Pathology of Breast Disorders

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Pathology of Breast diseases for medical students.

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Pathology of Breast Disorders

  1. 1. Knowledge is a burden, If it robs you of innocence, If it makes you feel you are special, If it gives you an idea you are wise, If it is not integrated into life, If it does not bring you joy, If it does not set you free. Sri Sri Ravi Shankar, humanitarian and founder of the Art of Living Foundation, Bangalore, India. (quote from Clinical Pathology 2005;58:785; doi:10.1136/jcp.2005.030247)
  2. 2. CPC 4.4 - 45 Year Woman. <ul><li>Mrs. JM, 45y woman, primary school teacher, living in Weipa. ‘I have noticed a odd change in my left breast when I was showering last week’ </li></ul><ul><li>History: </li></ul><ul><ul><li>Duration. Noticed it 8 days ago ? </li></ul></ul><ul><ul><li>What: ‘My left breast feels a bit thicker – just here’ (points to upper outer breast) </li></ul></ul><ul><ul><li>Pain? No - ? </li></ul></ul><ul><ul><li>Nipple discharge: No - ? </li></ul></ul><ul><ul><li>Trauma to breast: No - ? </li></ul></ul><ul><ul><li>Menstrual cycle: regular - ? </li></ul></ul><ul><ul><li>Mastalgia: not usually ? </li></ul></ul><ul><li>Differential Diagnosis - ??? </li></ul>
  3. 3. CPC 4.4- 45 Year Woman. <ul><li>LMP : about 4/52 ago; K due ? </li></ul><ul><li>Age of menarche :13 years ? </li></ul><ul><li>Parity : none ? Importance? </li></ul><ul><li>Appetite: : normal ? </li></ul><ul><li>Weight: : stable ? </li></ul><ul><li>All other systems : negative </li></ul><ul><li>Meds : Was on COCP 17yrs – 30 yrs ? </li></ul><ul><li>Imms : up to date </li></ul><ul><li>Cervical smear : up to date; has never had abnormal smear ? </li></ul><ul><li>Differential Diagnosis ??? </li></ul>
  4. 4. CPC 4.4- Examination <ul><li>R breast NAD, L breast firm thickening upper outer axillary tail; no discrete mass; no skin tethering / changes; no nipple inversion; no areola changes, no axillary or supracla. LN. </li></ul><ul><li>What Differentials: </li></ul><ul><li>Benign proliferations & Breast malignancy </li></ul><ul><li>What further investigations? </li></ul><ul><li>Mammogram, FNAB, CT Scan, Bone Scan, Biopsy+immunochemistry. </li></ul>
  5. 5. CPC 4.4- Examination <ul><li>Mammogram – solid infiltrating irregular mass lying at the 10 o’clock position of the L breast. Mass has prominent radiating spicules ; 2 x small calcifications within the mass. Overall mass 1x 1.5x 1cm. </li></ul><ul><li>USS guided FNAB : high grade infiltrating ductal carcinoma </li></ul><ul><li>CT scan : no sign metastasic disease liver or lung </li></ul><ul><li>Bone scan: no sign bony metastases </li></ul><ul><li>Immunochemistry : ER : positive PR : negative HER2 : +++positive </li></ul>
  6. 6. “ Strength does not come from winning, Struggles & Hardship develop strength….! Arnold Schwarzenegger Bodybuilder, Actor & now Leader..! We gain knowledge by studying not by passing exam….!
  7. 7. Pathology of Breast Dr. Venkatesh M. Shashidhar Associate Prof. & Head of Pathology
  8. 8. Introduction <ul><li>Modified sweat glands. </li></ul><ul><li>Lobes and lobules of gland </li></ul><ul><li>in fat tissue stroma. </li></ul><ul><li>Ducts emerge from acini of glands </li></ul><ul><li>Smaller ducts join to form lactiferous ducts </li></ul><ul><li>Lactiferous ducts merge just beneath the nipple to form a lactiferous sinus. </li></ul><ul><li>Then individually open on nipple </li></ul>
  9. 9. Anatomy:
  10. 10. Breast Physiology:
  11. 11. Normal Breast
  12. 12. Normal Breast – glands & stroma Dense stroma Loose stroma Acinus
  13. 13. Breast - Acini
  14. 14. Involution @ Menopause <ul><li>Acinar cell loss. </li></ul><ul><li>Connective & Fat tissue increases. </li></ul><ul><li>Loose to dense fibrous connective tissue. </li></ul><ul><li>Thickened basement membranes. </li></ul><ul><li>Fibro - cystic change – common. </li></ul>
  15. 15. Disorders of Breast: <ul><li>Congenital </li></ul><ul><ul><li>Aplasia – turners, Juvenile hypertrophy </li></ul></ul><ul><ul><li>Accessory breasts – along milk line. </li></ul></ul><ul><li>Inflammatory </li></ul><ul><ul><li>Acute/Chronic Mastitis </li></ul></ul><ul><ul><li>Trauma - Fat necrosis </li></ul></ul><ul><ul><li>Duct ectasia - discharge, sinus, Galactocele </li></ul></ul><ul><li>Proliferative Conditions </li></ul><ul><ul><li>Fibrocystic disease – common cause of lumps </li></ul></ul><ul><ul><li>Cysts, Adenosis, Metaplasia & mixed. </li></ul></ul><ul><li>Neoplastic </li></ul><ul><ul><li>Benign - Fibroadenoma </li></ul></ul><ul><ul><li>Malignant – Carcinoma – several types. </li></ul></ul>
  16. 16. Differentials in a Breast clinic:
  17. 17. Lump in Breast: Diagnosis & Features Nipple adenoma Nipple adenoma       Paget's disease Paget's disease Nipple adenoma Nipple adenoma Nipple ulceration, eczema In situ carcinoma In situ carcinoma       Duct papilloma Duct papilloma Uncommon Uncommon Bloody Duct ectasia Duct ectasia Uncommon Uncommon Clear Nipple discharge Fat necrosis         Carcinoma Carcinoma Carcinoma* Uncommon Firm lump ± tethering (fixed)     Sclerosing adenosis     Uncommon Fibrocystic change Fibrocystic change Uncommon Ill-defined lump/s or lumpy areas Phyllodes tumour Fibroadenoma Phyllodes tumour Fibroadenoma Fibroadenoma Mobile lump (single) >55 years 35-55 years 25-35 years <25 years Clinical presentation
  18. 18. Diagnosis: History First….! <ul><li>Mammorgraphy </li></ul><ul><li>Fine Needle Aspiration Biopsy </li></ul><ul><li>Core/Needle Biopsy </li></ul><ul><li>Excision Biopsy </li></ul><ul><li>Ultrasound </li></ul><ul><li>Frozen section </li></ul><ul><li>Immunoperoxidase – HER2, Estrogen rec. </li></ul><ul><li>Molecular techniques – Gene detection. </li></ul>Triple Assessment  Clinical, Imaging & pathology.
