Breast Cancer

1. Breast Cancer Seyed Morteza Mahmoodi

2. Contents Breast Cancer OVERVIEW WORK UP TREATMENT PROGNOSIS

4. OVERVIEW  Anatomy  Histology  Physiology  Pathology  Presentation

11. Lymphatics of the Mammary Gland Superficial lymphatics From the skin except nipple and areola a. Upper marginal >>apical nodes after piercing CP fascia. >>infraclavicular nodes. b. Upper lateral with axillary tail>>pectoral group c. Lower lateral >> pectoral + ant. Abdominal wall d. Medial >>sternal group of same and opposite side. a b d c Sternum

12. Deep lymphatics From the parenchyma and glandular tissue + Skin of nipple and areola •75% to axillary nodes- anterior or pectoral group. •20% to internal mammary nodes •5% to posterior to posterior intercostal nodes •Some pass to abdominal cavity from lower medial quadrant.

13. a b&c Sternum From retromammary space a. Upper part >>Apical group d b. Upper lateral parts>>pectoral c. Lower lateral>>pectoral + ant abdominal wall d. Upper medial>>sternal group of same and opposite side. e. Dangerous area >> plexus on rectus sheath; along falciform ligament to hepatic nodes and into peritoneal cavity c e Rectus sheath Peritoneal cavity

14. Hormones  Estrogen ►  Progesterone ►  Development of the breast and lactiferous ducts Secretory acinar tissue – lobules Prolactin ► Synergizes the effect of estrogen and progesterone

16. The female breast: Normal breast anatomy & anatomical location of common breast lesions

17. Breast – Neoplastic diseases:  Benign:  Fibroadenoma.  Phyllodes tumor.  Papilloma. Stromal tumors  Malignant:  Carcinoma in situ:  Ductal carcinoma in situ (DCIS).  Lobular carcinoma in situ (LCIS).  Invasive carcinoma:  No special type carcinoma (NST “ductal”).  Lobular.  Tubular / cribriform.  Mucinous (colloid) carcinoma.  Medullary carcinoma.  Papillary carcinoma.  Metaplastic carcinoma.

19. In situ (noninvasive ) carcinoma – Morphology: C

20. In situ (noninvasive) carcinoma – Morphology:

23. Invasive (infiltrating) carcinoma – Morphology: Invasive ductal carcinoma

24. Invasive (infiltrating) carcinoma – Morphology: Invasive lobular carcinoma.Parallel arrays of single files of small, poorly cohesive cells are embedded within a dense fibrous stroma

25. Invasive (infiltrating) carcinoma – Morphology: Colloid carcinoma.

26. Invasive (infiltrating) carcinoma – Morphology: Medullary carcinoma with lymphoid infiltrates,

27. Invasive (infiltrating) carcinoma – Morphology: Tubular carcinoma.

28. Syndrome Breast/ovarian Gene BRCA1 Inheritance Cancers Other Features AD* Breast, ovarian Cancer syndrome BRCA2 AD Li-Fraumeni syndrome TP53 AD Breast, ovarian, Fanconi anemia in prostate, homozygotes pancreatic Breast, brain, soft tissue sarcomas, leukemia, adrenocortical, others Cowden disease PTEN AD Breast, ovary, follicular thyroid, colon Adenomas of thyroid, fibroids, GI polyps Peutz-Jegher syndrome STKII/LKB1 AD GI, breast Ataxiatelangiectasia ATM AD Breast Site-specific CHEK2 AD Breast Hamartomas of bowel, pigmentation of buccal mucosa Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias Low penetrance

29. Li-Fraumeni Syndrome ► Mutation  of p53 gene Tumor suppressor ► Premenopausal     breast CA Childhood sarcoma Brain tumors Leukemia Adrenocortical CA ► Accounts for 1% of breast CA

30. Cowden Syndrome ► Major criteria       ► Thyroid CA (follicular) Marcocephaly Cerebellar tumors Endometrial CA Breast CA – 25%-50% risk Skin and mucosal lesions Minor criteria      Thyroid lesions GU tumors GI hamartomas Fibrocystic breast Mental retardation

31. Tumor Grade  Histologic grade  Well differentiated, >75% tubule  Moderately differentiated, 10-75% tubule formation  Poorly differentiated, < 10% tubule formation, worse prognosis Intermediate grade Low grade – Small nuclei, no necrosis Grading of breast carcinomas • Most classification systems rely primarily on nuclear morphology and have 3 grades

