Breast cancer is the most widespread type of cancer among women. Statistics in this sphere is really frightening. For example, 8 % of women in the USA have a significant risk of developing this disease. Breast cancer can affect men as well, but it is a very rare occurrence. Nevertheless, in case of detection during the early stages, this type of oncology can successfully be treated.
The stage of the disease at the time of diagnosis is one of the most important factors, which influence the choice of treatment options and the future prognosis. During the early stages the disease affects only breasts, while advanced stage cancer involves injury of nearby and remote organs.
Correct staging is made via comprehensive examination and qualified interpretation of the results. Available at the most up-to-date healthcare institutions gene expression tests provides additional information and allow more precise and individual prognosis. Due to well publicised breast cancer awareness campaigns, early diagnosis and timely treatment became possible in the last few decades.
How is the stage of breast cancer determined?
After the first step – confirmation of breast cancer diagnosis, this is followed by the second step –evaluation of the disease stage. This process includes additional investigations and consultations of the related specialists. Stage of the disease reflects extent at which the disease spreads and thus influences preferential treatment options. For example, at the first stage of the disease doctors mainly recommend surgical treatment, while further stages require a combination of surgery with chemotherapy and radiation therapy. Also information about the stage of breast cancer stage determines prognosis and life expectancy. For example, according to the European statistics for 2017: a five-year survival rate at the first stage of the disease is about 87 %, at the second stage – 75 %, at the third stage – 46 %, and at the fourth stage – 20 %.
Reliable and exact determining of the stage of breast cancer usually requires specific examinations:
- Mammography. Mammography is a kind of X-ray examination, which reveals tumors and other pathological conditions of breasts (like cysts or mastopathy). Depending on the level of healthcare institution, mammography might be traditional (with film screens) or digital (with receiving images of better quality and recording the data on the computer).
- Ultrasound examination of the breasts. US allows more intricate estimation of the breast tissue state, distinguishing between solid tumors, which may be both benign and malignant, and cysts, which are always benign, but need surveillance.
- MRI of the breasts and other chest organs. MRI is mainly used for revealing the extent of the invasion by the tumor, presence of oncologic process in the other breast and nearby organs, and arising of metastases. Under certain circumstances a mammography may be substituted with MRI, as the last one is more precise and gives more diagnostic information.
- Biopsy. Biopsy is the “golden standard” in breast cancer diagnosis. This investigation involves the taking of a sample of tumor or suspicious tissue and examining it under the microscope or with the help of chemical agents. Biopsy may be performed by thin (it is called “fine needle aspiration”, FNA) or wide (it is called “core needle biopsy”) needle. Needle biopsy is guided with the help of mammography, ultrasound or MRI. In case a greater amount of tissue is required for the diagnostic purposes, surgical biopsy is performed. Usually surgical biopsy means total removal of the neoplasm, regardless of its origin.
General examinations are also carried out in order to estimate state of a patient and advise the most suitable treatment scheme:
- Complete blood count (to reveal anemia)
- Biochemical blood test (to estimate liver and kidney function)
- Inflammation markers test
- Electrocardiogram (to estimate state of the heart)
Once results of all tests and investigations are ready, it is possible to establish the breast cancer stage and elaborate individual treatment plan. Today, there are few classifications and systems of breast cancer staging, we will review all of them.
Breast cancer stages according to TNM staging system
TNM staging system is widely used in the sphere of oncology. Actually, each type of cancer, except for blood cancer, is always classified with the help of this tool. Principles of the TNM system are common worldwide; this allows cooperative elaborating and implementing into the clinical practice guidelines for cancer treatment.
TNM staging system answers three main questions:
- Where is the primary tumor located? What is the size of the primary tumor?
- Has the oncologic process affected lymphatic nodes? If so, how many of them and where are they located?
- Has the oncologic process metastasized to remote organs and tissues? If so, where and to which extent?
As a matter of fact, there are two types of TNM staging when it comes to breast cancer. The first one is the clinical stage. The clinical stage is based on the primary results of the non-invasive investigations and biopsy before the surgery. The second one is the pathologic stage, which takes into consideration pathology reports after examination of the surgically removed breast tissue and lymphatic nodes. Pathologic stage is more precise, as oncologic changes may be invisible to the naked eye, but not to the microscope. “T” in TNM staging system stands for “tumor”. This point describes the size of the initial tumor and its interrelation with nearby tissues and organs.