  19. 19. Gynecomastia: <ul><li>Breast enlargement in men. </li></ul><ul><li>Estrogen excess – Klinefelter’s, Hyperthyroidism, pituitary & adrenal tumors, testicular failure, hormonal. </li></ul><ul><li>Liver failure, cirrhosis </li></ul><ul><li>Lung, Testicular Cancer </li></ul><ul><li>diethylstilbestrol therapy of prostatic carcinoma. </li></ul><ul><li>Drugs (Spironolactone, H2 antagonists, Neuroactive agents). </li></ul><ul><li>Microscopy – only duct & stromal hyperplasia. </li></ul>
  20. 20. Acute Mastitis: <ul><ul><li>Non Lactational (central, rare) </li></ul></ul><ul><ul><li>Lactational (periphery, common) </li></ul></ul><ul><li>First few weeks after delivery. </li></ul><ul><li>Crack in the nipple or keratotic plug at the orifice of a duct. </li></ul><ul><li>Staphylococcus aureus , Strep. pyogenes. </li></ul><ul><li>Localized inflammation, Swelling erythema & pus. </li></ul><ul><li>Complications - Breast abscess, septicemia. </li></ul><ul><li>Rarely other infections. TB, Fungal, etc. </li></ul>WBC in gland
  21. 21. Duct Ectasia: <ul><li>>50y, multiparous. Present with a poorly defined palpable periareolar mass & thick cheesy nipple secretion. </li></ul><ul><li>Duct obstruction, fatty contents, periductal Inflammation. </li></ul><ul><li>Pain/erythma uncommon, may have skin retraction mimics Ca. </li></ul><ul><li>Recurrent abscess / fistula draining pus. </li></ul><ul><li>Usually affect one duct.. Rarely multiple. </li></ul><ul><li>Irregular dilated, duct with periductal inflammation. Foamy macrophages in the lumen. </li></ul><ul><li>Scarring results in nipple inversion is 30% cases – mimics Ca. </li></ul>
  22. 22. Duct Ectasia: Cheesy discharge
  23. 23. Fibrocystic Disease <ul><li>Synonyms: Fibroadenosis, Fibrocystic change </li></ul><ul><li>Hormone induced – Oestrogens. </li></ul><ul><li>Commonest (10-50%) cause of lumps, 20-40y. </li></ul><ul><li>Periodic discomfort – cyclic pain (menstrual) </li></ul><ul><li>Irregular palpable firm lumps – mimic ca. </li></ul><ul><li>Epithelial hyperplasia – premalignant </li></ul><ul><li>Fibrosis & cysts, metaplasia, hyperplasia, dysplasia (atypical). Ca in-situ  Ca. </li></ul>
  24. 24. Fibrocystic Disease: A. Simple Fibrocystic change. B. Lobular hyperplaisa without atypica (adenosis) C,D - Ductal hyperplasia without atypia (E. with atypia - cribriform) F. Lobular hyperplasia.
  25. 25. Fibrocystic Disease <ul><li>Common cause of lumps & surgery. </li></ul><ul><li>20-40 years of age </li></ul><ul><li>hyperplasia of glands & stroma. </li></ul><ul><li>Estrogen excess / estrogen-progesterone imbalance / varying response to them. </li></ul><ul><li>Irregular multiple nodules with cysts. </li></ul><ul><li>Epithelial hyperplasia – risk of cancer. </li></ul><ul><ul><li>Apocrine metaplasia, </li></ul></ul><ul><ul><li>Radial scar </li></ul></ul>
  26. 26. Cysts & Fibrosis Apocrine Metaplasia Rubin Essentials of Pathology Apocrine Metaplasia
  27. 27. Fibrocystic Disease
  28. 28. Fibrocystic Disease Fibrosis Cyst
  29. 29. Fibrocystic Disease-Blue dome cyst
  30. 30. Fibrocystic Disease: Cysts & fibrosis
  31. 31. Fibrocystic Disease: Cysts & fibrosis adenosis (1), papilloma formation (2), epithelial hyperplasia (3) and small cysts (4).
  32. 32. Fibrocystic Change
  33. 33. Sclerosing Adenosis:
  34. 34. Sclerosing Adenosis
  35. 35. Fibrocystic Disease
  36. 36. Ductal Hyperplasia
  37. 37. DCIS- High grade
  38. 38. Education must instill the fundamental human values; it must broaden the vision to include the entire world and all mankind. Education must equip man to live happily . … Am I educated ?
