Recommended
More Related Content
Similar to Breast-CA-IM.pptx
Similar to Breast-CA-IM.pptx (20)
Recently uploaded
Recently uploaded (20)
Breast-CA-IM.pptx
- 2. • To have a review of on the Basic and Clinical Sciences in relation to Breast Cancer with emphasis on the diagnosis and management of the disease OBJECTIVE
- 5. GROSS ANATOMY 15-20 lobes composed of several lobules
- 6. GROSS ANATOMY Cooper’s suspensory ligaments connective tissue insert perpendicularly into the dermis provide structural support
- 7. GROSS ANATOMY BOUNDARIES Superior: 2nd or 3rd rib Inferior: inframammary fold – 6th or 7th rib Medial: lateral border of sternum Lateral: anterior axillary line
- 8. GROSS ANATOMY BOUNDARIES Deep: Fascia of pectoralis major serratus anterior external oblique rectus sheath
- 9. GROSS ANATOMY Retromammary Bursa between investing fascia of breast pectoralis major
- 10. GROSS ANATOMY Axillary tail of Spence extends laterally across anterior axillary fold
- 11. GROSS ANATOMY
- 13. GROSS ANATOMY Batson’s vertebral venous plexus invests the vertebrae from base of skull to sacrum metastases to vertebrae, skull, pelvic bones and CNS
- 14. GROSS ANATOMY Lateral cutaneous branches of 3rd – 6th intercostal nerves Cutaneous branches from Supraclavicular nerve Intercostobrachial nerve
- 15. GROSS ANATOMY Axillary vein group 4-6 lymph nodes medial or posterior to the vein receives most of the lymph drainage from upper extremity
- 16. GROSS ANATOMY External mammary grou 5-6 lymph nodes lower border of pectoralis minor contiguous with late thoracic vessels
- 17. GROSS ANATOMY Central group 3-4 lymph nodes embedded in fat of axilla posterior to pectorali minor muscle
- 18. GROSS ANATOMY Scapular group 5-7 lymph nodes posterior wall of axill from lower posterior neck, posterior trun and posterior shoul
- 19. GROSS ANATOMY Subclavicular group 6-12 lymph nodes posterior and superio to upper border of pectoralis minor
- 20. GROSS ANATOMY Rotter’s group 6-12 lymph nodes posterior and superio to upper border of pectoralis minor
- 21. GROSS ANATOMY Level I: axillary vein external mammary scapular groups Level II: central group interpectoral groups Level III: subclavicular groups
- 24. MICROSCOPIC ANATOMY ACINUS Layers: 1. Myoepithelial cell 2. Luminal/glandular epithelial cell STROMA 1. Interlobular - Dense fibrous connective tissue 2. Intralobular - Loose fibrous connective tissue
- 25. MICROSCOPIC ANATOMY RESTING ACTIVE/LACTATING OLD AGE BREAST DEVELOPMENT
- 26. PHYSIOLOGY
- 27. PHYSIOLOGY COLOSTRUM - produced during the first few days after birth - rich in cells (lymphocytes, monocytes ), lactalbumin, fat -soluble vitamins, & minerals and contains lgA MILK - secreted by the third or fourth day after birth - consists of proteins (caseins, IgA, lactalbumin), many lipid droplets, & lactose - released from the mammary glands via the milk ejection reflex SECRETIONS OF MAMMARY GLAND
- 28. PHYSIOLOGY PROLACTIN - is the major hormone responsible for lactogenesis - is structurally homologous to growth hormone Actions: 1. Stimulates milk production in the breast 2. Stimulates breast development 3. Inhibits ovulation by decreasing synthesis and release of gonadotropin- releasing hormone (GnRH) 4. Inhibits spermatogenesis (by decreasing GnRH)
- 29. PHYSIOLOGY Regulation of Secretion: Hypothalamic control by dopamine and thyrotropin-releasing hormone (TRH) - tonically inhibited by dopamine (prolactin-inhibiting factor [PIF]) - TRH increases prolactin secretion. Negative feedback control - inhibits its own secretion by stimulating the hypothalamic release of dopamine
- 30. PATHOLOGY
- 31. BREAST CANCER • a malignant proliferation of epithelial cells lining the ducts or lobules of the breast • Epithelial malignancies of the breast are the most common cause of cancer in women (excluding skin cancer), accounting for about one third of all cancer in women. • Breast cancer is the most common non-skin malignancy in women and the second most common cause of cancer deaths. • The most important risk factors are estrogenic stimulation and age. • All cancers arise by the accumulation of DNA alterations and epigenetic changes. • Tumorigenesis also requires changes in the normal supporting cells—alteration of the normal crosstalk and function of stromal cells may be an important determinant of stromal invasion.
