Breast Cancer

Breast cancer generally presents with a palpable mass in the breast in postmenopausal women, histologically showing irregularly shaped cells with increased nuclear-cytoplasmic ratio, while mammographically demonstrating a spiculated mass or calcifications.

Description

Breast cancer is a heterogeneous group of malignancies that originates from the epithelial cells lining the ducts or lobules of the breast. It is the most common cancer in women worldwide and the second most common cause of cancer-related death in women.

Pathogenesis

The pathogenesis of breast cancer is a complex process involving both genetic and environmental factors. At the cellular level, it is marked by the dysregulation of cell proliferation and apoptosis, leading to the progressive accumulation of genetic and epigenetic alterations.

Inherited mutations in the BRCA1 and BRCA2 genes contribute to a significant number of familial breast cancers, though they only represent a small fraction of total cases. These genes are involved in DNA repair, and their mutation leads to genomic instability and increased susceptibility to cancer.

Hormonal factors also play a key role, with oestrogen exposure known to promote the proliferation of breast epithelial cells and potentially induce carcinogenesis. Certain conditions associated with increased lifetime exposure to oestrogen, such as early menarche, late menopause, and hormone replacement therapy, are known risk factors.

Molecular subtyping has revealed distinct subtypes of breast cancer with different pathogenesis, prognosis, and treatment responses. These include Luminal A, Luminal B, HER2-enriched, and triple-negative breast cancers. Luminal cancers are typically estrogen receptor-positive and are further stratified based on human epidermal growth factor receptor 2 (HER2) status and the expression of other genes related to cell proliferation. Triple-negative breast cancers lack estrogen receptors, progesterone receptors, and HER2.

Environmental and lifestyle factors, such as diet, physical activity, and alcohol consumption, can also influence breast cancer risk through complex interactions with genetic and hormonal factors.

Subtypes

Breast cancer has several histological and molecular subtypes. The vast majority are adenocarcinomas (99%).

Histological Subtypes

• Ductal Carcinoma In Situ (DCIS): Non-invasive, carcinoma originating in the milk ducts with intact basement membrane. Also referred to as comedocarcinoma.
• Lobular Carcinoma In Situ (LCIS): Non-invasive, originating in the lobules (milk-producing glands).
• Invasive Ductal Carcinoma (IDC): Originates in the milk duct and invades the surrounding tissue. Most common subtype, accounting for around 70% of all breast cancers.
• Invasive Lobular Carcinoma (ILC): Originates in the lobules and invades the surrounding tissue accounting for about 10% of invasive breast cancers.
• Invasive breast carcinoma of no special type: Most common type of breast cancer (70-80%). It is an infiltrating and malignant proliferation of neoplastic cells in the breast tissues

Special IDC Histological Subtypes

• Tubular Carcinoma: A special type of IDC, resembling small tubes under a microscope. They use oestrogen to support growth. Slow growing and most benign subtype with usually the best prognosis (5-year survival 95-98%). It makes up less than 2% of all breast cancer cases. Usually seen in younger women.
• Mucinous Carcinoma (Colloid): A rare form of IDC. The tumour is formed from abnormal cells that float in pools of mucin. Usually has a better prognosis than more common types of invasive breast cancers. Usually seen in older women.
• Medullary Carcinoma: A rare type of IDC. The tumour is a soft, fleshy mass that resembles a part of the brain called the medulla. Medullary carcinoma is less likely to involve the lymph nodes, is more responsive to treatment, and may have a better prognosis than more common types of breast cancer. Usually seen in younger women.
• Papillary Carcinoma: A rare type of IDC. The tumour forms in thin, small, finger-like projections (papules), much like a sea anemone. It has a better prognosis than invasive ductal or invasive lobular carcinoma.
• Metaplastic Carcinoma: A very rare type of IDC. This type of cancer starts in the glandular tissue of the breast but changes as it grows, becoming more like cells of the skin, bone, or muscle. It tends to grow larger and faster than other types of breast cancer, and it’s often triple-negative.

Molecular Subtypes

Classified based on the presence or absence of receptor proteins that play a role in cell growth; oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).

