Breast Malignancy

>95% are adenocarcinomas, all thought to arise from the TDLU. Lifetime risk of breast carcinoma is 1/8 (12.5%; 1% per year), mortality in 1/3 of these. 30% of all female cancer. F:M 200:1. Uncommon <25yo, 1/3 in <50yo, peaking at 75-80yo. Generally younger women tend to have more agressive malignancy due to increased hormones. Increased risk of ipsilateral (30%), contralateral (15%) breast or endometrial cancer. 10% more on left, 4% bilateral or sequential in the same breast. 50% upper outer quadrant, 10% in each of remaining quadrants, 20% central/subareolar. The major risk factors are hormonal and genetic.

  • Genetic factors – Higher risk in 1st degree relative. <20% with hereditary cancers have the AD BRCA genes. Other syndromes include Li-Fraumeni syndrome (multiple sarcomas and carcinomas), Cowden disease (multiple hamartoma, 10q), ATM gene (ataxia-telangiectasia).
    • BRCA1 – tumour suppressor and DNA repair gene on chromosome 17. 70% risk of breast cancer, 30-60% ovarian, high risk prostate and colon, medullary and ductal carcinomas.
    • BRCA2 – tumour suppresor and DNA repair gene on chromosome 13. 60% risk of breast cancer, increased risk male breast cancer, ovary, bladder, prostate, pancreas.
  • Hormonal influences – Hormonal imbalance with oestrogen excess. Increased risk with early menarche, late menopause, nulliparity, 1st child >30yo. Small or no increased risk with OCP or HRT. Pregnancy transiently increases risk of cancer (?inducing in-situ to invasive carcinoma), but later reduced risk (?milk-producing terminal differentiation is protective).
  • Environmental factors – Postmenopausal obesity. Reduced risk with obesity <40yo (due to association with anovulatory cycles and lower progesterone). Higher risk with Western life style. No association with smoking.
  • Other factors – White females, history of atypical hyperplasia on biopsy, increased breast density (correlates with hormonal exposure), radiation exposure, carcinoma of contralateral breast or endometrium.

Tumours become palpable ~20mm, density on mammography when reaches ~10mm. Extension to skin causes fixation, retration, dimpling. Local lymphatic occlusion causes nipple retraction. Inflammatory carcinoma – involvement of dermal lymphatics causing enlarged erythematous, tender breast, lymphoedema and thickening with tethering of skin by Cooper ligaments creating orange peel appearance (peau d’orange); usually localy advanced with systemic metastases, poor prognosis.

50-85% have oestrogen receptors (more common if postmenopausal). 70% regress with hormonal therapy (higher if oestrogen and progesterone receptor positive), only 5% if receptor negative. Receptor positive tumours tend to develop bone metastases; receptive negative brain metastases.

1/3 have LN metastases at time of diagnosis. Lymphatic spread to axilla, supraclavicular and cervical nodes, contralateral breast, abdominal viscera and nodes, chest along internal mammary chain. Can be considered malignant if axillary node depth:width ratio >0.8.

Distant metastases to virtually any organ including lung, bone, liver, adrenal, brain, meninges, orbit.

Prognosis is excellent if cancer <10mm, regardless of histological grade or node status (95% 16y survival).

Pregnancy-associated breast cancer is during or within 1yr postpartum. Increased oestrogen may accelerate growth.

In-Situ/Noninvasive Carcinoma (15-30%)

Proliferation is limited to ducts and lobules by the basement membrane. Distinction between DCIS and LCIS is artificial, based on differentiation at cell and tissue level (not by site or origin).

Ductal Carcinoma In Situ (DCIS, 80%)

(Intraductal carcinoma, non-invasive carcinoma, tumour in situ – TIS). Malignant epithelial cells confined by basement membrane, but can spread throughout ductal system and involve entire sector of a breast. Rarely bilateral. Hyperplastic breast changes (radial scar, juvenile papillomatosis, fibrocystic change, sclerosing adenosis) may be associated with intermediate/low grade DCIS.

