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260 Cards in this Set
- Front
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1. What is the prevalence of breast CA?
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Breast CA is the most common non-skin CA in women and the 2nd leading cause of CA death (after lung CA) among women in the US.
In 2005, approx 213,00 women were diagnosed w/invasive breast CA, and over 40,000 died of breast CA. |
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2. What are the risk factors for breast CA?
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Risk factors include older age, family Hx of beast CA, early menarche, late menopause, first-term pregnancy after 25, nulliparity, prolonged use of exogenous estrogen, and postmenopausal obesity.
Exposure to ionizing radiation, as is used in the Tx of Hodgkin's disease, also increases the risk of breast CA. |
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3. What about genetic factors and breast CA?
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Only 5-10% of pts with breast CA are associated w/the breast CA susceptibility genes, BRCA1 and BRCA2.
Pts w/multiple affected family members or those with personal or family history of male breast CA, bilateral breast CA, or ovarian CA should be offered genetic counseling and genetic testing for BRCA1 and BRCA2. |
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4. What is the morphology of most breast CAs?
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Most are infiltrating ductal adenocarcinomas. A smaller proportions are infiltrating lobular adenocarcinomas.
Tubular and mucinous carcinomas are associated w/a better prognosis. |
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5. What about estrogen or progesterone status of breast CAs?
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The estrogen and progesterone receptor status of the primary tumor should be assessed in all cases of invasive breast CA. The oncoprotein oncogene HER-2/neu is important in defining prognosis and Tx.
***Tumors that are negative for the estrogen and progesterone receptor and for overamplification of the HER2 oncogene are associated w/a poorer prognosis.*** *Such tumors are characteristic of those that develop in women who have the BRCA1 breast cancer susceptibility gene. |
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6. Where does breast CA metastasize to?
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Recurrent breast CA most commonly exhibits metastases in the bone, liver, lung, adrenals, and CNS, but breast CA can recur in any organ of the body.
Women w/a Hx of breast CA are also at an increased risk of breast CA in the contralateral breast. |
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7. Why is breast CA sometimes suspected in women w/o a palpable mass?
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Inflammatory breast CA is a clinical Dx in a woman with breast induration and erythema, often w/o a palpable mass.
The skin findings are due to tumor emboli in the dermal lymphatics; skin biopsy is negative for CA in 50% of pts. |
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8. What are the surgical treatments for women with breast CA?
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For women w/small breast tumors, breast conserving therapy with lumpectomy followed by radiation therapy is standard therapy.
Women w/large tumors or w/2 or more tumors in separate quadrants of the breast should undergo mastectomy. Some women also prefer mastectomy, with or w/o breast reconstruction. Women who have had previous radiation to the breast, either for a previous breast CA or other malignancies, are generally treated w/mastectomy. |
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9. What is primary or neo-adjuvant chemotherapy?
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Chemo administered before surgical treatment (primary or neo-adjuvant chemotherapy) may allow breast conservation in women with large tumors who would otherwise not be able to undergo a lumpectomy.
*Adjuvant therapy with chemo and hormonal therapy improves relapse free and overall survival rates in premenopausal and postmenopausal women who are at high risk of metastatic relapse. |
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10. What is the name of the drug that treats HER2 positive breast CA?
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The monoclonal antibody trastuzumab, directed at the HER-2 pathway, improves disease free survival in pts w/tumors that have overamplification of the HER-2 oncoprotein.
It can be sued in combo with chemo, hormonal therapy, or as a single agent. |
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11. What can be given to pts to decrease the pain associated w/bone metastases and the risk of fracture in women with skeletal metastases?
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Bisphosphonates, such as zoledronate and pamidronate are given via IV to decrease the pain associated with bone metastases and prevent fractures.
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12. How is DCIS treated?
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DCIS is treated with either lumpectomy followed by radiation therapy or mastectomy. Women with multifocal or palpable DCIS should have assessment of lymph node status b/c a small but measurable proportion will have positive lymph node involvement that indicate foci of invasive CA.
In these pts, systemic Tx is identical to that given to women with a clearly invasive breast primary tumor. |
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13. What are some prophylactic Tx options for women with BRCA1 or BRCA2 susceptibility genes?
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Prophylactic bilateral mastectomy is offered. An alternative approach is close clinical surveillance, including monthly self examination, freq examination by a physician, and regular mammography or MRI.
Oophorectomy or anti-estrogen therapy can be used to decrease the risk of breast CA in these women and in other women at high risk of the disease. |
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14. Ipratropium and tiotropium
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MOA: Anticholinergics that are antagonists at muscarinic receptors on airway smooth muscle and glands, leading to decreased bronchoconstriction and mucus secretion
PURPOSE: Asthma, COPD, rhinitis ADVERSE: Paralytic ileus, angioedema, bronchospasm, abnormal taste, dry mouth, dry nasal mucus, constipation, tachycardia, urinary retention CONTRA: Hypersensitivity to ipratropium and tiotropium; and to soya lecithin or related food products NOTES: Tiotropium has a long duration of action b/c of slow dissociation kinetics from M1 and M3 receptors |
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15. Epinephrine
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MOA: Epinephrine is a non-selective adrenergic agonist that binds to α, β1, and β2 receptors. It acts through a stimulatory G protein to cause smooth muscle relaxation and bronchodilation.
PURPOSE: Asthma, anaphylaxis, cardiac arrest, open-angle glaucoma ADVERSE: Cardiac arrhythmias, hypertensive crisis, pulmonary edema, tachycardia, palpitations, sweating, nausea, vomiting, tremor, nervousness, dyspnea CONTRA: Narrow-angle glaucoma (ophthalmic form); within 2 weeks of MAOI use NOTES: Causes cardiac stimulation via β1 receptors and hypertension via α receptors |
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16. Isoproterenol
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MOA: Isoproterenol stimulates both β1 and β2 receptors and therefore causes both bronchodilation and cardiac stimulation.
PURPOSE: Asthma, cardiac arrest, decreased vascular flow, heart block, shock, Stokes-Adams syndrome ADVERSE: Tachyarrhythmia, palpitations, dizziness, headache, tremor, restlessness CONTRA: Tachyarrhythmias, angina pectoris, digitalis-induced tachycardia or heart block |
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17. What are the names of the newer agents that are selective agonists at β2 receptors?
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Isoetharine
Metaproterenol Terbutaline Albuterol Levalbuterol Pirbuterol Bitolterol |
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18. Isoetharine
Metaproterenol Terbutaline Albuterol Levalbuterol Pirbuterol Bitolterol |
MOA: These agents are selective at β2 receptors. Terbutaline, albuterol, pirbuterol, and bitolterol bind to β2 receptors 200-400x more strongly than to β1 receptors, and cause fewer cardiac effects.
PURPOSE: Asthma, COPD ADVERSE: Similar to isoproterenol, except with significantly fewer cardiac effects due to β2 receptor selectivity CONTRA: Hypersensitivity NOTES: *Levalbuterol has stronger β2 binding affinity and is more β2 selective than racemic albuterol* |
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19. Formoterol and Salmeterol
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MOA: Due to their lipophilic side chains that resist degradation, formoterol and salmeterol are long acting β2 agonists, causing smooth muscle relaxation and bronchodilation
PURPOSE: Asthma, COPD ADVERSE: Similar to isoproterenol, except with significantly fewer cardiac effects due to β2 receptor selectivity CONTRA: Hypersensitivity NOTES: These have a duration of action lasting 12-24 hours. ***Salmeterol should not be used for acute asthma flares due to its slow onset of action*** |
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20. What are the names of the methylxanthines?
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Theophylline and Aminophylline
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21. Theophylline and Aminophylline
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MOA: Theophylline and Aminophylline are *nonselective phosphodiesterase inhibitors* that prevent the degradation of cAMP; also act as adenosine receptor antagonists. The combined effect is smooth muscle relaxation and bronchodilation.
PURPOSE: Asthma, COPD ADVERSE: Ventricular arrhythmia, seizure, tachyarrhythmias, vomiting, insomnia, tremor, restlessness CONTRA: Hypersensitivity |
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22. Therapeutic notes for Theophylline and Aminophylline (6 of them)
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1. Theophylline and Aminophylline are nonspecific inhibitors or phosphodiesterases that inhibit phosphodiesterase in both airway smooth muscle and inflammatory cells.
2. While inhibition of phosphodiesterase type 3 and 4 in smooth muscle results in bronchodilation, inhibition of phosphodiesterase type 4 in T cells and eosinophils causes an immunodulatory and anti-inflammatory effect. 3. Plasma levels must be monitored to prevent toxic levels of these agents 4. Avoid coadministration with fluvoxamine, enoxacin, emxilectine, propranolol, and troleandomycin due to increased risk of theophylline toxicity 5. Avoid coadministration with zafirlukast b/c theosphylline can decrease plasma concentration of zarfirlukast 6. Structural relative or caffeine |
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23. What are the inhaled corticosteroids used to treat asthma?
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Beclomethasone
Triamcinolone Fluticasone Budesonide Flunisolide Mometasone Ciclesonide |
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24. What is the advantage to using these inhaled corticosteroids? What is a specific feature of their structure that can help with inhalation?
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B/c inhaled corticosteroids produce higher local drug concentrations in the airway than an equivalent dose of systemically administered corticosteroids, a lower overall dose can be administered, reducing the likelihood of significant systemic effects.
*Although all corticosteroids are active in asthma when given systemically, substitution at the 17α position increases topical absorption and allows them to be active when given by inhalation. |
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25. What are the 3 main effects of these corticosteroids on the cytokines?
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1. Increase the transcription of genes coding for the β2 adrenergic receptor and a number of anti-inflammatory proteins such as IL-10, IL-12, and IL-1ra (IL-1 receptor antagonist)
2. Decrease transcription of genes coding for pro-inflammatory proteins, such as IL-2 thru IL-6, IL-11, IL-13, IL-15, TNF-α, GM-CSF, SCF, iNOS, COX, phospholipase A2, endothelin-1 3. Corticosteroids induce apoptosis in a number of inflammatory cells, particularly eosinophils and TH2 lymphocytes. |
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26. What are the 2 important cytokines that are inhibited by corticosteroids in asthma?
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***Inhibition of IL-4 and IL-5 markedly reduces the inflammatory response in asthma.***
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27. Beclomethasone
Triamcinolone Fluticasone Budesonide Flunisolide Mometasone Ciclesonide |
MOA: Inhibit COX-2 action and prostaglandin biosynthesis by inducing lipocortins, activating endogenous anti-inflammatory pathways, and other mechanisms
PURPOSE: Asthma, COPD ADVERSE: Osteopenia or osteoporosis in adults, delay in growth in children, local adverse effects, such as oropharyngeal cadidiasis and hoarseness to to oropharyngeal deposition CONTRA: Systemic fungal infection NOTES: ***Newer steroids (all but beclomethasone and triamcinolone) are subject to first-pass metabolism in the liver, such that much of the inadvertently swallowed dose does not reach the systemic circulation. This limits the incidence of adverse effects. Rinse mouth after inhalation to limit oropharyngeal candidiasis. |
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28. Cromolyn and Nedocromil
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MOA: Cromolyns inhibit chloride ion transport, which in turn affects calcium gating to prevent granule release, possibly decreasing mast cell response to inflammatory stimuli.