- 32. BREAST CANCER • the most common cause of a breast mass in postmenopausal patients • occurs most frequently in the upper outer quadrant of the breast • metastasis include axillary lymph nodes, lung, liver, and bone
- 33. RISK FACTORS Germ line mutations First-degree relatives with breast cancer Race/Ethnicity Age Age at Menarche Age at first live Estrogen Exposure Breast density Radiation Exposure Diet Obesity Exercise Breastfeeding Environmental
- 34. GENETICS • Familial – 8-10% of breast cancer • BRCA-1 (maps to chromosome 17q21) mutations account for about 5%. • BRCA-1 - involved in transcription coupled DNA repair; an increased risk of ovarian cancer in women and prostate cancer in men • BRCA-2 on chromosome 11 may account for 2–3% of breast cancer; Mutations are associated with an increased risk of breast cancer in men and women. • Germ-line mutations in p53 • Germ-line mutations in PALB2, hCHK2, and PTEN • Sporadic breast cancers • overexpression of HER2/neu in 25% of cases • p53 mutations in 40% • loss of heterozygosity at other loci
- 35. PATHOPHYSIOLOGY
- 36. BREAST CANCER TYPES 1. Ductal Carcinoma-In-Situ a. Comedo Carcinoma b. Non-Comedo 2. Lobular Carcinoma-In-Situ 3. Invasive Ductal Carcinoma 4. Invasive Lobular Carcinoma 5. Medullary Carcinoma 6. Mucinous (Colloid) Carcinoma 7. Tubular Carcinoma
- 37. 1. Ductal Carcinoma-In-Situ • Neoplastic lesions where cells are limited to ducts by the basement membrane • Frequently presents as mammographic calcifications • Myoepithelial cells are preserved • With microinvasion and atypia Sub-types: a. Comedo Carcinoma b. Non-Comedo
- 38. a. Comedo Ductal Carcinoma-In-Situ O High-grade DCIS O Center: nidus of necrosis
- 39. b. Non-Comedo 1. CRIBRIFORM - cookie-cutter like appearance 2. PAPILLARY- papillary fronds with fibrovascular core 3. MICROPAPILLARY- Papillary fronds emanating from the fronds, no fibrovascular
- 40. b. Non-Comedo 1. CRIBRIFORM - cookie-cutter like appearance 2. PAPILLARY- papillary fronds with fibrovascular core 3. MICROPAPILLARY- Papillary fronds emanating from the fronds, no fibrovascular
- 41. b. Non-Comedo 1. CRIBRIFORM - cookie-cutter like appearance 2. PAPILLARY- papillary fronds with fibrovascular core 3. MICROPAPILLARY- Papillary fronds emanating from the fronds, no fibrovascular
- 42. b. Non-Comedo 1. CRIBRIFORM - cookie-cutter like appearance 2. PAPILLARY- papillary fronds with fibrovascular core 3. MICROPAPILLARY- Papillary fronds emanating from the fronds, no fibrovascular
- 43. 2. Lobular Carcinoma-in-situ • Always an incidental finding on biopsy • Bilateral on diagnosis
- 44. 3. Invasive ductal carcinoma • Firm and hard with an irregular border • Produce a grating sound when cut or scraped • Microscopic:
- 45. 4. Invasive lobular carcinoma • Palpable mass • Greater incidence or bilateral • Histologic: Indian file pattern – discohesive infiltrating tumor cells arranged in a file • E-cadherin mutation – causes formation of discohesive cells
- 46. 5. Medullary Carcinoma • Soft, fleshy, well defined mass • Better prognosis • Histologic: Solid syncytium-like sheets of large cells with vesicular nuclei and prominent nucleoli • Moderate to marked lymphoplasmacytic infiltrate surrounding the tumor • Pushing borders • Poor differentiation
- 47. 6. Mucinous (colloid) carcinoma • Small islands of cells within large lakes of mucus • Seen in older women • Very good prognosis • Pale gray-blue gelatin mucinous substance
- 48. 7. Tubular carcinoma • No myoepithelial layer
- 49. IMMUNOSTAINS: • for medication or therapy and prognostication NUCLEAR STAINS: Estrogen Receptor (ER) & Progesterone Receptor (PR) - Hormonally Responsive, Tamoxifen MEMBRANOUS STAIN: Human Epidermal Receptor 2 (HER2NEU) - Poorer Prognosis, Trastuzumab NOTINGHAM HISTOLOGIC SCORE ER/PR + Score: 2 + HER2NEU + Score: 3 +
- 50. IMMUNOSTAINS:
- 51. GENE EXPRESSION SUBTYPES TYPES / IMMUNOSTAIN RESULT CHARACTERISTICS Luminal A ER +, PR +, HER2NEU - Express cytokeratins 8 and 18, have the highest levels of estrogen receptor expression, tend to be low grade, are most likely to respond to endocrine therapy, and have a favorable prognosis, tend to be less responsive to chemotherapy. Luminal B ER +, PR +, HER2NEU - Tumor cells are also of luminal epithelial origin, but with a gene expression pattern distinct from luminal luminal A. Prognosis is somewhat worse that luminal A. HER2 amplified ER -, PR -, HER2NEU + These tumors have amplification of the HER2 gene on chromosome 17q and frequently exhibit coamplification and overexpression of other genes adjacent to HER2. Historically the clinical prognosis of such tumors was poor. However, with the advent of trastuzumab and other targeted therapies the clinical outcome of HER2-positive patients is markedly improving. Basal ER -, PR -, HER2NEU - These estrogen receptor/progesterone receptor–negative and HER2 -negative tumors (so-called triple triple negative) are characterized by markers of basal/myoepithelial cells. They tend to be high grade, and express cytokeratins 5/6 and 17 as well as vimentin, p63, CD10, a-smooth muscle actin, and epidermal growth factor. Patients with BRCA mutations also fall within this molecular subtype. They also have stem cell characteristics. Normal breast–like Gene expression profile reminiscent of nonmalignant “normal” breast epithelium. Prognosis is similar to to the luminal B group. Somewhat controversial and may represent contamination of the sample by normal mammary epithelium.
- 52. DIAGNOSIS
- 53. DIAGNOSIS
- 54. DIAGNOSIS
- 55. SCREENING GUIDELINES TEST/PROCEDURE RECOMMENDATION POPULATION PERIOD Self-examination ≥ 20 y/o An option Clinical Examination 20-39 y/o Every 3 years ≥ 40 y/o Annually Mammography ≥ 40 y/o Annually, good health 50-74 y/o Every 2 years ≥ 75 y/o No evidence MRI With > 20% risk* Annually plus mammogram With 15-20% risk* Option, plus mammogram
- 56. STAGING
- 57. STAGING
- 58. STAGING
- 59. STAGING
- 60. • NON-INVASIVE BREAST CANCER • Ductal Carcinoma In-Situ • Surgery + Radiation Therapy + Tamoxifen • Lobular Carcinoma In-Situ • may be a premalignant lesion • treated with an SERM or an aromatase inhibitor for 5 years • Semi-annual – Physical examination • Annual - Mammography TREATMENT
- 61. • INVASIVE BREAST CANCER • Operable (Stage I and II) • Locally advanced (Stage III) • Metastatic (Stage IV) TREATMENT
- 62. • INVASIVE BREAST CANCER • Operable • Primary therapy = Modified Radical Mastectomy or Lumpectomy followed by Radiation Therapy • Node Involvement: Axillary Lymph Node dissection → Sentinel Node biopsy No additional therapy • Tumor <1cm, Negative Axillary node + Adjuvant Combination Chemotherapy (6 months) • Tumor <1cm, Positive Axillary node, Pre-menopausal; • Large Tumor (Poor Prognostic Features), Negative Axillary node, Pre/Post- menopausal; • Post-menopausal, Positive Axillary node, ER/PR Negative TREATMENT
- 63. • INVASIVE BREAST CANCER • Operable + Aromatase Inhibitor • >1cm tumor, ER/PR Positive, +/- Lymph node involvement + Adjuvant Chemotherapy + Hormonal Therapy • ER/PR positive, Lymph Node positive, Pre/Post-menopausal + Adjuvant Chemotherapy • ER/PR negative, Lymph Node positive, Pre/Post-menopausal TREATMENT
- 64. • INVASIVE BREAST CANCER • Operable + Aromatase Inhibitor • >1cm tumor, ER/PR Positive, +/- Lymph node involvement + Adjuvant Chemotherapy + Hormonal Therapy • ER/PR positive, Lymph Node positive, Pre/Post-menopausal + Adjuvant Chemotherapy • ER/PR negative, Lymph Node positive, Pre/Post-menopausal MOST EFFECTIVE REGIMEN: 4 Cycles of Doxorubicin + Cyclophosphamide → 4 cycles of Paclitaxel TREATMENT
- 65. • INVASIVE BREAST CANCER • Operable + Trastuzumab • HER2NEU Positive Tumors + Tamoxifen Adjuvant Therapy or Aromatase Inhibitor • Post-menopausal, ER/PR positive, -/+ node, Large tumor (Poor prognostic feature) feature) TREATMENT
- 66. • INVASIVE BREAST CANCER TREATMENT