  39. 39. Benign Neoplasms: <ul><li>Fibroadenoma </li></ul><ul><li>Duct Papilloma </li></ul><ul><li>Adenoma </li></ul><ul><li>Connective tissue tumors * rare </li></ul><ul><li>Fibroadenoma – Features. </li></ul><ul><ul><li>Young age 3 rd decade. </li></ul></ul><ul><ul><li>Single*, rounded, mobile, painless lump </li></ul></ul><ul><ul><li>No scarring or calcification. </li></ul></ul><ul><ul><li>Slit like glands in loose fibrous stroma </li></ul></ul><ul><ul><li>“ Mouse in the breast”.. </li></ul></ul>
  40. 40. Fibroadenoma Note well demarcated, mobile, capsulated, nodular tumour
  41. 41. Fibroadenoma Note well demarcated, capsulated, nodular tumour
  42. 42. Mammogram - Benign
  43. 43. Fibroadenoma Slit like glands Gross: Well demarcated, capsulated, nodular tumour Micro: Compressed slit like glands in cellular stroma. Fibrous stroma
  44. 44. Fibroadenoma
  45. 45. P P P In In Fibroadenoma C = capsule; In = intracanicular pattern; P = pericanicular pattern
  46. 46. Fibroadenoma
  47. 47. Fibroadenoma
  48. 48. Breast Fibroadenoma Elongated duct like structures surrounded by loose connective tissue
  49. 49. Phyllodes Tumor <ul><li>On gross examination exhibit “leaf-like” clefts and slits - Cystosarcoma phyllodes. </li></ul><ul><li>Resembles fibroadenoma but may grow to large size (10-15 cm in diameter) - giant fibroadenoma. </li></ul><ul><li>Benign to malignant varieties. </li></ul><ul><li>Local recurrence common, metastasis 15% </li></ul><ul><li>Both stroma and epithelium may show malignant change. </li></ul><ul><li>Hypercellurity, anaplasia in malignant. </li></ul>
  50. 50. Phylloides Tumor: Giant Fibroadenoma
  51. 51. Cystosarcoma Phyllodes:
  52. 52. Benign Cystosarcoma Phyllodes
  53. 53. Fibroadenoma – Giant Fibroadenoma Flat slit like glands, loose fibrous stroma Branching leaf like glands, Cellular stroma
  54. 54. Intraductal Papilloma <ul><li>Not common, middle-age. </li></ul><ul><li>Variant of ep. hyperplasia (fibrocystic disease) </li></ul><ul><li>Presents as blood-stained or serous nipple discharge. </li></ul><ul><li>Usually solitary in large ducts </li></ul><ul><li>Papillary structures, with fibrovascular core covered by benign epithelium. </li></ul><ul><li>Benign but recurrent (if inadequately excised) </li></ul>
  55. 55. <ul><li>Bloody nipple dischage </li></ul><ul><li>Intraductal papillary Proliferation </li></ul><ul><li>Lined by duct epithelium and myoepithelial cells. </li></ul><ul><li>No risk of malignancy. </li></ul>Intraductal papilloma Fibrovascular core
  56. 56. Intraductal papilloma Fibrovascular core
  57. 57. Education has two important characteristics. One is learning of a subject. The other is the personality to apply this knowledge to the benefit of community. Skill & Attitude One without the other …. ???
  58. 58. Breast Carcinoma <ul><li>Second common cause of cancer death in women. (next to lung) </li></ul><ul><li>20% of all cancers in women </li></ul><ul><li>Commonest cause of death in young < 55y </li></ul><ul><li>In UK 1 in 10-12 woman, 1 in 8 in US </li></ul><ul><li>Much less incidence in Asia, japan. </li></ul><ul><li>Majority of cancers arise in the ducts. </li></ul><ul><li>Rare before age 30. (30-50 genetic, >50 sporadic) </li></ul>
  59. 59. Etiology of Breast Carcinoma: <ul><li>Overexposure to oestrogens and underexposure to progesterone </li></ul><ul><li>No definite relationship to oral contraceptives </li></ul><ul><li>Some tumours contain hormone receptors and respond to hormone manipulation </li></ul><ul><li>No good evidence for viral involvement </li></ul>Genetics Hormone Environment
  60. 60. Genetic - BRCA Hormone - Estrogens. Environment- Diet, Obesity…     Less Well-Established Influences Exogenous estrogens, Oral contraceptives, Obesity, High-fat diet, Alcohol consumption Cigarette smoking. 6.9-12.0    Lobular carcinoma in situ >2.0    Proliferative disease with atypical hyperplasia 1.6    Proliferative disease without atypia   Benign breast disease 3.0    Nulliparous 2.0-3.0    First live birth after age 35yr 1.9    First live birth after age 30yr 1.5    First live birth from ages 25 to 29yr   Pregnancy 1.5-2.0    Age at menopause >55yr 1.3    Age at menarche <12yr   Menstrual history 4.0-5.4    Postmenopausal and bilateral 1.5    Postmenopausal 8.5-9.0    Premenopausal and bilateral 3.1    Premenopausal 1.2-3.0    First-degree relative with breast cancer   Family history Increases after age 30yr Age Varies in different areas Geographic factors   Well-Established Influences Relative Risk Breast Cancer Risk Factors
  61. 61. Pathogenesis of Breast Cancer. Hyperplasia  Dysplasia  DCIS  Carcinoma Duct Ca. in-Situ DCIS
  62. 62. Clinical Features: <ul><li>Physiologic vs Pathologic changes </li></ul><ul><li>Lump / lumps </li></ul><ul><li>Lumps are much more common than Ca </li></ul><ul><li>Characters of lump * and age * </li></ul><ul><li>Discharge in many conditions. </li></ul><ul><li>Hard, soft, inflammation </li></ul><ul><li>Skin fixation / Skin retraction * </li></ul>
