Normal anatomy of breast
- Milk-producing Lobules -> duct -> Nipple.
- Fatty tissue.
- Most breast cancer arise from duct or lobule.
Normal Histology of breast
- Lobules are the functional unit of the mammary gland.
- Lobules contain clusters of epithelium-lined ductules or acini.
- The larger duct systems (6-10) branch into smaller ducts, branch into terminal ducts, then give rise to lobules or acini.
- The stroma of the breast is made up of fibroconnective tissue and adipose tissue (interlobular stroma) and also contains elastic fibers around larger ducts.
- Terminal duct + lobule = terminal duct lobular unit or T.D.L.U.
- At around the age of forty, due to the decrease of estrogen, areas that are fibrous become fatty, and the lobules may atrophy, the breast becomes mostly fat; the time when mammogram monitoring starts.
Histopathologic findings of breast lumps
- 40% fibrocystic changes
- 30% no disease
- 13% miscellaneous benign
- 7% fibroadenoma
- 10% cancer
- Benign changes can happen at any age.
- aka fibrocystic disease
- Applied to changes consisting of cyst formation and fibrosis. Dilated lobules filled with secretion type material, can become large, rupture, cause inflammation and pain.
- Most common breast abnormality seen in premenopausal women.
- Consequence of the cyclic breast changes that occur normally in the menstrual cycle.
- Divided into proliferative and nonproliferative changes.
Nonproliferative Fibrocystic Changes
- Often multifocal, ill-defined, bilateral changes.
- Diffusely increased densities and nodularity on mammography.
- Range from 1 to 5 cm in diameter and grossly consist of blue dome cysts (with fibrous tissue in between) filled with watery fluid.
- The cysts form by dilation and unfolding of lobules; The pink lining of them is apocrine metaplasia - usually benign.
- Fibrosis is caused by the rupture of cysts due to the irritation of the stroma by the secretory material.
Proliferative Breast Disease without Atypia - Epithelial Hyperplasia
- Multiple layers of duct epithelium, consist of ductal and myoepithelial cells.
- Proliferating cells may appear as solid masses encroaching duct lumen.
Proliferative Breast Disease without Atypia - Sclerosing Adenosis
- Proliferation of luminal spaces lined by epithelial cells and myoepithelial cells.
- Commonly present as mammographic calcifications, mimicking a cancer-like appearance but is actually benign.
- Myoepithelial cells are preserved and increased.
- Marked stromal fibrosis.
Relationship of Fibrocystic Changes to Breast Carcinoma
- Fibrocystic Changes can be classified as nonproliferative or proliferative.
- Proliferative lesions include hyperplasia and adenosis.
- Minimal or no increased risk - fibrosis, cysts, apocrine metaplasia, mild epithelial hyperplasia.
- Slightly increased risk (1.5-2x) - moderate to florid hyperplasia without atypia, ductal papillomatosis, sclerosing adenosis.
- Significantly increased risk (5x) - atypical hyperplasia, whether ductal or lobular.
INFLAMMATORY PROCESSES of breast
- Acute Mastitis
- Duct Ectasia (Plasma Cell Mastitis)
- Plasma Cell Mastitis
- Usually related to the first month of breast feeding.
- Most common organism: S. aureus access through the ducts.
- The breast is erythematous and painful.
- The tissue is infiltrated by neutrophils and may be necrotic.
Duct Ectasia (Plasma Cell Mastitis)
- The 5th-6th decade of multiparous women.
- Chronic inflammation surrounding the ducts - most commonly plasma cells, Occasionally granulomas.
- Periareolar mass commonly associated with thick white nipple discharge and sometimes skin retraction.
- Dilated ducts filled with granular debris and macrophages .
- Painless or painful palpable mass, skin thickening or retraction, mammographic density or calcifications.
- Mostly associated with trauma.
- Acute lesions may be hemorrhagic with central areas of necrotic adipose tissue.
- Early acute lesions contain numerous neutrophils mixed with macrophages and giant cells.
- Fat necrosis of other parts of the body have the same look.
TUMORS OF THE BREAST - STROMAL TUMORS AND PAPILLOMA
- Phyllodes Tumor
- Intraductal Papilloma
- Most common benign tumor of the female breast.
- Most common in 3rd decade.
- Sharply circumscribed, freely mobile, rubbery nodule.
