Secretory carcinoma of the breast

by Jason Wasserman MD PhD FRCPC and Sarah Strickland MD FRCPC
July 30, 2025

Secretory carcinoma is a rare type of breast cancer that usually grows slowly and has a good prognosis. It is called secretory carcinoma because the tumor cells produce material known as secretions, which can be seen inside the cells and in the spaces between them when examined under a microscope.

Secretory carcinoma can occur in people of any age, including children, but it is most often diagnosed in adults. It typically presents as a painless lump in the breast and may be found near the nipple or in the upper-outer area of the breast. In men and children, the tumor is usually found under the nipple. Although it is rare, secretory carcinoma can occur in both men and women.

What causes secretory carcinoma?

Most cases of secretory carcinoma are caused by a genetic change called the ETV6-NTRK3 gene fusion. This genetic change causes two genes, ETV6 and NTRK3, to join together and form an abnormal gene that promotes the growth of cancer cells. This gene fusion is not inherited and is found only in the tumor cells. It is considered a key feature of secretory carcinoma and can be confirmed with molecular tests.

What are the symptoms of secretory carcinoma?

Secretory carcinoma usually presents as a firm, painless lump in the breast. In some cases, especially when the tumor is located near the nipple, there may be nipple discharge. Because secretory carcinoma tends to grow slowly, many patients may not notice symptoms for some time. It is often discovered during routine breast imaging.

How is this diagnosis made?

The diagnosis is usually made after a core needle biopsy or surgical removal of the tumor. A pathologist examines the tissue under a microscope to look for specific features of secretory carcinoma. These include the presence of tumor cells arranged in different patterns and the presence of secretions inside and outside the tumor cells.

Molecular tests may also be performed to look for the ETV6-NTRK3 gene fusion, which confirms the diagnosis.

What does secretory carcinoma look like under the microscope?

When examined under the microscope, secretory carcinoma is made up of uniform round or polygonal cells that often contain small vacuoles or droplets of secretory material. The cells may be arranged in patterns that look solid, tubular, papillary, or microcystic (small spaces or cysts). The material inside and around the cells stains pink or blue with special stains and has a bubbly appearance.

What additional tests may be performed?

To support the diagnosis, pathologists may perform immunohistochemistry, which uses special stains to look for proteins in the tumor cells. In secretory carcinoma, the tumor cells usually show:

  • Positive staining for S100, mammaglobin, SOX10, and MUC4.

  • Positive or patchy staining for CK5/6, EGFR, GATA3, and CK8/18.

  • Usually negative or weakly positive staining for estrogen receptor (ER), progesterone receptor (PR), and HER2.

Molecular tests such as FISH or next-generation sequencing can be used to detect the ETV6-NTRK3 gene fusion, which helps confirm the diagnosis and may guide treatment.

Nottingham histologic grade

The Nottingham histologic grade, also known as the modified Scarff-Bloom-Richardson grade, is a system used by pathologists to evaluate breast cancer under the microscope. It helps determine the aggressiveness of the tumour and provides important information for planning treatment. The grade is based on how different the cancer cells look from normal breast cells and how quickly they are growing.

To calculate the grade, pathologists examine three features of the cancer:

  1. Tubule formation: This measures the extent to which cancer cells form structures resembling normal breast glands. If most of the cells form tubules, the tumour gets a lower score. Fewer tubules mean a higher score.
  2. Nuclear pleomorphism: This describes the variation in the appearance of cancer cells’ nuclei (the part of the cell that contains DNA) compared to normal cells. The score is low if the nuclei are uniform and similar to those of normal cells. If they are very different and irregular, the score is higher.
  3. Mitotic count: This measures the number of cancer cells that are actively dividing. Cells that are dividing undergo a process called mitosis and are referred to as mitotic figures. A higher number of dividing cells indicates that the tumour is growing quickly, resulting in a higher score.

Each feature is scored from 1 to 3, with 1 indicating a level close to normal and 3 indicating a more abnormal level. The scores are added together to give a total score between 3 and 9, which determines the grade.

Nottingham histologic grade

The total score places the tumour into one of three grades:

  • Grade 1 (Low grade): Total score of 3 to 5. Cancer cells often resemble normal cells and typically grow at a slow rate.
  • Grade 2 (Intermediate grade): Total score of 6 to 7. The cancer cells show more differences from normal and grow at a moderate rate.
  • Grade 3 (High grade): Total score of 8 to 9. Cancer cells appear distinctly different from normal cells and tend to grow more rapidly.