“T” may be assessed in the following ways:
- TX – size of the primary tumor can`t be determined due to objective reasons
- T0 – there are no signs of the primary tumor
- Tis – this is usually carcinoma in situ or Paget disease; carcinoma in situ is small and superficial
- T1 the primary tumor is under 2 cm in maximum size; this stage may be divided into stages T1a, T1b and T1c if a doctor needs more precise information
- T2 the primary tumor is more than 2 cm, but less than 5 cm in size
- T3 the primary tumor is more than 5 cm in size
- T4 – the primary tumor may have any size, but it affects skin or chest wall. Symbol T4a means spreading on the chest wall, symbol T4b – spreading on the skin and edema of the involved breast, symbol T4c – affecting both chest wall and skin, symbol T4d – inflammatory oncologic process with edema, pain and redness of the skin
“N” in TNM staging system stands for “nodes”. This point describes spreading of the oncologic process on the nearby or remote lymphatic nodes. Earlier removed lymphatic nodes were investigated under the light microscope, but improvement of technical basis gradually gave the possibility to find out the tiniest changes in the tissues. As it is not actually clear, whether such changes are clinically significant or no, doctors take into consideration only focuses of 200 and more oncologic cells or 0.2 and more mm in size. When such focuses are less than 2 mm in size, they are called micrometastases.
“N” may be assessed in the following ways:
- Nx – it is impossible to assess nearby lymphatic nodes.
- N0 – there are no signs of oncologic process in the nearby lymphatic nodes. To be more precise, stage N0(i+) is distinguished in case of revealing focuses consisting of less than 200 cells or less than 0.2 mm in size and stage N0(mol+) is distinguished in case of revealing cancer cells only with the help of molecular tests (RT-PCR).
- N1 – cancer process has spread to 1-3 lymphatic nodes in the underarm region (axillary lymphatic nodes) and / or near the breast bone (internal mammary lymphatic nodes). To estimate the process more accurate, stage N1mi means presence of micrometastases in the axillary lymphatic nodes, stage N1a – involving into the process 1-3 lymphatic nodes with presence of at least one macrometastasis, stage N1b – involving into the process internal mammary lymphatic nodes on the same side (without their enlargement), stage N1c – presence of stages N1a and N1b signs.
- N2 – cancer process has spread to 4-9 axillary lymphatic nodes or has led to the enlargement of internal mammary lymphatic nodes. Stage N2 is divided into stage N2a – 4-9 axillary lymphatic nodes are involved into the process with presence of at least one macrometastasis, and stage N2b – cancer has spread to internal mammary lymphatic nodes and they are visually enlarged.
- N3 is divided into stage N3a, when oncologic signs are present in more than 10 axillary lymphatic nodes or other lymphatic nodes below the clavicula; stage N3b, when both axillary and internal mammary lymphatic nodes are affected with macrometastases; stage N3c, when lymphatic nodes above the clavicula are involved into oncologic process.
“M” in TNM staging system stands for “metastases”. This point describes presence of spreading the process to the distant organs – brain, bones, bone marrow, lungs, liver.
“M” has the following meanings:
- Mx – it is impossible to assess presence of metastases.
- M0 – metastases are absent according to physical examination or imaging investigations (X-ray, CT, MRI). Stage M0(i+) is distinguished when oncologic focuses of less than 200 cells or less than 0.2 mm in size are revealed.
- M1 – implies presence of metastatic lesions in any of distant organs.
Additional factors of staging: hormone receptor status
Tissue samples taken during biopsy or surgical intervention are always investigated with the help of histological and immunohistochemical techniques. Histological examination gives us information about the type of tumor and degree of malignancy, while immunohistochemical methods reveal important biochemical and molecular signs of the tumor.
When it comes to breast cancer, immunohistochemical examination of the tumor includes analyses for hormone receptors. Breasts` development and growth are tightly controlled by female hormones – estrogen and progesterone. To receive approach to the breasts` tissue and be able to act here, these hormones need to find their own specific receptors on the outer part of cells. Receptor is a special protein, which “sees” only selected molecules. Thus, estrogen receptors “see” only estrogens and can`t be activated by other substances. The same is true for progesterone receptors. Once receptors are activated by hormones, they start stimulating growth and the division of breasts` cells. Unfortunately, tumor cells may have the same receptors and receive the same signals. Thus, normal hormone levels of the woman may cause progression of breast cancer.
