Metastatic Secretory Carcinoma Of The Breast: Unraveling The Enigma

Metastatic secretory carcinoma of the breast: an overview

Breast cancer is a complex and diverse group of diseases, and within its spectrum lies a rare and enigmatic subtype known as Metastatic Secretory Carcinoma (MSC) of the breast. MSC is characterized by its unique histological features and clinical behaviour, setting it apart from more common forms of breast cancer. 

In this comprehensive article, we will delve into the intricacies of MSC, exploring its epidemiology, pathogenesis, clinical presentation, diagnostic methods, treatment options, and recent advancements in research. Whether you're a medical professional or a concerned individual seeking to understand this rare breast cancer subtype, this article aims to provide a clear and informative overview, bridging the gap between scientific knowledge and layman's understanding.

Epidemiology and prevalence

Metastatic secretory carcinoma: a rare find

While breast cancer is one of the most prevalent cancers in people assigned female at birth (people AFAB) worldwide, Metastatic Secretory Carcinoma is exceedingly rare, accounting for a minuscule fraction of all breast cancer cases. To put this into perspective, the World Cancer Research Fund estimated that breast cancer accounted for 2.3 million new cases globally in 2020. In contrast, MSC represents only a small fraction of these cases. MSC tends to affect individuals at a younger age compared to more common breast cancer types, often occurring in people AFAB  in their 20s to 40s, although cases in people assigned male at birth (people AMAB) have also been reported.

Genetic factors

Genetic factors play a significant role in the development of Metastatic Secretory Carcinoma (MSC) of the breast. The most well-established genetic alteration associated with MSC is the ETV6-NTRK3 fusion gene. This fusion gene arises from a chromosomal translocation event, where portions of the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15 are rearranged, resulting in the abnormal fusion of these genes. The ETV6-NTRK3 fusion gene is considered a driver mutation in MSC, as it leads to the activation of signalling pathways that promote uncontrolled cell growth and tumour formation.

In addition to the ETV6-NTRK3 fusion gene, other genetic alterations may contribute to the development and progression of MSC. Research is ongoing to identify additional mutations or genetic variations that may play a role in the disease.

Hormonal influences

Hormonal influences have been explored in the context of Metastatic Secretory Carcinoma, particularly in cases where the tumour is hormone receptor-positive. Hormone receptor-positive breast cancers are influenced by the hormones estrogen and progesterone. In such cases, these hormones can stimulate the growth of cancer cells.

However, it's important to note that MSC often exhibits different hormone receptor status compared to more common types of breast cancer. MSC is more likely to be hormone receptor-negative, meaning that hormonal therapies like tamoxifen or aromatase inhibitors, which are commonly used for hormone receptor-positive breast cancer, may not be effective. This distinction highlights the unique biological characteristics of MSC and the importance of tailored treatment approaches.

Environmental factors

While genetic factors are fundamental in the development of MSC, environmental factors also play a role, although their precise contributions are still being studied. Some environmental factors that have been associated with an increased risk of breast cancer in general, which may potentially apply to MSC, include:

• Radiation Exposure: Exposure to ionizing radiation, especially at a young age, is a known risk factor for breast cancer. This includes radiation therapy used for other medical conditions.
• Lifestyle Factors: Factors such as diet, physical activity, alcohol consumption, and smoking have been studied in relation to breast cancer risk. Maintaining a healthy lifestyle may contribute to reducing the risk of all breast cancer subtypes, including MSC.
• Reproductive Factors: Delayed childbearing, nulliparity (not having children), and late menopause are reproductive factors that have been associated with an increased risk of breast cancer in general.
• Hormone Replacement Therapy (HRT): The use of hormone replacement therapy, particularly combined estrogen and progestin therapy, has been linked to an elevated risk of breast cancer. This may also apply to MSC, although further research is needed to establish a direct link.
• Chemical Exposures: Exposure to certain chemicals and environmental pollutants has been explored as potential risk factors for breast cancer. However, the specific chemicals or pollutants that may be associated with MSC remain unclear.
• Other Risk Factors

In addition to genetic, hormonal, and environmental factors, several other risk factors may influence the development of Metastatic Secretory Carcinoma of the breast. These include:

• Age: MSC tends to occur in younger individuals, often in their 20s to 40s, although it can affect people of any age. Age can be a significant factor in the risk assessment.
• Gender: While breast cancer is more commonly associated with people assigned female at birth (people AFAB), MSC has been reported in people assigned male at birth (people AMAB) as well. It's important to consider gender as a risk factor when evaluating cases of MSC.
• Family History: A family history of breast cancer, especially if it involves specific genetic mutations like BRCA1 or BRCA2, can increase the risk of developing MSC. Genetic counselling and testing may be recommended for individuals with a family history of breast cancer.
• Race and Ethnicity: There may be variations in the incidence and characteristics of MSC among different racial and ethnic groups. Research in this area is ongoing to better understand these patterns.
• Breast Health: Conditions such as atypical hyperplasia or lobular carcinoma in situ (LCIS) can increase the risk of developing breast cancer, including MSC. Regular breast screenings and follow-up care are crucial for individuals with these conditions.

It's important to note that while these risk factors may increase the likelihood of developing MSC, they do not guarantee its development. Many individuals with one or more risk factors never develop MSC, while others with no known risk factors may still be affected. The interplay of genetic, hormonal, environmental, and other factors in the context of MSC remains a subject of ongoing research to further understand and mitigate the risk of this rare breast cancer subtype.

Understanding the molecular underpinnings of metastatic secretory carcinoma

Pathology and histology

Metastatic Secretory Carcinoma (MSC) of the breast is characterized by distinctive histological features that set it apart from more common breast cancer subtypes. Pathology and histology are crucial in diagnosing and understanding MSC.

Tumor growth and spread

Metastatic Secretory Carcinoma typically exhibits a slow-growing and indolent course, which is often in contrast to more aggressive forms of breast cancer. This slower growth pattern contributes to its favourable prognosis when diagnosed and treated early.

MSC is known for its propensity to remain confined to the breast for an extended period, which is why it is often diagnosed at an early stage. However, the risk of metastasis, where cancer spreads to distant organs or lymph nodes, remains a concern. The presence of metastasis can significantly impact prognosis and treatment decisions.

Microscopic features and staining patterns

Microscopic examination of MSC reveals several distinctive features:

• Secretory Structures: MSC is characterised by the presence of secretory structures within the tumour. These structures, known as secretory lumina, are filled with eosinophilic secretions and can be observed under a microscope.
• Papillary Growth Pattern: MSC often exhibits a papillary growth pattern, where tumour cells form finger-like projections into the secretory lumina. This papillary architecture is a hallmark of MSC.
• Mucin Production: Mucin is a gel-like substance that is produced by some cancer cells. MSC is known for its mucin-producing properties, which contribute to the secretory appearance of the tumour.
• Staining Patterns: Immunohistochemistry plays a crucial role in the diagnosis of MSC. Specific staining patterns are used to confirm the presence of the ETV6-NTRK3 fusion gene and differentiate MSC from other breast cancer subtypes. Immunohistochemical markers such as ETV6, NTRK3, and mammaglobin (a protein that if highly expressed works as a biomarker for breast cancer) are used to detect the fusion protein and confirm the diagnosis.

Immunohistochemistry for MSC typically reveals positive staining for ETV6 and NTRK3, indicating the presence of the fusion gene. In contrast, markers associated with other breast cancer subtypes, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), are often negative or expressed at low levels in MSC. This distinct staining pattern is a critical diagnostic feature.

In summary, the pathology and histology of Metastatic Secretory Carcinoma of the breast are characterized by unique cellular features, slow tumour growth, and distinctive microscopic and staining patterns. These characteristics play a pivotal role in the accurate diagnosis and differentiation of MSC from other breast cancer subtypes, guiding treatment decisions and prognosis assessment.

Clinical presentation and symptoms

Metastatic Secretory Carcinoma (MSC) of the breast often presents with clinical features that may differ from those associated with more common breast cancer subtypes. Recognizing the signs and symptoms is crucial for early diagnosis and prompt intervention.

