Female Reproductive Pathology PDF

Vaginal Cancer Jason Ryan, MD, MPH Vaginal Malignancies Vaginal carcinoma Clear cell carcinoma Embryonal rhabdomyosarcoma (infants) Vaginal Carcinoma Very rare Usually squamous cell carcinoma Almost always involves HPV Same risk factors as cervical cancer Rarely a primary...

Vaginal Cancer Jason Ryan, MD, MPH Vaginal Malignancies Vaginal carcinoma Clear cell carcinoma Embryonal rhabdomyosarcoma (infants) Vaginal Carcinoma Very rare Usually squamous cell carcinoma Almost always involves HPV Same risk factors as cervical cancer Rarely a primary tumor of vagina Most commonly: extension of cervical carcinoma Lymphatic Drainage Upper vagina From Mullerian duct Iliac nodes Lower vagina From urogenital sinus Inguinal nodes Wikipedia/Public Domain Clear Cell Carcinoma Rare malignancy of cervix or vagina Associated with maternal diethylstilbestrol (DES) Nonsteroidal estrogen Used to prevent miscarriage, premature birth Removed from US market 1971 Female babies: Reproductive tract abnormalities Pixabay/Public Domain Diethylstilbestrol Abnormal uterus, cervix Vaginal adenosis Vaginal clear cell adenocarcinoma High rate of infertility Vaginal Adenosis Upper vagina: Mullerian duct Lower vagina: Urogenital sinus Adenosis Mullerian tissue in outer cervix/vagina Columnar epithelium in vagina Lack of normal squamous epithelium Associated with in utero DES exposure May lead to clear cell carcinoma Sarcoma botryoides Embryonal Rhabdomyosarcoma Rare vaginal tumor of young children May also develop in boys “Paratesticular tumors” Scrotal or inguinal enlargement Derives from embryonal rhabdomyoblasts Immature muscle cells Sarcoma botryoides Embryonal Rhabdomyosarcoma Occurs in children < 5 years old Clear, grape-like mass growing from vagina Botryoid = appearance of bunch of grape May invade peritoneum  obstruct bladder Treatment: surgery and chemotherapy Desmin Muscle filament Part of Z-disks in sarcomeres Marker of rhabdomyosarcoma 99% of rhabdomyosarcomas positive for desmin Myosin Actin Z disk Cervical Cancer Jason Ryan, MD, MPH Cervix Wikipedia/Public Domain Cervical Cancer 3rd most common gynecologic cancer in US Human papilloma virus detected in 99.7% cases Identifiable in precursor stage via Pap smear Cervical Neoplasia Epithelial neoplasia Occurs in the squamocolumnar junction Junction between squamous and columnar epithelium Endocervix: columnar epithelium Ectocervix: squamous epithelium Transformation zone 95% cancers arise here Extends outward Public Domain Cervix Uterus Columnar Squamous Vagina Squamocolumnar Junction Ed Uthman/Wikipedia Cervical Cancer Risk Factors Human Papillomavirus infection Immunodeficiency state Cannot clear HPV Cigarette smoking Affects secretions in endocervical glands Sexual intercourse at a young age Multiple sexual partners Wikipedia/Public Domain Human Papillomavirus Non-enveloped Double stranded, circular DNA virus Multiple subtypes: 1, 2, 6, 11, 16, 18 Most common sexually transmitted infection Clinical disease depends on subtype: Cutaneous warts Genital warts Cancer HPV Cancer Risk Persistent infection over years can lead to cancer Malignancies associated with HPV infection: Cervical Anal, Penile Oropharyngeal squamous cell cancers (mouth, throat) Usually types 16 and 18 High risk sub types for cancer HPV Cancer Risk High prevalence HPV among sexually active women Most will clear infection Some will have infection persist Vaccine available (capsid proteins) Some target types 16/18 Others also target 11/6 (genital warts) HPV Virology Two key oncogenes: E6 and E7 E6 gene Codes for protein that inhibits p53 suppressor gene p53 protein: controls cell cycle G1 to S phase progression Inhibited p53  uncontrolled growth E7 gene product Codes for protein that inhibits RB suppressor gene Rb protein inactivates E2F transcription