PURPOSE: Asthma, allergic rhinitis, keratitis, keratoconjunctivitis, mast cell disorder, vernal conjunctivitis ADVERSE: Abnormal taste, burning sensation in eye, cough, throat irritation CONTRA: Hypersensitivity NOTES: Used primarily as prophylactic therapy in pts with allergic asthma associated w/specific triggers; useful in patients w/exercise induced asthma; can be taken immediately prior to exercise; More effective in children and young adults than in older pts; excellent safety profile, but less efficacious than other asthma medications |
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29. What are the 3 leukotriene modifying agents used in the treatment of asthma?
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Zileuton
Montelukast Zafirlukast |
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30. Zileuton
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MOA: Zileuton inhibits LOX-5, which catalyzes the formation of leukotrienes from arachidonic acid
PURPOSE: Asthma ADVERSE: Increased LFT's, urticaria, abdominal discomfort, dizziness, insomnia CONTRA: Active liver disease, elevated LFT's NOTES: Avoid concurrent use of dihydroergotamine, ergoloid mesylates, ergonovine, methylergonovine due to an increased risk of ergotism (nausea, vomiting, vasospastic ischemia). |
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31. Montelukast and Zafirlukast
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MOA: Selective antagonists of the cysteinyl leukotriene (CysLT) type-1 receptor
PURPOSE: Chronic asthma, perennial allergic rhinitis (montelukast), seasonal allergic rhinitis (montelukast) ADVERSE: Allergic granulomatosis angiitis, hepatitis, GI distress, hallucinations, agitation, Churg-Strauss syndsrome CONTRA: Hypersensitivity NOTES: Montelukast and zafirlukast are not indicated for acute asthma attacks and are generally not appropriate as monotherapy for asthma. Both drugs are excreted in breast milk. Not as effective as inhaled corticosteroids b/c the leukotriene pathway is just one of many involved in causing asthma |
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32. Omalizumab
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MOA: Humanized mouse monoclonal antibody against the high-affinity IgE-receptor (FcεRI)-binding domain on human IgE. Prevents IgE from binding to FcεRI on mast cells and APCs; also, decreases the quantity of circulating IgE. The combined effect is a decrease in allergic response in asthma.
PURPOSE: Severe cases of asthma ADVERSE: Extremely rare anaphylactic reactions; injection site reaction, rash, headache CONTRA: Hypersensitivity NOTES: Affects both the early- and late-phase asthmatic responses to challenge by an inhaled allergen. Administered subcutaneously every 2-4 weeks; high cost limits its use to severe cases of asthma |
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33. What are the clinical characteristics of mild intermittent (step 1) asthma? Tx?
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Step 1:
Symptoms ≤ 2x/week Nocturnal awakenings ≤ 2x/month Exacerbations: brief Lung function normal btwn exacerbations Limited peak flow variability Tx in short term: Short acting β-agonist as needed for symptoms or prior to expected exposures |
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34. What are the clinical characteristics of mild persistent (step 2) asthma? Tx?
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Step 2:
Symptoms > 2x/week Nocturnal awakenings > 2x/month Exacerbations: brief and may affect activity Lung function normal when asymptomatic Peak flow decreased 20-30% when symptomatic Tx in short term: Short acting β-agonist as needed for symptoms Tx in long term: Inhaled low-dose corticosteroid |
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35. What are the clinical characteristics of moderate persistent (step 3) asthma? Tx?
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Step 3:
Daily symptoms Nocturnal awakenings > 1 time/week Frequent exacerbations lasting days, affecting activity Lung function 60-80% of predicted Peak flow variability > 30% Tx in short term: Short acting β-agonist as needed for symptoms Tx in long term: Inhaled low- to medium-dose corticosteroid and long acting inhaled β-agonist. Alternatives include steroid + sustained release theophylline; or low dose steroid + leukotriene pathway modifier |
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36. What are the clinical characteristics of severe persistent (step 4) asthma? Tx?
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Step 4:
Continual symptoms Limited activity Freq nocturnal awakenings Freq, severe exacerbations Lung function < 60% of predicted Peak flow variability > 30% Tx in short term: Short acting β-agonist as needed for symptoms Tx in long term: Inhaled high-dose corticosteroid and long acting inhaled β-agonist. *Oral corticosteroids if needed* |
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37. What are milkline remnants?
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Supernumerary nipples or breasts result from the persistence of epidermal thickening along the milk line, extending from the axilla to the perineum, both below the adult breast and above it in the anterior axillary fold.
The disorders that affect the normally situated breast may rarely arise in these heterotopic foci, occasionally, the cyclic changes of the menstrual cycle cause painful premenstrual enlargements. |
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38. What is accessory axillary breast tissue?
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In some women, the normal ductal system extends into subcutaneous tissue of the chest wall and into the axillary fossa. A mastectomy might remove the entire breast but not remove all breast epithelium.
Therefore, prophylactic masectomies markedly reduce but do not completely eliminate the risk of developing breast CA. |
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39.What is congenital nipple inversion, and why is it important?
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The failure of the nipple to evert during development is common and may be unilateral.
Nipple inversion is of clinical significance b/c it may be confused with acquired retraction of the nipple, which is sometimes associated with an invasive CA or inflammatory disease of the nipple. |
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40. What is macromastia?
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The appropriate breast size is subjective. However, some women develop severe back pain and disability b/c of very large breasts. The large size may be due to variations in body habitus or to an unusual tissue response to hormonal changes during puberty resulting in massive rapid breast growth (juvenile hypertrophy).
Reduction mammoplasty removes breast tissue but preserves the nipple. |
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41. What is the most common complication associated with breast implants?
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The formation of a thick fibrous capsule that causes cosmetic deformity.
The typical histologic response is a chronic inflammatory infiltrate of lymphocytes, macrophages, and giant cells with associated fibrosis. Silicone gel seeps thru intact shells and is freq seen in the surrounding tissue. This gel can be transported into axillary lymph nodes. |
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42. What are 3 general points that can be made about the frequency of various breast problems?
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1. Breast symptoms and signs are common problems in clinical practice.
2. It is fortunate that the majority of breast symptoms or lesions will prove to have a benign etiology. 3. The physical, psychological, and financial costs of investigating benign breast disease, primarily to exclude malignancy, are substantial. |
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43. What are the most common symptoms reported by women regarding their breasts?
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Pain, a palpable mass, or nipple discharge.
*Pain is the most common breast symptom. Noncyclical pain is usually associated with a focal site in the breast. |
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44. What are the most commonly encountered breast lesions, and where do they occur?
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The most commonly encountered lesions are invasive CAs, fibroadenomas, and cysts.
Approx 50% of CAs arise in the upper outer quadrant, 10% in each of the remaining quadrants, and about 20% in the central or subareolar region. |
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45. What are the most common etiologies for nipple discharge?
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Solitary large duct papillomas, cysts, or CA.
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46. What are the characteristics of palpable masses?
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Most are simple cysts that can be completely aspirated w/resolution of the mass. Masses become less common w/age, while the likelihood of CA increases (10% of masses in women under 40 are malignant, compared to 60% of masses in women over 50).
Over 90% of palpable CAs are invasive. These CAs average 2.4 cm in size and 58% have lymph node metastases. |
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47. What are the types of mammographic abnormalities?
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Mammographic abnormalities requiring biopsy occur in about 2% of screened asymptomatic women. A malignant lesion is found in 25-30% of cases. Densities due to malignancy will be invasive CA in over 90% of cases and only rarely DCIS.
CAs associated with calcifications are due to DCIS in 71% of cases and small invasive CAs in the remainder. |
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48. So, what is the most common malignancy associated with calcifications?
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DCIS
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49. What is acute mastitis?
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Almost all cases of acute mastitis occur during lactation; most of these arise during the first month of nursing.
During the early weeks of nursing, the breast is vulnerable to bacterial infection b/c of the development of cracks and fissures in the nipples. From this portal of entry, usually Staph aureus, or less commonly, streptococci invade the breast tissue. |
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50. What are the clinical features of acute mastitis?
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Women present with an erythematous painful breast, usually accompanied by a fever. At the outset, only one duct system or sector of the breast is involved. If not treated, the infection may spread to the entire breast.
Most cases of lactational mastitis are easily treated w/appropriate antibiotics and complete drainage of milk from the breast. Rarely, surgical drainage may be required. |
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51.What is the morphology of acute mastitis?
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Staph infections tend to produce a localized area of acute inflammation that may progress to the formation of single or multiple abscesses.
Streptococcal infections tend to cause, as they do in all tissues, a diffuse spreading infection that eventually involves the entire breast. The involved breast tissue may be necrotic and is infiltrated by neutrophils. |
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52. What is periductal mastitis?
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In this condition (AKA Zuska disease, recurrent subareolar abscess), women, as well as men, present w/a painful erythematous subareolar mass, which is usually clinically though to be an infectious process
*More than 90% of pts with periductal mastitis are smokers. This condition is not associated w/lactation or age. In recurrent cases, a fistula tract often tunnels under the smooth muscle of the nipple and opens into the skin at the edge of the areola. |
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53. What is the pathogenesis of periductal mastitis?
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Many women w/this condition have an inverted nipple secondary to fibrosis and scarring, and it has been suggested that this condition might contribute to the squamous metaplasia of the ducts.
However, in most women, the inversion is more likely a secondary phenomenon due to the inflammatory response. The strong association with smoking may be due to a vitamin A deficiency that alters the differentiation of the ductal epithelium. |
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54. What is the morphology of periductal mastitis?
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The main histologic feature is keratinizing squamous epithelium extending to an abnormal depth into the orifices of the nipple ducts.
Keratin is trapped within the ductal system and causes dilation and eventually rupture of the duct. An intense chronic and granulomatous inflammatory response develops to keratin spilled into periductal tissue. If secondary infections w/skin bacteria or with mixed anaerobes occur, acute inflammation is also present. |
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55. How is periductal mastitis treated?
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Appropriate clinical management requires removing the involved duct and fistula tract in continuity, which, in most cases is curative.
Incision drains the abscess cavity, but the offending keratinizing epithelium remains and recurrences are common. If a superimposed infection is present, antibiotic therapy must be directed toward the bacteria present, as standard staphylococcal therapy is usually ineffective. |
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56. What is mammary duct ectasia?
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This disorder tends to occur in the 5th or 6th decade of life, usually in multiparous women, and, unlike periductal mastitis, it is not associated with smoking.
Pts present w/a poorly defined palpable periareolar mass, sometimes with skin retraction, often accompanied by thick, white nipple secretions. Pain and erythema are uncommon. *This lesion is of clinical significance b/c the formation of an irregular mass can be mistaken for a CA by palpation and by mammogram. |
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57. What is the morphology of mammary duct ectasia?
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This lesion is characterized *chiefly by dilation of ducts, inspissation of breast secretions, and a marked periductal inflammatory reaction.*** The dilated ducts are filled by granular debris that contains principally lipid-laden macrophages.
The periductal and interductal inflammation is manifested by heavy infiltrates of lymphocytes and macrophages, with a striking predominance of plasma cells in some cases. On occasion, granulomatous inflammation forms around cholesterol deposits. Fibrosis may eventually produce skin and nipple retraction. Squamous metaplasia of nipple ducts is not a feature of this disorder. |
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58. What is fat necrosis of the breast?
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Fat necrosis can present as a painless palpable mass, skin thickening or retraction, a mammographic density, or mammographic calcifications. The majority of women will give a history of trauma or prior surgery.
*The major clinical significance of this condition is its possible confusion w/breast CA as a palpable mass or mammographic calcifications. |
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59. What is the morphology of fat necrosis of the breast?