  63. 63. Histological Types Histologic Type Freq. (UK) Infiltrating Duct Ca 63.6 (75) Lobular Carcinoma 5.9 (10) Infiltrating Ductal & Lobular Ca 1.6 Medullary Carcinoma 2.8 (3) Mucinous (colloid) Carcinoma 2.1 (3) Comedocarcinoma 1.4 Carcinoma-In-Situ 5%
  64. 64. Breast Ca
  65. 65. Breast Ca
  66. 66. Mammogram - Ca
  67. 67. Mammogram - Ca
  68. 68. Breast Carcinoma
  69. 69. Good prognostic features: <ul><li>Less than 2 cm in size </li></ul><ul><li>Without axillary lymph node involvement </li></ul><ul><li>That are non-invasive ductal carcinoma and LCIS </li></ul><ul><li>With ER and PR positivity </li></ul><ul><li>Which lack of aneuploidy </li></ul>
  70. 70. Ductal Carcinoma in Situ, DCIS <ul><li>Malignant cells within ducts, but no invasion. </li></ul><ul><li>Increasing incidence of DCIS due to mammographic screening </li></ul><ul><li>Lack the capacity to invade beyond basement membrane </li></ul><ul><li>No distant metastasis, however, can spread through ductal system to produce extensive lesions involving an entire sector of a breast. </li></ul><ul><li>DCIS types: comedocarcinoma, solid cribriform, papillary, and micropapilary. Most commonly mixed pattern. </li></ul>
  71. 71. Breast Carcinoma <ul><li>Irregular, hard, gritty Painless nodule. </li></ul><ul><li>Tethering, fixation </li></ul><ul><li>Nipple retraction </li></ul><ul><li>Oedema </li></ul><ul><li>Lymphnodes </li></ul>
  72. 72. Breast Carcinoma <ul><li>Irregular, hard, gritty Painless nodule. </li></ul><ul><li>Tethering, fixation </li></ul><ul><li>Nipple retraction </li></ul><ul><li>Oedema </li></ul><ul><li>Lymphnodes </li></ul>L.Node Tum
  73. 73. Infiltrating Duct Carcinoma: small hard
  74. 74. Breast Carcinoma
  75. 75. Infiltrating Duct Carcinoma: Advanced
  76. 76. Ca Breast – fat removal
  77. 77. ADH is recognised by its histologic resemblance to ductal carcinoma in situ (DCIS), including 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 the ductal spaces. Atypical Ductal Hyperplasia
  78. 78. Ductal Carcinoma in Situ, DCIS Solid & Cribriform pattern
  79. 79. Intraductal in-situ Carcinoma
  80. 80. Intraduct Carcinoma-in-situ
  81. 81. Intraduct Carcinoma
  82. 82. Solid DCIS completely fills the involved spaces. Ductal Carcinoma in Situ (Solid type)
  83. 83. Intraduct Carcinoma (DCIS)
  84. 84. Intraduct Carcinoma (DCIS)
  85. 85. Myoepithelial Cells in DCIS (imunoperoxidase stain note intact BM & ME cells) <ul><li>All ducts, ductules and acini are separated from the interlobular and intralobular connective tissue (stroma) by a basement membrane & Myoepithelial cells. </li></ul>DCIS Myoepithelial cells
  86. 86. Duct Ca In Situ - DCIS Intact ME cells DCIS
  87. 87. Intraduct Carcinoma (DCIS) Intact ME cells DCIS Necrosis/comedo
  88. 88. Breast Carcinoma - Schirrous Nipple
  89. 89. Infiltrating Duct Carcinoma: small hard
  90. 90. Medullary Carcinoma: Large soft
  91. 91. Infiltrating Duct Carcinoma Fibrosis Glands
  92. 92. Infiltrating Duct Carcinoma
  93. 93. Infiltrating Duct Carcinoma: Fibrosis India file arrangement with duct formation
  94. 94. Medullary Carcinoma: Inflammation.
  95. 95. Inflammatory Carcinoma
  96. 96. Tumours shows tubules lined by minimally atypical cells within dense fibrotic stroma giving the tumour a hard consistency on palpitation. (difficult to distinguish from benign sclerosing lesions.). Typical Invasive Ductal Carcinoma / Duct Ca (NOS)
  97. 97. Lobular carcinoma in situ (LCIS) consists of small cells that have round or oval nuclei with small nucleoli that loosely adhere to one another. LCIS rarely distorts the underlying architecture, and the involved acini remain recognisable as lobules. Lobular Carcinoma in situ (LCIS)
  98. 98. The histologic hallmark of lobular carcinoma is the pattern of single infiltrating tumour cells, often only one cell in width (in the form of single file; often described as ‘ Indian files ’)) or in loose clusters or sheets. The cells have the same cytologic features as LCIS and lack cohesion, without the formation of tubules or papillae. Tumour cells are frequently arranged in concentric rings surrounding ducts (not illustrated here). Invasive Lobular Carcinoma
  99. 99. The arrow points to an Indian file arrangement of tumour cells. Invasive Lobular Carcinoma
  100. 100. Immunoperoxidase stain demonstrating Estrogen receptor (ER) in nuclei – +ve -ve
  101. 101. Infiltrating Lobular Carcinoma
  102. 102. Lobular Carcinoma Lobular Ca In-Situ Lobular Ca. Infiltration
  103. 103. Lobular Carcinoma - India file arrangement
  104. 104. Breast Ca. Lymphatic spread Pathogenesis of Peu-de Orange appearance. Tumor in lymph Vessel Arrows: Tumour emboli within lymphatic vessels
  105. 105. Breast Ca – Peau d’orange ? Pathogenesis
  106. 106. Spread of Breast Carcinoma:
  107. 107. Pagets Disease
  108. 108. Pagets Disease
  109. 109. Pagets Disease (Epidermal invasion)
  110. 111. Tumor Markers in Breast Ca. ER: Estrogen Receptors. PR: Progesterone Receptors. HER2/neu: Human Epidermal growth factor Receptor 2 E-Cadherin: Cell adhesion protein. BRCA: Breast Carcinoma Antigen.