Signs and symptoms

• Painless Breast Lump: One of the most common signs of MSC is the presence of a painless lump or mass in the breast. Patients or healthcare providers may notice a palpable lump during breast self-examinations or routine clinical breast exams. The lump is often firm or nodular in consistency.
• Axillary (Armpit) Lymph Node Enlargement: In some cases, MSC can lead to the enlargement of lymph nodes in the axillary (armpit) region. This may be discovered during a physical examination or when patients notice swollen lymph nodes.
• Nipple Discharge: MSC may occasionally be associated with nipple discharge, which can range from clear or bloody to a mucous-like consistency. Nipple discharge may occur spontaneously or upon manipulation of the breast.
• Skin Changes: Changes in the skin overlying the breast affected by MSC are less common but can occur. These changes may include redness, dimpling, or thickening of the skin, resembling the symptoms of more aggressive breast cancers.
• Breast Discomfort: Some individuals with MSC may experience breast discomfort, tenderness, or a feeling of fullness in the affected breast. This discomfort is typically not associated with pain.

Diagnostic methods and tools

Accurate and timely diagnosis of MSC is essential for appropriate management. Healthcare providers utilise  a combination of diagnostic methods and tools to confirm the presence of MSC:

• Imaging Studies: Various imaging techniques are employed to visualise the breast lump and assess its characteristics. Mammography, ultrasound, and magnetic resonance imaging (MRI) are commonly used to evaluate the extent of the tumour and its relationship to surrounding tissues.
• Biopsy: A biopsy is the gold standard for diagnosing MSC. During a biopsy, a tissue sample is collected from the breast lump for histopathological examination. Fine-needle aspiration, core needle biopsy, or surgical biopsy may be used to obtain the tissue sample.
• Immunohistochemistry (IHC): Immunohistochemistry is a critical component of the diagnostic process for MSC. Specific antibodies are used to stain the tissue samples, allowing pathologists to assess the expression of various markers, including ETV6, NTRK3, and mammaglobin. Positive staining for ETV6 and NTRK3 confirms the presence of the ETV6-NTRK3 fusion gene, a hallmark of MSC.
• Molecular Testing: Molecular testing, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), may be performed to detect the ETV6-NTRK3 fusion gene directly. This genetic confirmation is an essential step in diagnosing MSC.

Differential diagnosis

Several breast conditions and cancers can mimic the clinical presentation of MSC, making a thorough differential diagnosis critical to ensure accurate management. Conditions that may be considered in the differential diagnosis of MSC include:

• Invasive Ductal Carcinoma (IDC): IDC is the most common type of breast cancer and can present with a breast lump and changes in the breast tissue. Distinguishing IDC from MSC relies on histopathological and immunohistochemical analysis.
• Fibroadenoma: Fibroadenomas are benign breast tumours that can sometimes resemble breast cancer on imaging. Biopsy and pathology can differentiate them from MSC.
• Papillary Carcinoma: Papillary carcinoma of the breast can have a papillary growth pattern similar to MSC. However, immunohistochemistry can help distinguish the two.
• Cystic Lesions: Cysts filled with fluid can also cause breast lumps and may be mistaken for malignancy. Imaging and fluid aspiration can help differentiate cystic lesions from MSC.
• Inflammatory Breast Cancer: This aggressive subtype of breast cancer can lead to skin changes, redness, and swelling that mimic some symptoms of MSC. Biopsy and molecular testing are essential for diagnosis.

Accurate diagnosis requires a multidisciplinary approach involving clinical evaluation, imaging studies, histopathological examination, and immunohistochemistry. It is crucial to differentiate MSC from other breast conditions to guide appropriate treatment decisions and ensure the best possible outcome for the patient.

Prognosis and staging

Prognosis and staging are essential aspects of managing Metastatic Secretory Carcinoma (MSC) of the breast. Staging helps determine the extent of the disease, while prognostic factors provide insights into the likely course of the disease and guide treatment decisions.

Staging systems

Staging in cancer refers to the process of determining the extent of the disease based on various factors, including tumour size, lymph node involvement, and the presence of distant metastasis. Staging helps healthcare providers understand the severity of the cancer and plan appropriate treatment. For MSC, the American Joint Committee on Cancer (AJCC) TNM staging system is commonly used:

• Tumor (T): This component assesses the size of the primary tumour and its extent within the breast tissue. T0 indicates no evidence of a primary tumour, while higher numbers (T1, T2, T3, and T4) denote increasing tumour size or extension.
• Lymph Nodes (N): The N category evaluates the presence and extent of lymph node involvement. N0 indicates no regional lymph node involvement, while N1, N2, and N3 signify increasing numbers or sizes of affected lymph nodes.
• Metastasis (M): The M category assesses whether the cancer has spread to distant organs or tissues. M0 indicates no distant metastasis, while M1 indicates the presence of distant metastasis.