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Grossly, the lesion may consist of hemorrhage in the early stages and later central liquefactive necrosis of fat.
Still later, it may appear as an ill-defined nodule of gray-white, firm tissue containing small foci of chalky white or hemorrhagic debris. The central focus of necrotic fat cells is initially surrounded by macrophages and an intense neutrophilic infiltration. Then, during the next few days, progressive fibroblastic proliferation, increased vascularlization, and lymphocytic and histiocytic infiltration wall of the focus. Subsequently, foreign body giant cells, calcifications, and hemosiderin make their appearance, and eventually the focus is replaced by scar tissue or is encysted and walled off by collagenous tissue. |
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60. What is lymphocytic mastopathy (sclerosing lymphocytic lobulitis)?
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This condition presents with single or multiple hard palpable masses. In some cases, the masses are bilateral or are detected as mammographic densities.
The lesions are so hard that it can be difficult to obtain tissue with a needle biopsy. *This condition is most common in women with type 1 DM, or autoimmune thyroid disease. Therefore, it is hypothesized that this is an autoimmune disease of the breast. The only clinical significance is to distinguish this condition from CA. |
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61. What is the morphology of lymphocytic mastopathy (sclerosing lymphocytic lobulitis)?
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Microscopically, they show collagenized stroma surrounding atrophic ducts and lobules.
The epithelial basement membrane is often thickened. A prominent lymphocytic infiltrate surrounds epithelium and blood vessels. |
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62. What is granulomatous mastitis?
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Granulomas in the breast are caused by a wide variety of diseases, all of them rare, and are present in fewer than 1% of all breast biopsies. Systemic granulomatous disease (e.g., Wegener granulomatosis, sarcoidosis) may involve the breast; on occasion, the breast may be the presenting site of involvement.
Infections (mycobacterial, fungal) occur, most commonly in immunocompromised pts or in the setting of a breast prothesis or nipple piercing. |
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63. What about Granulomatous lobular mastitis?
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Granulomatous lobular mastitis is an uncommon breast-limited disease distinguished by granulomas involving lobular epithelium.
Only parous women are affected, and it is hypothesized that the disease is a hypersensitivity reaction mediated by prior alterations in lobular epithelium during lactation. |
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64. What are the 3 groups of benign epithelial lesions in the breasts?
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1. Nonproliferative breast changes
2. Proliferative breast disease 3. Atypical hyperplasia |
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65. What are the nonproliferative breast changes (fibrocystic changes)?
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This group includes a miscellany of alterations in the female breast. These lesions might come to clinical attention when they mimic CA by producing palpable lumps, mammographic densities or calcifications, or nipple discharge.
The involved areas, by palpation, may have an ill-defined diffuse increase in consistency as well as discrete nodularities that can make detection of other breast masses more difficult. |
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66. What are the 3 principal patterns of morphologic nonproliferative breast change?
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1. Cyst formation, often with apocrine metaplasia
2. Fibrosis 3. Adenosis |
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67. What is the morphology of the cysts in nonproliferative breast change?
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Small cysts form by the dilation and unfolding of lobules. When cystic lobules coalesce, larger cysts are formed. Unopened cysts are brown to blue (blue-dome cysts)) owing to the contained semi-translucent, turbid fluid.
Cysts are lined either by a flattened atrophic epithelium or by cells altered by apocrine metaplasia. Metaplastic cells have an abundant granular, eosinophilic cytoplasm, with round nuclei, resembling the apocrine epithelium of sweat glands. Papillary projections may be present in cysts are calcifications are common. "Milk of calcium" is a term radiologists use to describe calcifications in large cysts that look as if they are lining the bottom of a rounded cysts on mammography. |
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68. What is the morphology of the fibrosis in nonproliferative breast change?
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Cysts freq rupture, with release of secretory material into the adjacent stroma.
The resulting chronic inflammation and fibrous scarring contribute to the palpable firmness of the breast. |
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69. What is the morphology of the adenosis in nonproliferative breast change?
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Adenosis is defined as an increase in the number of acini per lobule. A normal physiologic adenosis occurs during pregnancy throughout the breast. In nonpregnant women, adenosis can occur as a focal change.
The acini are enlarged (blunt duct adenosis) and are not distorted as is seen in sclerosing adenosis,. Calcifications are occasionally present within lumens. |
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70. What are lactational adenomas?
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Lactational adenomas present as palpable masses in pregnant or lactating women. They are formed by normal-appearing breast tissue w/physiologic adenosis and epithelial lactational changes.
These lesions are probably not true neoplasms but an exaggerated focal response to hormonal influences. |
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71. What is proliferative breast disease w/o atypia?
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These changes rarely form palpable masses. More commonly, they are detected as mammographic densities (e.g., complex sclerosing adenosis), or as incidental findings in biopsies performed for other reasons.
More than 80% of large duct papillomas present as nipple discharge, the remainder as small palpable masses or mammographic densities. |
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72. What can cause bloody vs. non-bloody discharge from a nipple in papillomas?
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A large papilloma can spontaneously infarct, possibly b/c of torsion on the stalk, resulting in a bloody discharge.
Non-bloody discharge probably results from intermittent blockage and release of normal breast secretions or irritation of the duct by the papilloma. |
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73. What are the 5 entities that are considered proliferative breast disease w/o atypia?
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1. Moderate or florid epithelial hyperplasia
2. Sclerosing adenosis 3. Complex sclerosing lesions 4. Papillomas 5. Fibroadenoma with complex features |
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74. What is the morphology of epithelial hyperplasia?
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In the normal breast, only myoepithelial cells and a single layer of luminal cells are present above the basement membrane. Epithelial hyperplasia is defined by the presence of more than 2 cell layers. Hyperplasia is moderate to florid when there are more than 4 cell layers.
The proliferating epithelium, often including both luminal and myoepithelial cells, fills and distends the ducts and lobules. Irregular lumens (fenestrations) can usually be discerned at the periphery of the cellular masses. |
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75. What is the morphology of sclerosing adenosis?
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The number of acini per terminal duct is increased to at least 2x the number found in uninvolved lobules. The normal lobular arrangement is maintained. The acini are compressed and distorted in the central portions of the lesion but characteristically dilated at the periphery.
Myoepithelial cells are usually prominent. On occasion, stromal fibrosis may completely compress the lumens to create the appearance of solid cords or double strands of cells lying within dense stroma, a histologic pattern that at times closely mimics the appearance of invasive CA. Calcifications are freq present w/in the lumens of the acini. |
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76. What is the morphology of complex sclerosing lesions (radial scar)?
|
Radial scars are stellate lesions characterized by a central nidus of entrapped glands in a hyalinized stroma. These lesions can resemble irregular invasive CAs mammographically or on gross exam.
The term "scar" refers to the morphologic appearance, as these lesions are not associated with prior trauma or surgery. |
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77. What is the morphology of the papillomas in proliferative breast disease w/o atypia?
|
Papillomas are composed of multiple branching fibrovascular cores, each having a connective tissue axis lined by luminal and myoepithelial cells.
Growth occurs within a dilated duct. Epithelial hyperplasia and apocrine metaplasia are frequently present. Large duct papillomas are usually solitary and situated in the lactiferous sinuses of the nipple. Small duct papillomas are commonly multiple and located deeper w/in the ductal system. |
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78. What is the significance of small duct papillomas?
|
Small duct papillomas have been shown to be a component of proliferative breast disease and increase the risk of subsequent CA.
|
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79. What is proliferative breast disease w/atypia?
What are the two types? |
Proliferative breast disease w/atypia includes atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH).
ADH is present in 5-17% of biopsies performed for calcifications and is found less frequently in biopsies for mammographic densities or palpable masses. Occasionally, ADH is associated with radiologic calcifications; more commonly it is adjacent to another calcifying lesion. ALH is an incidental finding and is found in fewer than 5% of biopsies. |
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80. What is the morphology of atypical ductal hyperplasia
|
ADH is recognized by its histologic resemblance to DCIS, includign a monomorphic cell population, regular cell placement, and round lumina. However, the lesions are characteristically limited in extent, and the cells are not completely monomorphic in type or they fail to completely fill ductal spaces.
*ADH lacks sufficient qualitative or quantitative features for a Dx of DCIS. |
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81. What is the morphology of atypical lobular hyperplasia?
|
ALH refers to a proliferation of cells identical to those of LCIS but the cells do not fill or distend more than 50% of the acini within a lobule. ALH can also extend into ducts, and this finding is associated with an increase risk of developing invasive CA.
*ALH lacks sufficient qualitative or quantitative features for a Dx of LCIS. |
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82. What is the clinical significance of benign epithelial changes?
|
Multiple epidemiologic studies have classified benign histologic changes in the breast and determined the subsequent risk these changes confer for the later development of invasive CA. Nonproliferative changes do not increase the risk of CA, while proliferative disease is associated w/a mild increase in risk.
Proliferative disease w/atypia (ADH and ALH) confer a moderate increase in risk. |
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83. What is the prevalence of carcinoma of the breast?
|
CA is the most common malignancy of the breast, and breast CA is the most common non-skin malignancy in women.
A woman who lives to age 90 has a 1/8 change of developing breast CA. |
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84. What are the 6 most common risk factors for the development of breast CA?
|
1. Age (rarely before 25)
2. Age at menarche (women who reach menarche when younger than 11 have a increased risk) 3. First live birth (older age higher the risk) 4. First degree relatives w/breast CA 5. Breast biopsies (increase risk with previous biopsies showing atypical hyperplasia) 6. Race (African-Americans usually present at a more advanced stage than white women. Caucasian women have the highest rates of breast CA). |
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85. What are 10 additional risk factors for breast CA?
|
1. Estrogen exposure (estrogen and progesterone together increase the risk more than estrogen alone)
2. Radiation exposure 3. CA of the contralateral breast or endometrium 4. Geographic influence (breast CA rates are 4-7x higher in the US and Europe) 5. Diet (reduced risk with increased beta-carotene intake, but a higher risk with alcohol) 6. Obesity 7. Exercise 8. Breast feeding (the longer women breast feed, the greater is the reduction in the risk of breast CA) 9. Environmental toxins 10. Tobacco |
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86. What is the model for calculating the absolute risk of breast CA for individual women?
|
For example, a 60 y/o woman who first gave birth when shew as more than 30 y/o (but w/no other risk factors that would increase her risk) has a 2% risk of developing breast CA over the next 5 years, compared to the 1% risk for a similar 60 y/o woman who had her first child when she was under the age of 20.
*A risk of 1.7% of developing breast CA in the next 5 years was used as the entry criterion for the chemoprevention trials. |
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87. With the exception of DCIS, all other risk factors for the development of breast CA can affect both breasts equally. What are the prophylactic measures in these cases?
|
Bilateral prophylactic mastectomy can prevent the development of 89% of breast CAs in women who are at moderate risk for the disease owing to family history.
Chemoprevention is another option for women who are at risk for developing invasive breast CA. Tamoxifen is also used in to reduce the incidence of breast CA, however; it also increases the risk of venous thromboembolism, endometrial CA, and cataracts. |
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88. What are the 2 major risk factors for the development of breast CA?
|
1. Hormonal
2. Genetic |
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89. What is hereditary breast CA?
|
About 25% of familial CAs (or around 3% of all breast CAs) can be attributed to two highly penetrant autosomal dominant genes: BRCA1 and BRCA2.
The general lifetime breast CA risk for female carriers is 6-85%, and the median age at Dx is about 20 years earlier compared to women w/o these mutations. |
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90. What are the main differences between BRCA1 and BRCA2?
|
Mutated BRCA1 also markedly increases the risk of developing ovarian CA, which is as high as 20-40%.