- 67. • INVASIVE BREAST CANCER • Locally Advanced • Neoadjuvant Combination Chemotherapy (Cyclophosphamide, Doxorubicin, 5- Fluorouracil) for monthly cycle, 6 cycles → Surgery → Radiation Therapy TREATMENT
- 68. • INVASIVE BREAST CANCER • Metastatic Disease • Depends on ER/PR status and treatment philosophy • No therapy is known to cure patients • Median survival: 22 months with conventional treatment • Aromatase Inhibitor: ER/PR positive • Combination Chemotherapy: ER/PR negative • Trastuzumab: HER2NEU positive TREATMENT
- 69. SURGERY
- 70. • RADICAL MASTECTOMY by HALSTED • extensive surgical removal of the breast and its related structures, including the pectoralis major and minor muscles, axillary lymph nodes and fascia, and and part of the thoracic wall. • MODIFIED RADICAL MASTECTOMY • PATEY’S OPERATION - excision of the entire breast and axillary lymph nodes (I-III) and minor muscles, with preservation of the pectoralis major • SCANLON’S OPERATION – Pectoralis minor incised; Level III LN removed • AUCHINLONCLOSS’ OPERATION – Pectoralis minor left intact, Level III LN not removed • LUMPECTOMY (TYLECTOMY) • surgical excision of only the palpable mass. SURGERY
- 71. PHARMACOLOGY
- 72. PHARMACOLOGY STAGE I & II DISEASE (6) CMF protocol cyclophosphamide methotrexate fluorouracil (6) FAC protocol fluorouracil doxorubicin cyclophosphamide
- 73. PHARMACOLOGY STAGE I & II DISEASE (6) FEC protocol fluorouracil epirubicin cyclophosphamide (4) cycles of doxorubicin cyclophosphamide
- 74. PHARMACOLOGY SUBCLASS/DRUG MOA ACUTE TOXICITIES CHRONIC TOXICITIES Alkylating agent Cyclophosphamide Forms DNA cross-links, resulting in inhibition of DNA synthesis and function Nausea, vomiting Myelosuppression, alopecia, hemorrhagic cystitis Antimetabolite Methotrexate Inhibits DHFR, resulting in inhibition of synthesis of thymidylate, purine nucleotides, serine, and methionine Mucositis, diarrhea Myelosuppression Antimetabolite 5-Fluorouracil Inhibits thymidylate synthase, and its metabolites are incorporated into RNA and DNA, all resulting in inhibition of DNA synthesis and function and in RNA processing Nausea, mucositis, diarrhea Myelosuppression, neurotoxicity Anthracycline Doxorubicin Epirubicin Oxygen free radicals bind to DNA causing strand breakage; inhibits topoisomerase II; intercalates into DNA Nausea, arrhythmias Alopecia, myelosuppres sion, cardiomyopathy, myelosuppression
- 75. PHARMACOLOGY SUBCLASS/DRUG MOA ACUTE TOXICITIES CHRONIC TOXICITIES Taxane Paclitaxel Interferes with microtubule disassembly, resulting in impaired mitosis Nausea, vomiting, hypotension, arrhythmia, hypersensitivity Myelosuppression, peripheral sensory neuropathy
- 76. PHARMACOLOGY STAGE I & II DISEASE TRASTUZUMAB • monoclonal antibody against the HER-2/ neu receptor • added to anthracycline- and taxane-containing adjuvant chemotherapy • for women with HER-2-overexpressing breast cancer
- 77. PHARMACOLOGY STAGE I & II DISEASE TAMOXIFEN • beneficial in postmenopausal women when used alone or in combination with cytotoxic chemotherapy • present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection
- 78. PHARMACOLOGY SUBCLASS/DRUG MOA ACUTE TOXICITIES CHRONIC TOXICITIES Growth factor receptor inhibitor Trastuzumab Inhibits the binding of EGF to the HER-2/neu growth receptor Nausea, vomiting, chills, fever, headache Cardiac dysfunction Antiestrogen/SERM Tamoxifen Estrogen antagonist actions in breast tissue and CNS, estrogen agonist effects in liver and bone Hot flushes, thromboembolism, endometrial hyperplasia
- 79. PROGNOSIS
- 80. PREVENTION • With Breast Cancer – 0.5% per year risk of developing second breast cancer • Increased Risk of Breast Cancer • Reduce risk by 49% by taking Tamoxifen or an Aromatase inhibitor for 5 years • With BRCA-1 mutation • Reduce risk by 90% with Simple Mastectomy
Editor's Notes
- Carcinoma of the breast is the most common non-skin malignancy in women and is second only to lung cancer as a cause of cancer deaths.