Growth pattern types depending on architecture:

  • Comedocarcinoma DCIS (60%) – Solid sheets with central necrosis commonly calcifying (clusters or linear branching). Periductal fibrosis/chronic inflammation.
  • Noncomedo DCIS (40%) – calcifications usually of intraluminal secretions.
    • Solid DCIS – Solid sheets
    • Cribriform DCIS – Regular intra-epithelial spaces
    • Papillary DCIS – Grows along fibrovascular cores, usually lacking myoepithelial layer
    • Micropapillary DCIS – Bulbous protrusion without fibrovascular core

Paget disease of the nipple – Extends from nipple ducts to nipple and areola (fissures, eczema-like, ulceration, ooze). Paget cells = adenocarcinoma in keratinising epithelium of nipple epidermis. Palpable underlying mass in 50%. Associated with carcinoma in breast or nipple in 95%, mostly DCIS (high grade, comedo, solid types).

Low grade DCIS produces mucin distending TDLUs; high grade causes necrosis and calcifications. Causes new ducts to forms (hence not technically in situ). DCIS with microinvasion – <1mm foci invading the stroma, mostly comedocarcinoma.

70-80% present with calcifications. High grade/poorly differentiated typically casting or crushed stone calcifications. Low/moderate grade powdery calcifications in single or multiple clusters (confined to distended lobules) in cotton ball appearance; indistinguishable from sclerosing adenosis ± atypia. Malignancy may be several cm larger than the area of calcifications. Histologically calcification may be dystrophic/amorphous or psammoma body-lie/’onion ring-like’. Casting type calcification includes:

  • Variant A – fragmented, rod-like, irregular, dense, casting type, scattered within large part of lobe confined to distended ducts (solid cell proliferation). DDx plasma cell mastitis (if focal and unilateral think DCIS), fibroadenomas (may have elongated casting calcs). Microfocus magnification may show smaller casting type and crushed stone calcifications in DCIS, but not plasma cell mastitis or fibroadenomas.
  • Variant B – ‘dotted casting’/’dot-dash’ type, ‘snake skin’ like, scattered outlining most of the lobe (mixed growth pattern solid and micropapillary/cribriform). No benign DDx.

20% present with asymetric density with architectural distortion (distended TDLUs with desmoplastic reaction), solitary or multiple circular/oval masses (intermediate-low grade intracystic papillary carcinoma), or ductal filling defects/duct amputations on galactography (rarely high grade, associated unilateral serous or blood nipple discharge). 7% of serous and 14% of blood nipple discharges are malignant.

Low grade DCIS has high risk of invasive cancer 8-10x/32% (100% ductal carcinoma) at 1% per year. Treated with surgery followed by radiation with good prognosis. If <40mm WLE, >40mm mastectomy (for cosmetic purposes, depends on breast size).

Lobular Carcinoma In Situ (LCIS, 20%)

Rare lesion, usually incidental on histology, incidence highest during reproductive years and decreases with age. Proliferation in one or more terminal ducts or ductules. Monomorphic, rarely distorts architecture, bilateral in 50-70%. Signet ring cells containing mucin. Rarely calcifies, never forms a mass. High risk of invasive carcinoma 8-10x (50% ductal, 50% lobular). No distinct features on mammography and seldom produces signs/symptoms, but is often found adjacent indeterminate benign calcifications or sclerosing adenosis. 15-30% chance of developing an infiltrating ductal or lobular carcinoma in either breast. 18-25% are upgraded to more invasive cancer at surgical excision; hence excisional biopsy should always be performed.

Invasive Carcinoma (70-85%)

(Infiltrative carcinoma). Growth has breached the basement membrane into the breast stroma. Carcinomas are usually cellular hence FNAB may suffice, but core biopsy if <10mm, impalpable and/or well differentiated.

Ductal Carcinoma

Invasive Carcinoma, No Special Type (NST) (75%)

(Not otherwise specified NOS). Cannot be classified as any other subtype. Accumulation of cells in TDLU causing swelling and distortion of lobules, subsequent break in basement membrane with stromal invasion. Scirrhous carcinoma – dense fibrous stroma. Stony hard nodules 10-50mm, fixation to chest wall, dimpling skin, retraction of nipple, small foci of calcification. Cells in cords, solid cell nests, tubules, anastomosing masses. Either stellate (with focal necrosis, very poor prognosis) or circular/oval (1/3, better prognosis). Molecular classes correlate with prognosis and response to therapy:

  • Luminal A (40-55%) – ER positive and HER2/neu negative. Most are well or moderately differentiated, most postmenopausal. Slow growing, respond well to hormonal treatments, but poor response to standard chemotherapy.
  • Luminal B (15-20%, ‘triple-positive’) – ER positive, HER2/neu positive. Generally high grade with LN metastases, may respond to chemotherapy.
  • Normal breast-like (6-10%) – ER positive, HER2/neu negative, similar gene expression to normal tissue. Usually well-defined.
  • Basal-like (13-25%, ‘triple-negative’) – ER, PR and HER2/neu negative, lack myoepithelial cell markers. Other triple-negative tumours include medullary and metaplastic carcinomas. Generally high grade, frequent brain and visceral metastases, poor prognosis. May respond to chemotherapy.
  • HER2 positive (7-12%) – ER negative, HER2/neu positive. Usually poorly differentaited, common brain metastases.

Mucinous Carcinoma (5%)

(Colloid, gelatinous). Older postmenopausal women (mean 70yo), slow growing, favourable prognosis. Soft, pale grey-blue gelatin-like, well circumscribed or partially ill-defined mimicing a benign lesion, low density radiopaque. Rarely calcifies. Large mucin lakes with islands of neoplastic cells. Most exhibit hormone receptors. Pure (>75% mucinous cells, excellent prognosis) or mixed (mucinous and invasive NST elements, prognosis similar to ductal NST). 2/3 associated with DCIS.

Medullary Carcinoma (5%)

(Circumscribed carcinoma, bulky adenocarcinoma). Younger age (50s), higher risk in BRCA1 (account for 13%). Typical or atypical types. Soft, mobile, usually UOQ. Fastest growing breast cancer, necrotic foci often lead to cystic change. Soft, fleshy, well-defined, nodular, 20-50mm lesion without striking desmoplasia. Can be mistaken for fibroadenoma. Rarely calcifies. Pale brown. Solid syncytium-like sheets with little stroma, lymphoplasmacytic infiltrate, pushing (noninfiltrative) border. All are poorly differentiated with high nuclear grade, aneuploidy, absent hormone receptors, p53, high proliferative rate. Retention/overexpression of E-cadherin adhesion molecules (?causing pushing borders and limited mets). Locally agressive. Core Bx may only suggest diagnosis. Tx mastectomy. Slightly better prognosis than NOS.

Tubular Carcinoma (1-2%)

(Cribriform carcinoma). Proliferation of glands or tubules resembling mammary ductules, haphazardly distributed. Spiculated masses. Arises from micropapillary or cribriform DCIS. Late 40s. 1/4 multifocal, 1/4 bilateral. 40% have 1st degree FHx. 40% associated with atypical lobular hyperplasia, LCIS or DCIS. Well-formed tubules, absent myoepithelial layer (Anti-Actin stain, preserved in sclerosing adenosis and radial scar). Cribriform spaces, apocrine snouts, calcification in lumen. Favourable prognosis, restricted to tumours with at least 75% tubular elements. >95% are ER positive, HER2/neu negative. 5-yr survival 95%. Tubulolobular carcinoma has features of both, rare, good prognosis.

Papillary Carcinoma (1-2%)

Rare. Frond-forming growth pattern on microscopy filling duct lumen ?arising from solitary large duct papillomas. Older women. Nipple discharge in 40%. Solid or cystic types. Almost always well circumscribed, round/oval, lobulated ± multiple in one quadrant. Rarely fine granular calcification. No profuse fibrotic reaction. Oestrogen receptor rich. Low frequency of axillary node metastases. 5-yr survival 90%. Tx excision ± SNB/dissection.

Lobular Carcinoma (15%)

Bilateral in 5-10% (similar to NST, previously biased to 20%), can be multicentric in same breast; hence need for MRI. ‘Single-file’ of cells infiltrating breast. No intense desmoplastic reaction. Diffusely infiltrating. May cause architectural distortion without a discrete density/mass despite gross clinical abnormality. Often changes appearance between views, may only be seen on one view esp CC. Calcification is rare. Indistinguishable from ductal carcinoma on imaging. Signet-ring cells common. Almost all (including LCIS) lack cell-cell adhesion molecule E-cadherin (cf 52% invasive ductal carcinomas) creating dyscohesive rounded cells without attachment to adjacent cells. Subtypes include:

  • Classical – diffusely invasive, no architectural distortion, cells in narrow chords 1-2 cells thick (Indian files, often single file of cells loosely dispersed in fibrous matrix).
  • Tubulolobular – microtubular structures in tangential pattern on background of classical
  • Solid/cellular – large groups/sheets/nests of cells with little stroma
  • Alveolar – globular rests simulating ductules of LCIS
  • Signet ring – variable definition
  • Histiocytoid – prominent foamy/granular cytoplasm
  • Mixed

Strongest prognostic factor is node status. Low grade tumours are ER positive HER2/neu negative; high grade vice versa. Metastasize to CSF, serosal surfaces, ovary, uterus, bone marrow. Staging, treatment and prognosis similar to ductal apart from high rate of bilaterality and multicentricity.