factor Inhibited Rb  E2F activation  uncontrolled growth P53 Protein DNA Damage Cdk Inhibition Growth Arrest P53 P53 Unstable Protein P21 Stable Rapid Breakdown P53 P21 gene G1-S Checkpoint P Active Cyclin P P Cdks E2F Inactive E2F Cell Growth Cervical Neoplasia Progresses slowly through stages to carcinoma Classified as “cervical intraepithelial neoplasia” CIN1: Low grade lesion Often regresses Not always treated CIN2 and CIN 3: High grade lesions High risk of progression Usually require treatment Cervical Neoplasia CIN1 Ed Uthman/Wikipedia Cervical Neoplasia CIN3 Ed Uthman/Wikipedia Cervical Carcinoma Most commonly squamous cell carcinoma 2nd most common adenocarcinoma (endocervix origin) Almost always in women with HPV infection Usually occurs in 40s/50s Usually in a woman who do not get screened Lee, Makin, Mtengezo, and Malata Cervical Carcinoma Usually asymptomatic May present as vaginal bleeding Irregular/heavy menses Post-coital bleeding Can invade locally: bladder, rectum Cervical Carcinoma Diagnosis Colposcopy Use of a colposcope Illuminated, magnified view of cervix Biopsy Usually done after abnormal Pap smear Pap Smear Secondary prevention of cervical neoplasia Screening test for cervical dysplasia and carcinoma Used to detect Koilocytes Epithelial cell infected by HPV Large, darkened nuclei Best at detecting squamous cell carcinoma Public domain/Wikipedia Endometrial Disorders Jason Ryan, MD, MPH Uterus Myometrium: Smooth muscle Endometrium: Mucosal surface Glands and stroma BruceBlaus/Wikipedia BruceBlaus/Wikipedia Glands and Stroma BruceBlaus/Wikipedia Endometrium Growth and shedding during menstrual cycle Estrogen = stimulates growth Progesterone = stimulates secretory activity Progesterone withdrawal = menstruation Endometrium Smallbot/Wikipedia Endometrium Proliferative phase Estrogen driven ↑ glands and stroma Secretory phase Progesterone driven ↓ proliferation Endometrium Secretory vacuoles appear Prominent spiral arterioles Myometrium P. Choudhary Dysfunctional Uterine Bleeding Abnormal menstrual bleeding Not due to a structural cause “Functional” Uterus, endometrium: normal structure Very common gynecologic problem Most common cause: anovulatory cycle Anovulatory Cycle Menstrual cycle without ovulation No ovulation  no corpus luteum formation Absence of luteal phase of ovary No switch to progesterone secretion Excessive endometrial growth from estrogen “Unopposed growth” from lack of progesterone Irregular bleeding Anovulatory Cycle Common at menarche Underdeveloped hypothalamus-pituitary-ovary axis Common approaching menopause Loss of ovulation Continued estrogen production Also may result from other disorders Thyroid disease Obesity Endometritis Inflammation of the endometrium Acute or pregnancy-related Chronic or non-pregnancy related Nephron/Wikipedia Acute Endometritis Pregnancy-Related Endometritis Occurs post-partum Bacterial infection after delivery or miscarriage Key risk factor: cesarean section delivery Prophylactic antibiotics used before C-section Often also involves myometrium (“metritis”) Fever, abdominal pain, uterine tenderness Usually diagnosed clinically Acute Endometritis Pregnancy-Related Endometritis Polymicrobial infections Gram positives, gram negatives, anaerobes Staph, strep, E. coli, Bacteroides Broad-spectrum antibiotics used Classic regimen: clindamycin plus gentamycin Cure rate >90% Alternative: ampicillin-sulbactam RPOC Retained Products of Conception Placental/fetal tissue remaining in uterus May occur after delivery or miscarriage Uterine bleeding and pelvic pain Tissue becomes necrotic Prone to infection by flora from cervix/vagina Leads to acute endometritis Diagnosis by history and imaging Treatment: antibiotics +/- surgery Chronic Endometritis Intrauterine devices (IUDs) Pelvic Inflammatory Disease Ascending