BRCA2 confers a smaller risk for ovarian CA, but is associated more frequently w/male breast CA. BRCA1 and BRCA2 carriers are also susceptible to other CA, such as colon, prostate, and pancreas, but to a lesser extent. |
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91. What are the 3 functions of the BRCA1 and BRCA2 genes?
|
1. Tumor suppressor
2. Transcriptional regulation via halting the cell cycle 3. Role in DNA repair |
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92. BRCA1
|
Age at onset of breast CA: Younger (40-50's)
Greater incidence of medullary CAs, poorly differentiated CAs, ER-, PR-, and Her2/neu-negative CAs, and CAs with p53 mutations *BRCA1, but not BRCA2, interacts with the ER and is involved in X chromosome inactivation - two features that may be related to its gender-specific risk. |
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93. BRCA2
|
Age at onset: 50 years
Similar to sporadic breast CAs More common in male breast CAs |
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94. In hereditary CAs, how do the mutations accumulate?
|
In hereditary CAs, one mutant BRCA allele is inherited, and the second allele is inactivated by somatic mutations.
*In most cases, this is accomplished by a combination of loss of heterozygosity (LOH) and methylation of the promoter to inactivate both alleles. |
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95. How common is hypermethylation of the promoter in hereditary breast CAs?
|
Hypermethylation of the promoter is detected in 13% of unselected CAs but is more common in medullary CAs (67% of tumors) and mucinous CAs (55% of tumors) - histologic subtypes that are more commonly found in BRCA1 carriers.
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96. What are 5 other gene mutations that can potentially lead to hereditary breast CA?
|
1. Mutations in the cell cycle checkpoint kinase gene (CHEK2), which is an important component of the recognition and repair of DNA damage and which activates BRCA1, may account for 5% of familial cases
2. Women with the Li-Fraumeni syndrome (due to a germ-line mutation in the p53 gene) have an 18x risk of developing breast CA before 45. 3. Cowden syndrome, due to a mutation of the PTEN gene confers a 25-50% lifetime risk of breast CA 4. Women with the Peutz-Jeghers syndrome, caused by truncating mutations in the LKBI gene, are at an increase risk of breast CA 5. The role of the ATM gene in breast CA in ataxia telangiectasia has yet to be elucidated but may be an important mutation to consider |
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97. Do all women w/hereditary breast CA have only one mutated gene?
|
No, it is suggested that most breast CAs arise in a minority of women carrying combinations of these susceptibility genes.
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98. What is the major risk factor for sporadic breast CA?
|
The major risk factors for sporadic breast CA are related to hormone exposure: gender, age at menarche and menopause, reproductive history, breast-feeding, and exogenous estrogens.
The majority of these CAs occur in postmenopausal women and overexpress ER. |
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99. How does estrogen itself play a role in breast CAs?
|
Estrogen itself has at least two major roles:
1. Metabolites of estrogen can cause mutations or generate DNA-damaging free radicals 2. Via its hormonal actions, estrogens drive the proliferation of premalignant lesions as well as CAs. *However, other mechanisms also undoubtedly play a role, as a significant subset of breast CAs are ER-negative or occur in women w/o increased estrogen exposure. |
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100. In hereditary breast CA, one or more genetic alterations is facilitated by the inheritance of germ-line mutations.
What are some examples of these? |
Each of the new capability can be achieved by a change in one of many genes. FOr example, changes in ER, EGF-R, RAS, or HER2/neu may result in self-sufficiency in growth signals.
On the other hand, one cellular alteration (e.g., a change in a gene such as p53) can affect more than one of these capabilities. |
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101. What morphologic change is associated with the smallest increased risk of breast CA?
|
***Lesions with increased numbers of epithelial cells (proliferative changes).***
This suggests that these early changes are related to evasion of growth-inhibiting signals, evasion of apoptosis, and self-sufficiency in growth signals. |
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102. What is the proposed mechanism for the final step of the transition to carcinogenesis - limited by the basement membrane to ducts and lobules (carcinoma in situ)
|
It is possible that this transition is primarily due to the loss of the basement membrane and tissue integrity caused by the abnormal function of myoepithleial and stromal cells rather than to the gain of the ability of malignant cells to invade thru the basement membrane and into stroma.
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103. What are estrogen receptor positive CAs?
|
70-80% of breast CAs express ER and are thought to arise from intrinsically ER-positive luminal cells. ER-positive ductal CAs are usually well to moderately differentiated and often show tubule formation.
Dozens to hundreds of genes may be under transcriptional control by ER, and this is reflected by a set of common genes showing increased transcription in these CAs. *In fact, the expression of these downstream genes in ER-positive tumors might ultimately be more predictive of tumor behavior and response to estrogen blockign agents than is the presence of the receptor itself. |
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104. What about lobular CAs and their relation to other ER-positive CAs?
|
Lobular CAs can be identified by the distinctive morphologic pattern of infiltration as single cells or loosely cohesive cell clusters.
*This appearance has been linked to the loss of the normal cell adhesion molecule e-cadherin, which is retained in most other CAs within the ER positive group. By expression profiling, however, the lobular CAs cluster together and are most closely related to the other ER-positive CAs. |
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105. What are the 2 expression profiles of the ER-negative CAs?
|
1. HER2-positive CAs
2. Basal-like CAs |
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106. What are HER2-positive CAs?
|
This group of CAs was previously identified by overexpression of the HER2/neu protein.
The expression profile reveals not only increased copies of HER2/neu mRNA, but also increase transcription of other adjacent genes that are amplified w/in this segment of DNA. *These CAs do not overexpresss the genes that are characteristic of other subtype of CAs in this arrays, but do express e-cadherin. |
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107. What are basal-like CAs?
|
This group of CAs is distinguished by the expression of keratins that are more typical of myoepithleial cells or potential breast progenitor cells.
B/c the myoepithelial cell is located in the basal are of the lobules and ducts, in the absence of knowing the specific cell of origin, this group of CAs was termed basal like. In addition to the expression of specific keratins, they also show expression of p-cadherin as well as numerous genes related to cell proliferation. |
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108. Which category of gene expression would BRCA1 mutations go under?
|
CAs arising in women w/BRCA1 mutations also cluster within the basal-like CA group.
BRCA1 CAs are similar to basal-like CAs in being poorly differentiated, lacking ER and HER2/neu overexpression, and expressing basal-like keratins. However, most women with basal-like CAs not not have germ line BRCA1 mutations. |
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109. What does carcinoma in situ mean?
|
CIS refers to a neoplastic population of cells limited to ducts and lobules by the basement membrane.
In some cases, the cells can extend to the overlying skin w/o crossing the basement membrane (Paget disease). However, CIS does not invade into lymphatics and blood vessels and cannot metastasize. |
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110. What does invasive carcinoma mean?
|
Invasive CA (AKA infiltrating) has invaded beyond the basement membrane into stroma.
Here the cells might also invade into the vasculature and thereby reach regional lymph nodes and distant sites. Even the smallest breast CAs have some capacity to metastasize. |
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111. What is the prevalence of DCIS?
|
The number of cases of DCIS has rapidly increased in the past two decades. Among mammographically detected CAs, almost half are DCIS.
DCIS most frequently present as mammographic calicfications. Less typically, DCIS presents as a mammographic density or a vaguely palpable mass or nipple discharge or is incidental in a biopsy for another lesion. The majority of cases of DCIS cannot be detected by either palpation or visual inspection of the involved tissue. |
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112. What is DCIS?
|
DCIS consists of a malignant population of cells limited to ducts and lobules by the basement membrane. The myoepithelial cells are preserved, although they may be diminished in number.
DCIS is a clonal proliferation and usually involves only a single ductal system. However, the cells can spread throughout ducts and lobules and produce extensive lesions involving an entire sector of a breast. When DCIS involves lobules, the acini are often distorted and unfolded and take on the appearance of small ducts. |
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113. What are the 5 architectural subtypes of DCIS?
|
1. Comedocarcinoma
2. Solid 3. Cribriform 4. Papillary 5. Micropapillary |
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114. What is the morphology of the comedocarcinoma subtype of DCIS?
|
Comedocarcinoma is characterized by solid sheets of pleomorphic cells with high-grade nuclei and central necrosis.
The necrotic cell membranes commonly calcify and are detected on mammography as clusters or linear and branching microcalcifications. Periductal concentric fibrosis and chronic inflammation are common, and extensive lesions are sometimes palpable as an area of vague nodularity. |
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115. What is the morphology of the noncomedo DCIS?
|
Noncomedo DCIS consists of a monomorphic population of cells with nuclear grades ranging from low to high.
In cribriform DCIS, intraepithelial spaces are evenly distributed and regular in shape (cookie-cutter like). Solid DCIS completely fills the involved spaces. Papillary DCIS grows into spaces and lines fibrovascular cores typically lacking the normal myoepithleial cell layer. |
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116. What is the morphology of the micropapillary DCIS?
|
Micropapillary DCIS is recognized by bulbous protrusions without a fibrovascular core, often forming complex intraductal patterns.
Calcifications may be associated with central necrosis but more commonly form in intraluminal secretions. |
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117. What is the morphology of Paget disease of the nipple?
|
Paget disease of the nipple is a rare manifestation of breast cancer and presents as a unilateral erythematous eruption with a scale crust. Pruritus is common, and the lesion might be mistaken for eczema.
*Malignant cells, referred to as Paget cells, extend from DCIS within the ductal system into nipple skin without crossing the basement membrane. The tumor cells disrupt the normal epithelial barrier, and this allows ECF to seep out onto the nipple surface. The Paget cells are easily detected by nipple biopsy or cytologic preparations of the exduate. |
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118. What are the clinical features of Paget disease?
|
A palpable mass is present in 50-60% of women with Paget disease, and almost all of these women will have an underlying invasive CA. In contrast, fewer than half of women w/o a palpable mass will have invasive CA. The CAs are usually poorly differentiated and overexpress HER2/neu.
*The production of keratinocytes of heregrulin-alpha, which acts via the HER2/neu receptor, may play a role in the pathogenesis of this disease. |
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119. What is DCIS with microinvasion?
|
DCIS with microinvasion is defined by foci of tumor cells less than 0.1 cm in diameter invading the stroma.
Microinvasion is most commonly seen in association with comedocarcinoma. |
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120. Can DCIS be detected visually or via palpation?
|
The majority cannot be detected by palpation or visual inspection.
Occasional cases of comedocarcinoma are associated with sufficient periductal fibrosis to produce a thickening of the tissue, and punctate areas of necrosis (comedone-like) can be seen grossly. |
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121. What are the clinical features of DCIS?
|
Many cases of small low grade DCIS, and probably most cases of high-grade and extensive DCIS, progress to invasive CA.
Mastectomy for DCIS is curative in over 95% of cases. Rare recurrence and/or death are usually due to residual DCIS in ducts in subcutaneous adipose tissue that was not removed during surgery. Radiation therapy is used. Tamoxifen reduces the risk of recurrence but the benefit is limited to women with ER-positive DCIS. |
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122. What are the 3 major risk factors for recurrence of DCIS?
|
1. Grade
2. Size 3. Margins |
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123. What is LCIS?
|
LCIS is always an incidental finding in a biopsy performed for another reason, as LCIS is not associated w/calcifications or a stromal reaction that would form a density.