- The breast is composed of *15 to 20 lobes, which are each *composed of several lobules
- Cooper’s suspensory ligaments which are *fibrous bands of connective tissue travel through the breast, *insert perpendicularly into the dermis, and *provide structural support.
- The mature female breast extends from the level of the second or third rib to the inframammary fold at the sixth or seventh rib. It extends transversely from the lateral border of the sternum to the anterior axillary line.
- The deep or posterior surface of the breast rests on the fascia of the pectoralis major, serratus anterior, and external oblique abdominal muscles, and the upper extent of the rectus sheath.
- The retromammary bursa may be identified on the posterior aspect of the breast between the investing fascia of the breast and the fascia of the pectoralis major muscles.
- The axillary tail of Spence extends laterally across the anterior axillary fold. The upper outer quadrant of the breast contains a greater volume of tissue than do the other quadrants.
- The breast receives its principal blood supply from: *(a) perforating branches of the internal mammary artery; *(b) lateral branches of the posterior intercostal arteries; and *(c) branches from the axillary artery, including the *highest thoracic, *lateral thoracic, and *pectoral branches of the thoracoacromial artery (Fig. 17-5). The second, third, and fourth anterior intercostal perforators and branches of the internal mammary artery arborize in the breast as the medial mammary arteries. The lateral thoracic artery gives off branches to the serratus anterior, pectoralis major and pectoralis minor, and subscapularis muscles. It also gives rise to lateral mammary branches.
- The veins of the breast and chest wall follow the course of the arteries, with venous drainage being toward the axilla. The three principal groups of veins are: *(a) perforating branches of the internal thoracic vein, (b) perforating branches of the posterior intercostal veins, and *(c) tributaries of the axillary vein..
- Batson’s vertebral venous plexus, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system
- Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. Cutaneous branches that arise from the cervical plexus, specifically the anterior branches of the supraclavicular nerve, supply a limited area of skin over the upper portion of the breast. The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm.
- Lymph vessels generally parallel the course of blood vessels. The boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the position of the axillary lymph nodes. The six axillary lymph node groups recognized by surgeons are: the axillary vein group (lateral), which consists of four to six lymph nodes that lie medial or posterior to the vein and receive most of the lymph drainage from the upper extremity;
- the external mammary group (anterior or pectoral group), which consists of five to six lymph nodes that lie along the lower border of the pectoralis minor muscle contiguous with the lateral thoracic vessels and receive most of the lymph drainage from the lateral aspect of the breast;
- the central group, which consists of three or four sets of lymph nodes that are embedded in the fat of the axilla lying immediately posterior to pectoralis minor muscle and receive lymph drainage both from the axillary vein, external mammary, and scapular groups of lymph nodes, and directly from the breast;
- the scapular group (posterior or subscapular), which consists of five to seven lymph nodes that lie along the posterior wall of the axilla at the lateral border of the scapula contiguous with the subscapular vessels and receive lymph drainage principally from the lower posterior neck, the posterior trunk, and the posterior shoulder
- the subclavicular group (apical), which consists of six to twelve sets of lymph nodes that lie posterior and superior to the upper border of the pectoralis minor muscle and receive lymph drainage from all of the other groups of axillary lymph nodes
- the interpectoral group (Rotter’s lymph nodes), which consists of one to four lymph nodes that are interposed between the pectoralis major and pectoralis minor muscles and receive lymph drainage directly from the breast.
- The lymph node groups are assigned levels according to their anatomic relationship to the pectoralis minor muscle. *Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. *Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral groups. *Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which consist of the subclavicular group.