infection May involve uterus, fallopian tubes, ovaries Salpingitis, oophoritis, endometritis Chlamydia or gonorrhea Treatment: antibiotics Tuberculosis Hematogenous spread from lungs Biopsy: Acid- Fast Bacilli Chronic Endometritis Associated with infertility Indication for biopsy Biopsy hallmark: plasma cells White blood cells may be normal in endometrium Plasma cell indicates chronic inflammation Wikipedia/Public Domain Endometrial Polyps Hyperplastic growth of glands and stroma Most (95%) benign Project from endometrium (“exophytic mass”) Often asymptomatic May cause painless uterine bleeding Removed surgically Stop bleeding Prevent infection Small chance malignancy BruceBlaus/Wikipedia Endometrial Polyps Histology: Stroma Glands May see smooth muscle Associated with unopposed estrogen Common near menopause Ovarian estrogen production Chronic anovulation  lack of progesterone Tamoxifen Selective estrogen receptor modulator (SERM) Competitive antagonist of breast estrogen receptor Used in ER positive (ER+) breast cancer Estrogen agonist in other tissues (bone/uterus) Tamoxifen Partial agonist to endometrium Endometrial proliferation Hyperplasia Polyp formation (up to 36% of women) May cause endometrial cancer Endometriosis Jason Ryan, MD, MPH Endometriosis Endometrial tissue outside uterus Glands and stroma May occur anywhere Several common locations Ovary/Fallopian Tubes Uterosacral ligaments Rectovaginal septum Pelvic peritoneum BruceBlaus/Wikipedia Endometriosis Pathogenesis Exact etiology unknown, several theories Retrograde flow Movement of menstrual tissue through fallopian tubes Travels to ovaries, peritoneum Metastasis Spread through venous or lymphatic system Metaplasia Endometrium from coelomic epithelium in development Stem cells Progenitor cells develop into endometrial tissue Endometriosis Symptoms Ectopic endometrial tissue hormone-sensitive Growth from estrogen Atrophy from progesterone withdrawal Growth, bleeding, inflammation in ectopic sites Estradiol (17β-estradiol) Progesterone Endometriosis Classic Symptoms Cyclic pelvic pain Dysmenorrhea, menorrhagia Growth/bleeding of ectopic tissue Painful periods (dysmenorrhea) Heavy bleeding (menorrhagia) Infertility Many women unaware of disorder Ovarian/fallopian lesions  infertility ~40% infertile woman have endometriosis Endometriosis Other Symptoms Dyspareunia Painful intercourse Ectopic tissue near vagina Dyschezia Painful defecation Ectopic tissue near rectum Dysuria Painful urination Ectopic tissue near bladder BruceBlaus/Wikipedia Endometriosis Diagnosis Physical exam may be normal Vaginal tenderness Nodules in posterior fornix Upper vagina behind cervix Ovarian mass Endometriosis Diagnosis Normal uterus size Enlarged uterus: adenomyosis Retroverted uterus Uterus tipped backwards Detected on physical exam May be seen in normal women More common in women with endometriosis Endometriosis Diagnosis Definitive diagnosis: biopsy of lesion Often requires surgical exploration Classic ovarian finding: chocolate cyst Wikipedia/Public Domain Endometriosis Other Features Classically occurs in women of reproductive age Improves at menopause and in pregnancy Increased risk of ovarian epithelial cancer Wikipedia/Public Domain Endometriosis Treatment Definitive treatment: surgical removal Nonsteroidal anti-inflammatory drugs (NSAIDs) Reduce inflammation Wikimedia Commons Endometriosis Treatment Oral contraceptive pills (OCPs) First line therapy Suppress ovarian function Key component: progestins Suppress ovaries  cause anovulation Anti-estrogen  limit endometrial growth BruceBlaus/Wikipedia Leuprolide GnRH agonist Binds to receptors in pituitary Down-regulation of GnRH receptor Pituitary desensitization  ↓ LH/FSH ↓ estrogen production from ovaries Danazol Steroid Weak androgen and progesterone activity Inhibits LH surge  