- Diameter - 1 to 15 centimeter.
- Common site - Upper outer quadrant.
- Gray-white cut section with slit like spaces.
- Biopsy might be necessary, since mammography doesn't help much in young women.
- New growth in the glandular space of fibroblastic stromal, resembling normal stroma, and epithelial elements, surrounded and compressed or distorted by stroma.
- In older women the stroma becomes hyalinizedand the epithelium atrophic.
Any solid breast lesion at any age has to be evaluated, via biopsy or mammography.
- Arises from intralobular stroma, stromal proliferation.
- Presents after 6th decade.
- 15% are malignant.
- Three Types
- – Benign
- – Low grade malignant
- – High grade malignant
- Size - from small to very large.
- Color - from tan to brown; higher grade lesions are hemorrhagic.
- Bulbous growth, hence the name (phyllodes is Greek for leaf-like).
- Needs to be completely excised.
Histological features distinguishing phyllodes tumor from fibroadenoma
- In phyllodes tumor,
- Stromal cellularity and mitoses.
- Nuclear pleomorphism.
- Infiltrative borders.
- Edges of the epithelium spreading out like leaves.
- Multiple fibrovascular cores lined by ductal and myoepithelial cells grow within a dilated duct.
- Very common type of benign breast lesion.
- The tumors grow on stalks, on papillae
- Have some association with breast cancer, make sure the surrounding tissue doesn’t have breast cancer.
Key Points-Breast Carcinoma
- Lifetime risk 1 in 8
- 75% diagnosed after the age of 50
- 10% are caused by inherited mutations
- D.C.I.S. typically found mammographically
- L.C.I.S. typically incidental finding
- L.C.I.S. can result in invasive ductal or lobular carcinoma.
- Mets can develop many years after initial diagnosis.
- Prognostic factors - tumor size, lymph node involvement, mets at presentation, tumor grade, histologic type.
- ER, PR, and Her2 status help determine response to treatments.
Epidemiology and Risk Factors of breast carcinomas
- - Risk increases steadily after age 30, especially after menopause, and peaks at roughly 80.
- - 75% of women with breast cancer are older than 50.
- - 5% of women with breast cancer are younger than 40.
- Geographic variations
- - Risk is significantly higher in North America and Northern Europe.
- - Incidence and mortality are 5xs higher in the US than in Japan.
- - Environmental, rather than genetic.
- - Diet, reproductive patterns, and nursing habits.
- - Highest rate is seen in white women.
- - Hispanics, African Americans develop more aggressive tumors at younger ages and are diagnosed at later stage.
Breast Carcinoma - Classification
- In Situ Carcinoma - most common type picked up by mammogram, esp. D.C.I.S due to the calcification
- - Ductal carcinoma in situ (D.C.I.S., more)
- - Lobular carcinoma in situ (L.C.I.S.)
- Invasive carcinomas - most get ductal
- - Ductal carcinoma, N.O.S. (Not Otherwise Specified)
- • Tubular carcinoma
- • Colloid (mucinous) carcinoma
- • Medullary carcinoma
- • Papillary carcinoma
- • Metaplastic carcinoma
- - Lobular carcinoma
- • Pleomorphic lobular carcinoma
Ductal Carcinoma in Situ (D.C.I.S.)
- Not palpable; Half of mammographically detected lesions are D.C.I.S.; calcifications are often associated. Enlarged duct just like firbrocystic disease, but filled with breast cancer changes.
- Malignant clonal population of cells without invasion through the basement membrane.
- Myoepithelial cells are present, but in diminished numbers.
- Can involve the Terminal Duct Lobular Units as well as larger ducts.
- Has five architectural sub-types and can be graded by nuclear pleomorphism.
- Non-comedo D.C.I.S. - D.C.I.S. without central necrosis; nuclear grades low (to high). Calcifications may be present.
- Comedo D.C.I.S. - a.k.a. comedocarcinoma; solid sheets of cells, central necrosis, high nuclear grade.
- Microinvasion - foci of tumor cells less than 1mm invading stroma, most often seen with highest grade D.C.I.S.
- Still curable - surgical removal and radiation therapy.
Paget Disease of Breast
- In-situ breast cancer
- A form of poorly differentiated D.C.I.S. that extends from the lactiferous ducts into the skin of the nipple, causing the nipple becomes crusty, flaky, ulcerated.