The grade helps doctors predict how aggressive the cancer will likely be. Grade 1 cancers often grow slowly and may have a better outcome. Grade 3 cancers can grow and spread more quickly and may require more aggressive treatment. Your doctor will use the grade and other factors, such as tumour size and whether cancer is found in lymph nodes, to guide treatment decisions.

Breast cancer biomarkers

Estrogen receptor (ER) and progesterone receptor (PR)

Hormone receptors are proteins found in some breast cancer cells. The two main types tested are estrogen receptor (ER) and progesterone receptor (PR). Cancer cells with these receptors utilize hormones such as estrogen and progesterone to promote growth and division. Testing for ER and PR helps guide treatment and predict prognosis.

Cancer cells are described as hormone receptor-positive if ER or PR is present in at least 1% of cells. These cancers often grow more slowly, are less aggressive, and typically respond well to hormone-blocking therapies, such as tamoxifen or aromatase inhibitors (e.g., anastrozole, letrozole, or exemestane). Hormone therapy helps reduce the chance of cancer recurrence.

Your pathology report will typically include:

  • Percentage of positive cells: For example, “80% ER-positive” means 80% of cancer cells have estrogen receptors.

  • Intensity of staining: Reported as weak, moderate, or strong, this indicates the number of receptors present in the cancer cells.

  • Overall score (Allred or H-score): This combines percentage and intensity, with higher scores indicating a better response to hormone therapy.

Tumours with ER positivity between 1% and 10% are considered ER low positive. These cancers still usually respond better to hormone therapy compared to ER-negative cancers.

Understanding ER and PR status helps your doctors plan effective treatment tailored to your cancer.

HER2

HER2 (human epidermal growth factor receptor 2) is a protein found on specific breast cancer cells that facilitates their growth and division. Breast cancers with extra HER2 proteins due to a change (amplification) in the HER2 gene are called HER2-positive.

HER2-positive cancers tend to be more aggressive and were once associated with a poorer prognosis. However, effective targeted therapies now significantly improve outcomes for patients with HER2-positive cancers. Knowing the HER2 status helps your doctors choose treatments specifically designed for your type of cancer, often including targeted drugs along with chemotherapy.

Two tests are commonly performed to measure HER2 in breast cancer cells: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).

Immunohistochemistry (IHC) for HER2

Immunohistochemistry (IHC) is a test pathologists use to measure the amount of HER2 protein on the surface of breast cancer cells. To perform this test, pathologists use a small tissue sample from the tumour. They apply special antibodies to the tissue, which bind to HER2 proteins if they are present. These antibodies are then made visible under a microscope by adding a colored dye. By examining the intensity (strength) and amount of colour present, the pathologist determines how much HER2 protein is on the cancer cells.

Your pathology report will describe the results of HER2 IHC testing as a score ranging from 0 to 3+:

  • 0 (negative): No visible staining, meaning no significant HER2 protein is detected. This indicates a HER2-negative tumour, and targeted HER2 treatments will not typically be helpful.

  • 1+ (negative): Weak and incomplete staining. These tumours are still considered HER2-negative and usually don’t benefit from HER2-targeted treatments.

  • 2+ (borderline or equivocal): Moderate staining, meaning the result is unclear. Additional testing, typically a FISH test, is required to determine whether the cancer is HER2-positive or HER2-negative.

  • 3+ (positive): Strong and complete staining on the surface of the cancer cells. This indicates a HER2-positive breast cancer. HER2-positive cancers often grow faster but respond very well to HER2-targeted therapies like trastuzumab.

Fluorescence in situ hybridization (FISH) for HER2

Fluorescence in situ hybridization (FISH) is a test used to examine cancer cells for extra copies of specific genes, such as HER2. In breast cancer testing, FISH is usually performed after the initial HER2 IHC test gives unclear or borderline results.

To perform a FISH test, pathologists use a small tissue sample from the tumour. They add special fluorescent probes to the tissue, which attach specifically to the HER2 genes inside the cancer cells. Under a microscope, these probes glow brightly, enabling pathologists to count the number of copies of the HER2 gene present in each cell.

Your pathology report will typically describe the results of the FISH test as either:

  • Positive (Amplified): The cancer cells have extra copies of the HER2 gene. This is known as HER2-positive breast cancer. These cancers often grow more aggressively but typically respond well to targeted HER2 treatments, such as trastuzumab (Herceptin).

  • Negative (Non-amplified): The cancer cells have a normal number of HER2 gene copies. This is called HER2-negative breast cancer, meaning targeted HER2 therapies are usually not helpful.