anovulation Suppresses ovarian function Rarely used due to side effects Danazol Danazol Adverse Effects Androgen effects Weight gain Edema Decreased breast size Danazol Acne and oily skin Increased hair growth Deepening of the voice Low estrogen effects: hot flashes Intracranial hypertension (pseudotumor cerebri) Headache, papilledema Adenomyosis Endometrial glands/stroma in myometrium Hyperplasia of basal endometrium into myometrium Diffusely enlarged uterus (“globular”) Two major symptoms: Heavy menstrual bleeding Painful menstruation Often co-exists with endometriosis Adenomyosis Less responsive to medical therapy Definitive treatment: hysterectomy Hic et nunc/Wikipedia Endometrial Cancer Jason Ryan, MD, MPH Leiomyoma Fibroid Benign tumor of myometrium (smooth muscle) Usually multiple tumors Occur in pre-menopausal women Growth stimulated by estrogen Usually resolve at menopause (↓ estrogen) Hic et nunc/Wikipedia Leiomyoma Fibroid Histology: Smooth muscle cell proliferation KGH/Wikipedia Leiomyoma Fibroid Usually asymptomatic Often detected as pelvic mass on exam Can be visualized with ultrasound May cause: Irregular bleeding (often heavier, longer menstrual flow) Infertility Pelvic pain Leiomyosarcoma Malignant smooth muscle tumor of uterus Arise de novo (not from fibroids) Occur in post-menopausal women Usually a single large mass Endometrial Hyperplasia Stimulation of endometrium by unopposed estrogen Absence of progesterone stimulation/withdrawal Usually occurs in peri/postmenopausal women Menstruation has slowed or stopped Anovulation  no progesterone from ovary Any estrogen source  hyperplasia Endometrial Hyperplasia Sources of Estrogen Obesity Increased conversion androgens  estrogens (estrone) Polycystic ovarian syndrome (PCOS) Obesity/anovulation Tamoxifen Estrogen agonist Hormone replacement therapy (estrogen only) Ovarian granulosa cell tumor Secrete estrogen May present with uterine bleeding and adnexal mass Endometrial Hyperplasia Clinical Features Presents as abnormal uterine bleeding Same presentation as endometrial carcinoma Same risk factors as endometrial carcinoma Diagnosis: endometrial biopsy Abundant, crowded glands Endometrial Hyperplasia Clinical Features obgymgmcri Endometrial Hyperplasia Risk for endometrial carcinoma Graded based on histology Simple, complex Presence of atypical cells Complex, atypical: high risk of cancer Endometrial Hyperplasia Treatment Low risk forms: Progestins Oppose estrogen effects Reverse hyperplasia Improve bleeding High risk forms: Hysterectomy Endometrial Carcinoma Most common gynecologic cancer Most common in post menopausal women Average age of diagnosis ~60 years old Menopause: anovulation  more estrogen exposure Classic presentation: abnormal uterine bleeding Endometrial Carcinoma Diagnosis: endometrial biopsy Often preceded by endometrial hyperplasia Often driven by unopposed estrogen Usually detected early Often treated with total abdominal hysterectomy Endometrial Carcinoma Pathophysiology Classified histologically Major types: Endometriod and serous Endometrioid subtype (Type I) Estrogen-dependent hyperplasia Serous subtype (Type II) Estrogen independent Endometrial Carcinoma Endometrioid Subtype Due to estrogen-dependent hyperplasia Risk factors: more estrogen = more risk Resembles endometrium (“endometriod”) Nephron/Wikipedia Endometrial Carcinoma Serous Subtype Estrogen-independent tumors Pink, serous material on biopsy Arise from atrophic endometrium post-menopause Most frequently altered gene: p53 tumor suppressor Present in 90% tumors Poor prognosis (more aggressive type) Nephron/Wikipedia HNPCC Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome Germline mutation in DNA mismatch repair genes Leads to colon cancer Also increased risk of endometrial cancer Most common non-colon malignancy Lifetime