Metaplastic Carcinoma (<1%)

(Adenosquamous/squamous carcinoma). Adenocarcinoma with other epithelial or mesenchymal elements. Circumscribed large, ± ossification, takes up Tc99m. Squamous type – cell nests, spindle cell or pseudoangiosarcomatous/angiomatoid. Pseudosarcomatous type – matrix producing (chondrosarcomatous, chondro-osseous or osteosarcomatous). ER PR and HER2/neu negative (triple negative), express myoepithelial proteins. Infrequent LN, but poor prognosis.

Staging

Most important prognostic factors (in descending order) are metastases, axillary node status, and tumour size. AJCC staging:

  • Stage 0 – DCIS or LCIS (5-year survival 92%)
  • Stage I – invasive </= 20mm including microinvasion (survival 87%)
  • Stage II – 20-50mm, no or 1-3 mobile axillary nodes (survival 75%)
  • Stage III – >50mm, fixed or >3 axillary nodes, ipsilateral internal mammary LN, skin/chest wall fixation, oedema, inflammation; (survival 46%). Locally advanced breast cancer (LABC), Tx chemotherapy for ?responsiveness, tumour shrinkange/’down-staging’ for possible surgery/radiation.
  • Stage IV – metastases, including supraclavicular nodes (survival 13%)

Histologic grade is determined by cytologic features of differentiation, extent of tubule formation, mitotic rate. Classified as grade I/low (well differentiated), II/intermediate (moderate), III/high (poorly differentiated, high rate of axillary LN, more recurrences, higher mortality). Nuclear grading evaluates tumour nucleus structure cf normal cells.

Malignant Stromal and Other Breast Tumours

Cystosarcoma Phyllodes

See Benign Breast Disease

Adenoid Cystic Carcinoma

(Cylindroma). Rare adenocarcinoma. Subareolar, glandular, tubular or solid. Slow-growing, reduced incidence of LN or metastases. Excellent prognosis.

Sarcomas of the Breast

Tumours of extrinsic connective tissue (interlobular stroma), associated with previous radiotherapy. Angiosarcoma (spontaneous or after radiotherapy, chronically oedematous arm after mastectomy = Stewart-Treves syndrome), rhabdomyosarcoma, liposarcoma, leiomyosarcoma, chondrosarcoma, osteosarcoma. Sarcomatous differentiation in cystosarcoma phyllodes, carcinomas (metaplastic carcinomas). Rarely metastasize to LN, commonly to lung.

Breast Lymphoma

Primary or secondary, <0.5% of breast cancer. Most are diffuse large B cell NHL, unilateral, variable course. Burkitt’s in younger, pregnant/lactating, bilateral, rapidly fatal. Ovarian metastases may -> lymphoblastic leukaemia. Circumscribed/lobulated or ill-defined. No spiculation, noncalcified.

Metastatic Disease to the Breast

From contralateral breast (cross-lymphatics), melanoma, lung, soft tissue sarcoma, ovarian; less often stomach, kidney, cervix, thyroid, colon, uterus, prostate, lymhoma/leukaemia. May present as circumscribed nodule, but magnification compression reveals irregularitly. Most commonly solitary with multiple/bilateral nodules only forming late in disease. Rarely spiculating or calcifications.

Male Breast Carcinoma

<1% (200:1 F:M ratio), increased in Western countries, 1st degree relatives with breast cancer, age, infertility, obesity, exogenous oestrogens, previous benign breast disease, radiation, decreased testicular function, BRCA2 (but not BRCA1), 20x risk in Kinefelter. Gynaecomastia is not a risk factor. DCIS and LCIS are rare. More likely to have oestrogen receptors. 91% ductal, higher proportion papillary and lower proportion of lobular/medullary than female. Rapid skin/thoracic wall fixation. Higher stage at presentation, but similar prognosis as women when matched with stage.