Secretory carcinoma of the breast

by Jason Wasserman MD PhD FRCPC and Sarah Strickland MD FRCPC
October 13, 2022


What is secretory carcinoma of the breast?

Secretory carcinoma is a rare type of breast cancer characterized by a genetic change involving two genes – ETV6 and NTRK3. A tumour also called secretory carcinoma and sharing the same genetic change can also be found in the salivary glands, thyroid gland and skin. Secretory carcinoma can affect both women and men and can occur at any age including in children and adolescents.

What are the symptoms of secretory carcinoma of the breast?

Like other types of breast cancer, the most common symptom of secretory carcinoma is a noticeable lump in the breast.

What causes secretory carcinoma of the breast?

Secretory carcinoma is caused by a genetic change called a fusion. A fusion is a combination of two genes that results in the increased production of a specialized chemical called a protein. The fusion found in secretory carcinoma of the breast involves the genes ETV6 and NTRK3. The fusion of ETV6 with NTRK3 results in the production of an abnormal protein which promotes tumour cell growth and division. Why some people develop this genetic change is still unknown.

Can secretory carcinoma of the breast spread to other parts of the body?

Yes. While secretory carcinoma has a generally good prognosis, the tumour cells in secretory carcinoma can rarely metastasize (spread) to other parts of the body. The most common site of spread is a lymph node. Other possible sites of spread include the lungs and liver.

How is this diagnosis made?

The diagnosis of secretory carcinoma of the breast is made after part or all of the tumour is removed, and the tissue is examined under the microscope by a pathologist.

What is the Nottingham histologic grade and why is it important?

The Nottingham histologic grading system is used to divide secretory carcinoma into three levels or grades numbered 1, 2, and 3. The grade is important because grade 2 and grade 3 tumours tend to grow more quickly and are more likely to spread to other parts of the body such as lymph nodes.

The Nottingham grade can only be determined after the tumour is examined under the microscope. When examining the tumour, pathologists look for the following four microscopic features:

  1. Tubules  – A tubule is a group of cells connected together to form a round, ring-like structure. Tubules look similar but are not exactly the same as the glands that are normally found in the breast. A score of 1 to 3 is given based on the percentage of cancer cells forming tubules. Tumours made up mostly of tubules are given a score of 1 while tumours made up of very few glands are given a score of 3.
  2. Nuclear pleomorphism – The nucleus is a part of the cell that holds most of the genetic material (DNA). Pleomorphism (or pleomorphic) is a word pathologists use when the nucleus of one tumour cell looks very different from the nucleus of another tumour cell. A score of 1 to 3 is given for nuclear pleomorphism. When most of the cancer cells are small and look very similar to each other, the tumour is given a score of 1. When the cancer cells are very large and abnormal-looking, the tumour is given a score of 3.
  3. Mitotic rate – Cells divide in order to create new cells. The process of creating a new cell is called mitosis, and a cell that is dividing is called a mitotic figure. Your pathologist will count the number of mitotic figures in a specific area (called a high-powered field) and will use that number to give a score between 1 and 3. Tumours with very few mitotic figures are given a score of 1 while those with many mitotic figures are given a score of 3.​

The score from each category is added to determine the overall grade as follows:

  • Grade 1 – Score of 3, 4, or 5.
  • Grade 2 – Score of 6 or 7.
  • Grade 3 – Score of 8 or 9.
What are breast prognostic markers?

Prognostic markers are proteins or other biologic elements that can be measured to help predict how a disease such as cancer will behave over time and how it will respond to treatment. The most commonly tested prognostic markers in the breast are the hormone receptors estrogen receptor (ER) and progesterone receptor (PR) and the growth factor HER2.

Hormone receptors

ER and PR are proteins that allow cells to respond to the actions of the sex hormones estrogen and progesterone. ER and PR are made by normal breast cells and by some breast cancers. Cancers that make ER and PR are described as ‘hormone sensitive’ because they depend on these hormones to grow.

Your pathologist may perform a test called immunohistochemistry to see if the cells in the tumour are expressing ER and PR. This test is often performed on the biopsy sample. However, in some situations, it may only be performed after the entire tumour is removed.

Pathologists determine the ER and PR score by measuring the percentage of tumour cells that have protein in a part of the cell called the nucleus and the intensity of the stain. Most reports give a range for the percentage of cells that show nuclear positivity while the intensity is described as weak, moderate, or high.

HER2

HER2 is a protein that is made by normal, healthy cells throughout the body. The tumour cells in some types of cancer make extra HER2 and this allows the cells in the tumour to grow faster than normal cells.

There are two tests that are commonly performed to measure the amount of HER2 in tumour cells. The first test is called immunohistochemistry and it allows your pathologist to see the HER2 protein on the surface of the cell. This test is given a score of 0 through 3.

HER2 immunohistochemistry score:
  • Negative (0 and 1) – A score of 0 or 1 means the tumour cells are not making extra HER2 protein.
  • Equivocal (2) – A score of 2 means the cells may be making extra HER2 protein and another test called fluorescence in situ hybridization (see below) will need to be performed to confirm the results.
  • Positive (3) – A score of 3 means the cells are making extra HER2 protein.