risk up to 70% (3% in general population) Ovarian Cysts Jason Ryan, MD, MPH Ovarian Cysts Often detected by ultrasound James Heilman, MD/Wikipedia Often “functional” From normal ovarian structure Follicle Corpus luteum Lyrl/Wikipedia Ovarian Follicle Egg surrounded by cells Two key cell types: theca and granulosa cells Granulosa Antrum Cells (fluid) Theca Cells Oocyte Hormone Synthesis Estrogens Theca cells Convert cholesterol into androstenedione (androgen) Stimulated by LH Granulosa cells Convert androstenedione into estradiol (estrogen) Stimulated by FSH Follicular Cysts Common cause of ovarian mass in young women Derive from an ovarian follicle (1st half cycle) Failure of ovarian follicle to rupture Or when follicle ruptures and reseals Lyrl/Wikipedia Follicular Cysts Lined by granulosa cells Filled with estrogen May continue to release estrogen May stimulate endometrial growth Classic symptoms: pain plus irregular bleeding Lyrl/Wikipedia PCOS Polycystic Ovarian Syndrome Multiple follicular cysts Amenorrhea Excess androgens Insulin resistance/diabetes Corpus Luteal Cyst Corpus luteum: large structure Forms 2nd half of menstrual cycle Failure to involute  cyst Lyrl/Wikipedia Ed Uthman Corpus Luteal Cyst May continue producing progesterone May delay menstruation Classic presentation Pain Missed period Adnexal mass Lyrl/Wikipedia Ed Uthman Theca-lutein Cysts Usually bilateral, multiple cysts Luteinized theca cells with edema Hyperplasia of theca cells Benign Associated with high β-hCG levels Twins Molar pregnancy Usually regress Ovarian Epithelial Tumors Jason Ryan, MD, MPH Ovary Structures Oocytes (eggs) Germ cell tumors Supporting cells Theca/granulosa Fibroblasts Sex cord stromal tumors Surface epithelium Adenomas/Carcinomas Wikipedia/Public Domain Ovarian Surface Epithelium Simple cuboidal epithelium Single layer of cells Derived from coelomic epithelium Epithelial lining of intraembryonic celom Space that gives rise to thoracic and abdominal cavities Forms outer layer of male/female gonads Also forms lining of body wall, liver, lungs, GI tract Epithelial Cell Tumors Clinical Features Often a “silent” disease Classic presentation: adnexal mass Identified on pelvic exam or imaging Vague abdominal symptoms Bloating Early satiety Pelvic/abdominal pain Average age: 63 years old Epithelial Cell Tumors Clinical Features Rarely can present with acute symptoms Often in advanced disease Bowel obstruction Local spread through peritoneum Ascites Pleural effusion Malignant pleural effusion (pleural metastasis) Cancer cells in pleural fluid Venous thromboembolism Epithelial Cell Tumors Most common type of ovarian tumors Serous (40%) Secrete serum (water) Mucinous (25%) Secrete mucous Endometrioid (10%) Similar to endometrium Benign, malignant, or borderline Benign: adenoma Malignant: adenocarcinoma Serous Cystadenoma Often bilateral Cyst filled with watery fluid Thin wall of single cells lining cyst Ed Uthman, MD/Wikipedia Nephron/Wikipedia Serous Cystadenocarcinoma Most common malignant ovarian tumor Complex cysts with watery fluid Growth of epithelial layer Cells similar to fallopian tube cells KGH/Wikipedia Psammoma Bodies Images courtesy of Michael Blechner, MD Mucinous Tumors Mucinous cystadenoma Thin walled cyst filled with mucous Often larger than serous tumors Often “multiloculated”: many small cavities, recesses Mucinous cystadenocarcinoma Malignant variant of cystadenoma Pseudomyxoma Peritonei Mucinous spread to abdomen “Mucinous ascites” Diffuse gelatinous material in abdomen/pelvis Bowel obstruction may occur Seen in appendix cancer Endometrioid Tumors Contain tubular glands similar to endometrium Often occur in patients with endometriosis Good prognosis Often identified at early stage Sensitive to chemotherapy Wikipedia/Public Domain Brenner Tumor Rare subtype of epithelial