- LOBE: 10 in whole breast LOBULE: many per lobule ACINUS: may per lobule DUCT: intra- or inter- lobular, lead to lactiferous ducts of Nipple So the breast is fatty / fibrofatty and glandular
- ACINUS- Histologically the smallest component) Composed of two cell layers: Myoepithelial cell: Actin, weak S-100 (immunostains) Not easily identified in H&E; needs immunostain Breached during cancer Luminal/glandular epithelial cell: EMA, keratin, milk fat globule membrane, alpha lactalbumin 100 (immunostains) INTERLOBULAR: dense fibrous connective tissues admixed with fatty tissue INTRALOBULAR: Loose fibrous CT, hormonally-responsive fibroblast-like cells admixed with scattered lymphocytes
- RESTING: 50:50 gland and stroma ration Resting mammary glands are composed of lactiferous sinuses and ducts lined in most areas by a stratified cuboidal epithelium, with a basal layer consisting of scattered myoepith e l i a l c e l ls. A basal lamina separates the epithelial components from the underlying stroma. LACTATING: glands predominate over stroma mammary g l ands are enlarged during pregnancy by the development of a lveo l i . 1 . Alveolar c e l l s (secretory cells) (Figure 19.6) a . Alveolar cells line the alveoli of active mammary glands and are surrounded by an incomplete layer of myoepith e l i a l cells. b. They are richly endowed with RER a n d contain several Golgi complexes, numerous mitochondria, lipid droplets, and vesicles containing milk protein (caseins) and lactose. ATROPHIC: stroma predominates over glands In puberty, estrogen and progesterone contribute to the development of the breast
- D . Secretions o f t h e mammary g l a nds 1. Colostrum (prote i n-rich yel lowish fluid) a. Colostrum is produced during the first few days after birth. b. It is rich in cells (lymphocytes, monocytes ), lactalbumin, fat -soluble vitamins, and minerals and contains immunog l o b u l i n A ( l gA). 2. M i l k a. Milk begins t o b e secreted b y the third or fourth day after birth. b. Milk consists of proteins (caseins, IgA, lactalbumin), many lipid droplets, and lactose. c. It is released from the mammary glands via the m i l k ejection reflex in response to a variety of external stimuli related to suckling. The milk ej ection reflex involves release of oxytoc i n (from axons i n the pars nervosa of the pituitary gland), which induces contraction of the myoepith e l i a l cel ls, forcing milk into the larger ducts and out of the breast.
- Prolactin ■■ is the major hormone responsible for lactogenesis. ■■ participates, with estrogen, in breast development. ■■ is structurally homologous to growth hormone. Actions of prolactin (1) Stimulates milk production in the breast (casein, lactalbumin) (2) Stimulates breast development (in a supportive role with estrogen) (3) Inhibits ovulation by decreasing synthesis and release of gonadotropin-releasing hormone (GnRH) (4) Inhibits spermatogenesis (by decreasing GnRH)
- a. R egulation of prolactin secretion (Figure 7.7 and Table 7.3) (1) Hypothalamic control by dopamine and thyrotropin-releasing hormone (TRH) ■■ Prolactin secretion is tonically inhibited by dopamine (prolactin-inhibiting factor [PIF]) secreted by the hypothalamus. Thus, interruption of the hypothalamic– pituitary tract causes increased secretion of prolactin and sustained lactation. ■■ TRH increases prolactin secretion. (2) Negative feedback control ■■ Prolactin inhibits its own secretion by stimulating the hypothalamic release of dopamine.
- Risk Factors. Beyond female sex, the major risk factors are related to hereditary factors, lifetime exposure to estrogen and, to a lesser extent, environmental or lifestyle factors. Among the large number of identified risk factors are the following: About 15% to 20% of women with breast cancer have an affected first degree relative (mother, sister, or daughter), Non-Hispanic white women have the highest incidence risk rises throughout a woman’s lifetime, peaking at 70 to 80 years Menarche at ages younger than 11 years increases risk by 20% Age at first live birth. A full-term pregnancy before the age of 20 halves the risk Estrogen exposure. Menopausal hormone therapy increases the risk of breast cancer, particularly when estrogen and a progestin are given together for a period of years. Breast density. Women with very dense breasts on mammography have a four- to six-fold higher risk OBESITY which is attributed to the synthesis of estrogens in fat depots. Exercise. There is a probable small protective effect Breastfeeding. The longer women breastfeed, the greater the reduction in risk. Env Toxins definitive associations have yet to be made.
- Perhaps 8–10% of breast cancer is familial. BRCA-1 mutations account for about 5%. BRCA-1 maps to chromosome 17q21 and appears to be involved in transcription coupled DNA repair. Ashkenazi Jewish women have a 1% chance of having a common mutation (deletion of adenine and guanine at position 185). The BRCA-1 syndrome includes an increased risk of ovarian cancer in women and prostate cancer in men. BRCA-2 on chromosome 11 may account for 2–3% of breast cancer. Mutations are associated with an increased risk of breast cancer in men and women. Germ-line mutations in p53 (Li-Fraumeni syndrome) are very rare, but breast cancer, sarcomas, and other malignancies occur in such families. Germ-line mutations in PALB2, hCHK2, and PTEN may account for some familial breast cancer. Sporadic breast cancers show many genetic alterations, including overexpression of HER2/ neu in 25% of cases, p53 mutations in 40%, and loss of heterozygosity at other loci.
- Major pathways of breast cancer development. Three main pathways have been identified. The most common pathway (yellow arrow) leads to ER positive carcinomas. Recognizable precursor lesions include flat epithelial atypia nad atypical hyperplasia. A less common pathway (blue arrow) leads to carcinomas that are negative for ER and HER2. The box with a question mark indicates that no precursor lesion have been identified perhaps lesions progress quickly to carcinoma. The third pathway (green arrow) consist of HER2 positive concers which may be ER positive or negative. Amlification of the HER2 gene is also presnt in a subset of atypical apocrine lesions, which may represent a precursor lesion. Each molecular subtype has a characteristic gene expression profile termed luminal.
