Breast Cancer (FL INITIAL Autonomous Practice- -Differential Diagnosis)

Non-modifiable risk factors for breast cancer include the following (CDC, 2024a; Casaubon et al., 2021):

• Genetic Mutations: Genetic mutations increase a woman's risk of developing breast cancer. Specifically, those with BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) are at a much higher risk of developing breast cancer; this risk is called a hereditary predisposition. BRCA1 and BRCA2 genes cause up to 10% of all breast cancer diagnoses and over 50% of inherited genetic risk diagnoses.
• Reproductive History: When women are exposed to hormones for more extended periods of time, they are at an increased risk of developing breast cancer. Girls who start their periods before age 12 and women who begin menopause after 55 years old are at an increased risk of breast cancer.
• Personal and Family History: Women with a personal or family history of breast cancer have an increased risk of this diagnosis. Women who have a first-degree relative (mother, sister, or daughter) with breast cancer have a much higher chance of developing this disease. Women who have multiple relatives on both maternal and paternal sides with breast cancer should be screened regularly. Those who have had breast cancer once may develop it a second time.
• Radiation Therapy: Receiving radiation therapy places women at a higher risk of developing breast cancer, especially if the woman is 30 years old and younger and receives radiation to the chest.
• Diethylstilbestrol (DES): Between 1940 and 1970, many women were given DES to prevent miscarriage. Women who took DES may develop breast cancer later in life. Children whose mothers took DES while pregnant may also be at risk.

Modifiable risk factors for breast cancer include the following (CDC, 2024a; Casaubon et al., 2021):

• Exercise: Women who do not get the recommended amount of weekly physical activity are at an increased risk of breast cancer.
• Weight: Women considered overweight or obese are at a higher risk of being diagnosed with breast cancer.
• Hormone Therapy: Estrogen and progesterone, hormone replacement therapy, are sometimes taken during menopause. If these medications are taken longer than five years, the risk of breast cancer is increased. Some contraceptives can also contribute to this risk.
• Reproduction: There are many risk factors concerning reproduction that are associated with the development of breast cancer. Women wanting to become pregnant are advised to do so before they are 30 years old. They are also advised to breastfeed if possible.
• Alcohol: The more alcohol a woman consumes over her lifetime, the greater the chance of being diagnosed with breast cancer.

Mammograms use low-dose X-rays to examine the breasts. For a mammogram to be performed, a patient stands in front of a machine while the breast is placed between two plastic plates, and then images are taken.

Breast tomosynthesis is a 3D version of the mammogram that takes pictures of the breasts from various angles to create a 3D image.

Contrast-enhanced digital mammography (CEDM) combines digital mammography with contrast dye. Breast tumors absorb the dye and are highlighted on imaging.

With breast magnetic resonance imaging (MRI), radio waves and a magnet create detailed breast images.

Sound waves create pictures when an ultrasound is performed on the breast. A probe is placed on the breast that produces sound waves; these waves are transformed into images.

Clinical breast exams are performed by trained professionals who look for any signs of breast cancer.

Providers should inquire about the relevant history of the patient with a breast mass. Besides characteristics of the mass (pain, duration, redness, swelling, etc.), other important factors include diet and medications, family history, medical and social history, and personal characteristics.

Factors such as current medications, history of hormone treatments, breast surgeries or recent trauma, lactation status, and smoking are essential aspects to consider. Further examinations and diagnostics are sometimes warranted.

Fine needle aspirations (FNAs) are usually performed if the provider feels the mass/lump may be a cyst with fluid around it (American Cancer Society, 2022b). A hollow, thin needle aspirates fluid and breast tissue from the area of concern. If a biopsy is required, the needle can be used as a guide for the provider.

Two biopsies are typically used when breast cancer is of concern. Core-needle biopsy (CNB) uses a larger hollow needle guided by diagnostics (MRI, ultrasounds) to sample the area of concern. Excisional biopsy, most often used in breast cancer cases, is performed in the operating room, and the entire mass/lesion is removed.

