Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA IL CARCINOMA DELLA MAMMELLA. II. Prof. Alberto Riccardi

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1 Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA IL CARCINOMA DELLA MAMMELLA. II. Prof. Alberto Riccardi

2 BREAST CANCER. II. EVALUATION OF BREAST MASSES

3 BREAST ANATOMY

4 BREAST ANATOMY. I.

5 BREAST ANATOMY. II. Breast profile: A: ducts; B: lobules; C: dilated section of duct to hold milk; D: nipple; E: fat; F: pectoralis major muscle; G: chest wall / rib cage Enlargement: A: normal duct cells; B: basement membrane; C: lumen (centre of duct)

6 BREAST ANATOMY. III. Lymph node areas adjacent to breast area A: pectoralis major muscle; B: axillary lymph nodes: level I; C: axillary lymph nodes: level II; D: axillary lymph nodes: level III; E: supraclavicular lymph nodes; F: internal mammary lymph nodes

7 EVALUATION OF BREAST MASSES IN MEN AND WOMEN. I. * breast examination = essential part of physical examination (abnormal breasts = common site of potentially fatal malignancy in women, but also provide clues to underlying systemic diseases in both men and women, including gynecomastia, abnormal hormonal secretion, infectious granuloma and mastitis, sarcoidosis and diabetic mastopathy); - unfortunately, internists frequently do not examine breasts in men, and, in women, often defer evaluation to gynecologists; - due to plausible association between early detection and improved outcome duty of every physician to distinguish breast abnormalities at earliest possible stage to institute diagnostic workup

8 EVALUATION OF BREAST MASSES IN MEN AND WOMEN. II. * women be trained in breast self - examination (BSE); - although BC in men is unusual, unilateral lesions should be evaluated as in women (with recognition that gynecomastia in men sometimes begin unilaterally and is often asymmetric); - virtually all BCs diagnosed by biopsy of nodule detected either on mammogram or, much more frequently, by palpation

9 THE PALPABLE BREAST MASS

10 THE PALPABLE BREAST MASS. I. * women strongly encouraged to examine breasts monthly (potentially flawed study from China suggests that BSE does not alter survival, but given its safety, procedure be encouraged; at worst, this likelihood of detecting a mass at smaller size, to be treated with limited surgery)

11 CLINICAL BREAST EXAMINATION. I. pt in sitting position for inspecting breasts for size, shape, symmetry, color, texture and condition of nipples pt raises arms overhead for inspection of axillary prolongement

12 CLINICAL BREAST EXAMINATION. II. while in sitting position, pt relaxes and then contracts pectoralis major muscle by pressing in on her hips

13 CLINICAL BREAST EXAMINATION. III. with arm in supine position, patterns of search include wedge, circular and vertical strip circular search pattern

14 THE PALPABLE BREAST MASS. II. * breast examination by physician be performed in good light (for retractions and other skin changes); - nipple and areolae be inspected, and attempt be made to elicit nipple discharge; - regional lymph nodes be examined, and any lesions be measured; - physical examination alone cannot exclude malignancy

15 THE PALPABLE BREAST MASS. IIbis. * breast examination by physician be performed in good light (for retractions and other skin changes); - nipple and areolae inspected, with attempt to elicit nipple discharge; - regional lymph nodes examined, and any lesions measured; - physical examination alone cannot exclude malignancy

16 CLINICAL BREAST EXAMINATION. III. examination of axillae searching for swollen axillary lymph nodes examination of supraclavicular lymph nodes

17 CLINICAL BREAST EXAMINATION. IV. anatomical extent of breast tissue perimeter of breasts be noted

18 THE PALPABLE BREAST MASS. V. * hard, irregular, tethered or fixed, or painless lesions more likely cancerous; - negative mammogram in presence of persistent lump in breast does not exclude malignancy

19 THE PALPABLE BREAST MASS. VI. * palpable lesions additional diagnostic procedures including biopsy; * in premenopausal women, equivocal or nonsuspicious lesions on physical examination re - examined in 2-4 wks, during follicular phase of menstrual cycle (days 5-7 = best time for breast examination)

20 THE PALPABLE BREAST MASS. VI. * dominant mass in postmenopausal woman or dominant mass persisting through a menstrual cycle in premenopausal woman aspirated by fine - needle biopsy or referred to surgeon; - if non bloody fluid obtained = diagnosis (cyst) and therapy accomplished together; * persistent or recurrent or complex solid lesions or bloody cysts mammography and biopsy