  111. 112. Estrogen receptor (ER) in nuclei
  112. 113. Immunoperoxidase stain: Neg 1+ 2+ 3+
  113. 114. Estrogen Receptor & Prognosis: <ul><li>Estrogen receptor expression is proportional to differentiation of tumor </li></ul><ul><li>inversely proportional to prognosis and response to tamoxifen (receptor antagonist) therapy. </li></ul><ul><li>Demonstrated by Immunoperoxidase special stain. </li></ul>
  114. 115. HER2 (Human Epidermal growth factor Receptor 2) <ul><li>The HER2 proto-oncogene encodes a cell surface receptor that is over expressed in approximately 25%-30% of breast cancers. (normally 2 copies). </li></ul><ul><li>HER2 positive breast cancers grow quickly and spread more than others. </li></ul><ul><li>Trastuzumab (Herceptin®) is the first monoclonal antibody that targets the extra cellular domain of the HER2 protein, and inhibits growth of breast cancer cells that over express this protein. </li></ul><ul><li>HER2 testing (Immunohistochemistry/FISH) results are critical to ensuring that patients who may benefit from the anti-HER2 antibody therapy. </li></ul>
  115. 116. BRCA1 (FISH) BRCA2 <ul><li>52% of gentic type (2%) </li></ul><ul><li>Young age. </li></ul><ul><li>Risk of Ca – 40-90% </li></ul><ul><li>Poorly diff., Triple negative / medullary. </li></ul><ul><li>Over express HER2/neu </li></ul><ul><li>Associated with ovarian prostate, pancreas ca. </li></ul><ul><li>Chromosome 17q </li></ul><ul><li>32% (1%) </li></ul><ul><li>Not specific. </li></ul><ul><li>Risk of Ca 30-90% </li></ul><ul><li>No specific patterns. </li></ul><ul><li>No HER2 over exp. </li></ul><ul><li>Associated with male breast ca. </li></ul><ul><li>Chromosome 13q. </li></ul>
  116. 117. Progression of Breast Ca: (new)
  117. 118. Prognostic Classification: (new) <ul><li>Luminal A – 50% of NST. ER+, HER2/neu –ve . Well differentiated, slow growing, post menopausal, respond to harmone therapy. </li></ul><ul><li>Luminal B – 20% of NST. ER+, HER2/neu +ve . (triple positive ca.) high grade, respond to chemo. </li></ul><ul><li>Basal like – 15% of NST. ER-, HER2/neu –ve (triple negative ca.) BRCA1, young. </li></ul><ul><li>HER2 positive – 10% ER- HER2 + high grade, poorly diff, early brain metastases. (  Trastuzumab) </li></ul>
  118. 119. Common Ca. Breast: NST Stellate Lesion on Mammogram Hard irregular - Schirrhous tubules in dense fibrous stroma. Infiltrating duct Carcinoma.
  119. 120. Breast Cytology - FNAB Benign Malignant
  120. 121. Breast Cytology - FNAB Benign Malignant
  121. 122. <ul><li>Life is a challenge, meet it.  </li></ul><ul><li>Life is a dream, realize it.  </li></ul><ul><li>Life is a game, play it.  </li></ul><ul><li>Life is love, share & enjoy it. </li></ul>
  122. 123. CPC-3.4 – Core learning Issues <ul><li>Pathology - Core Learning Issues: </li></ul><ul><ul><li>Pathology of breast diseases – over view </li></ul></ul><ul><ul><li>Congenital, Inflammatory & neoplastic disorders. </li></ul></ul><ul><ul><li>Breast Lumps - Differential diagnosis. </li></ul></ul><ul><ul><li>Breast cancer – etiology, pathogenesis, morphology & complications. </li></ul></ul><ul><li>Basic science - Core Learning Issues: </li></ul><ul><ul><li>Anatomy of breast </li></ul></ul><ul><ul><li>Histology of breast. </li></ul></ul><ul><ul><li>Physiology – hormonal control, menstrual cycle. </li></ul></ul><ul><ul><li>Neoplasia, Carcinogenesis, genetic basis for breast cancer. </li></ul></ul>
  123. 124. 47y F Mastalgia, discharge ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Pagets disease </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  124. 125. 47y F cyclical Mastalgia. Breast ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Pagets disease </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  125. 126. 71y F, scaly lesion Breast over a 5cm mass. ER/PR neg., Her2 pos. ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Paget’s disease </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Basal cell carcinoma </li></ul><ul><li>Psoariasis. </li></ul>
  126. 127. 71y F, scaly lesion Breast over a 5cm mass. Image shows biopsy. ? Feature shown by arrow. <ul><li>Dyskeratosis. </li></ul><ul><li>Lymphatic invasion. </li></ul><ul><li>Vascular invasion. </li></ul><ul><li>Infiltrating Ad. Ca </li></ul><ul><li>Inflammation. </li></ul>
  127. 128. 51y F, slowly enlarging mass for 4 years. No family history, 7cm, firm mobile mass. Mammography. ? diagnosis. <ul><li>Schirrhous carcinoma. </li></ul><ul><li>Medullary carcinoma. </li></ul><ul><li>Cystosarcoma phyllodes. </li></ul><ul><li>Fibroadenoma. </li></ul><ul><li>Blue dome cyst. </li></ul>
  128. 129. 41y F, biopsy following suspicious result on mammography. ? What microscopy feature is seen . <ul><li>Branching leaf like glands. </li></ul><ul><li>Epithelial proliferation. </li></ul><ul><li>Fibrocystic change. </li></ul><ul><li>Slit like glands in loose stroma. </li></ul><ul><li>Infiltrating Adeno Carcinoma. </li></ul>
  129. 130. 26y F, 3wk postpartum. Swollen painful mass RUOQ breast. Gross and microscopy. ? What is the diagnosis? <ul><li>Duct papilloma. </li></ul><ul><li>Duct ectasia. </li></ul><ul><li>Infiltrating duct Ca. </li></ul><ul><li>Acute mastitis. </li></ul><ul><li>Granulomatous mastitis. </li></ul>
  130. 131. 51y F, Retracted atrophic nipple. ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Pagets disease </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  131. 132. 21y F, mobile lump becomes tender and large before each menstrual cycle. Mammography. ? diagnosis. <ul><li>Schirrhous carcinoma. </li></ul><ul><li>Medullary carcinoma. </li></ul><ul><li>Cystosarcoma phyllodes. </li></ul><ul><li>Fibroadenoma. </li></ul><ul><li>Blue dome cyst. </li></ul>
  132. 133. Q: A 35-year-old nulliparous woman complains that her breasts are swollen and nodular upon palpation. A mammogram discloses foci of calcification in both breasts. A breast biopsy (shown) reveals cystic duct dilation and ductal epithelial hyperplasia without atypia. What is the appropriate diagnosis?