32. Presentation & Assessment  Symptoms Lump 80% Painful lump or lumpiness Pain Nipple discharge Nipple change Miscellaneous  Triple Assessment  Clinical examination 99% accurate

33. Symptoms & possible diagnosis 1.Lump Fibroadenoma Juvenile Fibroadenoma Giant fibroadenoma Phyllodes tumours Cysts Galactocele 2.Pain Mastalgia : Cyclical & Non cyclical 3.Nipple Physiological Bloodstained in pregnancy Intraductal papillomas and associated conditions Duct Ectasia Galactorrhoea discharge 4.Nipple change Developmental inversion of nipple Acquired nipple retraction : duct ectasia, periductal mastitis etc Eczema Paget’s disease etc. Infections : Lactational & Non lactational 5.Cosmetic Comon cosmetic problems : size, shape & symmetry of breast & other mound problems Uncommon cosmetic problems : developmental & acquired Trauma Rare problems

34. Charecterestics of nipple discharges

36. Laboratory Studies Genetic and molecular testing  Oncotype DX  Serum markers 

37. BRCA BRCA (breast cancer) tumor suppressor gene,  breast cancer type susceptibility protein  Chromosome 17,  Chromosome 13 

38. BRCA ► Account to 25% of early-onset breast Ca ► 36%-85% lifetime risk of breast CA ► 16-60% lifetime risk of ovarian CA ► BRCA 1 gene  Ovarian CA ► BRCA    2 gene Male breast CA Prostate CA Pancreatic CA

40. BRCA is it a Screening tool or a Prognostic tool?

41. Screening (Significant FH) 2 or more first-degree relatives  2 or more second-degree relatives (on the same side of the family) who meet the following:  Breast cancer age less than 50 years  Breast and ovarian cancer in the same bloodline or in the same individual  Male relative breast cancer age less than 50 years  Family members bilateral breast cancer 

42. BRCAPRO is a statistical model, with associated software, for assessing the probability that an individual carries a germline deleterious mutation of the BRCA1 and BRCA2 genes, based on family history of breast and ovarian cancer, including male breast cancer and bilateral synchronous and asynchronous diagnoses

43. BRCA + ► Management    Monthly BSE beginning18yo 6 mo CBE & annual mammo beginning 25yo Discuss risk reducing options Prophylactic mastectomies ► Salpingo-oophorectomy – upon completion of child bearing ►  6 mo transvaginal US & CA125 – 35 yo

44. Prognostic Breast cancer age less than 40 years  Males with breast cancer  Two or more cancers 

45. BRCA1 Has a medullary histology  "triple negative"  high nuclear grade  Has a higher rate of proliferation  Overexpresses p53 

46. Hormone Receptor (HR) status  ER + Indicator of growth not metastatic potential  More likely to be well differentiated lower fraction of dividing cells  Less likely to be associated with mutations, loss of breast cancer related genes such as p53, HER-2/neu, or EGFR  In early stage 5-10% lower likelihood of recurrence  More likely to metastasize to bone, soft tissues or genital sites   ER More likely to metastasize to brain, liver associated with shorter survival

47. Breast, adenocarcinoma, immunohistochemical stain for estrogen receptor - Low and medium power Antibodies used to stain a section from the biopsy specimen show that virtually all of the tumor cells express estrogen receptor protein (brown stain). 1.Staining for estrogen and progesterone receptors Positive for both receptors

48. Does ER- patients benefit from tamoxifen?

49. Since tamoxifen can potentially affect cellular functions by binding to calmodulin or inhibiting protein kinase C , it has been used for its ability to inhibit cell growth and induce apoptosis independently of the presence of ER

50. New prognostic factors  HER-2/neu receptor status     + relatively resistant to adjuvant endocrine therapy + tumors may benefit from anthracyclinebased chemotherapy Trastuzumab (Herceptin) Bevacizumab (Avastin)

51. Breast cancer, immunohistochemical stain for HER2/neu High power Immunohistochemical detection of HER2 protein expression in a section of tissue containing the tumor shows an intense cell-surface staining pattern.