MSC is known for its relatively indolent course and the tendency to remain localized within the breast for an extended period. Therefore, it is often diagnosed at an earlier stage (e.g., T1 or T2, N0) when the tumour is confined to the breast and has not spread to lymph nodes or distant sites. This early stage of diagnosis contributes to the generally favourable prognosis associated with MSC.

Prognostic factors

Prognostic factors are characteristics or variables that provide insights into the likely course of the disease and help predict outcomes. In the context of MSC, several prognostic factors are considered:

• Tumour Size: Smaller tumour sizes at diagnosis are associated with a better prognosis. Tumours that are detected and treated early tend to have more favourable outcomes.
• Lymph Node Involvement: The absence of lymph node involvement (N0) is a positive prognostic factor. Lymph node involvement (N1, N2, N3) indicates a higher risk of disease progression.
• Hormone Receptor Status: While MSC is often hormone receptor-negative, hormone receptor-positive status can influence treatment decisions and prognosis. Hormone receptor-positive tumours may respond to hormone therapy.
• Metastasis: The presence of distant metastasis (M1) significantly impacts prognosis, typically indicating a more advanced stage of the disease with a less favourable outlook.
• Genetic Characteristics: The presence of the ETV6-NTRK3 fusion gene, which is a defining genetic alteration in MSC, can influence prognosis and treatment options. Targeted therapies that inhibit this fusion protein may offer improved outcomes.

Survival rates and outcomes

Survival rates for MSC are generally more favourable compared to more aggressive breast cancer subtypes. However, the exact survival rates can vary based on factors such as the stage at diagnosis, the presence of metastasis, and the effectiveness of treatment. It's important to note that survival rates are estimates and do not predict individual outcomes.

While specific survival rate data for MSC may be limited due to its rarity, patients with early-stage MSC typically have a good prognosis with high survival rates. Those with advanced disease or metastasis may face a more challenging prognosis, emphasising the importance of early detection and intervention.

Treatment approaches for MSC are tailored to the individual patient's circumstances, including the stage of the disease, hormone receptor status, and the presence of genetic alterations. Multidisciplinary care teams, including oncologists, surgeons, pathologists, and genetic counsellors, collaborate to develop personalised treatment plans aimed at optimising outcomes and quality of life for individuals with MSC.

Overall, the prognosis and outcomes for Metastatic Secretory Carcinoma of the breast are influenced by various factors, with early detection and appropriate treatment playing a pivotal role in improving the likelihood of a favourable outcome. Patients should consult with their healthcare providers to better understand their individual prognosis and treatment options.

Treatment options 

The management of Metastatic Secretory Carcinoma (MSC) of the breast involves a multimodal approach that considers the stage of the disease, the presence of specific genetic alterations, and individual patient factors. Treatment options for MSC aim to control the tumour, manage symptoms, and improve the overall quality of life. Here, we delve into the various treatment modalities:

• Lumpectomy: In cases where MSC is detected at an early stage and the tumour is relatively small, a lumpectomy may be performed. This procedure involves the removal of the tumour and a small margin of surrounding healthy tissue, preserving as much of the breast as possible.
• Mastectomy: In some cases, particularly when the tumour is large or extensive, a mastectomy may be recommended. During a mastectomy, the entire breast is removed, which may also involve the removal of nearby lymph nodes (axillary dissection) if they are affected.
• Radiation Therapy: Radiation therapy may be used following surgery (lumpectomy or mastectomy) to target any remaining cancer cells in the breast or chest wall. It can help reduce the risk of local recurrence. Radiation is also employed for palliative purposes to alleviate symptoms in cases of advanced or metastatic disease.
• Chemotherapy: In cases where MSC has advanced or spread to distant organs, chemotherapy may be recommended. Chemotherapy involves the administration of drugs that target and kill rapidly dividing cancer cells throughout the body. The choice of chemotherapy agents and regimens will depend on the individual patient's circumstances and the stage of the disease.
• Hormonal Therapy: Hormone receptor status plays a role in treatment decisions for MSC. While MSC is often hormone receptor-negative, in some cases, it may be hormone receptor-positive. Hormone therapy, such as tamoxifen or aromatase inhibitors, may be considered for hormone receptor-positive MSC. These medications work by blocking the effects of estrogen, which can stimulate the growth of hormone receptor-positive cancer cells.
• Targeted Therapy: The presence of the ETV6-NTRK3 fusion gene in MSC has opened up opportunities for targeted therapies. Drugs that specifically inhibit NTRK fusion proteins, such as larotrectinib and entrectinib, have shown promise in clinical trials. Targeted therapies offer a more tailored approach to treatment, aiming to block the specific molecular drivers of MSC.
• Immunotherapy: Immunotherapy is an emerging field in cancer treatment that harnesses the body's immune system to target and destroy cancer cells. While immunotherapy has shown remarkable success in certain cancers, its role in MSC is still being explored. Clinical trials may investigate the potential benefits of immunotherapy in the treatment of MSC. 

