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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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Stingl J, Eirew P, Ricketson I, et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006;439(7079):993–997.
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Asselin-Labat ML, Shackleton M, Stingl J, et al. Steroid hormone recep- tor status of mouse mammary stem cells. J Natl Cancer Inst 2006;98(14): 1011–1014.
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Sleeman KE, Kendrick H, Robertson D, et al. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol 2007;176(1):19–26.
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Booth BW, Smith GH. Estrogen receptor-alpha and progesterone recep- tor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands. Breast Cancer Res 2006;8(4):R49.
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Dontu G, Abdallah WM, Foley JM, et al. In vitro propagation and tran- scriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003;17(10):1253–1270.
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Lima SC, Hernandez-Vargas H, Herceg Z. Epigenetic signatures in cancer: Implications for the control of cancer in the clinic. Curr Opin Mol Ther 2010;12(3):316–324.
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Rice JC, Ozcelik H, Maxeiner P, et al. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis 2000;21(9):1761–1765.
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Klarmann GJ, Decker A, Farrar WL. Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics 2008;3(2):59–63.
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Lehmann U, Hasemeier B, Christgen M, et al. Epigenetic inactiva- tion of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol 2008;214(1):17–24.
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Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulat- ing evidence and unresolved questions. Nat Rev Cancer 2008;8(10):755–768.
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Stingl J, Caldas C. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat Rev Cancer 2007;7(10):791–799.
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Martinez-Climent JA, Andreu EJ, Prosper F. Somatic stem cells and the origin of cancer. Clin Transl Oncol 2006;8(9):647–663.
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Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift.
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Polyak K. Breast cancer stem cells: a case of mistaken identity? Stem Cell Rev 2007;3(2):107–109.
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Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3(7):730–737.
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Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumori- genic prostate cancer stem cells. Cancer Res 2005;65(23):10946–10951.
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Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007;104(24): 10158–10163.
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Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67(3):1030–1037.
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Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a sub- population of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 2007;104(3):973–978.
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Kai K, Iwamoto T, Kobayashi T, et al. Ink4a/Arf(-/-) and HRAS(G12V) trans- form mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f(-) quiescent cells. Oncogene, 2013.
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Driessens G, Beck B, Caauwe A, et al. Defining the mode of tumour growth by clonal analysis. Nature 2012;488(7412):527–530.
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Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblas- toma growth after chemotherapy. Nature 2012;488(7412):522–526.
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Schepers AG, Snippert HJ, Stange DE, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 2012;337(6095):730–735.
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Sakariassen PO, Immervoll H, Chekenya M. Cancer stem cells as media- tors of treatment resistance in brain tumors: status and controversies. Neoplasia 2007;9(11):882–892.
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Tang C, Chua CL, Ang BT. Insights into the cancer stem cell model of gli- oma tumorigenesis. Ann Acad Med Singapore 2007;36(5):352–357.
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Kim M, Turnquist H, Jackson J, et al. The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 2002;8(1): 22–28.
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Smalley MJ, Clarke RB. The mammary gland “side population”: a puta- tive stem/progenitor cell marker? J Mammary Gland Biol Neoplasia 2005;10(1):37–47.
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Gauthaman K, Manasi N, Bongso A. Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells. Br J Pharmacol 2009;157(6):962–973.
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Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evalu- ate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205–216.
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Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, et al. Tumour char- acteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 2007;43(5):867–876.
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Arnould L, Arveux P, Couturier J, et al. Pathologic complete response to trastuzumab-based neoadjuvant therapy is related to the level of HER-2 amplification. Clin Cancer Res 2007;13(21):6404–6409.
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Yu F, Deng H, Yao H, et al. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene 2010;29(29):4194–4204.
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Yu F, Yao H, Zhu P, et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007;131(6):1109–1123.
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Korkaya H, Paulson A, Iovino F, et al. HER2 regulates the mammary stem/ progenitor cell population driving tumorigenesis and invasion. Oncogene 2008;27(47):6120–6130.
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Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008;100(9):672–679.
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Magnifico A, Albano L, Campaner S, et al. Tumor-initiating cells of HER2- positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res 2009;15(6):2010–2021.
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Ithimakin S, Day KC, Malik F, et al. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 2013;73(5):1635–1646.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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Dontu G, Jackson KW, McNicholas E, et al. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 2004;6(6):R605–615.
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Harrison H, Farnie G, Howell SJ, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010;70(2):709–718.
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Kondratyev M, Kreso A, Hallet RM, et al. Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer. Oncogene 2011;31(1):93–103.
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Pece S, Serresi M, Santolini E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 2004;167(2):215–221.
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Schott AF, Landis MD, Dontu G, et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res 2013;19(6):1512–1524.
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Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006;66(12):6063–6071.
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Panigrahi AR, Pinder SE, Chan SY, et al. The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. J Pathol 2004;204(1): 93–100.
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Korkaya H, Paulson A, Charafe-Jauffret E, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol 2009;7(6):e1000121.
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Korkaya H, Kim GI, Davis A, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell 2012;47(4):570–584.