Before biopsies occur, a mammogram is performed. Findings from the mammogram are reported using the Breast Imaging Reporting and Diagnostic System (BIRADS) (American Cancer Society, 2022b; Castro et al., 2017).

The most common cause of benign lumps in the breast is fibroadenomas (Stachs et al., 2019). They are usually painless, soft, round, with a rubber-like feel, can be easily moved, and usually do not cause pain. They are typically found in women between the ages of 20-30.

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Fibroadenoma

Fibrocystic changes often occur due to a hormone fluctuation, most commonly seen with a menstrual cycle. These changes cause lumps to increase in size near the cycle time and can cause mild tenderness (Stachs et al., 2019).

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Fibrocystic Breast Changes

Papillomas are small wart-like growths that form near the nipple and can cause bleeding. These benign growths are often seen in females aged 30-50 (Stachs et al., 2019).

Necrosis occurs when there is trauma to the breast. Fat in the breast forms into a small lump or mass that is often painless. They may disappear over time and usually do not cause problems (Stachs et al., 2019).

Lobular carcinoma in situ (LCIS) is a rare form of neoplasia that develops in the milk glands. Most often, it is painless with no symptoms. In rare cases, women may notice a lump that was not there before. It is usually not seen on a mammogram and requires a biopsy for diagnosis. As this neoplasia is not considered cancerous, no treatment is performed. It places a patient at a higher risk of developing breast cancer.

The most common form of breast cancer diagnosed is invasive ductal carcinoma (IDC) (Cleveland Clinic, 2024). It makes up over 80% of breast cancers. This form of cancer arises in the milk glands but invades surrounding tissue, meaning metastasis is more likely to be seen in this cancer. Survival rates are high when it is caught early. It is often detected on a mammogram and can be visibly seen on an MRI or ultrasound. Treating IDC involves surgery, lumpectomy or mastectomy, followed by chemotherapy or radiation (Cleveland Clinic, 2024).

The second most common type of breast cancer diagnosed is invasive lobular carcinoma (Luveta et al., 2020). It is commonly seen in post-menopausal women who have received hormone therapy. It can be clinically challenging to diagnose as there may be no presenting masses/lumps, and its margin is typically poorly defined. Breast-conserving surgery (BCS) is often used to treat this cancer along with adjuvant therapies, dependent on metastasis (Luveta et al., 2020).

It is estimated that 1 in 5 women diagnosed with breast cancer will be diagnosed with ductal carcinoma in situ (DCIS) (American Cancer Society, 2021a). This form of breast cancer is very curable and is considered non-invasive. It is rated as a Stage 0 breast cancer. It usually does not metastasize to other parts of the body, increasing the success of treating it. If the tumor spreads out of the breast duct, there is potential metastasis. To treat DCIS, women often elect to have BCS or a simple mastectomy. If BCS is used, radiation is usually performed after the surgery (American Cancer Society, 2021b).

Inflammatory breast cancer (IBC) is the rarest form of breast cancer and comprises only 5% of diagnoses (Moulder-Thompson & Mitri, 2016). With IBC, swelling and redness (inflammation) are caused by cells and vessels in the breast blocked by a tumor. It is also challenging to diagnose as there is no lump, which is often not seen on a mammogram. IBC is more common in younger Caucasian females who are overweight or obese. It can be an aggressive form of breast cancer as it can grow and metastasize at a quick rate, decreasing the success rate of treatment (Moulder-Thompson & Mitri, 2016).

Paget's breast disease is a rare form of breast cancer that accounts for up to 3% of cases (Dubar et al., 2017). This form of breast cancer is generally associated with invasive glandular carcinoma in nearly 90% of cases. The presentation includes inflammation, bleeding, and/or nipple erosion. There are no identified risk factors. However, it usually affects post-menopausal women (Dubar et al., 2017).

Triple-negative breast cancer (TNBC) accounts for up to 15% of breast cancer diagnoses. Patients more at risk of developing TNBC include Black women under the age of 40 who have the BRCA1 mutation (American Cancer Society, 2023). This type of cancer is considered aggressive and is a product of impaired expression of estrogen and progesterone receptors and human growth factor receptor 2 (Almansour, 2022). Symptoms of TNBC are similar to other forms of breast cancer.