LCIS is bilateral in 20-40% of women when both breasts are biopsied. LCIS is also more common in young women, with 80-90% of cases occurring prior to menopause. |
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124. Is LCIS a true neoplasm?
|
B/c LCIS is freq multicentric and bilateral and subsequent CAs occur at equal frequency in both breast, it has been suggested that LCIS is not a true neoplasm but rather is a marker of breast CA risk.
However, the cells of LCIS are invasive lobular CA are identical in appearance, and both lack expression of e-cadherin, the transmembrane protein that is responsible for epithelial cell adhesion. The loss of expression correlates with the histologic appearance of lobular CAs as single detached cells. LCIS can have the same genetic changes (such as LOH on 16q), as an adjacent are of invasive CA, supporting its role as a true precursor of invasive CA in some vases. |
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125. What is the morphology of LCIS?
|
The abnormal cells of atypical lobular hyperplasia, LCIS, and invasive lobular CA are identical and consist of small cells that have oval or round nuclei with small nucleoli that do not adhere to one another.
Signet-ring cells containing mucin are present commonly. *LCIS rarely distorts the underlying architecture, and the involved acini remain recognizable as lobules. LCIS almost always expresses estrogen and progesterone receptors, and overexpression of HER2/neu is not observed. |
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126. What are the clinical features of LCIS?
|
Women with LCIS develop invasive CA at a freq similar to that of women with untreated DCIS.
The ipsilateral breast may be at greater risk in women with lobular neoplasia. Invasive CAs developing in women after a Dx of LCIS are 3x mroe likely to be of lobular type compared with CAs overall, but the majority do not show specific lobular morphology. Treatment choices include bilateral prophylactic mastectomy, tamoxifen, or more typically, close clinical follow-up and mammographic screening. |
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127. What are the characteristics of invasive CA?
|
In young women or in older women not undergoing mammographic screening, invasive CA almost always presents as a palpable mass.
*By the time a CA becomes palpable, over half the pts will have axillary lymph node metastases. Large CAs may be fixed to the chest wall or cause dimpling of the skin. Lymphatics may become so involved as to block the local are of skin drainage and cause lymphedema and peau d'orange. Tethering of the skin to the breast by Cooper ligaments mimics the appearance of an orange peel. When the tumor involves the central portion of the breast, retraction of the nipple may develop. |
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128. What does the term inflammatory carcinoma mean?
|
Inflammatory carcinoma refers to the clinical presentation fo a CA extensively invovling dermal lymphatics, resulting in an enlarged eythematous breast.
The underlying CA usually has a diffuse infiltrative pattern and typically does not form a discrete palpable mass. This can result in confusion with inflammatory conditions and delay in Dx. |
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129. What are the most common histologic types of breast adenocarcinomas?
|
In Situ CA: ---15-30%---
-DCIS: (80%) -LCIS: (20%) Invasive CA: ---70-85%--- -Ductal: (79%) -Lobular: (10%) -Medullary and mucinous: (2%) |
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130. What is invasive CA, no special type (NST - invasive ductal CA)?
What is the morphology? |
This type includes the majority of CAs (70-80%) that cannot be classified as any other subtype.
On gross exam, most CAs are firm to hard and have an irregular border. W/in the center of the CA, there are small pinpoint foci or streaks of chalky white elastotic stroma and occasionally small foci of calcification. There is a characteristic grating sound when cut or scraped. Less frequently, CAs have a well-circumscribed border and may be soft to firm in consistency. |
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131. CAs of NST have a wide spectrum of appearances... what are they?
|
Well differentiated tumors consist of tubules lined by minimally atypical cells and can occasionally be difficult to distinguish from benign sclerosing lesions. Such CAs typically express hormone receptors and do not overexpress HER2/neu.
Others are composed of anastomosing sheets of pleomorphic cells and are less likely to express hormone receptors and more likely to overexpress HER2/neu. *The majority of invasive ductal CAs lie in btwn these two extremes. |
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132. What is a scirrhous CA?
|
Most CAs induce a marked increase in dense, fibrous desmoplastic stroma, giving the tumor a hard consistency on palpation and replace fat, resulting in a mammographic density (scirrhous CA).
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133. What usually accompanies CAs of NST?
|
CAs of NST are accompanied by varying amts of DCIS. The grade of the DCIS usually correlates with the grade of the invasive CA.
CAs associated with a large amt of DCIS require large excisions w/wide margins to reduce local recurrences. |
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134. What is invasive lobular CA?
|
Invasive lobular CA usually presents like CAs of NST as a palpable mass or mammographic density.
However, about 1/4 have a diffuse pattern of invasion w/o prominent desmoplasia and might produce only a vaguely thickened area of the breast or subtle architectural changes on mammography. *Lobular CAs have been presorted to have a greater incidence of bilaterality. |
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135. What is the morphology of invasive lobular CA?
|
Grossly, most tumors are firm to hard w/an irregular margin. Occasionally, the tissue may feel diffusely thickened and a discrete tumor mass cannot be defined.
*The histologic hallmark of lobular CAs is the pattern of single infiltrating tumor cells, often only one cell in width or in loose clusters or sheets. The desmoplastic response may be minimal or absent. The cells have the same cytologic features as LCIS and lack cohesion, w/o formation of tubules or papillae. Signet ring cells are common. Tumor cells are freq arranged in concentric rings surrounding normal ducts. |
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136. What are the differences between well- and moderately- vs. poorly-differentiated invasive lobular CAs?
|
Well and moderately-differentiated invasive lobular CAs are usually diploid, express hormone receptors, and are associated with LCIS in the majority of cases. HER2/neu overexpression is very rare.
In contrast, poorly-differentiated invasive lobular CAs are usually aneuploid, lack hormone receptors, and may express HER2/neu. |
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137. Most lobular CAs show a loss of a region on which chromosome?
What genes does this region code for? |
Most lobular CAs show a loss of a region on chromosome 16q22.1 that includes a cluster of at least eight genes responsible for cell adhesion, including e-cadherin and β-catenin.
The gene for e-cadherin on the opposite chromosome is inactivated by mutations, methylation of the promoter, or decreased expression of transcription factors. |
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138. What type of patterns of metastasis do lobular CAs have?
|
***Lobular CAs have a different pattern of metastasis compared to other breast CAs.***
Metastases to the peritoneum and retroperitoneum, the leptomeninges (carcinomatous meningitis), the GI tract, and the ovaries and uterus are more frequently observed. These CAs are less likely to metastasize to the lungs and pleura. |
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139. What is medullary CA?
|
Medullary CA presents as a well-circumscribed mass and may be mistaken clinically and radiologically for a fibroadenoma. There is sometimes a history of rapid, almost explosive growth.
Medullary CAs have a slightly better prognosis than do CAs of no special type. Lymph node metastases are infrequent and rarely involve multiple nodes. |
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140. What is the morphology of medullary CAs?
|
These tumors do not have the striking desmoplasia of the usual CA and therefore are distinctly more yielding on external palpation and on cut section.
The tumor has a soft, fleshy consistency and is well circumscribed. All medullary CAs are poorly differentiated. DCIS is minimal or absent. Lymphatic or vascular invasion is never seen. *HER2/neu overexpression is not observed. |
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141. What are the three distinctive characteristics of medullary CAs?
|
1. Solid, syncytium-like sheets (occupying more than 75% of the tumor) of large cells with vesicular, pleomorphic nuclei, containing prominent nucleoli and frequent mitoses.
2. A moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor. 3. A pushing (noninfiltrative) border. |
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142. What is a mucinous (colloid) CA?
|
This unusual type (1% to 6% of all breast CAs) also commonly presents as a circumscribed mass.
It tends to occur in older women and may grow slowly during the course of many years. Mucinous CAs are usually diploid, and the majority express hormone receptors. The overall prognosis is slightly better than that of CAs of NST. |
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143. What is the morphology of mucinous (colloid) CA?
|
The tumor is extremely soft and has the consistency and appearance of pale gray-blue gelatin.
The tumor cells are seen as clusters and small islands of cells within large lakes of mucin that push into the adjacent stroma. |
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144. What are the common genetic alterations in both medullary and mucinous CAs?
|
Hypermethylation of the BRCA1 promoter in individuals without BRCA1 germ line mutations.
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145. What are tubular carcinomas?
|
Tubular CAs are typically less than 1 cm in diameter and are usually detected as irregular mammographic densities. Women usually present in their late forties.
Tumors are multifocal w/in one breast in 10-56% of cases and bilateral in 9-38%. More than 95% of all tubular CAs are diploid and express hormone receptors. All are well differentiated. *This subtype has an excellent prognosis. |
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146. What are invasive papillary CAs?
|
Invasive CAs with a papillary architecture are rare and represent 1% or fewer of all invasive CAs. Papillary architecture is more commonly seen in DCIS.
The clinical presentation is similar to that of CAs of NST, but the overall prognosis is better. |
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147. What is metaplastic CA?
|
Metaplastic CA includes a wide variety of rare types of breast CA, including conventional adenocarcinomas w/a chrondroid stroma, squamous cell CAs, and CAs with a prominent spindle cell component that might be difficult to distinguish from sarcomas.
Some of these CAs express genes in common with myoepithelial cells and likely arise from this cell type. |
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148. What determines prognosis for women w/breast CA?
|
Except for the few women with distant metastases at presentation or with inflammatory CA, prognosis is determined by the pathologic examination of the primary CA and the axillary lymph nodes.
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149. What are the 6 major prognostic factors?
|
1. Invasive CA or in situ disease
2. Distant metastases 3. Lymph node metastases 4. Tumor size 5. Locally advanced disease 6. Inflammatory CA |
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150. How is invasive CA or in situ disease a prognostic factor?
|
By definition, CA in situ cannot cause death. Deaths associated with CA in situ are due to the subsequent development of invasive CA or the presence of an occult area of invasion.
In contrast, about 1/3 of women with invasive CA will succumb to the disease. |
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151.How are distant metastases a prognostic factor?
|
Once distant metastases are present, cure is unlikely, although long-term remissions and palliation can be achieved.
Common sites of metastasis are lungs, bone, liver, adrenal, brain, and meninges. Fortunately, fewer than 10% of women present with metastases to distant sites. *The metastatic cells may be directed to specific sites by the expression of chemokine receptors in the cancer cells and the respective chemokines in target organs. |
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152. How are lymph node metastases a prognostic factor?
|
*Axillary lymph node status is the most important prognostic factor for invasive CA.
Breast CAs drain to one of two sentinel nodes in the ipsilateral axilla that can be identified by colored dye or radioactive tracer. Women with negative sentinel nodes can be spared the morbidity of a full axillary dissection. |
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153. What is the prognostic importance of macrometastases?
|
Macrometastases (> 0.2 cm) are of proven prognostic importance.
B/c sentinel nodes often undergo more intense scrutiny with additional sections thru the tissue, and immunohistochemistry or reverse transcriptase PCR to detect rare tumor cells, increased numbers of women with minute metastatic deposits in lymph nodes are being identified. |
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154. How is tumor size a prognostic factor?
|
The size of the CA is the second most important prognostic factor and is independent from lymph node status. However, the risk of axillary lymph node metastases does increase with size of CA.
Women with node-negative CAs under 1 cm have a prognosis approaching that of women w/o breast CA. On the other hand, over half of women with cancers over 2 cm in diameter present with lymph node metastases, and many of these women will eventually succumb to breast CA. |
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155. How is locally advanced disease a prognostic factor?
|
Tumors invading into skin or skeletal muscle are frequently associated with concurrent or subsequent distant disease.