52. Molecular changes associated with breast cancer progression  Increased expression of oncogenes   c-erb-B2, her2/neu, c-ras, c-myc Decreased expression of tumor suppressor genes  P53, RB, E-cadherins, Strong (3+) membrane immunoreactivity for HER2/neu in highgrade breast carcinoma. The HER2 proto-oncogene encodes a cell surface receptor that is over-expressed in approximately 25%-30% of breast cancers. • Trastuzumab (Herceptin®) is the first monoclonal antibody that targets the extracelluar domain of the HER2 protein, and inhibits growth of breast cancer cells that over express this protein. •

53. Oncotype DX recurrence score  21 gene expression used to predict recurrence in early stage invasive breast cancer    High risk females derived a significant benefit from chemotherapy Low risk females with tumors derived minimal benefit from chemotherapy Guides the type of chemotherapy use

54. Hybridization signals are detected using a confocal laser scanner and downloaded to a computer for analysis (red squares, expression of the gene is higher in tumor; green square, expression of the gene is higher in normal tissue; black squares, no difference in the expression of the gene between tumor and normal tissue). In the display, the horizontal rows correspond to each gene contained in the array; each ventrical row corresponds to single samples.

57. Serum Markers  CA 15-3, BR 27.29 (CA27.29), carcinoembryonic antigen (CEA), tissue polypeptide antigen, tissue polypeptide specific antigen, and HER-2 Screening?  Diagnosing?  Prognostic CA 15-3  Follow-up  Monitoring therapy   Indications have not been standardized American Society of Oncology

58. Mammography

59. Mammography Symmetry  Size  General density  Glandular distribution  Masses, densities, calcifications, architectural distortions,  Masses: shape, margins, density  BI-RADS category 

60. BI-RADS BI-RADS Classification Features 0 1 2 3 4 Need additional imaging Negative – routine in 1 yr Benign finding – routine in 1 yr Probably benign, 6mo follow-up Suspicious abnormality, biopsy recommended 5 Highly suggestive of malignancy; appropriate action should be taken

61. Screening ► American Cancer Society recommends annual mammography and examination by a physician beginning at age 40 years with no maximum upper age limit ► Family Hx  10 yrs younger than relative’s diagnosis ► BRCA  25 yo – annual mammography

70. Calcification               Malignant Greater density Irregular and (usually) spiculated margins small (<0.5 mm) Shapes pleomorphic or heterogeneous or fine granular, fine linear, or branching Benign Low density smooth margins Large specific shapes: eggshell: cyst walls, tramlike: arterial walls, popcorn type: fibroadenomas, large and rodlike with possible branching: ectatic ducts

71. Ultrasound ► ► ► ► ► ► ► ► ► Not a screening tool Palpable vs cystic Mammographic detected lesion Mammography has limitations, Dense breasts Extremely peripherally located masses Evaluation of axillary node status Examining breasts recently operated or acutely inflamed During pregnancy

72. Ultrasound ► Malignant     Hypoechoic, spiculated Taller than wide Duct extension microlobulation ► Benign     Intensely hyperechoic Elliptical shape (wider than tall) Lobulated Complete tiny capsule

76. MRI ► ► ► ► High risk patients  Personal history of breast ca  LCIS, atypia  1st degree relative with breast cancer  Very dense breast Axillary lymphadenopathy undetectable primary tumor Palpable lesions not visualized by diagnostic mammography or ultrasonography High sensitivity (95-100%)  10-20% will have a biopsy

78. Digital Breast Tomosynthesis

79. Scintimammography

80. CT laser mammography (CTLM)

81. Positron Emission Mammography

82. Thermography

83. Diagnosis ► Fine  Cytology ► Core   needle aspiration biopsy Image guided Stereotactic ► Excisional  biopsy Needle localization

86. Excisional Biopsy ► Atypical lesions ► LCIS ► Atypical papillary lesions ► Radiologic-pathologic discordance ► Inadequate tissue harvesting

88. Vacuum Assisted Biopsy

89. Sentinel Lymph Node Biopsy How to assess axillary LN metastasis?  Reports suggest that the sentinel lymph node has a high predictive value in determining the presence of axillary metastases. Identification of a sentinel lymph node that is free of metastatic tumor cells may eliminate the necessity of performing a standard axillary lymph node dissection with its attendant morbidity   The sensitivity of SLNB ranged from 67 to 100 per cent, with a pooled estimate of 88 (95 per cent confidence interval 85 to 90) percent