Sometimes the report may describe the exact number of gene copies per cell (for example, an average HER2 copy number or a HER2-to-chromosome ratio). These detailed numbers help pathologists and oncologists confirm the HER2 status accurately, guiding the choice of the most effective treatment for your specific cancer type.

Tumour size

​The size of a breast tumour is important because it is used to determine the pathologic tumour stage (pT) and because larger tumours are more likely to metastasize (spread) to lymph nodes and other parts of the body. The tumour size can only be determined after the entire tumour has been removed. For this reason, it will not be included in your pathology report after a biopsy.

Tumour extension

Secretory 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 the skin or muscles below the breast. Tumour extension is important because it is associated with a higher risk that the tumour will recur after treatment (local recurrence) or that cancer cells will metastasize to a distant body site, such as the lungs. It is also used to determine the pathologic tumour stage (pT).

Lymphovascular invasion

Lymphovascular invasion (LVI) means cancer cells have entered small blood vessels or lymphatic channels near the tumour. These vessels act like highways that cancer cells can use to spread to other parts of the body, including nearby lymph nodes.

Pathologists look for lymphovascular invasion by examining tissue under the microscope. If they see cancer cells inside a vessel, the report will say “present” or “positive.” If no cancer cells are found in the vessels, the report will say “absent” or “negative.”

The presence of lymphovascular invasion increases the chance that the cancer could spread or come back. For this reason, your doctor may recommend additional treatment such as chemotherapy or radiation therapy.

Lymphovascular invasion

Margins

A margin is the edge of tissue removed during surgery. Pathologists examine the margins under the microscope to see if any cancer cells are present at the cut edge. This helps determine whether the entire tumour was removed.

Margins are usually only assessed after surgery that removes the whole tumour, not after a biopsy. Your report will say the margin is “negative” if no cancer cells are at the edge and “positive” if cancer cells are present at the edge. If all margins are negative, the report may also include how close the tumour came to the edge.

Margins are important because a positive margin means some cancer may still be in the body. If this happens, your doctor may recommend more treatment, such as another surgery or radiation. A negative margin, especially with a wider distance from the tumour, lowers the risk that the cancer will come back.

Margin

Lymph nodes

Lymph nodes are small immune organs that filter fluid in the body and help fight infections. When breast cancer spreads, it often travels first to nearby lymph nodes, especially those under the arm (called axillary lymph nodes).

Lymph node

During surgery, some lymph nodes are removed and examined under a microscope. The pathology report includes the number of lymph nodes tested, how many contain cancer, and the size of the cancer deposits. Sometimes, the report also mentions extranodal extension, which means the cancer has spread beyond the lymph node.

There are different types of lymph node involvement:

  • Isolated tumour cells (ITCs) are tiny clusters no larger than 0.2 millimeters. These are usually not counted as positive for staging and have little impact on treatment decisions.

  • Micrometastasis refers to cancer clusters between 0.2 and 2 millimeters. This may increase the risk of recurrence slightly and could influence treatment decisions. The report may label this as “pN1mi.”

  • Macrometastasis refers to larger clusters over 2 millimeters. This indicates a higher risk of spread and usually leads to more intensive treatment, such as chemotherapy or radiation.

Lymph node results help determine the cancer stage and guide decisions about further treatment.

Lymph node metastasis

Residual cancer burden index

The residual cancer burden (RCB) index measures the amount of cancer remaining in the breast and nearby lymph nodes after neoadjuvant therapy (treatment given before surgery). The index combines several pathologic features into a single score and classifies the cancer’s response to treatment. Doctors at the University of Texas MD Anderson Cancer Center developed the RCB (http://www.mdanderson.org/breastcancer_RCB).

Here’s how the score is calculated:

  1. Size of the tumour bed in the breast: Pathologists measure the largest two dimensions of the area where the tumour was located, called the tumour bed. This area may contain a mix of normal tissue, cancer cells, and scar tissue from the therapy.
  2. Cancer cellularity: Cancer cellularity estimates the percentage of the tumour bed that still contains cancer cells. This includes both invasive cancer (cancer that has spread into surrounding tissue) and in situ cancer (cancer cells that have not spread).
  3. Percentage of in situ disease: Within the tumour bed, pathologists also estimate the percentage of cancer that is in situ, meaning that the cancer cells are confined to the milk ducts or lobules and have not spread into the surrounding tissue.
  4. Lymph node involvement: The number of lymph nodes containing cancer cells (positive lymph nodes) is counted, and the size of the largest cluster of cancer cells in the lymph nodes is also measured.

These features are combined using a standardized formula to calculate the RCB score.