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156. How is inflammatory CA a prognostic factor?
|
Women presenting with the clinical appearance of breast swelling and skin thickening have a particularly poor prognosis with a 3-year survival rate of only 3-10%.
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157. What are the 5 stages of breast CA?
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Stage 0: DCIS or LCIS
Stage 1: Invasive CA 2 cm or less without nodal invovlement Stage 2: Invasive CA 5 cm or less with up to three involved axillary nodes or invasive CA greater than 5 cm w/o nodal involvement. Stage 3: Invasive CA 5 cm or less with 4+ axillary noders; invasive CA greater than 5 cm with nodal involvement, invasive CA with involvement of the ipsilateral internal mammary lymph nodes or skin involvement, chest wall fixation, etc... Stage 4: Any breast CA with distant metastases. |
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158. What are the 7 minor prognostic factors?
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1. Histologic subtypes
2. Tumor grade 3. Estrogen receptors and progresterone receptors 4. HER2/neu 5. Lymphovascular invasion 6. Proliferative rate 7. DNA content |
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159.Histologic subtypes and prognosis
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The 30 year survival rate of women w/special types of invasive CAs (tubular, mucinous, medullary, lobular, and papillary) is greater than 60%, compared with less than 20% for women with CAs of NST.
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160. Tumor grade and prognosis
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85% of women with well differentiated grade 1 tumors, 60% of women with moderately differentiated grade 2 tumors, and 15% of women with poorly differentiated grade 3 tumors survive for 10 years.
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161. Estrogen receptors and progresterone receptors and prognosis
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50-85% of CAs express ERs, and such tumors are more common in postmenopausal women. Women with hormone receptor-positive CAs have a slightly better prognosis than do women with hormone receptor negative CAs.
80% of tumors with ER and progesterone receptors respond to hormonal manipulation, whereas only about 40% of those with only one type of receptor respond. Tumors w/neither ER nor PR have a less than 10% likelihood of responding. |
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162. HER2/neu and prognosis
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HER2/neu is overexpressed in 20-30% of breast CAs. In over 90% of cases, overexpression is associated with amplification of the gene on 17q21. Although not all studies have come to the same conclusion, many have shown that overexpression of HER2/neu is associated with a poor prognosis.
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163. What is trastuzumab (Herceptin)?
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Trastuzumab is a humanized monoclonal antibody to HER2/neu developed to specifically target tumor cells, and it is hoped to spare normal cells.
Unfortunately, cardiac toxicity, due to an unknown mechanism, could limit its use. |
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164. Lymphovascular invasion (LVI) and prognosis
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Tumor cells can sometimes be seen in lymphatics in the breast and this finding is a poor prognostic factor in women w/o lymph node metastases.
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165. Proliferative rate and prognosis
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Prolfieration can be measured by flow cytometry (as the S-phase fraction), by mitotic counts, or other methods.
A high proliferative rate is a poor prognostic factor. |
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166. DNA content and prognosis
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A DNA content equal to normal cells is a better prognostic factor than an abnormal DNA content.
However, marked chromosomal abnormalities may be present, even if an overall change in DNA content cannot be detected. |
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167. What are the two types of stromal tumors?
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1. Fibroadenoma
2. Phyloodes tumor |
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168. What is a fibroadenoma?
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This is the most common benign tumor of the female breast, occurring most often during the reproductive period, and regressing and calcifying after menopause.
Fibroadneomas present clinically as well-circumscribed palpable masses, ovoid mammographic densities, or mammographic calcifications. During pregnancy, fibroadenomas may grow in size and sometimes infarct. Although benign, they can exhibit proliferative changes and incur a slightly increase risk of CA. |
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169. What is the morphology of fibroadenomas?
1/2 |
Fibroadenomas grow as spherical nodules that are usually sharply circumscribed and freely movable in the surrounding breast substance.
They vary in size from less than 1 cm to large tumors. Grossly, the tumors, are well-circumscribed, rubbery, grayish white nodules that bulge above the surrounding tissue and often contain slitlike spaces *(popcorn)*. |
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170. What is the morphology of fibroadenomas?
1/2 |
The stroma is usually delicate, cellular, and often myxoid, resembling intralobular stroma, enclosing glandular and cystic spaces lined by epithelium.
The epithelium may be surrounded by stroma or compressed and distorted by it. In older women, the stroma typically becomes densely hyalinized and the epithelium atrophic. |
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171. What is the pathogenesis of fibroadenomas?
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Some fibroadenomas are polyclonal in origin and are probably due to focal hyperplasia of lobular stroma. For example, almost half of women receiving cyclospin A fter renal transplantation develop fibroadenomas.
The tumors are freq multiple and bilateral and are likely to be due to drug-related growth stimulation. |
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172. What are phyllode tumors?
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Phyllode tumors, like fibroadenomas, arise from intralobular stroma. Although they can occur at any age, most present in the sixth decade, 10-20 years later than the average presentation of a fibroadenoma.
Most present as palpable masses, but few are detected mammographically. Most behave in a relatively benign fashion and most are not cystic. |
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173. What is the morphology of phyllodes tumors?
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The tumors vary in size from a few cm to massive lesions involving the entire breast.
***The large lesion often have bulbous protrusions due to the present of nodules of proliferating stroma covered by epithelium. This growth patten can also occasionally be seen in large fibroadenomas. Phyllodes tumors are distinguished from the more common fibroadenomas on the basis of cellularity, mitotic rate, nuclear pleomorphism, stromal overgrowth, and infiltrative borders. |
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174. What are the clinical characteristics of phyllodes tumors?
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Phyllodes tumors must be excised with wide margins or by mastectomy to avoid the high risk of local recurrences.
The majority are low-grade tumors that may recur locally but only rarely metastasize. Rare high-grade lesions behave aggressively, with frequent local recurrences and distant hematogenous metastases in about 1/3 of cases. Only the stromal component metastasizes. |
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175. What are the breast sarcomas? What is Stewart-Treves syndrome?
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Sarcomas occur rarely in the breast. The most common sarcoma is angiosarcoma, which arises as a primary tumor in young women, after radiation therapy for breast CA, or in the skin of a chronically edematous arm after mastectomy (Stewart-Treves syndrome).
Sarcomatous differentiation can also occur in phyllodes tumors and CAs (some metaplastic CAs). |
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176. What is pseudoangiomatous stromal hyperplasia (PASH)?
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Pseudoangiomatous stromal hyperplasia (PASH) and fibrous tumors commonly present as circumscribed palpable masses or mammographic densities in premenopausal women or older women on hormone replacement therapy.
Histologically, they are benign proliferations of interlobular stroma. |
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177. What is fibromatosis in the breast?
|
Fibromatosis is due to a clonal proliferation of fibroblasts and myfibroblasts. It presents as an irregular mass that can involve both skin and muscle and closely mimics invasive CA.
Wide excision is mandatory, as recurrences are common and may be difficult to control. Although locally aggressive, this lesion does not metastasize. Most cases are sporadic, but some occur as part of familial adenomatous polyposis (FAP), hereditary desmoid syndrome, and Gardner syndrome. Mutations in the adenomatosis polyposis coli (APC) gene are found in pts with FAP as well as in sporadic cases of breast fibromatosis. |
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178. What are other malignant tumors of the breast?
|
Lymphomas may arise primarily in the breast, or breasts may be secondarily involved by a systemic lymphoma; most are of large B-cell origin.
Young women with Burkitt lymphoma may present with massive bilateral breast involvement and are often pregnant or lactating. Metastases to the breast are rare and most commonly arise from a contralateral breast CA. The most freq nonmammary metastases are from melanomas and lung CAs. |
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179. What is gynecomastia?
|
Gynecomastia may be unilateral or bilateral and presents as a button-like subareolar enlargement.
In advanced cases, the swellign can similate the adolescent female breast. The lesion must be differentiated only from the rare CA of the male breast. *Gynecomastia is chiefly of importance as an indicator of hyperestrinism, suggesting cirrhosis of the liver or the possible existence of a functioning testicular tumor. Can also occur as part of Klinefelter syndrome or in Leydig cell and Sertoli cell tumors. |
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180. What is the morphology of gynecomastia?
|
There is prolfieration of a dense collagenous connective tissue, but more striking are the changes in teh epithelium of the ducts. Marked micropapillary hyperplasia of the ductal linings occurs. The individual cells are fairly regular, columnar to cuboidal cells with regular nuclei. Lobule formation is rare.
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181. What about breast cancer in males?
|
Carcinoma of the male breast is rare. Risk factors and prognostic factors are similar to those for women. Male breast CA is strongly associated with BRCA2.
The same histologic types of breast CA are found in men and women. B/c of the scant amt of surrounding breast tissue in men, CAs tend to invade skin and chest wall earlier and present at higher stages. |
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182. Anasarca
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Severe systemic edema
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183. Four noninflammatory causes of edema
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1. Increased hydrostatic pressure forces fluid out of the vessels due to increased venous return from CHF, liver cirrhosis, venous obstruction, etc...
2. Reduced plasma osmotic pressure (hypoproteinemia or due to nephrotic syndrome) 3. Lymphatic obstruction 4. Sodium retention |
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184. Subcutaneous edema
|
May be diffuse or occur where hydrostatic pressures are greatest
Dependent edema is typical of CHF Edema resulting from hypoproteinemia is generally more severe and diffuse; it is most evident in the loss connective tissue (e.g. eyelids, causing periorbital edema) |
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185. Pulmonary edema
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Typical in left ventricular failure but is also seen with renal failure, adult respiratory distress syndrome, infections, and hypersensitivity reactions.
The lungs are 2-3x their normal weight; sectioning reveals a frothy, blood tinged mixture of air, edema fluid, and erythrocytes |
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186. Brain edema
|
May be localized to sites of injury or may be generalized (e.g. encephalitis, hypertensive crises, or obstruction to venous outflow)
When generalized, the brain is grossly swollen w/narrowed sulci and distended gyri flattened against the skull. |
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187. Hyperemia vs. congestion
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Both terms mean increased volume of blood in a particular site
Hyperemia is an active process due to augmented blood inflow from arteriolar dilation. Tissues are redder owing to engorgement with oxygenated blood. Congestion is a passive process caused by impaired outflow from a tissue. Isolated venous obstruction may cause local congestion; systemic venous obstruction occurs in CHF. Tissues are blue-red. |
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188. Acute congestion vs. chronic congestion
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Vessels are distended and organs are grossly hyperemic; capillary bed congestion is also commonly associated with interstitial edema.
In chronic congestion, capillary rupture may cause focal hemorrhage; subsequent erthrocyte breakdown result in hemosiderin laden macrophages. Grossly, tissues appear brown, contracted, and fibrotic. Lungs and liver are commonly affected. |
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189. When are the lungs involved?
When is the liver involved? |
Lungs are involved in left ventricular failure of any cause.
Liver is involved in right sided heart failure or rarely with hepatic vein or IVC obstruction. |
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190. Hemorrhage
|
Refers to blood extravasation following vessel rupture.
Hemorrhage may be external or enclosed within a tissue; the latter is called a hematoma. |
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191. How are hemorrhages categorized?
|
Petechia; minute 1-2 mm
Purpura; larger (=>3mm) Ecchymoses; larger (> 1-2cm) Large accumulations of blood in the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis, depending on the location. |
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192. Color changes in hemorrhages
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1. Erythrocytes in hemorrhages are degraded by macrophages.