ovarian tumor Contains bladder epithelial (transitional) cells Usually benign Often found incidentally “Coffee bean” nuclei seen on biopsy Nephron/Wikipedia Epithelial Cell Tumors Risk Factors More ovulation associated with more risk More Risk Less Risk Advanced age Pregnancy Early Menarche Breast Feeding Late Menopause Oral Contraceptive Pills Nulliparity Epithelial Cell Tumors Risk Factors Family history of ovarian cancer Infertility (any cause) Polycystic Ovarian Syndrome (PCOS) Endometriosis Tubal ligation: Protective (↓ risk) Possibly related to fallopian tube factors  cancer BRCA1 and BRCA2 BRCA1/BRCA2 genes  DNA repair proteins Gene mutation associated with breast/ovarian cancer Common among Ashkenazi Jews Non-Jewish population in US: 1 in 400 Ashkenazi Jewish population in US: 1 in 40 Juhu /Wikipedia HNPCC Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome Germline mutation in DNA mismatch repair genes Leads to colon cancer Also increased risk of: Endometrial cancer (most common non-colon malignancy) Ovarian cancer (epithelial serous) CA-125 Cancer Antigen 125 Biomarker for epithelial ovarian cancer Poor performance for screening Useful in evaluating adnexal mass Useful in monitoring response to treatment Serial measurement for follow-up Ovarian Stromal Tumors Jason Ryan, MD, MPH Ovary Structures Oocytes (eggs) Germ cell tumors Supporting cells Theca/granulosa Fibroblasts Sex cord stromal tumors Surface epithelium Adenomas/Carcinomas Wikipedia/Public Domain Stromal Cell Tumors “Sex cord stromal tumors” Fibroblasts, theca cells, granulosa cells Often produce hormones Estradiol (17β-estradiol) Granulosa Cell Tumors Most common ovarian stromal tumor Tumors derived of granulosa-type cells May contain theca cells (“granulosa-theca cell tumor”) Secrete estrogens Usually unilateral May become malignant (“malignant potential”) Granulosa Cell Tumors Adult subtype (95% cases) Median age 50 to 54 years Symptoms from excess estrogen production Juvenile subtype Develop before puberty “Sexual precocity” from excess estrogen production Puberty at very early age (usually < 8 years old) Granulosa Cell Tumors Clinical Features Often present as large adnexal mass Estrogen symptoms Endometrial hyperplasia  uterine bleeding Often bleeding in postmenopausal woman Breast tenderness Associated with endometrial carcinoma Endometrial biopsy often performed Granulosa Cell Tumors Histology Pathognomonic finding: Call-Exner bodies Cells surrounding space filled with pink material Nephron/Wikipedia Fibroma Benign tumors of fibroblasts Solid, white tumor Usually unilateral Ed Uthman, MD/Wikipedia No hormone activity Occur in postmenopausal women Usually present as a pelvic/adnexal mass Two classic clinical associations Ascites Meigs syndrome Ascites and Meigs Syndrome Ascites occurs in 40% cases of ovarian fibroma Meigs syndrome Ovarian fibroma Ascites Pleural effusion Etiology unclear Probably related to capillary leak from tumor factors Removal of tumor resolves ascites and effusion Thecoma Usually co-exist with fibromas (“fibrothecoma”) Pure thecoma: rare May produce estrogens May lead to endometrial hyperplasia/bleeding Sertoli-Leydig Cell Tumor Tumor of Sertoli and Leydig cells Often occur in males as testicular tumors May occur in the ovary Tumor produces androgens Breast atrophy Amenorrhea Sterility (anovulation) Hirsutism Wikipedia/Public Domain Ovarian Germ Cell Tumors Jason Ryan, MD, MPH Ovary Structures Oocytes (eggs) Germ cell tumors Supporting cells Theca/granulosa Fibroblasts Sex cord stromal tumors Surface epithelium Adenomas/Carcinomas Wikipedia/Public Domain Ovarian Germ Cell Tumors Occur in young women Usually 10 to 30 years old Many secrete AFP or β-hCG Tumors of germ cell derivatives Germ layers (Teratoma) Germ cells (Dysgerminoma) Yolk sack (Yolk sac tumors) Placental