It's essential to emphasize that the choice of treatment for MSC depends on several factors, including the stage of the disease, the presence of genetic alterations, hormone receptor status, and the patient's overall health. Treatment plans are often developed through a collaborative effort involving oncologists, surgeons, pathologists, and other healthcare professionals. 

Additionally, patients with advanced or metastatic MSC may receive palliative care to manage symptoms, improve quality of life, and provide emotional and psychological support. The treatment approach is individualized to address the unique circumstances of each patient, to optimize outcomes and enhance their well-being.

Management of metastatic disease

Palliative care

Palliative care is a specialised medical approach focused on providing relief from the symptoms and suffering associated with advanced or metastatic cancer. It is not limited to end-of-life care but is integrated into the overall management plan to improve the patient's well-being.

Palliative care teams, consisting of healthcare professionals such as palliative care physicians, nurses, and social workers, work alongside the oncology team to address the patient's physical, emotional, and psychological needs.

The goals of palliative care include pain management, symptom control (such as nausea, fatigue, and shortness of breath), emotional support, and assistance with decision-making. Palliative care can help patients and their families navigate the complex challenges of living with metastatic cancer.

Supportive therapies

In addition to palliative care, supportive therapies play a crucial role in managing the symptoms and side effects associated with metastatic disease and its treatment.

Supportive therapies may include pain management through medications, physical therapy to address mobility issues, nutritional support to maintain strength and energy, and psychological counselling to address anxiety, depression, and coping strategies. Integrative therapies like acupuncture, massage, and mindfulness-based practices may also be utilised to enhance the patient's overall well-being and reduce treatment-related discomfort.

Clinical trials and experimental treatments:

Clinical trials are research studies that investigate new treatment approaches, therapies, or medications for cancer. They are essential for advancing our understanding of cancer and improving treatment outcomes.

Patients with metastatic MSC may be candidates for clinical trials. These trials may involve novel targeted therapies, immunotherapies, or experimental treatments designed to specifically address the genetic and molecular characteristics of the tumour.

Participating in a clinical trial provides patients with access to cutting-edge treatments that may offer potential benefits not available through standard therapies. Patients and their healthcare teams can discuss the possibility of enrolling in clinical trials, considering the patient's specific circumstances, treatment history, and the availability of relevant trials.

It's important to note that the management of metastatic breast cancer, including MSC, is highly individualised. Treatment decisions are made in close collaboration between the patient, oncologists, palliative care specialists, and other healthcare professionals. Patients are encouraged to discuss their treatment goals, preferences, and concerns with their care team to develop a personalised plan that optimises their quality of life and overall well-being.

Additionally, staying informed about the latest advancements in breast cancer research and treatment options is essential, as discoveries may lead to more effective therapies and improved outcomes for individuals with metastatic breast cancer, including those with rare subtypes like MSC.

Summary

Metastatic Secretory Carcinoma of the breast is a rare and unique subtype of breast cancer characterised by its distinct histological features and genetic alterations. While it represents a small fraction of all breast cancer cases, its impact on those affected is significant. Early diagnosis and a multimodal treatment approach that includes surgery, radiation therapy, and targeted therapies can improve outcomes and quality of life for patients with MSC.

As ongoing research sheds light on the molecular mechanisms driving MSC, the future holds promise for more effective and tailored treatment options. For individuals diagnosed with MSC and their healthcare providers, staying informed about the latest developments in research and treatment options is crucial. Together, with continued research and awareness, we can advance our understanding and management of this rare breast cancer subtype, offering hope to those affected by it.