2. The hemoglobin (red-blue color) is converted to bilirubin and biliverdin (blue-green color) 3. These are then eventually converted to hemomsiderin (golden brown), accounting for the characteristic color changes in a bruise. Patients with extensive hemorrhages occasionally develop jaundice from massive erythrocyte breakdown and systemic bilirubin release. |
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193. What are 6 primary genetic causes of hypercoagulable states?
|
1. Factor 5 Leiden
2. Mutation in prothrombin gene 3. Mutation in methyltetrahydrofolate gene 4. ATIII deficiency 5. Protein C deficiency 6. Protein S deficiency |
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194. What is antiphospholipid antibody syndrome?
|
Occurs in patients with antibodies against anionic phospholipids that can putatively activate platelets or interfere with protein C activity.
Patients may have well defined autoimmune disease or may exhibit only a hypercoagulable state. |
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195. Cardiac and arterial thrombi - what do they look like?
|
Are gray-red and have gross microscopic laminations (lines of Zahn) produced by pale layers of platelets and fibrin alternating with darker erythrocyte rich layers.
Major sites include the left ventricle overlying an infarct ruptured atherosclerotic plaques, and aneurysmal sacs. |
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196. Venous thrombi - what do they look like?
|
AKA phlebothrombosis
Often creates a long red-blue cast of the vein lumen b/c it occurs in a relatively static environment. The thrombus contains more enmeshed erythrocytes among sparse fibrin strands (red or stasis thrombi). Fibrin and vessel wall attachment distinguish stasis thrombi from postmortem clots. Most commonly affects the veins of the lower extremities (>90% of cases). |
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197. Where else do thrombi form?
|
On heart valves
In infective endocarditis, organisms form large infected thrombotic masses causing underlying valve damage and systemic infection Also in nonbacterial thrombotic endocarditis, sterile vegetations also develop on noninfected valves in hypercoagulable states, particularly in those with malignancies. |
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198. What is the fate of the thrombi?
Four different fates... |
1. Propagation, causing complete vessel obstruction
2. Embolization to other sites in the vasculature is especially common with lower extremity venous thrombi embolizing to the lung. 3. Dissolution by fibrinolytic activity 4. Organization and recanalization, reestablishing flow by ingrowth of endothelial cells, smooth muscle cells, and fibroblasts to create vascular channels, or by incorporating the thrombus as a subendothelial swelling of the vessel wall. |
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199. Superficial thrombi
|
Usually occur in varicose saphenous veins, causing local congestion and pain but rarely embolizing.
Local edema and impaired venous drainage predispose to skin infections and varicose ulcers |
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200. Deep thrombi
|
Are in larger leg veins above the knee and more readily embolize.
Although they may cause pain and edema, venous obstruction is usually offset by collateral flow. Thus, deep vein thromboses are entirely asymptomatic in approx 50% of patients and are recognized only after embolization. |
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201. Clinical settings in which DVT occurs
|
1. Advanced age, bed rest, or immobilization
2. CHF 3. Trauma, surgery, and burns result in reduced physical activity, injury to vessels, release of procoagulant substances from tissues, and reduced tPA 4. The puerperal and postpartum states are associated w/amniotic fluid embolization and hypercoagulability 5. Tumor associate procoagulant release, causing the thrombosis seen with malignancies |
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202. Arterial thrombosis
|
Brain, kidneys, and spleen are prime targets.
MI w/dykinesis and endocardial damage may result in mural thrombi. Rhematic valvular disease can cause mitral valve stenosis, followed by left atrial dilation and thrombus formation within the atrium or auricular appendiages Major cause is from atherosclerosis! |
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203. Disseminated intravascular coagulation
|
Refers to widespread fibrin microthrombi in the microcirculation.
This is caused by disorders ranging from obstretric complications to advanced malignancy. DIC is not a primary disease but rather a complicationof any diffuse thrombin activation. The microthrombi can cause diffuse circulatry insufficiency, particularly in the brian, lungs, heart, and kidneys; there is also concurrent consumption of platelets and coagulation factors with fibrinolytic pathway activation, leading to uncontrollable bleeding. |
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204. Pulmonary thromboembolism
|
Greater than 95% of pulmonary emboli originate from deep leg vein thrombi; depending on the size, a pulmonary emoblus may occlude the main pulmonary artery, impact across the bifurcation or pass into smaller arterioles.
One PE puts a patient at risk for more. Sudden death, right sided heart failure (cor pulmonale) or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli. Multiple PE over time may cause pulmonary hypertension |
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205. Systemic thromboembolism
|
Refers to emboli in the arterial circulation.
Approx 80% arise from intracardiac mural thrombi Major sites are the lower extremities, brain, viscera, and upper extremities. |
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206. Fat embolism
|
The second most common form of embolism.
It results from release of microscopic fat globules after fractures of long bones or rarely, after burns or soft tissue trauma. Occurs in 90% of severe skeletal injuries; fewer than 10% have any clinical findings |
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207. Fat embolism syndrome
|
Fatal in approx 10% of cases, is heralded by sudden pulmonary insuffiency 1 to 3 days after injury
20 o 50% of patients have a diffuse petechial rash and may have neurological symptoms that progress to delirium or coma. Thombocytopenia and anemia can also occur. |
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208. Pathogenesis involved in fat embolism syndrome
|
Involves mechanical obstruction by microemboli of neutral fat, followed by local platelet and erthrocyte aggregation.
Subsequent fatty acid release causes toxic injury to endothelium; platelet activation and granulocyte recruitment contribute free radicals, proteases, and eicosanoids. |
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209. Dx of fat embolism syndrome
|
Depends on identifying microvascular fat globules. Because routine histologic solvents dissolve lipids out of tissues, documentation requires special fat stains.
Edema and hemorrhage may also be seen microscopically. |
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210. Air embolism
|
Refers to gas bubbles withing the circulation obstructing vascular flow and causing ischemia.
Air may enter during obstetric procedures or following chest wall injury; generally, more than 100 cc are required to have a clinical effect. |
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211. Decompression sickness
|
A special form of air embolism caused by sudden changes in atmospheric pressure.
Air breathed at high pressure causes increasing amounts of gas to be dissolved in blood and tissues. Subsequent rapid depressurization allows the dissolved gases to expand and bubble out of the solution to form gas emboli. Treatment consists of re-pressurizing to force gas bubbles back into solution, followed by subsequent slow decompression. |
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212. Caisson disease
|
Persistent gas emboli in poorly vascularized portions of the skeleton and leads to ischemic necrosis.
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213. Amniotic fluid embolism
|
Serious but uncommon complication of labor and postpartum period caused by amniotic fluid infusion into the maternal circulation.
Classic findings include fetal squamous cells, mucin, lanugo hair, and vernix caseosa fat in the maternal pulmonary microcirculation. Characterized by sudden server dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. Pulmonary edema, diffuse alveolar damage, and DIC ensure from release of toxic and thrombogenic substances in the amniotic fluid. |
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214. Where do red infarcts occur?
|
1. Venous occlusions
2. Loose tissues (lungs) 3. Tissues w/dual circulations (i.e. lung and small intestine) 4. Tissues previously congested because of sluggish venous outflow 5. Sites of previous occlusion and necrosis when flow is reestablished. |
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215. Where do white infarcts occur?
|
In solid organs (such as heart,spleen, and kidney) with end-arterial circulation (i.e. few collaterals)
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216. Common characteristics of infarcts
|
All infarcts tend to be wedge shaped; the occluded vessel marks the apex, and the organ periphery forms the base
Dominant histologic signs is ischemic coagulative necrosis, however, the brain does not exhibit this; instead, it results in liquefactive necrosis. Septic infarctions occur when infected heart valve vegetations embolize or when microbes seed an area of necrosis; the infarct then becomes an abscess. |
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217. What are 4 factors that influence development of an infarct?
|
1. Anatomic pattern of vascular supply
-dual circulations or anastomosing circulations protect against infarction. 2. Rate of development of occlusion 3. Vulnerability to hypoxia 4. Oxygen content of blood. |
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218. Shock
|
Shock is systemic hypoperfusion resulting from reduction in ether cardiac output or the effective circulating blood volume
The result is hypotension, followed by impaired tissue perfusion and cellular hypoxia. |
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219. Basic mechanism underlying cardiogenic and hypovolemic shock
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Low cardiac output
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220. Septic shock
|
Caused by systemic microbial infection and has a more complicated pathogenesis
Results form spread of an initally localized infection into the bloodsream Most cases are caused by gram-negative bacilli expressing endotoxin (endotoxic shock) |
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221. Bacterial lipopolysaccharides (LPS)
|
Released when cell walls are degraded
Consists of a toxic fatty acid core and a complex polysaccharide All the effects of septic shock are reproduced by LPS alone. LPS binds to CD14 molecules on leukocytes, endothelial cells and other cells types The LPS then interacts w/membrane toll-like receptor 4 (TLR-4) that transduces an intracellular signal |
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222. TLR-4
|
TLR-4 engagement profoundly activates cytokine and chemokine production; depending on LPS dosage and the numbers of macrophages activated there are different outcomes.
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223. Low doses of LPS
|
Mainly activates complement and monocyte/macrophages, leading to enhanced bacterial eradication.
Net effect is enhanced local inflammatory response and improved clearance of infections |
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224. Moderate doses of LPS
|
Cytokine induced secondary effectors (e.g. NO) become significant. Also, systemic effects of TNF and IL1 are seen (e.g. fever)
Also down regulates EC anticoagulation mechanisms (i.e. reduced thrombomodulin), tipping the coagulation cascade toward thrombosis |
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225. High doses of LPS
|
Septic shock supervenes with high-level cytokines and secondary mediators resulting in:
1. Systemic vasodilation 2. Diminished myocardial contractility 3. Widespread endothelial injury and activation 4. Activation of the coagulation system, culminating in DIC The resulting hypoperfusion causes multiorgan failure; unless the underlying infection (and LPS overload) is brought under control, the patient usually dies |
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226. Signs of organ shock (brain, heat, kidneys, lungs)
|
Brain: shows hypoxic encephalopathy
Heart: shows coagulation necrosis and contraction band necrosis Kidneys: develop extensive tubular ischemic injury, causing oliguria anuria, and electrolyte disturbances Lungs: seldom affected in pure hypovolemic shock; however, diffuse alveolar damage may occur in septic or traumatic shock |
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227. What happens if the patient survives the initial complications of shock?
|
Patients surviving the initial complications enter a second phase dominated by renal insufficiency and marked by a progressive fall in urine output, as well as sever fluid and electrolyte imbalances
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228. What does hemostasis mean?
|
Prevention of blood loss
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229. When a vessel is severed or ruptured, what four mechanisms are needed to achieve hemostasis?
|
1. Vascular constriction
2. Formation of a platelet plug 3. Formation of a blood clot as a result of blood coagulation 4. Eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently |
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230. What causes vascular contraction after rupture to a blood vessel?
|
1. Local myogenic spasm
-initiated by direct damage to the vascular wall -responsible for most of the vasoconstriction 2. Local autacoid factors from the traumatized tissues and blood platelets -releases thromboxane A2 3. Nervous reflexes -initiated by pain nerve impulses or other sensory impulses In general, the more severely a vessel is traumatized, the greater the degree of vascular spasm |
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231. What happens when platelets come in contact with a damaged vascular surface?
|
When platelets come in contact with a damaged vascular surface, especially with collagen fibers, the platelets immediately change.