90. lymphoscintography

91. Staging AJCC  Primary tumor = T         Tx - Primary tumor cannot be assessed T0 - No evidence of primary tumor Tis - Carcinoma in situ T1 - Tumor ≤2 cm in greatest dimension T2 - Tumor > 2 cm but ≤5 cm T3 - Tumor > 5 cm T4 - Tumor of any size with direct extension to chest wall or skin (including inflammatory carcinoma)

92. Staging Regional lymph nodes N  Nx - cannot be assessed  N0 - No regional lymph node metastases  N1 - Metastases to ipsilateral axillary lymph nodes without fixation  N2 - Metastases to ipsilateral axillary lymph nodes with fixation to each other (matted), with fixation to other structures N3 - Infraclavicular nodes have metastases with or without axillary lymph node involvement, 

93. Staging Distant metastases = M  Mx - Cannot be assessed  M0 - No metastases  M1 - Distant metastases, including ipsilateral supraclavicular lymph nodes 

94. Stage Primary tumor size (T) Lymph node involvement (N) Metastatic disease (M) 0 Tis N0 M0 1 T1 N0 M0 2a T0 N1 M0 2a T1 N1 M0 2a T2 N0 M0 2b T2 N1 M0 2b T3 N0 M0 3a T0 N2 M0 3a T1 N2 M0 3a T2 N2 M0 3a T3 N1 M0 3a T3 N2 M0 3b T4 N0 M0 3b T4 N1 M0 3b T4 N2 M0 3c Any N3 M0 4 Any Any M1

95. Stage 1 Tumor size less than 2 cm

96. Stage 2 2-5 cm with N1 or N0 More than 5cm but N0 Less than 2 cm or T0 but no more than N3

97. Stage 3 Larger than 5 cm with any N Less than 5 cm with nodal matting Less than 5 cm with supraclavicular LN involvement

98. Stage 3 Inflammatory breast

99. Stage 4 Metastatic breast cancer

101. Case 1  An annual screening mammogram in a 55year-old nurse administrator revealed suspicious microcalcifications. The patient is postmenopausal with no family history of breast cancer. Lobular carcinoma in situ was identified by biopsy; the lesion was not completely excised.

102. What are reasonable options to reduce this patient's risk of developing invasive breast cancer?  Re-excise the lesion until there are clear margins  Bilateral salpingo-oophorectomy  Treatment with raloxifene  Unilateral prophylactic mastectomy

103. Case 2     RG, a 77-year-old, white, former schoolteacher, presents with a palpable mass in the right breast and 1 palpable axillary lymph node. The breast mass measures 2.1 x 2.7 cm on mammography, and ultrasonography shows a prominent axillary lymph node. The biopsy reveals poorly differentiated invasive ductal carcinoma with the "triple-negative" phenotype The patient is classified as having stage IIb disease (T2N1M0). RG has several comorbid conditions for which she is prescribed numerous medications. She has hypertension, mitral and tricuspid regurgitation, atrial fibrillation, and a pacemaker. She takes atenolol, warfarin, and atorvastatin. The patient walks with a cane due to complications from osteoarthritis. RG also has early-stage dementia.

104. Case Cont.      What would you recommend as the initial management approach for this patient? Neoadjuvant chemotherapy followed by modified radical mastectomy and radiotherapy (RT) Lumpectomy followed by adjuvant chemotherapy and RT Lumpectomy with sentinel lymph node sampling followed by adjuvant RT Modified radical mastectomy followed by adjuvant endocrine therapy

105. Medical Therapy       Chemoprevention Selective estrogen receptor modulators (SERM) (tamoxifen) Aromatase inhibitors (AI) (anastrozole, letrozole, exemestane) Trastuzumab Neoadjuvant therapy (anthracycline or taxanebased) Adjuvant (anthracyclines, taxanes, and cyclophosphamide)

106. Chemoprevention     Tamoxifen use for 5 years reduces risk for at least 10 years in premenopausal women, particularly estrogen receptor (ER) positive invasive tumors Tamoxifen and raloxifene are equally effective in reducing risk of ER positive breast cancer in postmenopausal women. Recommendations  For women with increased risk for breast cancer, offer tamoxifen (20 mg/d for 5 y) to reduce risk of invasive breast cancer.  In postmenopausal women, raloxifene (60 mg/d for 5 y) may also be considered.  Aromatase inhibitors (eg, anastrozole, exemestane, letrozole), fenretinide, or other SERMs are not recommended outside of a clinical trial. American Society of Clinical Oncology (ACOG)