21 THE PALPABLE BREAST MASS. VIII.

22 THE PALPABLE BREAST MASS. IX. * in selected pts with not suspicious mass, so - called triple diagnostic technique (palpation, mammography, aspiration) can avoid biopsy

23 * ultrasound used in place of fine - needle aspiration to cysts from solid lesions; - not all solid masses detected by ultrasound a palpable mass not visualized on ultrasound presumed to be solid THE PALPABLE BREAST MASS. X. ultrasound mammography

24 THE PALPABLE BREAST MASS. XI. CYST MANAGEMENT

25 THE PALPABLE BREAST MASS. XIII. * points essential in management decision trees: -1st) no decision from risk - factor analysis (= presence or absence of risk factors of no value to decide on biopsy); -2nd) fine - needle aspiration only in centers with proven skill in obtaining and analyzing specimens (likelihood of BC low in setting of "triple negative" = benign - feeling lump + negative mammogram + negative fine - needle aspiration, but not = 0% pt and physician be aware of 1% risk of false-); -3rd) additional technologies (e.g., MRI, ultrasound, and 99mTc - sestamibi scintigraphy imaging) not used to exclude need for biopsy (although in unusual circumstances they may provoke biopsy)

26 THE ABNORMAL MAMMOGRAM

27 MAMMOGRAPHY. I. * diagnostic mammography (performed after detection of palpable abnormality) # from screening mammography; - confirms suspected mass and aims at evaluating rest of breast before biopsy (or, occasionally, part of triple - test strategy to avoid immediate biopsy)

28 MAMMOGRAPHY. II. normal breast

29 THE ABNORMAL MAMMOGRAM. I. * subtle abnormalities [including clustered micro - calcifications, densities (especially spiculated), and new or enlarging architectural distortion] first detected by screening mammography be evaluated carefully by compression or magnified views

30 THE ABNORMAL MAMMOGRAM. II. clustered micro - calcifications

31 THE ABNORMAL MAMMOGRAM. III. spiculated densities architectural distortion

32 THE ABNORMAL MAMMOGRAM. IV. fibroadenoma

33 THE ABNORMAL MAMMOGRAM. V. * for some nonpalpable lesions, ultrasound helpful either to identify cysts or to guide biopsy breast cancer nodule simple breast cyst fibroadenoma

34 THE ABNORMAL MAMMOGRAM. VI. * with no palpable lesion and detailed, unequivocally benign mammographic study routine follow - up appropriate to pt's age; - with non - palpable mammographic lesion with low index of suspicion mammographic follow - up in 3-6 mos

35 THE ABNORMAL MAMMOGRAM. VII. * workup of indeterminate and suspicious lesions rendered more complex by advent of stereotactic biopsies; - these procedures indicated for lesions requiring biopsy but likely to be benign (i.e., for cases in which procedure will eliminate additional surgery) cytology

36 THE ABNORMAL MAMMOGRAM. VIII. MAMMOTOME (ULTRASOUND GUIDED BREAST BIOPSY) histology

37 THE ABNORMAL MAMMOGRAM. IX. * with lesion probably malignant, open biopsy be performed with needle localization technique

38 THE ABNORMAL MAMMOGRAM. X. * need for definitive surgical procedures, especially with lesion probably malignant and breast conservation attempted, usually not eliminated by stereotactic or mammotome core biopsy (useful for suspected benign or non - palpable lesions, from economic grounds); - open biopsy for lesion probably malignant, because diagnosis leads to earlier treatment planning; -e.g., after breast biopsy with stereotactically or mammotome localization (i.e., local excision) of diagnosed malignancy, re - excision still necessary to achieve negative margins; [- these issues decided from referral pattern and availability of resources for stereotactic core biopsies]

39 THE ABNORMAL MAMMOGRAM. XI. MAMMOGRAPHY ALGORITHM

40 BREAST MASSES IN PREGNANT OR LACTATING WOMAN

41 BREAST MASSES IN PREGNANT OR LACTATING WOMAN. I. * during pregnancy, breast grows from influence of estrogen, progesterone, prolactin, and human placental lactogen (lactation suppressed by progesterone, blocking effects of prolactin); - after delivery, lactation promoted by fall in progesterone levels (leaving effects of prolactin unopposed)