Triple-positive breast cancer (TPBC) is another aggressive form of breast cancer and accounts for around 10% of all breast cancer diagnoses. With TPBC, there is increased expression of progesterone, estrogen, and human epidermal growth factor receptor 2. Risk factors for this type of cancer are unknown. Symptoms of TPBC are similar to other forms of breast cancer (MD Anderson Cancer Center, 2023b).

Radical mastectomies were commonly used in the past but have decreased in incidence in the last few decades. It is most often used when the breast cancer is in the chest wall. The lymph nodes in the armpit, the muscles in the chest wall, and the entire breast are removed during a radical mastectomy. This procedure almost always removes axillary and supraclavicular lymph nodes. The surgery generally is performed under general anesthesia and usually takes a few hours. A diagonal or horizontal incision is made to reach all of these areas.

A modified radical mastectomy removes the entire breast (skin, nipple, areola, etc.) and most of the axillary lymph nodes. The chest wall or pectoralis muscle is spared in this surgery. It is often indicated when there is a focally positive margin and the tumor is larger than 5 cm. The most common complications seen with a modified radical mastectomy include infection and skin necrosis.

A simple mastectomy, also known as a total mastectomy, removes all of the breast tissue, including the areola, nipple, and skin around the breast (American College of Surgeons, n.d.). This procedure was developed based on the idea that a radical mastectomy was not always necessary.

With a nipple-sparing mastectomy, the tissue that is contained within the skin around the breast is removed. The nipple, healthy breast skin, and areola are left intact (Cedars Sinai, n.d.).

BCS is often used in breast cancer and is commonly referred to as a lumpectomy or partial mastectomy (Cleveland Clinic, 2023b). A lumpectomy removes cancer in the breast and a small sample of healthy tissue. A lumpectomy is used to preserve as much of the breast as possible. Two procedures associated with a lumpectomy include wedge resection and quadrantectomy (Cleveland Clinic, 2023b). 

• A wedge resection removes a larger portion or wedge of breast tissue.
• With a quadrantectomy, only a quarter of the breast is removed.
• A portion of healthy tissue is removed to be examined to ensure the breast cancer has not invaded any surrounding tissue.
• A sentinel lymph node biopsy is often performed alongside a lumpectomy to ensure the cancer is not in the lymph nodes.

Chemotherapy is often used alongside surgery when treating breast cancer. There are two classes that chemotherapy can be divided into.

Neoadjuvant chemotherapy is administered before surgery (Rocky peterain Cancer Centers, 2021). The goal is to make surgery easier by shrinking the tumor and decreasing the chance of metastasis before the surgery. This form of chemotherapy is often started quickly after diagnosis.

Adjuvant chemotherapy is administered after surgery (Rocky Mountain Cancer Centers, 2021). The goal is to kill any cancer cells that are left after surgery. It also decreases the chances of breast cancer coming back. Treatment with adjuvant chemotherapy usually occurs within 30 days after surgery (Rocky Mountain Cancer Centers, 2021).

Radiation therapy is a standard adjuvant treatment used for breast cancer (American Cancer Society, 2021b). High-energy particles and rays are used to destroy cancer. Sometimes, radiation is used after BCS to prevent reoccurrence. Other times, it is used after a mastectomy or if there is metastasis. Brachytherapy and external beam radiation therapy (EBRT) are the two most common forms of radiation (American Cancer Society, 2021b).

There are different stages of radiation used to treat breast cancer. Whole breast radiation means the entire breast receives radiation. Hypofractionated radiation therapy is where the whole breast receives radiation, but it is in larger doses. This way, women only receive 3-4 weeks of radiation instead of receiving it for more extended periods of time (American Cancer Society, 2021b).

Hormone therapy is used in women to prevent breast cancer from spreading and re-occurring (American Cancer Society, 2024). It can help treat metastasized breast cancer. Selective estrogen receptor modulators prevent hormones from attaching themselves to cancer cells. These medications can also be used to avoid hormone production in the ovaries.

