Breast Pathology: Development and Disorders

• These notes cover breast pathology, including developmental disorders, clinical presentations, inflammatory disorders and, breast cancer

Normal Breast - Microscopic

• Ducts are lined by inner cuboidal epithelial cells and an outer layer of myoepithelium.
• Lobular units are also lined by the same epithelial cells and are surrounded by fibrocollagenous-fibroadipose stroma.

Disorders of Breast Development - Milk Line Remnants

• Supernumerary nipples or breasts result from the persistence of epidermal thickenings along the milk line, which extends from the axilla to the perineum.
• Disorders of normally situated breasts very rarely arise in heterotopic foci, most commonly noticed due to painful swelling before menstruation.
• Considered insignificant, but may cause painful swelling prior to menstruation.

Disorders of Breast Development - Accessory Axillary Breast Tissue

• The normal ductal system can extend into the subcutaneous tissue of the chest wall or the axillary fossa (axillary tail of Spence).
• This tissue might not be removed by prophylactic mastectomies.
• Prophylactic mastectomies reduce, but do not completely eliminate, the risk of breast cancer.
• Common in Asians.

Disorders of Breast Development - Congenital Nipple Inversion

• Failure of the nipple to evert during development is common and may be unilateral.
• Congenitally inverted nipples are usually not significant, correcting spontaneously during pregnancy, or can be everted by simple traction.
• Acquired nipple retraction can indicate invasive cancer or inflammatory nipple disease.
• Congenital nipple inversion must be distinguished from acquired nipple retraction because ANR is usually associated with malignancy or inflammatory nipple disorders.

Clinical Presentation of pain (mastalgia or mastodynia)

• Common symptom, cyclic with menses or noncyclic.
• Diffuse cyclic pain may be due to premenstrual edema.
• Noncyclic pain is localized, caused by ruptured cysts, injury, infections, and often no specific lesion is identified.
• Most painful masses are benign; ~5% are caused by breast cancer.

Clinical Presentation of Inflammation

• Most often caused by infections.
• During lactation and breastfeeding, nipples are prone to cracks/wounds, providing entry for pathogens, leading to inflammation of your breast.
• Inflammatory breast carcinoma can also be the cause.

Clinical Presentation of Nipple Discharge

• Milky discharge (galactorrhea) is associated with elevated prolactin levels (pituitary adenoma), hypothyroidism, or endocrine anovulatory syndromes.
• Milky discharge is associated with patients taking oral contraceptives, tricyclic antidepressants, methylopa, or phenothiazines and/or repeated nipple stimulation.
• Bloody or serous discharges are most commonly due to large duct papillomas or cysts, during pregnancy, rapid growth and remodeling of the breast
• A spontaneous, unilateral, and bloody discharge in older women is likely malignant.

Clinical Presentation of Lumpiness or Diffuse Nodularity

• Relates to diffuse nodularity of the breast
• A manifestation of normal glandular disease where presence of a discrete mass needs to be excluded

Clinical Presentation of Palpable Masses

• Generally detected when 2 to 3cm.
• Masses can be proliferation of stromal cells, or epithelial cells or both.
• Detection of masses is evident when they reach the size of 2-3 ст.
• Approximately 95% are benign.
• Benign masses have a round or oval contour, are usually rubbery and mobile, and have circumscribed borders.
• Malignant tumors usually invade tissue planes and are hard or scirrhous in character with irregular borders.
• Main reasons for primary investigation of breast among patients seeking consultation to rule out malignancy.
• Greater than 90% of symptomatic breast lesions are benign.
• Of women with cancer, about 45% have symptomatic disease, while the remainder come to attention through mammographic screening.

Inflammatory Disorders

• These of the breast are rare (accounting for less than 1% of breast symptoms).
• Caused by infections, autoimmune disease, or foreign body-type reactions to extravasated keratin or secretions.
• Inflammatory breast cancer mimics inflammation by obstructing dermal vasculature with tumor emboli and should always be considered.

Acute Mastitis

• Typically occurs during the first month of breastfeeding due to local infection.
• Breaks in the nipples from breastfeeding is a key portal of entry for pathogens like Staphylococcus aureus or Streptococcus
• The Erythematous & edematous breast is often painful, presenting with fever.
• Staphylococci infection often leads to single or multiple abscesses, whereas streptococci cause spreading infection in the form of cellulitis.
• Infection initially affects one lobule, spreading to others and developing into an abscess if untreated.

Squamous Metaplasia of Lactiferous Ducts

• Known as recurrent subareolar abscess, periductal mastitis, and Zuska disease.
• Normal nipple breast ducts are lined with cuboidal epithelium.
• In Squamous Metaplasia, squamous epithelium extends into the ducts and sometimes, keratin debris from squamous cells accumulates.
• Accumulation of keratin causes infection and rupture.
• Rupture can lead to fistula along the side of the areola.
• Women, and sometimes men, present with a painful erythematous subareolar mass that mimics a bacterial abscess.
• Patients will have an inverted nipple due to inflammation and scarring
• More than 90% of afflicted individuals are smokers where toxic substances/smoke alter ductal epithelium.
• Deficiencies in vitamin A associated with smoking is suggested.
• A key feature is Keratinizing squamous metaplasia which extends into the nipple duct
• Keratin shed from cells are trapped causing dilation and rupture.
• Chronic granulomatous inflammatory response develops once keratin spills.
• Recurrences may develop from secondary anaerobic bacterial infection.

