Systemic Pathology - Diseases of the Female Breast - Aisner/Fitzhugh

  1. Normal anatomy of breast
    • Milk-producing Lobules -> duct -> Nipple.
    • Areola.
    • Fatty tissue.
    • Most breast cancer arise from duct or lobule.
  2. 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.
  3. 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.
  4. Fibrocystic changes
    • 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
    • Acute Mastitis
    • Duct Ectasia (Plasma Cell Mastitis)
    • Plasma Cell Mastitis
  10. Acute 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.
  11. 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 .
  12. Fat Necrosis
    • 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.
    • Fibroadenoma
    • Phyllodes Tumor
    • Intraductal Papilloma
  14. Fibroadenoma
    • 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.
  15. Any solid breast lesion at any age has to be evaluated, via biopsy or mammography.
  16. Phyllodes Tumor
    • 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.
  17. 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.
  18. Intraductal Papilloma
    • 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.
  19. 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.
  20. Epidemiology and Risk Factors of breast carcinomas
    • Age
    • - 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.
    • Race/Ethnicity
    • - Highest rate is seen in white women.
    • - Hispanics, African Americans develop more aggressive tumors at younger ages and are diagnosed at later stage.
  21. 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
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. Invasive Lobular Carcinoma
    • Bilateral and multicentric.
    • Poorly circumscribed.
    • Diffuse invasive pattern - single cell lineup; different look vs ductal cancer.
    • Scarring.
    • Loose clusters and sheets may also be seen.
    • Loss of E-Cadherin.
    • Metastasize to CSF, serosa, BM and solid organs.
  27. 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.
    • 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.
  29. BRCA1
    • 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.
  30. BRCA2
    • 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.
  31. 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.
  32. HER2/neu
    • HER2 = Human Epidermal Growth Factor Receptor 2
    • Other names: neu, C-erb-B2
    • If have overexpression, can use herceptin.
  33. 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.
  34. Surgical Approaches
    • Lumpectomy
    • Mastectomy
  35. Lumpectomy
    • 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.
  36. Mastectomy
    • 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.
Card Set
Systemic Pathology - Diseases of the Female Breast - Aisner/Fitzhugh
Systemic Pathology - Diseases of the Female Breast - Aisner/Fitzhugh