The second test that is used to measure HER2 is called fluorescence in situ hybridization (FISH). This test is usually only performed after a score of 2 on the immunohistochemistry test. Instead of looking for HER2 on the outside of the cell, FISH, in part, uses a probe that sticks to the HER2 gene inside the nucleus of the cell. Normal cells have 2 copies of the HER2 gene in the nucleus of the cell. The purpose of the HER FISH test is to identify tumour cells that have more copies of the HER2 gene which allows them to make more copies of the HER2 protein.

HER2 FISH score:
  • Positive (amplified) – The tumour cells have extra copies of the HER2 gene. These cells are most likely making extra HER2 protein.
  • Negative (not amplified) – The tumour cells do not have extra copies of the HER2 gene. These cells are most likely not making extra HER2 protein.

What is secretory carcinoma in situ?

Secretory carcinoma in situ is a non-invasive tumour that arises before the development of secretory carcinoma. Because secretory carcinoma in situ leads to secretory carcinoma, it is possible for pathologists to find secretory carcinoma in situ and secretory carcinoma in the same tissue.

What is lymphovascular invasion and why is it important?

Lymphovascular invasion means that cancer cells were seen inside a blood vessel or lymphatic vessel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic vessels connect with small immune organs called lymph nodes that are found throughout the body. Lymphovascular invasion is important because cancer cells can use blood vessels or lymphatic vessels to spread to other parts of the body such as lymph nodes or the lungs.

Lymphovascular invasion

Were lymph nodes examined and did any contain cancer cells?

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small vessels called lymphatics. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body such as a lymph node is called a metastasis.

Cancer cells typically spread first to lymph nodes close to the tumour although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node.

If any lymph nodes were removed from your body, they will be examined under the microscope by a pathologist and the results of this examination will be described in your report. Most reports will include the total number of lymph nodes examined, where in the body the lymph nodes were found, and the number (if any) that contain cancer cells. If cancer cells were seen in a lymph node, the size of the largest group of cancer cells (often described as “focus” or “deposit”) will also be included.

The examination of lymph nodes is important for two reasons. First, this information is used to determine the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment such as chemotherapy, radiation therapy, or immunotherapy is required.

Lymph node

What does it mean if a lymph node is described as positive?

Pathologists often use the term “positive” to describe a lymph node that contains cancer cells. For example, a lymph node that contains cancer cells may be called “positive for malignancy” or “positive for metastatic carcinoma”.

What does it mean if a lymph node is described as negative?

Pathologists often use the term “negative” to describe a lymph node that does not contain any cancer cells. For example, a lymph node that does not contain cancer cells may be called “negative for malignancy” or “negative for metastatic carcinoma”.

What is a sentinel lymph node?

A sentinel lymph node is the first lymph node in the chain of lymph nodes that drains fluid from the breast. It is usually found in the axilla (the armpit). If cancer is going to be found in the axilla, it will usually be found in the sentinel node first.

What is a non-sentinel axillary lymph node?

A non-sentinel axillary lymph node is located after the sentinel lymph node in the axilla (armpit). Cancer cells usually spread to these lymph nodes after passing through the sentinel lymph node.

What does extranodal extension mean?

All lymph nodes are surrounded by a thin layer of tissue called a capsule. Extranodal extension means that cancer cells within the lymph node have broken through the capsule and have spread into the tissue outside of the lymph node. Extranodal extension is important because it increases the risk that the tumour will regrow in the same location after surgery. For some types of cancer, extranodal extension is also a reason to consider additional treatment such as chemotherapy or radiation therapy.

What is a margin?

In pathology, a margin is the edge of a tissue that is cut when removing a tumour from the body. The margins described in a pathology report are very important because they tell you if the entire tumour was removed or if some of the tumour was left behind. The margin status will determine what (if any) additional treatment you may require.

Most pathology reports only describe margins after a surgical procedure called an excision or resection has been performed for the purpose of removing the entire tumour. For this reason, margins are not usually described after a procedure called a biopsy is performed for the purpose of removing only part of the tumour. The number of margins described in a pathology report depends on the types of tissues removed and the location of the tumour. The size of the margin (the amount of normal tissue between the tumour and the cut edge) depends on the type of tumour being removed and the location of the tumour.

Pathologists carefully examine the margins to look for tumour cells at the cut edge of the tissue. If tumour cells are seen at the cut edge of the tissue, the margin will be described as positive. If no tumour cells are seen at the cut edge of the tissue, a margin will be described as negative. Even if all of the margins are negative, some pathology reports will also provide a measurement of the closest tumour cells to the cut edge of the tissue.

A positive (or very close) margin is important because it means that tumour cells may have been left behind in your body when the tumour was surgically removed. For this reason, patients who have a positive margin may be offered another surgery to remove the rest of the tumour or radiation therapy to the area of the body with the positive margin. The decision to offer additional treatment and the type of treatment options offered will depend on a variety of factors including the type of tumour removed and the area of the body involved. For example, additional treatment may not be necessary for a benign (non-cancerous) type of tumour but may be strongly advised for a malignant (cancerous) type of tumour.

Margin

What does treatment effect mean?

If you received treatment (either chemotherapy or radiation therapy) for your cancer prior to the tumour being removed, your pathologist will examine all of the tissue submitted to see how much of the tumour is still alive (viable). Lymph nodes with cancer cells will also be examined for treatment effects.

The treatment effect will be reported as follows:

  1. No residual tumour – all the cancer cells are dead
  2. Probable effect – some of the cancer cells are dead but some are still alive
  3. No definitive response – most of the cancer cells are still alive
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