- DCIS is a malignant clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane. The term “ductal” was used to describe this lesion because when it involves lobules, the expanded acini take on an appearance resembling small ducts. Myoepithelial cells are preserved in involved ducts/lobules, although they may be diminished in number. DCIS can spread throughout the ductal system and produce extensive lesions involving an entire sector of a breast. DCIS can be divided into two major architectural subtypes, comedo and noncomedo
- Comedo DCIS may occasionally produce vague nodularity, but more often it is detected on mammography as clustered or linear and branching areas of calcification (Fig. 23-17A). It is defined by two features: (1) tumor cells with pleomorphic, highgrade nuclei and (2) areas of central necrosis (Fig. 23-17B).
- Noncomedo DCIS lacks either high-grade nuclei or central necrosis. Several patterns may be seen. Cribriform DCIS may have rounded (cookie cutter–like) spaces (Fig. 23-17C) within the ducts, or a solid DCIS pattern.
- DCIS produces true papillae with fibrovascular cores that lack a myoepithelial cell layer.
- Micropapillary DCIS produces bulbous protrusions without a fibrovascular core, often arranged in complex intraductal patterns
- LCIS is a clonal proliferation of cells within ducts and lobules that grow in a discohesive fashion, usually due to an acquired loss of the tumor suppressive adhesion protein E-cadherin.
- Invasive carcinomas can be divided based on molecular and morphologic characteristics into several clinically important subgroups.
- Women should be strongly encouraged to examine their breasts monthly. In premenopausal women, questionable or nonsuspicious (small) masses should be reexamined in 2–4 weeks (Fig. 70-1). A mass in a premenopausal woman that persists throughout her cycle and any mass in a postmenopausal woman should be aspirated. If the mass is solid, the pt should undergo a mammogram and excisional biopsy.
- If the mass is a cyst filled with nonbloody fluid that goes away with aspiration, the pt is returned to routine screening. If the cyst aspiration leaves a residual mass or reveals bloody fluid, the pt should have a mammogram and excisional biopsy.
- Risk defined using online tools like the modified gail model. Screening mammograms performed every other year beginning at age 50 years have been shown to save lives.
- standard treatment for this disease was mastectomy. However, treatment of this condition by lumpectomy and radiation therapy gives survival that is as good as the survival for invasive breast cancer treated by mastectomy. Addition of tamoxifen to any DCIS surgical/radiation therapy regimen further improves local control. lobular neoplasia may be a premalignant lesion that suggests an elevated risk of subsequent breast cancer, rather than a form of malignancy itself, and aggressive local management seems unreasonable. Most patients should be treated with an SERM or an aromatase inhibitor (for postmenopausal women) for 5 years and followed with careful annual mammography and semiannual physical examinations.
- Ductal carcinoma in situ is noninvasive tumor present in the breast ducts. Treatment of choice is wide excision with breast radiation therapy. In one study, adjuvant tamoxifen further reduced the risk of recurrence. Invasive breast cancer can be classified as operable, locally advanced, and metastatic. In operable breast cancer, the outcome of primary therapy is the same with modified radical mastectomy or lumpectomy followed by breast radiation therapy. Axillary dissection may be replaced with sentinel node biopsy to evaluate node involvement. The sentinel node is identified by injecting a dye in the tumor site at surgery; the first node in which dye appears is the sentinel node. Women with tumors <1 cm and negative axillary nodes require no additional therapy beyond their primary lumpectomy and breast radiation. Adjuvant combination chemotherapy for 6 months appears to benefit premenopausal women with positive lymph nodes, pre- and postmenopausal women with negative lymph nodes but with large tumors or poor prognostic features, and postmenopausal women with positive lymph nodes whose tumors do not express estrogen receptors. Estrogen receptor–positive tumors >1 cm with or without involvement of lymph nodes are treated with aromatase inhibitors. Women who began treatment with tamoxifen before aromatase inhibitors were approved should switch to an aromatase inhibitor after 5 years of tamoxifen and continue for another 5 years. Adjuvant chemotherapy is added to hormonal therapy in estrogen receptor– positive, node-positive women and is used without hormonal therapy in estrogen receptor–negative node-positive women, whether they are pre- or postmenopausal. Various regimens have been used. The most effective regimen appears to be four cycles of doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, IV on day 1 of each 3-week cycle followed by four cycles of paclitaxel, 175 mg/m2, by 3-h infusion on day 1 of each 3-week cycle. In women with HER2+ tumors, trastuzumab augments the ability of chemotherapy to prevent recurrence. The activity of other combinations is being explored. In premenopausal women, ovarian ablation (e.g., with the luteinizing hormone–releasing hormone [LHRH] inhibitor goserelin) may be as effective as adjuvant chemotherapy.