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Singh JK, Farnie G, Bundred NJ, et al. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res 2013;19(3):643–656.
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Ginestier C, Liu S, Diebel ME, et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 2010;120(2):485–497.
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S E C T I O N I I
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Diagnosis and Management of Benign Breast Disease
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Obtaining a careful history is the initial step in a breast examination. Regardless of the presenting complaint, baseline information regarding menstrual status and breast cancer risk factors should be obtained. The basic elements of a breast his- tory are listed in Table 3-1. In premenopausal women, knowing the date of the last menstrual period and the regularity of the cycle is useful in evaluating breast nodularity, pain, and cysts. Postmenopausal women should be questioned about use of hormone replacement therapy, given that many benign breast problems are uncommon after menopause in the absence of exogenous hormones. Specific information about the patient’s presenting complaint is then elicited. A breast lump is most often the clinical breast problem that causes women to seek treatment, and remains the most common presentation of breast carcinoma. Haagensen (1) observed that 65% of 2,198 breast cancer cases identified before the use of screening mammography presented as breast masses. Breast pain, a change in the size and shape of the breast, nipple discharge, and changes in the appearance of the skin are infrequent symp- toms of carcinoma. The evaluation and management of these conditions are described in Chapters 5, 6, and 7. In general, the duration of symptoms, their persistence over time, and their fluctuation with the menstrual cycle should be assessed.
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A woman must be disrobed from the waist up for a complete breast examination. Although attention to modesty is appro- priate, and a gown or drape should be provided, inspection is an important part of the examination, and subtle abnor- malities are best appreciated by comparing the appearance of both breasts. Breast examination should be done with the patient in both the sitting and supine positions, and care should be taken at all times to be gentle. The steps of a breast examination are illustrated in Figure 3-1.
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The breasts should initially be inspected while the patient is in the sitting position with the arms relaxed (Fig. 3-1A). A comparison of breast size and shape should be made. If a size discrepancy is noted, its chronicity should be determined. Many women’s breasts are not identical in size, and the finding of small size discrepancies is rarely a sign of malignancy. Differences in breast size that are of recent onset or progressive in nature, however, may be owing to both benign and malignant tumors, and require
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further evaluation (Fig. 3-2). Alterations in breast shape, in the absence of previous surgery, are of more concern. Superficially located tumors can cause bulges in the breast contour or retraction of the overlying skin. The skin retrac- tion seen with superficial tumors may be caused by direct extension of tumor or fibrosis. Tumors deep within the sub- stance of the breast that involve the fibrous septa (Cooper’s ligaments) can also cause retraction. Retraction is not itself a prognostic factor except when caused by the direct exten- sion of tumor into the skin and, for this reason, it is not a part of the clinical staging of breast cancer (2). Although retraction is often a sign of malignancy, benign lesions of the breast, such as granular cell tumors (3) and fat necro- sis (4), also cause retraction. Other benign causes of retrac- tion include surgical biopsy and thrombophlebitis of the thoracoepigastric vein (Mondor’s disease) (5) (Fig. 3-3).
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The skin of the breasts and the nipples should also be carefully inspected. Edema of the skin of the breast (peau d’orange), when present, is usually extensive and readily apparent. Localized edema is frequently most prominent in the lower half of the breast and periareolar region, and is most noticeable when the patient’s arms are raised. Although breast edema usually occurs as a result of obstruc- tion of the dermal lymphatics with tumor cells, it can also be caused by extensive axillary lymph node involvement related to metastatic tumor, primary diseases of the axillary nodes, or axillary dissection. Some degree of breast edema is very common after irradiation of the breast and should not be considered abnormal in this circumstance. Erythema is another sign of a pathologic process that is evident on inspection (Fig. 3-4). It may be caused by cellulitis or abscess in the breast, but a diagnosis of inflammatory carcinoma should always be considered. The erythema of inflamma- tory carcinoma usually involves the entire breast; it is dis- tinguished from the inflammation caused by infection by the absence of breast tenderness and fever. A small percentage of large-breasted women have mild, dependent erythema of the most pendulous portion of the breast, a condition that resolves when they lie down, and that is of no concern.
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Examination of the nipples should include inspection for
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symmetry, retraction, and changes in the character of the skin. The new onset of nipple retraction should be regarded with a high index of suspicion, except when it occurs immediately after cessation of breast-feeding. Ulceration and eczematous changes of the nipple may be the first signs of Paget’s disease.
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25
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The initial nipple abnormality may be limited in extent, but, if untreated, it progresses to involve the entire nipple.
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After inspection with the arms relaxed, the patient should be asked to raise her arms to allow a more com- plete inspection of the lower half of the breasts (Fig. 3-5). Inspection is completed with the patient contracting the pectoral muscles by pressing her hands against her hips. This maneuver often highlights subtle areas of retraction that are not readily apparent with the arms relaxed.