107. Adjuvant Rx ► All tumors > 1cm ► All postmenopausal women with positive LN ► Postmenopausal women with lesion greater than 2 cm (T2 lesion)

108. Adjuvant Hormonal Rx ► All premenopausal women with tumor > 1cm ► All postmenopausal unless a contraindication

109. Adjuvant Radiation Rx ► All pts. With conservative Rx ► When > 4 LN, radiation to axilla

110. Surgical Therapy          Ductal excision Lumpectomy or wide local excision Quadrantectomy Completion Lymph Node Dissection (CLND) Axillary Lymph Node Dissection (AxLND) Total or simple mastectomy Modified radical mastectomy (MRM) Patey modified radical mastectomy Radical (Halsted) mastectomy

112. Needle localization

114. Contraindications to Breast Conservation ► Tumour >5cm ► Larger tumor to breast ratio ► Two large tumours in two separate quadrants ► Previous breast radiation ► Collagen Vascular disease (scleroderma & Lupus) ► Diffuse calcifications or subareolar tumor

115. Lymph Node Dissection

118. Patey modified radical mastectomy

120. Complications Seromas most frequent complication 30%  Closed-system suction drainage <30 mL per day  Wound infections skin-flap necrosis  Hemorrhage  lymphedema 10 to 20% 

121. LCIS LCIS chemoprevention with tamoxifen,  Bilateral total mastectomy  No benefit to excise LCIS 

122. DCIS DCIS and evidence of extensive disease (>4 cm of disease or disease in more than one quadrant) mastectomy  Limited disease, lumpectomy and radiation therapy  Low-grade DCIS of the solid, cribriform, or papillary subtype that is <0.5 cm in diameter, lumpectomy alone if the margins of resection are widely free of disease 

123. Early Invasive Breast Cancer (I, II) Mastectomy with axillary lymph node status and  Breast conserving surgery with axillary lymph node status and radiation therapy equivalent treatments  Axillary lymph node dissection  Breast conservation is considered for all patients because of the important cosmetic advantages  Adjuvant chemotherapy 

124. Advanced Local-Regional Breast Cancer (III) Neoadjuvant chemotherapy for all  Modified radical mastectomy,  Adjuvant radiation therapy  Adjuvant chemmotherapy 

125. Distant Metastases (IV) Hormonal therapies are preferred  Systemic chemotherapy  Role of Surgery is under investigation 

126. Local-Regional Recurrence Mastectomy vs. Lumpectomy  Surgical resection of the local-regional recurrence  Chemotherapy and  Antiestrogen therapy  Adjuvant radiation 

127. BSO BSO has been used to reduce the risk for breast cancer, as well as to decrease the risk for ovarian cancers in women with known BRCA mutations. In premenopausal women, BSO is estimated to decrease the risk for breast cancer by 50%

128. Prophylactic Mastectomy    To date, PM as well as the use of CPM in breast cancer patients have yet to show a decisive impact on survival In very high-risk patients with concerns about hereditary cancer, the use of CPM addresses and substantially reduces risk for CBC. Aggressive screening vs surgery in mutation carriers, PM and CPM are the most cost-effective strategies

130. Prognosis Biological, and independent patient factors  Genetic predisposition  Tumor size  receptor status  Axillary node involvement  Choice of treatment modality 

131. Prognosis 5-year survival rates for women in the United States have improved to 98% for disease localized to the breast  With nodal involvement, this decreases to 81%,  With distant metastases, the 5-year survival is only 26%. 

132. Male Breast Cancer Rare disease, accounting for ∼1% of all breast cancer cases  Similar to breast cancer in females in its etiology, family history, prognosis, and treatment  30% FH  Personal history of prostate cancer  liver cirrhosis  Testicular Disorders  Gynecomastia 

133. Breast Cancer Awareness Month October 2010 THANK YOU

136. Contents Acute Lymphoblastic Leukemia INTRODUCTION CLASSIFICATION EITIOLOGY CLINICAL PRESENTATION DIAGNOSIS TREATMENT

137. Contents Acute Lymphoblastic Leukemia INTRODUCTION CLASSIFICATION EITIOLOGY CLINICAL PRESENTATION DIAGNOSIS TREATMENT

138. Awareness Ribbons

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