Duct Ectasia

• Tends to occur in the 5th or 6th decade of life and more commonly in multiparous women
• Presents as a palpable periareolar mass often with thick, white nipple secretions and occasionally with skin retraction.
• Pain and erythema are uncommon.
• Granulomas may form around cholesterol deposits and secretions and result in fibrosis.
• The dilated ducts can rupture causing inflammation of surrounding tissues consisting of Lymphocytes
• Ectatic dilated ducts are filled with inspissated secretions and lipid-laden macrophages.
• Unlike squamous metaplasia of lactiferous ducts, not associated with cigarette smoking.

Fat Necrosis

• May closely mimic cancer and show Mammographic calcification
• Usually relates to history of breast trauma or surgery. These calcifications can also be found in your malignant lesions.
• May present as a painless palpable mass, skin thickening, or retraction.
• Acute lesions may be hemorrhagic and contain central areas of liquefactive fat necrosis with neutrophils and macrophages
• (Right Pic) shows can undergo fibrosis with areas of areas of hemorrhage

Lymphocytic Mastopathy (Sclerosing Lymphocytic Lobulitis)

• Presents with single or multiple hard palpable masses or mammographic densities.
• Masses are associated with densely collagenized stroma, a feature that makes it difficult to obtain lesional tissue by needle biopsy.
• Atrophic ducts and lobules with thickened basement membranes appear within stroma surrounded by prominent lymphocytic infiltrate.
• Associated with type 1 (insulin dependent) diabetes or autoimmune thyroid disease.
• Must be distinguished from breast cancer.

Granulomatous Mastitis

• Granulomatous inflammation with multinucleated giant cells and mixed inflammatory cells involving a breast lobule
• Is possibly manifestation of a systemic disease/inflammation/infection that commonly occures in parous women

Cystic Neutrophilic Granulomatous Mastitis

• Often caused by lipophilic Corynebacteria.
• Similar histologic pattern with Granulomatous Mastitis

Key Breast Cancer Facts

• 670 000 deaths globally in 2022.
• Roughly half of all breast cancers occur in women with no specific risk factors other than sex and age.
• Breast cancer is the most common cancer among women and a deadly malignancy of women globally.
• Breast cancer occurs in every country.
• Approximately 0.5-1% of breast cancers occur in men.

Molecular Groups in Breast Cancer

• Luminal cancers typically ER (+), HER2 (-).
  • There is a Luminal A type Both ER and PR are (+)
  • There is a Luminal B ER (+), PR (+)
• HER2 cancers typically HER2 (+), either ER (+/-).
• Triple negative breast cancers (TNBCs): ER (-), PR (-), HER2 (-).

Risk Factors for Developing Breast Cancer

• Female gender (99%).
• Increasing Age.
• First Degree family history
• Denser is good with detection
• Kung dako ka man boobs mas hig.her man ang chances of developing cancer.
• Environmental
• Early Menarche + Late Menopause
• Late First Pregnancy before age 35
• Nulliparity
• Absence of Breast Feeding
• Exogenous Hormones
• Post-menopausal Obesity
• 1st world countries ang damo nga cases sa breast cancer per 100,000.

Pathogenesis

• It is believed that 1/3 of breast cancers occur in inheritance of BRCA1 and BRCA2 gene mutations.
  • BRCA1- majority are triple negative breast cancers.
  • BRCA2- majority are ER (+)

Major pathways for breast cancer development.

• Three main pathways have been identified. The most common pathway leads to luminal (ER-positive) carcinomas.
• Recognizable non-obligate precursor lesions include flat epithelial atypia and atypical hyperplasia.

Carcinoma in Situ - Ductal Carcinoma in Situ (DCIS)

• "Carcinoma in its original place" where cancer cells are confined within ducts and lobules by a basement membrane, and has No capacity to metastasize. - Occurs at the Terminal Ducts and is Clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane.

Major Architectual patterns for DCIS

• Cribiform are Fenestrated proliferation with multiple, round, rigid extracellular lumens with a punched-out appearance.
• Micro-papillary are Papillary fronds where the Papillae have club-shaped cells comprising the micropapillae that are uniform in appearance.
• . Papillary fronds are frequently associated with Prominent fibrovascular septa projecting into duct lumen, the papillary cores generally lack myoepithelial cell layer.

Breast Cancer Grading

• The Low-grade are Monotonous, round nuclei with smooth contours and nuclei are Diffuse fine chromatin
  • In this category theSize requirement is >2mm and involving more than two complete spaces
• Intermediate Grade Moderate pleomorphism, with some Variability in nuclear size and occasional nucleoli . There is a loss of monotony, which can mimic usual ductal hyperplasia
  • The High Grade has large nuclei with irregular distribution, prominent nucleoli and Frequent

Microscopic patterns in Invasive Carcinoma

• invasive breast cancer by Invasive Breast Carcinoma composed of discohesive cells that are often individually dispersed or arranged in a single file linear pattern.

Luminal A Subtype

• characterized by Small, angulated to ovoid glands and tubules with open lumina set in fibrous, desmoplastic stroma. and Low -grade nuclei (>90% of tumor must have this morphology)

Luminal Breast Cancer In Situ (DCIS)

-Noninvasive, neoplastic proliferation of small, uniform, dyscohesive cells originates in the terminal duct lobular unit (TDLU)

TNM Staging

• Distant metastasis = M, Regional lymph nodes =N, Tumor = T, the survival rate diminishes with higher histologic grade.
• .The treatment would depend on gene expressions of the malignant tumors.

Male Breast Cancer

• Incidence is only 1% of that in women, which translates to a lifetime risk of 0.11%.
• Risk factors includeIncreasing age, and First- or 2nd degree relatives.
• Residing in westren Countries. The most crucial familial factor is germline mutation of the BRCA2 tumo.
• The carcomias are mostly situated near the skin. the. and follow te same treament as for female cancers.