42 BREAST MASSES IN PREGNANT OR LACTATING WOMAN. II. * BC in 1 / pregnancies; - stage for stage, BC in pregnant pts no from pre - menopausal BC non - pregnant pts; - persistent lumps in breast of pregnant or lactating women not be attributed to benign changes based on physical findings pts be promptly referred for diagnostic evaluation = development of dominant mass during pregnancy or lactation never be attributed to hormonal changes = dominant mass be treated with same concern in pregnant as any other woman

43 BREAST MASSES IN PREGNANT OR LACTATING WOMAN. II. * however, in pregnant women often more advanced disease because significance of breast mass not fully considered and / or because of endogenous hormone / cytokine stimulation

44 PREGNANCY - ASSOCIATED BC AND METASTASIS. I. a ascini from lactating gland with invasive micro - lesion; - during lactation, secretory mammary epithelial cells (MEC) surrounded by myoepithelial cells and intact basement membrane and individual ascini embedded within sparse intra- and inter- lobular stroma containing fibroblasts, vasculature and extracellular matrix (ECM); - small ductal tumor with locally invasive tumor cells (red dashes = local disruption in basement membrane at site of invading tumor cells)

45 PREGNANCY - ASSOCIATED BC AND METASTASIS. II. b matrix - proteinase - dependent phase of involution with attributes of wound - healing environment; - with involution massive cell death of secretory epithelium ascinar lumen fill with apoptotic debris; - with loss of epithelial cells, gland repopulated with adipocytes and intra- and inter- lobular stroma, partly due to deposition of fibrillar collagen by fibroblasts; - fibroblasts secrete proteases (arrows), degrading ECM proteins (fibronectin and laminin) release of bioactive matrix fragments with tumor growth-, motility- and invasion- promoting activities (immune cells, e.g.,macrophages and neutrophils, abundant, probably due to chemoattractant properties of proteolysed matrix)

46 PREGNANCY - ASSOCIATED BC AND METASTASIS. III. c involution - associated changes in microenvironment by tumor cells, switching finely - tuned inflammatory balance to overt inflammation: - fibronectin and laminin 5 fragments tumor cells to activate matrix metalloproteinase 9 (MMP9) and MMP2 further matrix degradation; - furthermore (due to compromised basement membrane at tumor site), leakage of highly immunogenic apoptotic debris from ductal lumen into interstitial space sustained influx of inflammatory cells; - recruited macrophages and neutrophils release additional cytokines [e.g., colony - stimulating factor 1, tumor - necrosis factor α, interleukin -1 (IL -1), IL -6, platelet -derived growth factor, epidermal growth factor (EGF), hepatic growth factor (HGF) and proteases (arrows)]; - previously quiescent tumor cells activated by cytokine - rich microenvironment motile and invasive traverse interstitial fibrillar collagen - rich matrix of involuting gland access to vasculature and lymphatics

47 BENIGN BREAST MASSES

48 BENIGN BREAST MASSES. I. * in only ~ 1 / 5-10 breast biopsies diagnosis of cancer (rate of +biopsies in different countries and clinical settings, related to interpretation, medico - legal considerations, and availability of mammograms); - most benign breast masses due to "fibrocystic disease, descriptive term for small fluid - filled cysts and modest epithelial cell and fibrous tissue hyperplasia; - however, fibrocystic disease is histologic, not clinical, diagnosis, and biopsed women with fibrocystic disease (benign finding) at risk of developing BC vs not biosied

49 BENIGN BREAST MASSES. II. * subset of biopsied women with ductal or lobular cell proliferation [~ 30% of pts, especially small fraction (3%) with atypical hyperplasia] 4 - fold risk of developing BC than unbiopsied women, and ~9 -fold risk for women having an affected 1st - degree relative careful follow - up of these pts required; -, pts with benign biopsy without atypical hyperplasia at little risk (be followed routinely)

50 BENIGN BREAST MASSES. III. RISK OF BREAST CANCER ACCORDING TO BREAST DENSITY (IN PREMENOPAUSAL AND POSTMENOPAUSAL WOMEN)

51 BENIGN BREAST MASSES. IV. PROGRESSION FROM BENIGN TO MALIGNANT LESION * levels of estrogen receptor - α (ER - α) and levels of ER - β) Santen RJ at al NEJM 2005; 353: 275

52 BENIGN BREAST MASSES. VI. CLASSIFICATION OF BENIGN BREAST LESIONS ACCORDING TO HISTOLOGIC EXAMINATION AND RELATIVE RISK OF BC