• Luminal A: ER+ and/or PR+, HER2-, and has low levels of the protein Ki-67. It tends to grow slowly and has the best prognosis. Most common form of invasive breast cancer. Most likely to metastasise to bone.
• Luminal B: ER+ and/or PR+, and either HER2+ or HER2- with high levels of Ki-67. It grows slightly faster than luminal A and the prognosis is slightly worse.
• HER2-enriched: ER-, PR-, and HER2+. It tends to grow faster than luminal cancers and has a worse prognosis, but it responds well to targeted treatments against HER2 (e.g. Herceptin). Second most common form of invasive breast cancer.
• Triple-negative/Basal-Like: ER-, PR-, and HER2-. It tends to grow and spread faster than other types and has a worse prognosis. Tend to occur in younger (premenopausal) black women with BRCA1 mutation.

Genetically, Luminal A and B breast cancers are often hormone receptor-positive. HER2-enriched cancers are commonly associated with overexpression or amplification of the HER2/neu gene. Triple-negative cancers, typically associated with BRCA1 mutations, younger age, and African ancestry.

Epidemiology, Risk Factors & Associations

Breast cancer remains the most common malignancy in women worldwide, constituting approximately 25% of all diagnosed cancer cases. In 2018, an estimated 2.1 million women were newly diagnosed with breast cancer, resulting in 627,000 deaths worldwide. The most important risk factors for breast cancer are female sex and advancing age.

• Age: Risk increases with age, with most invasive breast cancers diagnosed in women over 55. After the age of 30, the incidence of ER-positive cancer increases with age, whereas ER-negative and HER2-positive rates are constant. Risk peaks at 70 to 80 years. Breast cancer is rare under the age of 25.
• Gender: Women are 100 times more likely to develop breast cancer than men. Only 1% of breast cancers occur in men.
• Family history: A family history of breast cancer, particularly in a first-degree relative diagnosed before age 50, increases risk.
• Race: Non-Hispanic white women have the highest incidence. Black women present with more advanced malignancy and have higher mortality.
• Personal history of breast conditions: Previous atypical ductal or lobular hyperplasia (ADH/ALH), lobular carcinoma in situ (LCIS), flat epithelial aplasia, radial scar, intraductal papilloma/atypical papilloma is an intermediate factor. Contralateral breast cancer increases risk.
• Genomic changes: BRCA1 and BRCA2 gene mutations substantially increase risk, conferring a lifetime risk of breast cancer of up to 80%.
• Long-term oestrogen exposure increases risk:
  • Early menarche (< 12 yrs), late menopause (> 55 yrs), having a first child at an older age (> 35 yrs) or nulliparity.
  • Long-term use of hormone replacement therapy (HRT). Oral contraceptives may increase risk (controversial).
  • Post-menopausal obesity due to increased oestrogen production by adipocytes
  • Oophorectomy, breast feeding and hormonal blockade decrease risks.
• Dense breast tissue: Increased breast density can elevate risk and complicate detection.
• Alcohol consumption: Risk elevates with the quantity of alcohol consumed.
• Sedentary lifestyle: Regular physical activity confers a small risk reduction.
• Radiation exposure: Mantle radiation treatment to the chest in childhood or early adulthood, specifically therapy at least 8 years earlier (prior to age 30) is considered high ris.

Breast cancer is also associated with certain syndromes:

• Li-Fraumeni syndrome: Caused by a TP53 gene mutation resulting in an increased risk of breast cancer (50% of women affected) and several other cancers.
• Cowden syndrome (PTEN hamartoma tumour syndrome): Caused by mutations in the PTEN gene, resulting in an increased lifetime risk of developing breast cancer in 30-50% of women.
• Peutz-Jeghers syndrome: Caused by mutations in the STK11 gene, women with this syndrome have a 45-50% risk of developing breast cancer by age 70.
• Lynch syndrome (hereditary non-polyposis colorectal cancer or HNPCC): Women with Lynch syndrome, which is caused by mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM genes, have a lifetime risk of breast cancer that is 3 times greater than that of the general population.