1. They begin to swell 2. They assume irregular forms with numerous irradiating pseudopods protruding form their surfaces 3. Their contractile proteins contract forcefully and cause the release of granules that contain multiple active factors 4. They become sticky so that they adhere to collagen in the tissues and to vWF that leaks into the traumatized tissue from the plasma 5. They secrete large quantities of ADP 6. Their enzymes form thromboxane A2 7. The ADP and thromboxane in turn act on nearby platelets to activate them as well and recruits them to the injured site |
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232. How are trauma and clotting time related?
|
The clot begins to develop in 15-20 secs if the trauma to the vascular wall has been severe
If the trauma is minor, the clot forms in 1 to 2 minutes |
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233. When a blot clot has formed, what two options does it have?
|
1. It can become invaded by fibroblasts which subsequently form connective tissue all thru the clot
2. It can dissolve |
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234. Basic theory of blood coagulation
|
You've got procoagulants and anticoagulants
Whether blood will coagulate depends on the balance between these two groups of substances In the blood stream, the anticoagulants normally predominate so that blood does not coagulate while it is circulating in the blood vessels. But when a vessel is ruptured, procoagulants from the area of tissue damage become "activated" and override the anticoagulants, and then a clot does develop. |
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235. General mechanism of blood coagulation - three steps
|
Clotting takes place in three essential steps:
1. In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reactions occurs in blood. The net result is formation of a complex of activated substances called prothrombin activator 2. The prothrombin activator catalyzes conversion of prothrombin into thrombin 3. The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot. |
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236. Prothrombin
|
Plasma protein, an alpha2-globulin, having a molecular weight of 68,700.
Present in the normal plasma in a concentration of about 15 mg/dl. Can split into smaller compounds, i.e. thrombin Formed continuously in the liver, and is continually being used throughout the body for blood clotting; if the liver fails to produce it then normal blood coagulation is halted Vitamin K is required by the liver for normal formation of prothrombin as well as for formation of other factors. |
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237. Conversion of prothrombin to thrombin
|
1. Prothrombin activator is formed as a result of rupture of blood vessel or as a result of damage to special substances in the blood.
2. Prothrombin activator, in the presence of sufficient amounts of ionic calcium, causes conversion of prothrombin to thrombin 3. The thrombin causes polymerization of fibrinogen molecules into fibrin fibers within another 10-15 s. Thus, the rate limiting factor in causing blood coagulation is usually the formation of prothrombin activator and not the subsequent reactions beyond that point, because these terminal steps normally occur rapidly to form the clot itself. Side note: platelets also play important roles in this conversion b/c much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue. |
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238. Fibrinogen
|
A high molecular weight protein that occurs in the plasma in quantities of 100 to 700 mg/dl.
Formed in the liver, and liver disease can decrease the concentration in the blood. B/c of its large molecular size, little fibrinogen normally leaks from the blood vessels into the interstitial fluids, and because fibrinogen is one of the essential clotting factors, interstitial fluids ordinarily do not coagulate. When the permeability of the capillaries becomes pathologically increased, it does leak into the tissue fluids to allow clotting of these fluids in much the same way that plasma and whole blood can clot. |
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239. Action of thrombin on fibrinogen
|
Forms fibrin.
Thrombin is an enzyme w/weak proteolytic capabilities; it acts on fibrinogen to remove four low molecular weight peptide from each molecule of fibrinogen, forming one molecule of fibrin monomer that has the automatic capability to polymerize to form fibrin fibers. Therefore, many fibrin monomer molecules polymerize within seconds into long fibrin fibers that constitute the reticulum of the blood clot. |
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240. Fibrin monomer bonding
|
In the early stages of polymerization, the fibrin monomers are held together by weak non covalent hydrogen bonding, and the newly forming fibers are not cross-linked w/one another - the clot is weak and can be broken apart easily.
Later, a substance called fibrin-stabilizing factor is released from platelets entrapped in the clot. This stabilizing factor must be activated by thrombin. Once activated, it operates as an enzyme to cause covalent bonds between more and more of the fibrin monomers and adds cross linkage, thus adding to the strength of the fibrin meshwork. |
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241. Clot retraction
|
Within a few minutes after a clot is formed, it beings to contract and usually expresses most of the fluid from the clot within 20-60 min.
The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed. Platelets are necessary for clot retraction to occur as they activate platelet thrombosthenin, actin, and myosin molecules, which are all contractile proteins in the platelets and causes strong contraction of the platelet spicules attaches to the fibrin. This helps compress the fibrin meshwork into a smaller mass The contraction is activated and accelerated by thrombin as well as by calcium ions released from the organelles of platelets. |
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242. Vicious circle of clot formation
|
Once a blood clot has started to develop, it normally extends within minutes into the surrounding blood.
The clot itself initiates a vicious circle to promote more clotting. One of the most important causes of this is the fact that the proteolytic action of thrombin allows it to act on many of the other blood-clotting factors in addition to fibrinogen. For instance, thrombin has a direct proteolytic effect on prothrombin itself, tending to convert this into still more thrombin, and it acts on some of the blood-clotting factors responsible for formation of prothrombin activator. Once a critical amount of thrombin is formed, a vicious circle develops that causes still more blood clotting and more and more thrombin to be formed; thus the blood clot continues to grow until blood leakage ceases. |
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243. How is prothrombin activator formed?
|
By two ways that interact constantly with one another:
1. Extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues 2. Intrinsic pathway that begins in the blood itself Blood clotting factors play major roles and most are inactive forms of proteolytic enzymes; when converted to the active forms, their enzymatic actions cause the successive, cascading reactions of the clotting process. |
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244. Extrinsic pathway
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1. Release of tissue factor; this factor is composed especially of phospholipids from the membranes of the tissue plus a lipoprotein complex that functions mainly as a proteolytic enzyme.
2. Activation of Factor 10 via Factor 7 and tissue factor -The lipoprotein complex of tissue factor further compelxes with blodo coagulation Factor 7 and, in the presence of calcium ions, acts enzymatically on Factor 10 to form activated Factor 10a 3. Effect of activated Factor 10a to form prothrombin activator via Factor 5 -Factor 10a combines w/tissue phospholipids as well as with additional phospholipids released from platelets as well as with Factor 5 to form the complex called prothrombin activator. -Within a few seconds, in the presence of calcium ions, this splits prothrombin into thrombin and the clotting process proceeds. |
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245. Extrinsic pathway in a nutshell
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Tissue trauma
↓ Tissue factor ↓ 7 → 7a; via tissue factor ↓ 10 → 10a; via 7a and calcium ions ↓ Common pathway |
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246. Intrinsic pathway
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1. Blood trauma causes: activation of Factor 12 and release of platelet phospholipids
2. Activation of Factor 11 which requires HMW kininogen and is accelerated by prekallikrein 3. Activation of Factor 9 via Factor 11a, acting in concert with activated Factor 8a and with the platelet phospholipids and Factor 3 from the traumatized platelets activated Factor 10. 5. Action of activated Factor 10a to form prothrombin activator via common pathways |
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247. Intrinsic pathway in a nutshell
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Blood trauma
↓ 12 → 12a; via blood trauma ↓ 11 → 11a; via 12a and HMW kininogen and prekallikrein ↓ 9 → 9a; via 11a ↓ 10 → 10a; via 8a which provides surface area for 9a to activate 10a with Ca+ ions and phospholipids |
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248. Common cascade
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Activated Factor 10a combines with Factor 5 and platelet or tissue phospholipids to form the complex called prothrombin activator
The prothrombin activator in turn initiates within seconds the cleavage of prothrombin to form thrombin, thereby setting into motion the final clotting process. |
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249.Role of calcium ions in the intrinsic and extrinsic pathways
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Except for the first two steps in the intrinsic pathway, calcium ions are required for promotion or acceleration of all the blood-clotting reactions.
Without these ions, blood clotting by either pathway does not occur. This is why deionizing the calcium by causing it to react with substances such as citrate ion or oxalate ions prevents blood from clotting outside the body. |
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250. Important difference between the extrinsic and intrinsic pathways
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The extrinsic pathway can be explosive; once initiated, its speed of completion to the final clot is limited only by the amount of tissue factor released from the traumatized tissues and by the quantities of Factors 10, 7, and 5 in the blood.
With severe tissue trauma, clotting can occur in as little as 15 seconds. The intrinsic pathway is much slower to proceed, usually requiring 1 - 6 minutes to cause clotting. |
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251. What are the most important factors for preventing clotting in the normal vascular system?
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1. The smoothness of the endothelial cell surface, which prevents contact activation of the intrinsic clotting system
2. A layer of glycocalyx on the endothelium which repels clotting factors and platelets, thereby preventing activation of clotting 3. A protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. When bound to thrombin, this slows the clotting process and activates protein C, which acts as an anticoagulant by inactivated activated Factors 5 and 8. |
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252. Endothelial wall damage
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When the endothelial wall is damaged, its smoothness and its glycocalyx-thrombomodulin layer are lost, which activates both Factor 12 and the platelets, thus settingoff the intrinsic pathway of clotting.
If Factor 12 and platelets come in contact w/the subendothelial collagen, the activation is even more powerful. |
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253. Antithrombin III
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Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood.
The most powerful of these are: 1. The fibrin fibers that themselves are formed during the process of clotting 2. An alpha-globulin called antithrombin III or antithrombin-heparin cofactor The thrombin that does not absorb to the fibrin fibers soon combines w/antithrombin III, which further blocks the effect of thrombin on the fibrinogen and then also inactivates the thrombin itself. |
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254. Three important types of bleeding tendencies
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1. Vitamin K deficiency
2. Hemophilia 3. Thrombocytopenia |
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255. Thromboresistance of normal vascular endothelium
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Contributed to by several properties:
1. Endothelial cells are highly negatively charged, a feature that may repel the negatively charge platelets. 2. Endothelial cells synthesize prostaglandin I2 (PGI2), NO, vasodilators and powerful inhibitors of platelet aggregation 3. Endothelial cells also synthesize two cofactors that each inhibit the action of thrombin, thrombomodulin, and heparan sulfate. |
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256. Deficiency in the amount of functionality of protein C or protein S increases the risk for what?
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Venous thromboembolism.
Individuals who are homozygous for these mutations do not survive the neonatal period unless they are given replacement therapy. |
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257. Factor V Leiden
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Present in European populations, a point mutation in the Factor 5 gene causes the replacement of an Arg w/ a Gln in the preferred site for cleavage by activated protein C, rendering Factor 5a Leiden resistant to APC.
Heterozygous individuals have a 6 - 8x increased risk of deep vein thromboses, and homozygous individuals have a 30-140x increased risk. Inherited APC resistance is the most prevalent risk factor for familial thrombotic disease. |
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258. Virchow's triad
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The influence of endothelial injury, abnormal blood flow, and hypercoagulability on one another eventually causes thrombus.
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259. Prothrombin G20210a mutation
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Adenine is substituted for guanine in 3' on translated region of prothrombin gene
Leads to 30% increase in plasma prothrombin levels. and almost 3x increased risk of venous thromboses. |
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260. Heparin induced thrombocytopaenia
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Stimulates the immune system to generate circulating antibodies directed against a platelet Factor 4-Heparin complex.
B/c platelet Factor 4 is present on platelet surfaces and endothelial surfaces, when bound to the antibody, it causes coagulation via mediation by removal of platelets from the blood. In some patients, however, antibody platelet binding causes platelet activation, endothelial injury and prothrombotic state. LMW heparin has a lower incidence of thrombocytopaenia compared to unfractionated heparin |