One of the more common hormone therapies used is called aromatase inhibitors. This class of medications is more effective when used as an adjuvant treatment with chemotherapy. Anastrozole, letrozole, and exemestane are common aromatase inhibitors used in the treatment of certain forms of breast cancer (Peters & Tadi, 2023).

Another option for breast cancer treatment involves immunotherapy, which utilizes the patient's own immune system to help destroy the cancer cells. Targeted antibody treatments include Pertuzumab (Perjeta®), Margetuximab-cmkb (Margenza™), and Sacituzumab govitecan (Trodelvy®). Popular immunomodulators include Pembrolizumab (Keytruda®) and Dostarlimab (Jemperli) (Cancer Research Institute, n.d.).

Many breast cancer treatments cause patients to experience side effects. Chemotherapy side effects include hair loss, fatigue, gastrointestinal upset that includes nausea and vomiting, and a compromised immune system. Longer-term side effects include heart damage and infertility (Mayo Clinic, 2024). Radiation therapy side effects can also be categorized between short-term and long-term. Short-term side effects of radiation include fatigue and skin irritation. Increased skin irritation, specifically skin changes around the breast, occurs later in the radiation regimen (MD Anderson Cancer Center, 2023a). Side effects associated with hormone therapy include an increased risk of blood clots, stroke, bone loss, headaches, gastrointestinal upset, and fatigue (National Cancer Institute, 2022). There are also various side effects associated with immunotherapy; they include fatigue, gastrointestinal upset, and skin rashes. Infusion reactions may also occur, including symptoms such as fever, dizziness, and flushing. Patients may also experience autoimmune reactions where the patient's immune system attacks their body (Cleveland Clinic, 2023a).

Typically, breast cancer affects women. However, there are incidences of men being diagnosed with breast cancer. In fact, 1 out of every 100 men will be diagnosed with breast cancer (CDC, 2024b). DCIS, invasive lobular carcinoma, and invasive ductal carcinoma are the three forms of breast cancer most commonly diagnosed in men.

Risk factors for breast cancer in men include age (over 50), genetic mutations, obesity, liver disease, family history of breast cancer, Klinefelter syndrome, and previous trauma to the testicles (CDC, 2024b).

In men, breast cancer symptoms include a mass or lump near or on the breast, swelling, irritation, redness or flakiness of the skin, and nipple discharge (CDC, 2024b).

The breast undergoes many changes while a woman is pregnant (Lee & Bae, 2020). Lactation can also cause hormonal fluctuations. These changes can make diagnosing pregnancy-associated breast cancer (PABC) difficult (Lee & Bae, 2020). Breast enlargement is common in pregnancy and can decrease a mammogram's sensitivity by up to 90%. Pregnant patients with a palpable mass should alert their provider of the mass immediately. Mammograms are safe in pregnancy if warranted. However, ultrasounds are the best diagnostic tool to use in pregnancy as there is no exposure to radiation, and it is more sensitive in identifying a mass in a pregnant woman's breast.

Some benign masses and lumps may cause problems in pregnancy (Lee & Bae, 2020). A galactocele is a milk-filled cyst that blocks a lactating duct. It is most common in women who recently stopped lactating. A lactating adenoma develops due to the hormonal shift seen in pregnancy. It is closely related to fibroadenoma and often goes away after the woman gives birth and is no longer lactating (Lee & Bae, 2020).

PABC is a severe diagnosis that occurs in pregnant women or within one year of delivery. It usually starts as a painless mass in the breast. It is often mistaken for regular breast changes that occur with pregnancy and can be difficult to see on diagnostic imaging, leading to a delay in diagnosis. Usually, when it has been found, it has already been growing for a long time, and 50% of women have metastasis to the lymph nodes (Lee & Bae, 2020). Ultrasonography is the best option for visualizing PABC (Lee and Bae, 2020).

There are no strong indicators that breast implants cause breast cancer. However, Allergan's manufactured textured breast implants have been linked to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). BIA-ALCL usually develops in the tissue or fluid around the implant (U.S. Food and Drug Administration [FDA], 2019).