Clinical Features

Breast cancer may present as a palpable lump, nipple discharge (usually bloody), changes in the size or shape of the breast, or skin changes like dimpling or nipple retraction. May present following pathological fracture in metastatic disease.

Complications

Breast cancer can metastasise to the bones, lungs, liver, and brain. It can also recur locally after treatment. The spine is the most common site for bony metastasis.

Pathological Features

Histopathology

• DCIS – Centres of tumour may undergo necrosis, cheesy material expressed. Hetrogenous and exuberant calcification can be produced in the necrotic debris.
• LCIS
• IDC – Tumour has extensive collagen.
• ILC – Does not produced calcification
• Tubular Carcinoma – Well-formed tubules lacking the myoepithelial layer. Well-differentiated.
• Medullary Carcinoma – Highly cellular with little stroma. Typically striking lymphocytic infiltration.
• Mucinous Carcinoma
• Papillary Carcinoma – Tend to be subareolar and are intraductal. Complex cystic and solid mass. Has fibrovascular stalk. Intracystic haemorrhage is a common finding.
• Metaplastic Carcinoma

• Macroscopic: Breast cancers are often firm, irregular masses with indistinct margins.
• Microscopic: Typical features include cells with a high nuclear-cytoplasmic ratio, irregular nuclear contours, and conspicuous nucleoli.

Radiological Features

Mammography

• Characteristically demonstrates spiculated masses or microcalcifications.
• DCIS – More commonly presents with calcifications.
• ILC – Spiculated mass (most common), asymmetric density, opacity or architectural distortion, microcalcification, or mammographically occult.
• Tubular carcinoma – Commonly appear as a spiculated mass
• Papillary carcinoma – Tend to be subareolar, circumscribed solid or complex solid and cystic masses. May be evident as ductal obstruction, filling defects, or focal/diffuse ductal wall irregularity.
• Medullary carcinoma – Circular/oval mass lesion with ill-defined or circumscribed margins, varying degrees of lobulation. Calcification is not usually a feature.

Ultrasound

• Commonly shows a hypoechoic mass with posterior acoustic shadowing.
• ILC – Heterogeneous, hypoechoic mass with angular or ill-defined margins and posterior acoustic shadowing
• Medullary carcinoma – Homogenous hyperechoic or hypoechoic with mild heterogeneity. Posterior acoustic shadowing may be present.

MRI

• Linear distribution of non-mass enhancement implies a ductal process, possibly representing malignancy
• Papillary carcinoma – Round oval mass with well-defined margins. Typically heterogenous with multiple nodular masses of intermediate signal projecting from the periphery into the lumen. Intracystic fluid component varies according to degree of serous (low T1, high T2) and haemorrhagic (high T1/T2 with fluid-fluid levels).
• In Australia, breast MRI may be used to screen asymptomatic high risk patients under 60 years of age. The reduction in breast density that occurs after age 60 means mammography is comparatively sensitive and is therefore preferred. As per the Medicare Benefits Schedule, the following identifies a high risk patient;

• Genetic testing has identified the presence of a high risk breast cancer gene mutation in the patient or in a first degree relative of the patient;
• Both:
  • One of the patient’s first or second degree relatives was diagnosed with breast cancer at age 45 years or younger; and
  • Another first or second degree relative on the same side of the patient’s family was diagnosed with bone or soft tissue sarcoma at age 45 years or younger;
• The patient has a personal history of breast cancer before the age of 50 years;
• The patient has a personal history of mantle radiation therapy;
• The patient has a lifetime risk estimation greater than 30% or a 10 year absolute risk estimation greater than 5% using a clinically relevant risk evaluation algorithm

Australian Government, Department of Health and Aged Care, Medicare Benefits Schedule – Item 63464

Grading and Staging

Breast cancer is graded on the Nottingham system (taking into account tubule formation, nuclear pleomorphism, and mitotic rate) and staged according to the TNM system, which assesses the size and extent of the tumour, the involvement of lymph nodes, and the presence of distant metastases.