tissue (Choriocarcinoma) Teratoma Most common overall germ cell tumor Cells from all three germ layers Ectoderm (skin, hair follicles) Endoderm (lung, GI) Mesoderm (muscle, cartilage) Benign form: Dermoid cyst Malignant form: Immature teratoma Rare monodermal forms Dermoid Cyst Mature Cystic Teratoma “Dermoid” = skin like Contain hair, squamous cells, sebaceous (oily) material Walls may contain calcification, tooth-like material Wikipedia/Public Domain Dermoid Cyst Mature Cystic Teratoma Usually asymptomatic, unilateral 10-20% bilateral Characteristic features on ultrasound Mikael Häggström/Wikipedia Dermoid Cyst Mature Cystic Teratoma Usually removed surgically to avoid complications: Torsion Rupture  tumor material in abdominal cavity  peritonitis Small risk (60 years) Phyllodes = Greek word “leaf like” Leaf-like growths of stroma covered by epithelial cells Phyllodes Tumor Nephron/Wikipedia Mammary Duct Ectasia Benign inflammatory condition Affects older women (~50 years old) Classically in multiparous women Distension (ectasia) of subareolar ducts (nipple) Due to chronic inflammation and fibrosis Presents as breast mass with thick, white discharge Usually no pain, erythema Must be differentiated from breast cancer Mammary Duct Ectasia MD Specialclass Fat Necrosis Results from trauma Often biopsy, surgery Sports injury, seatbelt injury Prassa CBSR Many women do not recall a specific trauma Benign, inflammatory process Often mimics breast cancer May present as painless mass in breast Often asymptomatic Calcifications on mammogram Biopsy shows fat necrosis with inflammatory cells Lactational Mastitis Acute Mastitis Occurs in women during breast feeding Trauma to skin around nipple Breast erythema, tenderness Often fever, malaise Most commonly infection with S. Aureus Usual treatment: dicloxacillin or cephalexin Mother should continue nursing Can progress to abscess requiring drainage Periductal Mastitis Squamous Metaplasia of Lactiferous Ducts Inflammation of subareolar ducts More than 90% cases occur in female smokers Smoking toxic to subareolar ducts Smoking may cause relative vitamin A deficiency in ducts Pixabay/Public Domain Periductal Mastitis Squamous Metaplasia of Lactiferous Ducts Inflammation  squamous metaplasia Duct epithelium cuboidal  squamous Periareolar mass with redness, tenderness, warmth Often 2° infection requiring antibiotics Often requires incision/drainage Breast Disorders Summary Fibrocystic changes Cysts, fibrosis, apocrine metaplasia Benign Proliferative breast disorders Epithelial hyperplasia, sclerosis adenosis, papilloma Associated with increased risk Not usually precursors of cancer Stromal tumors Fibroadenoma Phyllodes tumor Breast Disorders Summary Mammary duct ectasia (white discharge) Fat necrosis (trauma) Mastitis (erythema, tenderness) Breast Carcinoma Jason Ryan, MD, MPH Breast Carcinoma Most common non-skin cancer in women 2nd most deadly cancer in women (lung) Mostly a disease of older postmenopausal women Rare before age 25 Incidence increases after age 30 Can occur in men (rare) Breast Carcinoma Risk Factors Female gender (99% of cases) Age (peak incidence 70-80 years) Race Non-Hispanic white women: greatest risk 1st degree relative with breast cancer Mother, sister, daughter Breast Carcinoma Risk Factors Increased estrogen exposure Earle menarche/late menopause Obesity Breast feeding = protective Age at first live birth Young (35) = higher risk Breast Carcinoma Detection Palpable breast mass Mammography Detects micro-calcifications Occur in malignant lesions Also seen in fat necrosis and sclerosing adenosis Wikipedia/Public Domain Breast Carcinoma Major Types Ductal versus lobular Ductal = resemble duct cells Lobular = resemble lobules Both types from TDLU In situ versus invasive In situ = limited by basement membrane Terminal