Based on the RCB score, patients are divided into four categories:

  • RCB-0 (pathologic complete response): No residual invasive cancer is detected in the breast or lymph nodes.
  • RCB-I (minimal burden): Very little residual cancer is present.
  • RCB-II (moderate burden): A moderate amount of cancer remains.
  • RCB-III (extensive burden): A large amount of cancer remains in the breast or lymph nodes.

The RCB classification helps predict a patient’s likelihood of staying cancer-free after treatment. Patients with an RCB-0 classification typically have the best outcomes, with the highest chances of long-term survival without recurrence. As the RCB category increases from RCB-I to RCB-III, the risk of cancer recurrence increases, which may prompt additional treatments to reduce this risk.

Pathologic stage for secretory carcinoma of the breast

The pathologic staging system for secretory carcinoma of the breast helps doctors understand how far the cancer has spread and plan the best treatment. The system mainly uses the TNM staging, which stands for Tumor, Nodes, and Metastasis. Early-stage cancers (like T1 or N0) might only require surgery and possibly radiation, while more advanced stages (like T3 or N3) may need a combination of surgery, radiation, chemotherapy, and targeted therapies. Proper staging ensures that patients receive the most effective treatments based on the extent of their disease, which can improve survival rates and quality of life.

Tumour stage (pT)

This feature examines the size and extent of the breast tumour. The tumour is measured in centimetres, and its growth beyond the breast tissue is assessed.

T0: No evidence of primary tumour. This means no tumour can be found in the breast.

T1: The tumour is 2 centimetres or smaller in greatest dimension. This stage is further subdivided into:

  • T1mi: Tumour is 1 millimeter or smaller.
  • T1a: Tumour is larger than 1 millimeter but not larger than 5 millimeters.
  • T1b: Tumour is larger than 5 millimeters but not larger than 10 millimeters.
  • T1c: Tumour is larger than 10 millimeters but not over 20 millimeters.

T2: The tumour is larger than 2 centimetres but not larger than 5 centimetres.

T3: The tumour is larger than 5 centimetres.

T4: The tumour has spread to the chest wall or skin, regardless of its size. This stage is further subdivided into:

  • T4a: Tumour has invaded the chest wall.
  • T4b: Tumour has spread to the skin, causing ulcers or swelling.
  • T4c: Both T4a and T4b are present.
  • T4d: Inflammatory breast cancer, characterized by redness and swelling of the breast skin.

Nodal stage (pN)

This feature examines if the cancer has spread to the nearby lymph nodes, which are small, bean-shaped structures found throughout the body.

N0: No cancer is found in the nearby lymph nodes.

N0(i+): Isolated tumour cells only.

N1: Cancer has spread to 1 to 3 axillary lymph nodes (under the arm).

  • N1mi: Micrometastases only.
  • N1a: Metastases in 1-3 axillary lymph nodes, at least one metastasis larger than 2.0 mm.
  • N1b: Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs

N2: Cancer has spread to:

  • N2a: 4 to 9 axillary lymph nodes.
  • N2b: Internal mammary lymph nodes without involvement of axillary lymph nodes.

N3: Cancer has spread to:

  • N3a: 10 or more axillary lymph nodes or two infraclavicular lymph nodes (below the collarbone).
  • N3b: Internal mammary lymph nodes and axillary lymph nodes.
  • N3c: Supraclavicular lymph nodes (above the collarbone).

What is the prognosis for secretory carcinoma?

Most patients diagnosed with secretory carcinoma have an excellent prognosis, especially when the tumor is diagnosed early. The cancer tends to grow slowly and rarely spreads to other parts of the body. Even when cancer is found in nearby lymph nodes, most patients do well with treatment.

The 5-year survival rate is over 90%, and many people live much longer without recurrence. However, in rare cases, especially in older adults, the cancer can come back many years after treatment. For this reason, regular follow-up is important.

How is secretory carcinoma treated?

Surgery is the main treatment for secretory carcinoma. This may involve removing just the tumor (lumpectomy) or removing the entire breast (mastectomy), depending on the size and location of the tumor.

If the cancer has spread to lymph nodes, your doctor may recommend additional treatment such as radiation therapy or chemotherapy. In some cases, especially when the ETV6-NTRK3 gene fusion is found, targeted therapy using medications that block this abnormal gene may be recommended. These drugs, called TRK inhibitors, have shown promising results in treating secretory carcinoma.

Questions to ask your doctor

  • What did my pathology report show about the type and grade of cancer?

  • Was the tumor completely removed?

  • Did the cancer spread to any lymph nodes?

  • Does my tumor have the ETV6-NTRK3 gene fusion?

  • Am I a candidate for targeted therapy or clinical trials?

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