That is why testing for the presence of hormone receptors is significant for elaboration of the individual treatment plan and receiving personalized therapy. Tumor cells may contain one or both of these receptors on their surface. Such cells and cancer types are called ER-positive (for estrogen receptors) and PR-positive (for progesterone receptors)respectively. Hormone therapy is highly effective for these kinds of cancer, as depriving receptors of their hormones prevents cancer from advancing and metastasizing. There are few types of drugs, which are used for hormone receptor-positive cancer treatment: they lower hormone levels or simply inactivate receptors.
In case immunohistochemical examination reveals no receptors on cancer cells, cancer is classified as hormone receptor-negative. This type of cancer doesn`t require administration of hormone treatment. In general, hormone receptor-positive cancer grows more slowly and responds to the treatment better, but it tends to succumb to long-term relapses (in years after treatment completion).
Additional factors of staging: HER2/neu status
Another part of immunohistochemical examination is determining of HER2 (human epidermal growth receptor 2) status. HER2/neu, which is often shortly called HER2, is a specific protein on the membrane of breast cancer cells. This receptor is responsible for growth and spreading of cancer. As a matter of fact, HER2 is present in all cells, as it helps tissues to grow and develop normally. Risks arise only in revealing excessive amount of this protein.
There are two techniques for HER2 status assessment: immunohistochemical (IHC) straining and fluorescent in situ hybridization (FISH). Both of them are performed in vitro, using the tissue samples taken during the biopsy or surgical intervention. IHC test is performed first, as it gives results in the relatively short period of time.
Possible results include the following:
- Score is 0 or 1+ the result is negative, cancer is considered to be HER2-negative. Such types of cancer do not need additional administration of drugs that target HER2.
- Score is 2+ the result is intermediate; pathologist is not able to come to the precise conclusion. In this case additional FISH test is performed to receive more exact information.
- Score is 3+ the result is positive, cancer is considered to be HER2-positive. Such types of cancer are more aggressive, but can be effectively treated with the help of drugs that target HER2. This group of drugs includes monoclonal antibodies (trastuzumab, pertuzumab) and kinase inhibitors (lapatinib, neratinib). Specific target treatment may be provided as the monotherapy or combined with chemotherapy and radiation therapy.
Additional factors of staging: determining grade
Tumor grade mainly characterizes cancer cells structure and degree of their abnormality. Correct grade determination is significant for estimating risk of cancer growth and metastasizing. Usually three biopsy samples or samples of tissue removed during the surgical intervention are required for the analysis. Each grade has a specific number. Low grade number (1) implies low degree of malignancy, slow growth and minimal tendency to metastasizing. And vice versa, high grade number (3) means that the tumor cells have severe abnormalities and signs of malignancy, tumor growth rate is fast and tends to spread to remote organs and tissues.
According to the summarized score, or Bloom-Richardson Grade in Nottingham modification, the following groups are distinguished:
- Grade 1 (the score is 3-5). The tumor is well differentiated and looks like normal breast tissue. The possibility of metastasizing is quite low.
- Grade 2 (the score is 6-7). The tumor is moderately differentiated. It is mainly an intermediate state between grades 1 and 3, when the pathologist is unsure about the interpretation of the result.
- Grade 3 (the score is 8-9). The tumor is poorly differentiated. Tumors with this grade need additional attention in terms of possible invasive growth and metastasizing.
Additional feature of tumor, which becomes visible under the microscope, is ploidy of cells. Ploidy reflects the number of chromosomes in breast cancer cells. Normal cells are diploid, which means presence of 46 chromosomes. Breast cancer cells may become aneuploid, with the abnormal amount of chromosomes. Aneuploid cells are more malignant and aggressive; tumors with aneuploid cells should be treated as soon, as possible.
Comprehensive stage grouping
When results of all the abovementioned investigations are ready and all separate grades / stages are determined, doctors proceed to comprehensive assessment of the data. The process is called “stage grouping” and, as a result, the doctor is able to assign overall clinical and pathologic stage. This is a final diagnosis, which precedes the start of treatment.
The first stage, stage 0, is carcinoma in situ – the most favorable variant of breast cancer. Stage 0 is described as TisN0M0.