Duct Lobule Terminal Duct Lobular Unit Breast Carcinoma Major Types Almost all (95%) are adenocarcinomas Arise from epithelial cells of ducts/lobules At diagnosis >70% have invaded basement membrane Terminal Duct Lobule Terminal Duct Lobular Unit DCIS Ductal Carcinoma In Situ Malignant growth of epithelial cells of TDLU Fills ductal lumen Limited by intact basement membrane Cribriform DCIS KGH/Wikipedia DCIS Ductal Carcinoma In Situ Forms microcalcifications (LCIS does not) Usually detected by mammography Many subtypes based on histology Comedo DCIS Central necrosis Large tumor cells Pleomorphic nuclei High risk Difu Wu/Wikipedia Paget Disease Erythema at nipple due to underlying malignancy Occurs when DCIS extends to nipple May cause bloody nipple discharge Paget cells seen on biopsy Wikipedia/Public Domain Paget Disease Palpable mass in >50% cases ~50% have mass on mammogram Usually invasive carcinoma found Wikipedia/Public Domain LCIS Lobular Carcinoma In Situ Proliferation of cells in ducts/lobules Limited by intact basement membrane “Discohesive growth:” loose intercellular connections Loss of adhesion protein E-cadherin Round cells clumped together Difu Wu/Wikipedia LCIS Lobular Carcinoma In Situ Does not lead to micro-calcifications Usually an incidental finding on biopsy Often bilateral May be multi-focal LCIS Lobular Carcinoma In Situ Risk factor for invasive carcinoma Non-invasive lesion Risk of carcinoma in both breasts Management: surveillance +/- chemoprevention Common drug: Tamoxifen (SERM) Blocks endogenous estrogen effects Tamoxifen Invasive Ductal Carcinoma Most common type (~80%) invasive carcinoma Biopsy: duct cells with stroma Difu Wu/Wikipedia Invasive Ductal Carcinoma Most commonly in outer quadrant of breast More breast tissue Lateral Midline ~50% cases Invasive Ductal Carcinoma Histologic Subtypes Lobular carcinoma Mucinous carcinoma Tubular carcinoma Papillary carcinoma Medullary carcinoma Common among BRCA1 gene carriers Inflammatory carcinoma Inflammatory Carcinoma Erythema, swelling of breast (peau d'orange) Dimpling of skin Similar to orange rind Tumor invasion of skin (dermal) lymphatic vessels Mimics infection High grade Poor prognosis Invasive Lobular Carcinoma Cells grow in “single file” Lack of E-cadherin adhesion protein expression Can’t stick together in clumps Often bilateral with multiple lesions Ed Uthman/Wikipedia Breast Carcinoma Prognosis Axillary lymph node metastases Most important prognostic factor for invasive cancer Detected by biopsy Sentinel node biopsy often performed Wikipedia/Public Domain Predictive Markers Important for prognosis and therapy Estrogen receptor positivity (ER+) Progesterone receptor positivity (PR+) Human epidermal growth factor receptor-2 (HER2) Cell surface tyrosine kinase receptor Estradiol (17β-estradiol) Progesterone Predictive Markers ER+ and PR+ tumors May respond to Tamoxifen (SERM) HER2+ tumors May respond to Trastuzumab “Triple negative” tumors Highly aggressive More common in women under 40 African-American women: highest risk Familial Breast Cancer Cause about 10% of breast cancers BRCA1 and BRCA2 gene mutation: Both gene mutations associated with breast cancer Cause of ~85% of single gene familial cases Genes code for DNA repair proteins Also associated with other malignancies BRCA1: Ovarian cancer BRCA2: Male breast cancer and pancreatic cancer BRCA1 and BRCA2 More common among Ashkenazi Jews Germline gene mutation Autosomal dominant Incomplete penetrance Not all individuals with disease mutation develop disease Juhu /Wikipedia Male Breast Cancer Incidence 1% compared to women Usually occurs 60 to 70 years of age Usually presents as subareolar mass +/- discharge Most breast tissue in males near nipple Key associations: Klinefelter syndrome (3 to 8% cases) BRCA2 gene mutations (4 to 14% cases)