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The next step in the examination is palpation of the regional nodes. Examination of the axillary and supraclavic- ular nodes is done optimally with the patient upright. The right axilla is examined with the physician’s left hand while the patient’s flexed right arm is supported (Fig. 3-1B). This position allows relaxation of the pectoral muscle and access to the axillary space, and is reversed to examine the left axilla. If lymph nodes are palpable, their size and character (soft, firm, tender) should be noted, as well as whether they are single, multiple, or matted together. An assessment of whether the nodes are mobile or fixed should also be made. Based on this information, the physician can assess whether the nodes are clinically suspect. Many women have palpable axillary nodes secondary to hangnails, minor abrasions of the arm, or folliculitis of the axilla, and nodes that are small (<1 cm), soft, and mobile (especially if bilateral) should
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FIGURE 3-1 Inspection of the patient in the upright position with arms relaxed (A). Palpation of the axillary nodes (B). The patient’s ipsilateral arm is supported to relax the pectoral muscle. Palpation of the breast in the upright position (C). Palpation of the breast in the supine position (D). The breast is stabilized with one hand.
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CHAPTER 3 | P H Y SICA L EX AMINATION OF THE B REAST
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27
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FIGURE 3-2 Marked breast asymmetry owing to a benign breast tumor.
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FIGURE 3-5 Retraction in the inferior right breast that is apparent only when the patient’s arms are raised.
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FIGURE 3-3 Breast retraction caused by thrombophlebitis of the thoracoepigastric vein (Mondor’s disease). Seen is the characteristic pattern of lateral retraction superior to the nipple and crossing to the midline below the nipple.
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FIGURE 3-4 Signs of locally advanced breast cancer that are apparent on inspection: breast asymmetry, erythema, and eczema owing to dermal involvement with tumor.
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not be regarded with a high level of suspicion. In contrast, palpable supraclavicular adenopathy is uncommon and is an indication for further evaluation.
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After the nodal evaluation is completed, palpation of the breasts should be done with the patient erect. Examination of the breast tissue in this position allows detection of lesions that might be obscured with the patient supine, such as those in the tail of the breast. The breast should be gently supported with one hand while examination is done with the flat portions of the fingers (Fig. 3-1C). Pinching breast tissue between two fingers always results in the perception of a mass and is a common error of inexperienced examiners and women attempting self-examination.
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The breast examination is completed with the patient in the supine position and the ipsilateral arm raised above the head (Fig. 3-1D). In patients with extremely large breasts, it may be necessary to place a folded towel or a small pil- low beneath the ipsilateral shoulder to elevate the breast, but this is not routinely necessary. The breast tissue is then systematically examined. Whether the examination is done using a radial search pattern or concentric circular pattern is unimportant, provided that the entire breast is examined. The examination should extend superiorly to the clavicle, inferiorly to the lower rib cage, medially to the sternal border, and laterally to the midaxillary line. Examination is done with one hand while the other hand stabilizes the breast. The degree of pressure needed to examine the breast tissue varies, but should not cause the patient discomfort.
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One of the most difficult aspects of breast examina- tion results from the nodular, irregular texture of normal breasts in premenopausal women. Normal breasts tend to be most nodular in the upper outer quadrants where the glandular tissue is concentrated, in the inframammary ridge area, and in the subareolar region. The characteristics that distinguish a dominant breast mass include the absence of other abnormalities of a similar character, density that dif- fers from the surrounding breast tissue, and three dimen- sions. Generalized lumpiness is not a pathologic finding. Comparing the breasts is often helpful in determining whether a questionable area requires further evaluation. If the patient notices a mass that is not evident to the exam- iner, she should be asked to indicate the area of concern. The location of the perceived abnormality and the character of the breast tissue in the region should be described in the
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
medical record. If uncertainty remains regarding the signifi- cance of an area of nodular breast tissue in a premenopausal woman, a repeat examination at a different time during the menstrual cycle may clarify the issue. If a dominant mass is identified, it should be measured, and its location, mobility, and character should be described in the medical record. The identification of a dominant mass is an indication for further evaluation. The steps in the evaluation of a palpable mass are described in Chapter 5.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
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REFERENCES
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
Haagensen CD. Diseases of the breast. Philadelphia, PA: WB Saunders; 1986:502.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
American Joint Committee on Cancer. Manual for staging of cancer. 6th ed.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
New York: Springer; 2002:227.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
Gold DA, Hermann G, Schwartz IS, et al. Granular cell tumor of the breast.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
Breast Dis 1989;2:211.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
|
TECHNIQUE OF BREAST EXAMINATION
| null | null |
Adair F, Munzer J. Fat necrosis of the female breast. Am J Surg 1947;74:117.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
Tabar L, Dean P. Mondor’s disease: clinical, mammographic and patho- logic features. Breast 1981;7:17.
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Stem Cells in Breast Development and Carcinogenesis: Concepts and
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TECHNIQUE OF BREAST EXAMINATION
| null | null |
C H A P T E R 4
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Management of the Palpable
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Breast Mass
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Management of the Palpable
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Richard J. Bleicher
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Management of the Palpable
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CHAPTER CONTENTS
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History
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Management of the Palpable
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CHAPTER CONTENTS
| null | null |
Physical Examination
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Management of the Palpable
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CHAPTER CONTENTS
| null | null |
Documentation The Axilla
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