  133. 134. 35y Nulliparous Fem, nodules ?Diagnosis <ul><li>Ductal carcinoma in situ </li></ul><ul><li>Fibroadenoma </li></ul><ul><li>Fibrocystic change </li></ul><ul><li>Granulomatous mastitis </li></ul><ul><li>Intraductal papilloma </li></ul>
  134. 135. Q: A 53-year-old woman discovers a lump in her breast and physical examination confirms a mass in the lower, outer quadrant of the left breast. Mammography demonstrates an ill-defined, stellate density measuring 1 cm with microcalcification. Following Needle aspiration, A modified radical mastectomy is performed. The surgical specimen is shown. Which of the following cellular markers would be the most useful to evaluate before considering therapeutic options for this patient?
  135. 136. 35y Nulliparous F nodules? Diagnosis <ul><li>P53 mutation </li></ul><ul><li>BRCA1 gene amplification </li></ul><ul><li>BRCA2 gene amplification </li></ul><ul><li>Estrogen receptors </li></ul><ul><li>Myeloperoxidase </li></ul>
  136. 137. 27y F Breast mass ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Pagets disease </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  137. 138. 32y F Breast large mass ?Diagnosis <ul><li>Infiltrating duct carcinoma </li></ul><ul><li>Cystosarcoma Phyllodes </li></ul><ul><li>Medullary adenocarcinoma </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  138. 139. 36y F breast mass 3m. Mammogram. ?Diagnosis <ul><li>Breast cancer NST. </li></ul><ul><li>Cystosarcoma Phyllodes </li></ul><ul><li>Medullary carcinoma </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  139. 140. 48y F Breast bloody discharge ? Diagnosis <ul><li>Papillary carcinoma </li></ul><ul><li>Cystosarcoma Phyllodes </li></ul><ul><li>Duct papilloma </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  140. 141. 48y F Breast bloody discharge ? Diagnosis <ul><li>Papillary carcinoma </li></ul><ul><li>Cystosarcoma Phyllodes </li></ul><ul><li>Duct papilloma </li></ul><ul><li>Ductal carcinoma in-situ </li></ul><ul><li>Duct ectasia </li></ul>
  141. 142. 51y F Breast ? Pathogenesis <ul><li>Inflammation </li></ul><ul><li>Duct carcinoma </li></ul><ul><li>Lymphaedema </li></ul><ul><li>Duct Papilloma </li></ul><ul><li>Fibroadenoma </li></ul>
  142. 143. 48y F Breast eczematous patch ? Diagnosis <ul><li>Papillary carcinoma </li></ul><ul><li>Paget’s disease </li></ul><ul><li>Fat necrosis </li></ul><ul><li>Peau d’orange </li></ul><ul><li>Duct ectasia </li></ul>
  143. 144. Q: A 20-year-old woman asks for your advice regarding her risk of developing breast cancer. Her mother, maternal aunt, and maternal grandmother all developed breast cancer. She would like to know if she has a genetic predisposition. Laboratory tests for mutations in which of the following genes would be most likely to answer your patient's question?
  144. 145. 20y Counselling. Which Mutation is important? <ul><li>C-myc </li></ul><ul><li>BRCA1 </li></ul><ul><li>Estrogen receptor </li></ul><ul><li>HER2/neu </li></ul><ul><li>Rb-1 </li></ul>
  145. 146. 48y F Mammogram? Diagnosis <ul><li>Papillary carcinoma </li></ul><ul><li>Medullary duct carcinoma </li></ul><ul><li>Traumatic Fat necrosis </li></ul><ul><li>Schirrous duct Carcinoma </li></ul><ul><li>Fibrocystic disease </li></ul>
  146. 147. Q: A 26-year-old woman presents with a breast mass that was detected on self-examination one week earlier. Mammography reveals a round, sharply demarcated 1-cm nodule in the right breast (shown). Biopsy of the breast mass shows neoplastic epithelial ductal structures situated within a fibromyxoid stroma. The patient refuses further treatment and informs you that she wishes to become pregnant. Which of the following is the most likely effect of pregnancy on this breast lesion?
  147. 148. 26y F Mammogram ?Prognosis <ul><li>Development of DCIS </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Progress to intraductal papilloma </li></ul><ul><li>Rapid growth. </li></ul><ul><li>Metastasis to LN </li></ul>
  148. 149. Q: A 35 year old woman consults her family physician because of painful swelling of her breats. Particularly as she approaches the end of her menstrual cycle. On self-examination she recently felt a tender nodule in the right breast. Physical examination reveals an irregular nodularity of both breasts with diffuse tenderness. Examination of the acilla is negative. A mammogram demonstrates irregular areas of density in the lower outer quadrants of both breasts. Which of the following histopathologic features is considered to be a risk factor for the development of carcinoma in this patient?
  149. 150. 35y F, painful nodules. Risk factor for ca.? <ul><li>Epithelial hyperplasia </li></ul><ul><li>Periductal inflammation </li></ul><ul><li>Cystic change </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Stromal fibrosis </li></ul>
  150. 151. Q: A 30y old woman presentas with white nipple discharge of 3 weeks duration. The patient has not menstruated for the past 4 months, and she is not pregnant. The breasts are firm and nontender. A cytologic smear of the discharge shows no evidence of acute of acute or chronic inflammatory cells. Which of the following is the most likely cause of galactorrhea in this patient?