- Involvement of epidermis by malignant cells.
- Only 1-4% of DCIS cases.
Lobular Carcinoma in Situ (L.C.I.S.)
- Proliferation in terminal duct or lobule (T.D.L.U.) of a monomorphic population of cells.
- Almost always an incidental finding - not usually mammographically detected.
- Dyscohesive cells with oval or round nuclei and small nuclei.
- Underlying architecture rarely distorted.
- Cell adhesion protein E cadherin is lost which results in discohesion.
- Almost always expresses estrogen and progesterone receptors.
- Overexpression of Her2/neu is not observed.
- Indicator of high risk breast cancer of either breast, not necessarily the one found with L.C.I.S.
Invasive Ductal Carcinoma, Not Otherwise Specified (NOS)
- Most are firm to hard - scarring around the tumor cells due to stromal reaction; most cancer induce this; not feeling the actual tumor.
- Scareous carcinoma - scar forming carcinoma.
- Tumor mass with irregular border-gritty.
- - Well differentiated have prominent tubule, small round nucleoli, and rare mitotic figures
- - Moderately differentiated may have tubules, but solid clusters or single infiltrating cells can be present.
- - Poorly differentiated often infiltrate as ragged nests or solid sheets of cells with enlarged nuclei.
Invasive Lobular Carcinoma
- Bilateral and multicentric.
- Poorly circumscribed.
- Diffuse invasive pattern - single cell lineup; different look vs ductal cancer.
- Loose clusters and sheets may also be seen.
- Loss of E-Cadherin.
- Metastasize to CSF, serosa, BM and solid organs.
Features of Invasive Carcinomas
- Large tumors can extend into the skin (“peau d’orange” - skin of orange), ominous sign, clinical indication of involvement of dermal lymphatics, packed with cancer cells.
- Inflammatory carcinoma - Involvement of dermal lymphatics.
- Lymphatic Spread - axillary and internal mammary nodes.
- Distant metastases to virtually any site (lungs, bone, liver, adrenals, meninges are favored sites), after a very long time.
BREAST CANCER GENETICS AND RECEPTORS
- Different locus, different allele, same phenotype
- BRCA1 and BRCA2 - hereditary breast and ovarian cancer.
- Mutations of RAS, MYC, PTEN (Cowden Syndrome), RB, p53 may be present.
- 95% breast cancer is not genetically linked.
- Molecular profiling of receptors help on selecting methods of treatment.
- 60-80% risk of breast cancer by age 70.
- Risk of ovarian cancer - 20-40%.
- Chromosome 17q21.
- Tumor suppressor, transcriptional regulator, dsDNA repair.
- >500 mutations.
- Younger age 40-50s.
- Frequency of mutation - 0.1 to 0.2%.
- Male and female breast cancer - <20%
- Other associated cancers - prostate, colon, pancreas.
- 60-80% risk of cancer
- Risk of ovarian cancer - 10-20%
- Chromosome 13q12.3
- tumor suppressor, transcriptional regulator, DNA repair
- >300 mutations
- 50 years
- Frequency of mutation - 0.1 to 0.2%
- Higher association with male breast cancer.
- Other associated malignancies - prostate, pancreas, stomach, melanoma, colon.
Estrogen and Progesterone Receptors
- 80% of double positives respond to hormone therapy, whereas only 40% of single positives respond.
- - E.R. positive alone cancers are less likely to respond to chemotherapy; may benefit from tamoxifen therapy.
- Double negative cancers are more likely to fail hormonal therapy but respond to chemotherapy.
- HER2 = Human Epidermal Growth Factor Receptor 2
- Other names: neu, C-erb-B2
- If have overexpression, can use herceptin.
Clinical Staging of Breast Cancer
- Detailed history with an EMPHASIS on symptoms suggestive of metastatic disease.
- Physical examination - positive lymph nodes are the single most important prognostic factor.
- Laboratory studies (CBC, liver function tests).
- Imaging studies.
- Tumors less than 5cm (occasionally performed for larger tumors).
- Lobular or ductal histology.
- Negative margins need to be achieved.
- Usually cosmetically acceptable.
- Axillary nodes (if present) should be mobile.
- When lumpectomy is contraindicated or will result in poor cosmesis.
- Patients at high risk for local recurrence
- Prophylactic mastectomy for high risk patients with genetic predisposition.