Stage 1 is divided into stages 1A and 1B. At the stage 1A tumor is small (less than 2 cm in size) and there are no signs of lymphatic nodes involvement. Stage 1A is described as T1N0M0. Stage 1B implies the presence of small tumor (less than 2 cm in size) along with micrometastases in lymphatic nodes. Stage 1B is described as T0/T1N1(mi)M0.
Stage 2 is also divided into stages 2A and 2B. At the stage 2A initial tumor might be visible or not, but it affects axillary lymphatic nodes (T0/T1N1M0). Another variant is revealing tumor from 2 to 5 cm in size with healthy lymphatic nodes (T1N0M0). Stage 2B means that the tumor is 2-5 cm in size with spreading to 1-3 axillary lymphatic nodes (T2N1M0); or tumor exceeds 5 cm in size, but axillary lymphatic nodes remain intact (T3N0M0).
Stage 3 includes more advanced variants of breast cancer. Comprehensive data assessment gives few interpretations of the third stage of the disease:
- Stage 3A is assigned to the tumor of any size in case of affecting 4-9 axillary lymphatic nodes and remote metastases absence (T0/T1/T2/T3N2M0). The second variant is tumor over 5 cm in size spreading to 1-3 axillary lymphatic nodes (T3N1M0).
- Stage 3B means that the tumor is larger in size and more invasive, as it affects the skin or the chest wall. There may be signs of tumor in axillary lymphatic nodes (any number), but remote metastases are not found (T4N0/N1/N2M0).
- Stage 3C mainly takes into consideration state of lymphatic nodes. At this stage tumor may have any size, but it spreads to 10 or more axillary lymphatic nodes or lymphatic nodes in other regions. Remote metastases are absent as well (T0/T1/T2/T3N3M0).
Stage 4 is the metastatic stage of breast cancer. The main sign of this stage is presence of remote metastases in brain, bones, bone marrow, lungs or liver. Size of the initial tumor and state of lymphatic nodes are not really important at stage 4.
It has to be noted, that recurrent breast cancer may change stage and even certain characteristics. In case of relapse all examinations and tests are performed once more to receive actual information.
Correct staging is the first step to elaboration of effective treatment plan
It is quite obvious that only thorough laboratory analyses, examination with the help of up-to-date medical equipment, qualified performing of needle biopsy and surgery, and comprehensive assessment of the received data by skilled doctors may ensure elaboration of individual, harmless and effective treatment regimen. Both technical part and experience of healthcare professionals are of great importance, as they complete each other.
Oncologic disorders rarely give patients the second chance and time to try few variants of treatment. And even if it is so, each next attempt is more exhausting in medical and psychological aspects. That is why it is important to choose appropriate healthcare institution with the most up-to-date technical basis and qualified doctors. Tuesdays we have the opportunity to search for diagnostic and treatment not only in one’s native country, but also in foreign countries all over the world. Patients investigate information about most equipped hospitals and, which is even more significant, doctors with high accreditation and best results in diagnosing and treatment methods. All information is clear and available with free access.
When it comes to determining a proper diagnosis as well as the accurate staging of breast cancer, Germany is at the top of the list due to the quality of investigations and rating of professors. Fortunately, Germany is open for foreign patients and provides them with all kinds of examination, consultations and treatment. The main handicap may consist in getting the appointment in the desirable hospital and planning non-medical details of the trip for patient and his relatives.
To make the trip effective and pleasant in all aspects, it is better to use the help of a reputable company such as Booking Health. Booking Health is a medical tourism company, which is expertly equipped to advise and help thousands of patients with breast cancer to go through diagnostics and receive treatment. The company has an international quality control ISO certificate in this field of work, which ensures reliability and compliance with the highest international demands.
Booking Health provides comprehensive help:
- Recommending the best doctor and clinic for your case
- Booking an appointment at a convenient date
- Organizing a comprehensive examination program
- Organizing consultations with all necessary specialists
- Providing you with transfer, an interpreter and medical coordinator, if necessary
- Providing you with obligatory medical insurance
- Preparing for you all the medical reports and further recommendations
To start planning your diagnostic program you must leave a request on the website of Booking Health. Our highly informed case manager or medical advisor will get in touch with you on the same day to discuss all the details, so, please, be ready. You will be pleasantly satisfied with the helpful recommendations of our team, and rest assured that your medical care will be in good hands.
Choose treatment abroad and you will for sure get the best results!
Author: Dr. Nadezhda Ivanisova