  151. 152. 30y F, non pregnant, defective vision & galactorrhea ?diagnosis <ul><li>Fibroadenoma of breast </li></ul><ul><li>Pituitary adenoma </li></ul><ul><li>Sheehan syndrome </li></ul><ul><li>Adrenal cortical adenoma </li></ul><ul><li>Fibrocystic change in Breast </li></ul>
  152. 153. 44y F Breast mass, Gross specimen ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Giant fibroadenoma (phyllodes) </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  153. 154. 44y F Breast mass, Gross specimen ? Diagnosis <ul><li>Breast carcinoma </li></ul><ul><li>Giant fibroadenoma (phyllodes) </li></ul><ul><li>Duct ectasia </li></ul><ul><li>Fibrocystic disease </li></ul><ul><li>Fibroadenoma </li></ul>
  154. 155. 44y F Breast mass, Gross specimen ? CORRECT <ul><li>Benign nipple adenoma. </li></ul><ul><li>Complete local excision effects a cure. </li></ul><ul><li>it is a malignant tumor. </li></ul><ul><li>Sclerosing adenosis. </li></ul><ul><li>“ Phyllodes” tumor. </li></ul>
  155. 156. CPC-3.3– KFP Questions: <ul><li>Trauma, Duct ectasia, fat necrosis. </li></ul><ul><li>Fibrocystic disease. </li></ul><ul><li>Fibroadenoma, giant fibroadenoma (Phyllodes) </li></ul><ul><li>Duct papilloma. </li></ul><ul><li>Duct carcinoma. </li></ul><ul><ul><li>Etiology, BRCA genes. </li></ul></ul><ul><ul><li>Types: Schirrhous, Medullary, lobular. </li></ul></ul><ul><ul><li>Gross & Microscopic features. </li></ul></ul><ul><ul><li>DCIS – ductal ca in-situ. </li></ul></ul><ul><ul><li>Spread, complications, Paget’s, Peau de’ orange. </li></ul></ul>
  156. 157. The power of Words: Words have the power to both destroy and heal. When words are both true and kind , they can change our world. Buddha
  157. 158. Mammorgram <ul><li>Breast Radiography using low radiation (0.1rad) </li></ul><ul><li>Breast is lightly compressed between plates to stabilize and spread its interior structures. </li></ul><ul><li>Asymptomatic women >40y should have yearly mammogram (American Cancer Society). </li></ul><ul><li>More for those at risk or symptoms. </li></ul>
  158. 159. Mammogram - Benign
  159. 160. Mammogram - Ca
  160. 161. Mammogram – Ca
  161. 162. Summary: <ul><li>Anatomy & Physiology. </li></ul><ul><li>Congenital, Inflammatory & Neoplastic dis. </li></ul><ul><li>Fat Necrosis, Abscess, Duct ectasia. </li></ul><ul><li>Proliferative Disorders: </li></ul><ul><ul><li>Fibrocystic Disease – hormonal, benign. </li></ul></ul><ul><li>Neoplastic Disorders </li></ul><ul><ul><li>Benign – Fibroadenoma, papilloma </li></ul></ul><ul><ul><li>Malignant – Invasive Duct Carcinoma, Lobular Carcinoma, </li></ul></ul><ul><ul><li>DCIS – Ductal carcinoma in-situ. </li></ul></ul>
  162. 163. Benign vs Malignant <ul><li>Young <35y </li></ul><ul><li>Multiple </li></ul><ul><li>Painful </li></ul><ul><li>No bleeding </li></ul><ul><li>Soft, cystic, rubbery </li></ul><ul><li>Regular, nodular </li></ul><ul><li>Mobile </li></ul><ul><li>No lymphnodes </li></ul><ul><li>No weight loss. </li></ul><ul><li>Old >35y </li></ul><ul><li>Single </li></ul><ul><li>Painless </li></ul><ul><li>Bleeding </li></ul><ul><li>Hard gritty </li></ul><ul><li>Irregular </li></ul><ul><li>Fixed </li></ul><ul><li>Lymphnodes </li></ul><ul><li>Weight loss </li></ul>
  163. 164. Possibly due to metastatic breast carcinoma or associated with hypercalcaemia BONE PAIN OR FRACTURE Often due to metastatic breast carcinoma AXILLARY NODES ++ Dystrophic calcification associated with benign changes, e.g. cysts, sclerosing adenosis, or in situ or invasive carcinoma MICROCALCIFICATION (ON MAMMOGRAPHY) Inflammatory lesion (e.g. mastitis) • ON PALPATION Benign breast changes • CYCLICAL BREAST PAIN Paget's disease of nipple (cancer) or eczema • ERYTHEMA AND SCALING Tethering by invasive carcinoma • RETRACTION Bloody-duct papilloma or carcinoma (rare)   White/green-duct ectasia   Milky-pregnancy or prolactinoma • DISCHARGE NIPPLE Increased blood flow due to inflammation or tumour • ERYTHEMA Invasion of skin by carcinoma • PUCKERING AND TETHERING Impaired lymphatic drainage due to carcinoma • OEDEMA (PEAU D'ORANGE) SKIN FEATURES Invasive neoplasm (carcinoma) • TETHERED Benign neoplasm (usually fibroadenoma) • MOBILE Neoplasm or solitary cyst • DISCRETE Fibrosis, epithelial hyperplasia and cysts in fibrocystic change • DIFFUSE LUMP Pathological basis Sign or symptom
  164. 165. Both lesions were described by Sir James Paget (1814-1899). There is no other relationship between these lesions. Paget's disease of the nipple & of bone The term medullary refers only to the soft consistency (resembling the medulla of the brain). There is no other relationship between these lesions. Medullary carcinoma of the breast & of the thyroid Radial scars and complex sclerosing lesions differ only in size: the latter are >10 mm diameter. Both mimic carcinomas radiologically and histologically, but they are benign non-neoplastic lesions. Radial scar & complex sclerosing lesion Ductal epithelial hyperplasia is a benign proliferation of duct epithelium, whereas ductal carcinoma in situ has undergone neoplastic transformation, although it is not yet invasive. These lesions can have morphological similarities. A proportion share genetic alterations. Ductal epithelial hyperplasia & ductalcarcinoma in situ both comprise neoplastic epithelial and fibrous tissue components. However, in phyllodes tumours the fibrous tissue component is more cellular and abundant, and the lesion has less well defined margins; borderline and malignant variants occur. Fibroadenoma & phyllodes tumour Fibroadenoma is a localized circumscribed benign neoplasm comprising epithelial cells and specialised fibrous tissue. Fibroadenosis is an obsolete name for fibrocystic change, a diffuse hyperplastic lesion. Fibroadenoma & Fibroadenosis Distinction and explanation Confusion
