Karsinoma Payudara

01Pathophysiology

Breast cancer arises from the epithelial cells lining the terminal duct-lobular unit. The two broad histologic categories are ductal (originating from ductal epithelium, approximately 70-80% of cases) and lobular (originating from lobular epithelium, approximately 10-15%). Each of these can be either in situ (confined within the basement membrane) or invasive (penetrating through the basement membrane into surrounding stroma), and this distinction is one of the most tested concepts in breast pathology.

Estrogen is the central hormonal driver in the majority of breast cancers. Estrogen binds to estrogen receptors on ductal epithelial cells and activates transcription of genes promoting cellular proliferation. This is why every major risk factor for breast cancer ties back to cumulative lifetime estrogen exposure: early menarche, late menopause, nulliparity, obesity in postmenopausal women (adipose tissue contains aromatase, which converts androgens to estrogen), and exogenous hormone replacement therapy. Understanding this hormonal axis explains why anti-estrogen therapies (tamoxifen, aromatase inhibitors) are cornerstones of treatment for receptor-positive disease.

In hereditary breast cancer, BRCA1 and BRCA2 are tumor suppressor genes involved in homologous recombination repair of double-stranded DNA breaks. Loss-of-function mutations in either gene impair DNA repair, leading to genomic instability and accelerated carcinogenesis. BRCA1 mutations are more frequently associated with triple-negative breast cancer (ER-negative, PR-negative, HER2-negative), which lacks targetable receptors and carries a worse prognosis. BRCA2 mutations tend to produce ER-positive tumors. Both confer elevated risk for ovarian cancer, which is why prophylactic bilateral salpingo-oophorectomy is discussed in confirmed carriers.

The physical findings in breast cancer are direct consequences of tumor biology. A spiculated, irregular mass results from desmoplastic reaction (fibrosis) around infiltrating tumor cells. Skin dimpling and nipple retraction occur when tumor invades and shortens the Cooper ligaments or the lactiferous ducts, respectively. Peau d'orange results from tumor cells obstructing dermal lymphatics, causing lymphedema with tethering at the points where skin is anchored to deeper structures by Cooper ligaments. In inflammatory breast cancer, tumor emboli extensively plug dermal lymphatics, producing diffuse edema, erythema, and warmth that mimics mastitis but without fever or leukocytosis and, critically, without a palpable discrete mass.

02Classification and Clinical Manifestation

Histologic Classification

Molecular Classification

Staging Overview (Simplified TNM)

03Diagnostic Workup

Mammography is the best initial test for any woman aged 40 or older presenting with a breast complaint. Standard screening recommendations begin at age 40-50 depending on the guideline source, performed every 1-2 years. The hallmark mammographic finding of invasive cancer is a spiculated mass with irregular borders. DCIS classically presents as clustered microcalcifications without a mass. The BI-RADS scoring system standardizes reporting: BI-RADS 0 requires additional imaging, BI-RADS 1-2 are negative or benign, BI-RADS 3 is probably benign (short-interval follow-up), BI-RADS 4-5 are suspicious or highly suggestive of malignancy (requiring biopsy), and BI-RADS 6 is known malignancy.

For women under 30, ultrasound is the initial imaging modality because younger breast tissue is dense and mammography has lower sensitivity in this group. Ultrasound is also used to determine whether a palpable mass is cystic (likely benign, can be observed or aspirated) or solid (requires biopsy if suspicious features are present).

Core needle biopsy is the confirmatory test. This is a critical exam concept: do not jump to excisional biopsy or mastectomy before tissue diagnosis. Core biopsy is preferred over fine-needle aspiration because it provides histologic architecture necessary for distinguishing invasive from in situ disease and allows receptor testing (ER, PR, HER2). A question presenting a palpable breast mass with suspicious imaging should lead to core needle biopsy as the next step, not immediate surgery.

Breast MRI has the highest sensitivity of any imaging modality for breast cancer but lower specificity (many false positives). It is reserved for screening BRCA mutation carriers, evaluating the extent of known cancer, assessing for multifocal or bilateral disease, and identifying an occult primary tumor when axillary node metastasis is found without a detectable breast lesion.

04Management and Treatment

Surgical Options

Breast-conserving surgery (lumpectomy) with adjuvant whole-breast radiation has equivalent overall survival to mastectomy for early-stage disease. This equivalence is one of the most commonly tested facts. Lumpectomy requires negative surgical margins; if margins are positive, re-excision or mastectomy is performed. Contraindications to lumpectomy include multicentric disease (tumor in more than one quadrant), prior radiation to the chest wall, inability to achieve negative margins, and pregnancy (radiation is contraindicated during pregnancy, though lumpectomy can be performed with radiation deferred to the postpartum period).

Sentinel lymph node biopsy (SLNB) has replaced routine axillary lymph node dissection for clinically node-negative patients. The sentinel node is identified by injecting technetium-99m sulfur colloid and/or isosulfan blue dye near the tumor or subareolarly. If the sentinel node is free of metastasis, no further axillary surgery is needed, significantly reducing the risk of lymphedema. If the sentinel node is positive, axillary lymph node dissection or axillary radiation is considered depending on the clinical scenario.

