most popular of which is tamoxifen. Another drug which belongs to this group is toremifine. There are, however, other groups of drugs including aromatase inhibitors, estrogen receptor regulators and luteinizing hormone-releasing hormone drugs. Drugs containing progesterone are also available. Sometimes the ovaries are removed (ovariectomy) as an alternative to hormone drug therapy. Receptor-negative tumours are usually treated with chemotherapy instead of hormone drugs.
HER2 belongs to the group of human epidermal growth factor receptors. This receptor is found in the tumorous tissue of roughly 15 – 30% of women with breast cancer. Unfortunately, the presence of this receptor is usually connected with a greater risk of metastasis and a less-favourable prognosis. An elevated number of these receptors are also found in patients with stomach cancer (7 – 34%), salivary duct carcinomas (30%), ovarian cancer, lung adenocarcinomas and the especially aggressive form of uterine cancer – serous endometrial carcinoma. Patients with HER2-positive breast cancer are usually prescribed a monoclonal antibody like trastuzumab, which blocks this specific receptor. Other drugs known to affect HER receptors are also available.