Nottingham System

The Nottingham System involves scoring three morphological features of the cancer, each on a scale of 1 to 3:

• Tubule formation: This assesses how much of the cancer forms tubular structures. A score of 1 is given if tubule formation is greater than 75%, 2 if it is between 10-75%, and 3 if less than 10% of the tissue examined contains tubules.
• Nuclear pleomorphism: This assesses the size and shape of the nucleus in the cancer cells. A score of 1 is given if the cells are small and uniform (similar to normal cells), 2 for moderate enlargement with some variation in size and shape, and 3 for marked variation, often with very large and darkly stained nuclei.
• Mitotic count: This measures the number of cells dividing (mitosis) in the cancer. Higher counts suggest faster growth. It’s scored as 1 if there are less than or equal to 7 mitoses per 10 high power field (HPF), 2 for 8-14 mitoses per 10 HPF, and 3 for more than 14 mitoses per 10 HPF.

The scores for each of these three features are then added together to give a total score out of 9. This is then translated into a grade:

• Grade 1 (well differentiated) is a total score of 3-5. The cancer cells look and behave somewhat like normal cells and grow slowly.
• Grade 2 (moderately differentiated) is a total score of 6-7. The cancer cells don’t look like normal cells and grow moderately quickly.
• Grade 3 (poorly differentiated) is a total score of 8-9. The cancer cells look very different from normal cells and may grow more aggressively.

Diagnosis

Diagnosis is made by a combination of imaging techniques (like mammography, ultrasound, or MRI) and histopathological confirmation through core needle biopsy or surgical biopsy.

Differential Diagnosis

• Fibroadenoma: This benign tumour is most commonly seen in young women and often presents as a smooth, firm, mobile lump in the breast. Mammographically appears as a well-defined, round or ovoid mass and sonographically appears as a hypoechoic mass with smooth, well-defined borders. In relation to enhancement kinematics, a centrifugal contrast uptake pattern may help in diagnosing a fibroadenoma, whereas a centripetal spread of contrast is more common in carcinomas
• Intraductal papilloma: These benign tumours of the breast typically present with nipple discharge. They may not be palpable and may not be visible on mammography. Sonographically appear as a dilated duct with an intraductal mass. Variable enhancement on MRI.
• Breast cysts: Fluid-filled sacs within the breast, most common in women aged 35-50. They may present as a palpable mass. Mammographically appears as a well-defined round mass. Sonographically appear as anechoic masses with well-circumscribed margins. Unlike breast cancer, they do not show enhancement on MRI.
• Breast abscess: This can present as a painful, tender mass, often subareolar region with associated skin changes. Usually appears as a hypoechoic or complex mass with posterior acoustic enhancement on ultrasound and a round or oval heterogenous mass with associated skin thickening on mammography. A breast abscess will show peripheral enhancement on MRI.
• Fat necrosis: This typically occurs following trauma to the breast and can mimic cancer clinically and radiologically. On mammography, fat necrosis can appear as calcifications or as a mass. On ultrasound, it can appear as a complex cystic and solid mass. On MRI, fat necrosis often has high signal intensity on T1-weighted images and variable signal intensity on T2-weighted images.
• Breast lymphoma: Though rare, primary lymphoma can occur in the breast and often presents as a painless mass. On imaging, it can have similar features to breast cancer, appearing as a mass on mammography and ultrasound, and showing enhancement on MRI. Pathological analysis is required for definitive diagnosis.
• Breast Metastases: Morphologically rounded, circumscribed, non-calcified mass without spiculations or architectural distortion. Haematomogeous spread from melanoma, haematologic (especially lymphoma), lung, mullerian, sarcoma and GI. Prostate is the most common source in males.

Management

Management of breast cancer is multi-modal and may include surgery (lumpectomy, mastectomy), radiation therapy, chemotherapy, hormonal therapy (for hormone receptor-positive cancers), and targeted therapy (for HER2 positive cancers).

LCIS – Usually incidental finding on biopsy for amorphous calcification. Excision is recommeded after core biopsy result of LCIS as there is upgrade to carcinoma in 27% of cases. The relative risk for developing cancer is 8 – 12 times.