Adjuvant Systemic Therapy

Endocrine therapy is indicated for all ER-positive and/or PR-positive tumors

For premenopausal women, tamoxifen 20 mg daily for 5-10 years is standard. Tamoxifen is a selective estrogen receptor modulator (SERM) that acts as an antagonist at the breast and an agonist at the uterus and bone. Because of its agonist effect on the endometrium, it carries an increased risk of endometrial cancer and thromboembolic events (deep vein thrombosis, pulmonary embolism). Any postmenopausal bleeding in a patient on tamoxifen should prompt endometrial biopsy.

For postmenopausal women, aromatase inhibitors (anastrozole, letrozole, or exemestane) are preferred because they block peripheral conversion of androgens to estrogen by inhibiting aromatase. They are more effective than tamoxifen in postmenopausal patients but cause bone loss (osteoporosis) and arthralgias as notable side effects. Aromatase inhibitors are contraindicated in premenopausal women because the resulting drop in estrogen triggers a compensatory rise in gonadotropin secretion, which stimulates the ovaries, paradoxically increasing estrogen levels.

Trastuzumab (Herceptin) is a monoclonal antibody targeting HER2 (ErbB2) and is added to chemotherapy for all HER2-positive tumors. Treatment duration is typically 1 year of adjuvant trastuzumab. The major side effect is cardiotoxicity (decreased left ventricular ejection fraction), requiring baseline and periodic echocardiography during treatment. Trastuzumab should not be given concurrently with anthracyclines (e.g., doxorubicin) because of overlapping cardiac toxicity; these are given sequentially instead.

Chemotherapy regimens commonly include anthracycline-based (doxorubicin + cyclophosphamide) followed by taxane-based (paclitaxel or docetaxel) protocols. Doxorubicin has a cumulative dose-dependent risk of dilated cardiomyopathy (lifetime dose limit approximately $450mg\mathrm{/}{m}^{2}450\backslash \; mg/m^2$). Cyclophosphamide carries risk of hemorrhagic cystitis (prevented with mesna hydration).

PARP inhibitors (olaparib, talazoparib) are approved for BRCA-mutated, HER2-negative breast cancer. PARP inhibitors exploit the concept of synthetic lethality: cells with defective homologous recombination (from BRCA mutation) cannot repair DNA damage when PARP-mediated base excision repair is also blocked, leading to cell death.

Risk Reduction in BRCA Carriers

Bilateral prophylactic mastectomy reduces breast cancer risk by approximately 90%. Bilateral salpingo-oophorectomy reduces ovarian cancer risk and, in premenopausal women, also reduces breast cancer risk by removing the primary source of estrogen. Enhanced screening with annual mammography alternating with breast MRI every 6 months (beginning at age 25-30) is recommended for carriers who decline prophylactic surgery.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common trap on breast cancer questions is confusing the next step in workup. When a woman over 30 presents with a palpable breast mass, the next step is mammography (or ultrasound if under 30), followed by core needle biopsy if imaging is suspicious. Students frequently jump straight to excisional biopsy or surgery without obtaining tissue diagnosis first. Similarly, a common error is selecting fine-needle aspiration over core needle biopsy; core biopsy is preferred because FNA cannot distinguish invasive from in situ disease and cannot provide receptor status.

Another frequently tested concept is the distinction between DCIS and LCIS. DCIS is a true precursor lesion confined to the duct, detected by microcalcifications on mammography, and treated with excision. LCIS does not form a mass or calcifications, is usually an incidental finding on biopsy for another indication, and is considered a bilateral risk marker rather than a direct precursor. LCIS increases the risk of developing invasive cancer in either breast, not just the ipsilateral side, which is why management is observation with enhanced screening or chemoprevention rather than excision.

The equivalence of lumpectomy plus radiation and mastectomy for early-stage disease is tested repeatedly. Students sometimes assume mastectomy is superior, but randomized controlled trials have shown no difference in overall survival. The critical caveat is that lumpectomy requires adjuvant radiation and negative margins.

For pharmacology, the key trap involves aromatase inhibitors in premenopausal women. Aromatase inhibitors should never be used in premenopausal patients unless ovarian suppression is achieved first (with GnRH agonists or oophorectomy), because intact ovarian function will compensate for peripheral aromatase blockade by increasing gonadotropin-driven estrogen production.

Tamoxifen's dual action is heavily tested: it is an estrogen antagonist at the breast (therapeutic) but an estrogen agonist at the endometrium (increasing the risk of endometrial hyperplasia and carcinoma) and at bone (protective against osteoporosis, unlike aromatase inhibitors which worsen bone loss).

Finally, any question presenting a breast that is diffusely erythematous, edematous, and warm without a discrete mass and without response to antibiotics should immediately raise concern for inflammatory breast cancer. The biopsy will show dermal lymphatic invasion. This is a clinical and pathologic diagnosis, staged as T4d regardless of tumor size, and requires neoadjuvant chemotherapy before any surgical intervention. Performing upfront mastectomy on inflammatory breast cancer is a classic incorrect answer.

The core competency being tested across breast cancer questions is the ability to correctly sequence the diagnostic workup (imaging before biopsy, biopsy before surgery), match the treatment to receptor and menopausal status, and recognize presentations that deviate from the typical painless lump (inflammatory breast cancer, Paget disease, male breast cancer).