- Tamoxifen adjuvant therapy (20 mg/d for 5 years) or an aromatase inhibitor (anastrozole, letrozole, exemestane) is used for postmenopausal women with tumors expressing estrogen receptors whose nodes are positive or whose nodes are negative but with large tumors or poor prognostic features. Breast cancer will recur in about half of pts with localized disease. High-dose adjuvant therapy with marrow support does not appear to benefit even women with high risk of recurrence.
- Pts with locally advanced breast cancer benefit from neoadjuvant combination chemotherapy (e.g., CAF: cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and 5-fluorouracil 500 mg/m2 all given IV on days 1 and 8 of a monthly cycle for 6 cycles) followed by surgery plus breast radiation therapy.
- Treatment for metastatic disease depends on estrogen receptor status and treatment philosophy. No therapy is known to cure pts with metastatic disease. Median survival is about 22 months with conventional treatment: aromatase inhibitors for estrogen receptor–positive tumors and combination chemotherapy for receptor-negative tumors. Pts whose tumors express HER2/neu have higher response rates by adding trastuzumab (anti-HER2/neu) to chemotherapy. Trastuzumab emtansine is a drug conjugate that targets HER2-expressing cells and has antitumor activity. Some advocate sequential use of active single agents in the setting of metastatic disease. Active agents in anthracycline- and taxane-resistant disease include capecitabine, vinorelbine, gemcitabine, irinotecan, and platinum agents. Pts progressing on adjuvant tamoxifen may benefit from an aromatase inhibitor such as letrozole or anastrozole. Half of pts who respond to one endocrine therapy will respond to another. Bisphosphonates reduce skeletal complications and may promote antitumor effects of other therapy. Radiation therapy is useful for palliation of symptoms.
- Radical mastectomy is the extensive surgical removal of the breast and its related structures, including the pectoralis major and minor muscles, axillary lymph nodes and fascia, and part of the thoracic wall. It may injure the long thoracic and thoracodorsal nerves and may cause postoperative swelling (edema) of the upper limb as a result of lymphatic obstruction caused by the removal of most of the lymphatic channels that drain the arm or by venous obstruction caused by thrombosis of the axillary vein. Modifi ed radical mastectomy involves excision of the entire breast and axillary lymph nodes, with preservation of the pectoralis major and minor muscles. (The pectoralis minor muscle is usually retracted or severed near its insertion into the coracoid process.) Lumpectomy (tylectomy) is the surgical excision of only the palpable mass in carcinoma of the breast.
- In this situation, postoperative use of systemic adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF protocol) or of fluorouracil, doxorubicin, and cyclophosphamide (FAC) has been shown to significantly reduce the relapse rate and prolong survival.
- Alternative regimens with equivalent clinical benefit include four cycles of doxorubicin and cyclophosphamide and six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Each of these chemotherapy regimens has benefited women with stage II breast cancer with one to three involved lymph nodes.
- Women with four or more involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premenopausal women who have been treated aggressively with multiagent combination chemotherapy. The results from three randomized clinical trials clearly show that the addition of trastuzumab, a monoclonal antibody directed against the HER-2/ neu receptor, to anthracycline- and taxane-containing adjuvant chemotherapy benefits women with HER-2-overexpressing breast cancer with respect to disease-free and overall survival.
- Breast cancer was the first neoplasm shown to be responsive to hormonal manipulation. Tamoxifen is beneficial in postmenopausal women when used alone or in combination with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit. Postmenopausal women who complete 5 years of tamoxifen therapy should be placed on an aromatase inhibitor such as anastrozole for at least 2.5 years, although the optimal duration is unknown. In women who have completed 2–3 years of tamoxifen therapy, treatment with an aromatase inhibitor for a total of 5 years of hormonal therapy is now recommended (see Chapter 40 ). Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35–50% over 15 years), this risk can be further reduced with adjuvant therapy.
- The most important prognostic variables are provided by tumor staging. The size of the tumor and the status of the axillary lymph nodes provide reasonably accurate information on the likelihood of tumor relapse. The relation of pathologic stage to 5-year survival is shown in the table.
- Women with breast cxancer have 0.5 % per year risk of developing a second breast cancer. Women at risk of breast cancer can reduce their risk by 49% by taking tamoxifen or an aromatase inhibitor for 5 years. Women with BRCA 1 mutations can reduce the risk by 90% with simple mastectomy.