  165. 166. Breast Examination: <ul><li>Lump * or lumps * are more common not cancer. Non Neoplastic – painful, varying, multiple </li></ul><ul><li>Neoplastic – single, progressive. </li></ul><ul><li>Characteristics of lump * and age * </li></ul><ul><ul><li>Multiple, pain, varying, cyclical – Fibrocystic dis. </li></ul></ul><ul><ul><li>Single, free, mobile, no LN – Fibroadenoma. </li></ul></ul><ul><ul><li>Single, painless, hard, fixed, LN+ - Carcinoma. </li></ul></ul><ul><li>Note discharge * </li></ul><ul><ul><li>Pus/white/serous – Duct Ectasia. </li></ul></ul><ul><ul><li>Blood – Papilloma/carcinoma </li></ul></ul>
  166. 167. What is this?  <ul><li>What is PET Scan? </li></ul><ul><li>What contrast is used? </li></ul><ul><li>What does it show? </li></ul><ul><li>What are its Indications ? </li></ul>
  167. 168. Mammogram – Benign
  168. 169. Fibroadenoma Types Solitary Few (< 5 / breast ) Multiple (> 5 / breast ) Giant (> 4 / 5 cms) & Juvenile Natural history Majority remain small & static 50% involute spontaneously No future risk of malignancy
  169. 170. Phyllodes tumours <ul><li>C omprise less than 1% of all breast neoplasms </li></ul><ul><li>May occur at any age but usually in 5th decade of life </li></ul><ul><li>No clinical or histological features to predict recurrence </li></ul><ul><li>16 - 30% may be malignant </li></ul><ul><li>Common sites of metastasis : l ungs , skeleton, heart, and liver </li></ul>
  170. 171. <ul><li>1. Primary treatment </li></ul><ul><li>L ocal excision with </li></ul><ul><li>a rim of normal tissue </li></ul><ul><li>2. Recurrence </li></ul><ul><li>Re excision </li></ul><ul><li>or </li></ul><ul><li>M astectomy with or without reconstruction </li></ul><ul><li>Response to chemotherapy and radiotherapy for recurrences and metastases poor </li></ul>Treatment of Phyllodes tumours
  171. 172. Cysts <ul><li>Common in the West ( 70 % of women ) </li></ul><ul><ul><li>50% are solitary cysts </li></ul></ul><ul><ul><li>30% 2 - 5 cysts & </li></ul></ul><ul><ul><li>rest have > 5 cysts </li></ul></ul><ul><li>Types </li></ul><ul><li>Apocrine cysts </li></ul><ul><ul><li>Lined by secretory epithelium </li></ul></ul><ul><ul><li>Cyst fluid has a Na : K ratio < 3 </li></ul></ul><ul><ul><li>Likely to have multiple cysts </li></ul></ul><ul><ul><li>Likely to develop further cysts </li></ul></ul><ul><li>Non apocrine cysts </li></ul><ul><ul><li>Cyst fluid has a Na : K ratio >3 </li></ul></ul><ul><ul><li>Resembles plasma </li></ul></ul><ul><li>Mixture of both </li></ul>
  172. 173. Management algorithm for cysts
  173. 174. Management protocol for musculo skeletal pain
  174. 175. Infections <ul><li>Lactational infections </li></ul><ul><li>Diminishing incidence </li></ul><ul><li>Usually caused by S.aureus </li></ul><ul><li>Clinical features : pain, redness, swelling, tenderness &systemic symptoms </li></ul><ul><li>Treatment : </li></ul><ul><li>Antibiotics (E.G. Flucloxacillin, Co amoxyclav etc) before pus formation </li></ul><ul><li>Abscess : Repeated aspiration / mini incision with topical anaesthetic cream ( I& D under GA occasionally) </li></ul><ul><li>May continue to breast feed </li></ul>
  175. 176. Infections <ul><li>2. Non Lactational infections : Central </li></ul><ul><li>Usually due to Periductal mastitis </li></ul><ul><li>Affects younger women. Often smokers in the West </li></ul><ul><li>May present as : inflammation +/- mass, abscess, mammary duct fistula </li></ul><ul><li>Aerobic + anaerobic organisms may be involved </li></ul><ul><li>Treatment : </li></ul><ul><li>Antibiotics (E.G. Co amoxyclav etc) before pus formation </li></ul><ul><li>Abscess : Repeated aspiration / mini incision with topical anaesthetic cream ( I& D under GA occasionally) </li></ul><ul><li>MDF : Excision fistula + Total duct excision </li></ul>
  176. 177. Management of nipple retraction
  177. 178. Breast Ca - DNA flowcytometry
  178. 179. <ul><li>Common cosmetic problems </li></ul><ul><li>Small /large volume breasts </li></ul><ul><li>Ptosis </li></ul><ul><li>Asymmetry of breast size, shape. </li></ul><ul><li>Treatment : </li></ul><ul><li>Augmentation / Reduction mammoplasty </li></ul><ul><li>2. Uncommon cosmetic problems </li></ul><ul><li>Congenital & </li></ul><ul><li>Acquired disturbances of breast development & growth </li></ul>5. Cosmetic problems
  179. 180. Fibrocystic Disease – Radial scar
  180. 181. Mammogram – Ca
  181. 182. Stage Definition 5-year Surv (%) 7-year Surv (%) I Tumor 2 cm or less without spread 96 92 II Tumor 2-5cm with regional lymph node involvement but without distant metastases, OR > 5 cm in diameter without spread 81 71 III Any size with skin/chest wall fixation, & axillary or internal mammary nodal involvement, without distant metastases 52 39 IV Tumor of any size with or without regional spread but with evidence of distant metastases 18 11

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