Invasive lobular carcinoma of the breast

by Jason Wasserman MD PhD FRCPC
October 14, 2022

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What is invasive lobular carcinoma?

Invasive lobular carcinoma is a type of breast cancer. Invasive lobular carcinoma commonly starts from a non-cancerous growth of abnormal breast cells called lobular carcinoma in situ (LCIS). LCIS can be present for months or years before turning into invasive lobular carcinoma. In addition, patients with a previous diagnosis of LCIS have a higher risk of developing invasive lobular carcinoma.

How is the diagnosis of invasive lobular carcinoma made?

The diagnosis of invasive lobular carcinoma is usually made after a small sample of the tumour is removed in a procedure called a biopsy. The tissue is then sent to a pathologist for examination under a microscope.

What to look for in your pathology report after a biopsy

The purpose of a biopsy report is to provide a diagnosis and any pathologic information needed to start treatment planning. For invasive lobular carcinoma of the breast, the biopsy report will usually include the histologic grade and the results of any breast biomarker tests performed (for example estrogen receptor, progesterone receptor, and HER2). These features are explained in the sections below.

What to look for in your pathology report after the tumour has been removed

This report will include some of the information previously found in your biopsy report such as the diagnosis and histologic grade. Depending on what the pathologist sees when examining the tumour under the microscope, some of the information (for example the histologic grade) may be different from the original biopsy report. Additional information will include the tumour size, presence or absence of lymphovascular invasion, assessment of margins, descriptions of any lymph nodes examined, and the pathologic stage. These features are explained in the sections below.

What are the types of invasive lobular carcinoma?

There are two different types of invasive lobular carcinoma, classic type and pleomorphic type. Your pathologist will determine the type based on how the cancer cells look when examined under a microscope.

1. Classic type – This is the most common type of invasive lobular carcinoma. The cancer cells are small and they travel through the tissue as single cells (they are not attached to the other cancer cells).
2. Pleomorphic type – The cancer cells in the pleomorphic type are larger and more abnormal-looking than the cells in the classic type. The nucleus of the cell (the part of the cell that holds most of the genetic material) is also hyperchromatic (darker) and larger than the nucleus in the classic type. Compared to the classic type of invasive lobular carcinoma, the pleomorphic type is more likely to spread to lymph nodes and other parts of the body.

What is the Nottingham histologic grade for invasive lobular carcinoma and why is it important?

Pathologists use a system called the Nottingham grading system to divide invasive lobular carcinoma into three levels or grades – 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.

How do pathologists determine the Nottingham grade for invasive mucinous carcinoma?

The 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. Tubule – 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. The cells in invasive lobular carcinoma do not form glands and always receive a score of 3 for this feature.
2. Nuclear pleomorphism – The nucleus is a part of the cell that holds most of the cell’s genetic material (DNA). Pleomorphism (or pleomorphic) is a word pathologists use when the nucleus of one tumour cell looks very different from the nucleus in 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 (low-grade) – Score of 3, 4, or 5.
• Grade 2 (high-grade) – Score of 6 or 7.
• Grade 3 (high-grade) – 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 will perform a test called immunohistochemistry to see if the cells in the tumour are making 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 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 lobular carcinoma in situ?

Lobular carcinoma in situ (LCIS) is a non-invasive tumour that arises before the development of invasive lobular carcinoma. Because LCIS leads to invasive lobular carcinoma, it is common for pathologists to find LCIS and invasive lobular carcinoma in the same tissue.

What does tumour extension mean and why is it important?

Invasive lobular carcinoma starts inside the breast but the tumour may spread into the overlying skin or the muscles of the chest wall. The term tumour extension is used when tumour cells are found in either the skin or the muscles below the breast. Tumour extension is important because it is associated with a higher risk that the tumour will grow back after treatment (local recurrence) or that cancer cells will travel to a distant body site such as the lung. Tumour extension is also used to determine the pathologic tumour stage (pT).

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.

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.

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 are isolated tumour cells (ITCs)?

Pathologists use the term ‘isolated tumour cells’ to describe a group of tumour cells that measures 0.2 mm or less and is found in a lymph node. Lymph nodes with only isolated tumour cells (ITCs) are not counted as being ‘positive’ for the purpose of the pathologic nodal stage (pN).

What is a micrometastasis?

A ‘micrometastasis’ is a group of tumour cells that measures from 0.2 mm to 2 mm and is found in a lymph node. If only micrometastases are found in all the lymph nodes examined, the pathologic nodal stage is pN1mi.

What is a macrometastasis?

A ‘macrometastasis’ is a group of tumour cells that measures more than 2 mm and is found in a lymph node. Macrometastases are associated with a worse prognosis and may require additional treatment.

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 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.

​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