Exam 2 Flashcards
The urinary and genital systems are developed from what layer embryologically?
Intermediate mesoderm
What are the three nephric structures?
- Pronephros: never functionally excretory, degenerates
- Mesonephros: functional for 4 to 6 weeks, degenerates
- Metanephros: definitive kidney
Intermediate mesoderm in cervical region gives rise to what in the fourth week of embryogenesis?
The mesonephric duct (Wolffian Duct)—> pronephros —> mesonephros —> metanephros
What does the mesonephric duct in males give rise to?
Ductus deferens and the ureteric bud (only ureteric bud in females)
Ureteric buds penetrate a portion of the sacral intermediate mesoderm to form what?
Metanephric blastema (which will eventually become the nephron/glomeruli
What makes up a uriniferous tubule?
- A nephron, derived from the metanephric blastema
- Collecting tubule, derived from the ureteric bud
Kidneys initially developed in the pelvic region, and ascend in what weeks?
Between the sixth and ninth week
Ascending kidneys are progressively revascularized by a series of arterial sprouts from the dorsal aorta. If one or more of these transient renal arteries fails to regress, what results?
Accessory renal arteries
What is an ectopic ureter?
Failure of ureter to open into the inferior lateral wall of the bladder, and instead opens to the neck of the bladder causing incontinence. Can also attach to uterus/vaginal wall
Why do supernumerary kidneys occur?
Duplication of ureteric bud before connecting with the metanephric blastema
What is crossed renal ectopia?
The left/right kidney crosses to the opposite side and fuses with that kidney (typically left)
What’s the difference between autosomal dominant and autosomal recessive polycystic kidney disease?
Autosomal recessive is diagnosed at birth (many perpendicular long cysts) and may cause renal insufficiency, pulmonary hypoplasia, and death
Bilateral renal agenesis from oligohydramnios can cause what?
Potter sequence: fatal
What is the cloaca?
A region that is partitioned by the urorectal septum into a ventral urogenital sinus (becomes splatter, pelvic urethra, genital tubercle) and dorsal anorectal canal
What are the different urachal malformations?
- Urachal fistula (urine dribbling from abdomen)
- Urachal sinus (discharge from sinus, no direct connection to the bladder)
- Urachal cyst (small or large, no opening to the outside or to bladder)
What is megacystis?
Pathologically large urinary bladder. Caused by congenital disorder that blocks outflow of urine from the bladder (typically seen in males), may lead to megacystitis and renal failure in early childhood
What is exstrophy of the bladder?
• typically seen in males
• exposure and protrusion of the mucosal surface of the posterior wall of the bladder to the outside world
• caused by incomplete median closure of the inferior part of the anterior abdominal wall and the anterior wall of the bladder
The primitive gonad first appears as what?
A genital ridge of the proliferating intermediate mesoderm on the medial surface of the mesonephros
What are the origins of the suprarenal (adrenal) glands?
- cortex: mesenchyme of the urogenital ridge
- medulla: neural crest cells from adjacent sympathetic ganglia
What is perimenopause?
• time before, during, and after menopause
• irregular menses for four years pre-menopause
• starts around 37-38 years old, when pool of oocytes starts depleting
What is menopause?
• permanent cessation of menses
• amenorrhea, hypoestrogenenemia
• median age of 51
• premature in smokers, ovarian insufficiency, PCOS, endometriosis
What are the concerns of a patient going through menopause?
HHAVOCS:
• hot flashes
• heat intolerance
• atrophy of vagina
• osteoporosis
• coronary artery disease
• sleep impairment, sexual dysfunction
Explain early perimenopause:
• estrogen levels relatively unchanged
• increased FSH level
• CBD risk factors: increased C-IMT and vascular remodeling, decreased endothelial function
Explain late perimenopause:
• decreased estrogen levels and decreased AMH
• very increased FSH
• increased fat mass (abdomen) and decreased lean muscle mass
• Decrease energy expenditure, increased energy intake
• CVD risk: dyslipidemia, increased C-IMT and vascular remodeling, decreased endothelial function, increased insulin resistance, increased sleep disturbance
Explain postmenopause:
- decreased estrogen for two years after, then stabilizes
- significantly increased FSH for two years, then stabilizes
- increased abdominal fat, decreased lean mass for two years then stabilizes
- decreased Sleep and physical activity expenditure, decreased fat oxidation
- CVD: lipidemia, insulin resistance, glucose intolerance, sleep disturbance
What are the hormonal changes of menopause?
• follicles decrease
• estrogen decreases
• inhibin decreases
• FSH increases (increases LH and GnRH due to lack of negative feedback from estrogen
Postmenopausal estrogen comes from where?
Aromatization of adrenal androgens in the muscle and adipose tissue
What happens when progesterone production stops?
• unopposed estrogen (leads to high levels)
• increased endometrial cancer in early menopause
• increased abnormal bleeding
• decreased androgen production from ovaries and adrenals
What are the indications for hormone replacement therapy in menopause?
• hot flashes, vaginal atrophy, osteoporosis high risk
What are the contraindications of hormone replacement therapy?
• pregnancy, undiagnosed vaginal bleeding, active VT, current gallbladder disease, liver disease, unopposed estrogen with uterus, cardiovascular disease
What are the side effects of hormone replacement therapy?
Vaginal bleeding, breast tenderness, mood changes
What is an FDA approved medication for hot flashes?
• Paxil (paroxetine), an SSRI
• Venlafaxine may also work (SNRI)
What are the screening recommendations for cervical cancer?
• begin screening at 21
• start HPV screen at 25
• <25 normal screening every three years
• >25 normal and negative HPV screen get every five years, if HPV every three years years
• discontinue at age 65 if adequate screening throughout the lifetime
What are some risk factors for cervical cancer?
• HPV, smoking, early coitarche, DES exposure, immunocompromised, multiple sexual partners
Both squamous cell and adenocarcinoma of the cervix come from what problem?
Disordered epithelial gross at the basal layer of the transformation zone (squamoepithelial junction)
Why are HPV 16, 18 the highest risk for cervical cancer?
They produce the E6 gene that inhibits P53, and E7 that inhibits pRb
~ can cause cervical, anal, penile, oral, tongue, throat, vulvar cancer
What are the levels of cervical cancer results?
- Negative intraepithelial lesion or malignancy
- ASCUS (atypical squamous cells of unknown significance)
- LSIL (low-grade squamous intraepithelial lesion)
- HGSIL (high-grade squamous intraepithelial lesion)
What is a colposcopy?
• putting vinegar (acetic acid) on the transformation zone of the cervix—> if cells change to white, this is indicative of disease
• biopsy required for white changes
• Endocervical curettage (ECC)
• endometrial biopsy if a typical glandular cells present
What is kisspeptin?
- a neuropeptide that controls the activation of gonadotrophin releasing hormone (GnRH) neurons, and contains estrogen receptors for feedback
- located in the anteroventral periventricular nucleus and the arcuate nucleus of the hypothalamus
Kiss-1 of the AVPV is responsible for what?
surge
• activates GnRH neuron by projection onto and direct stimulation of the preoptic area
Kiss-1 of the ARC (arcuate nucleus) is responsible for what?
pulse
* inhibits GnRH
* co-expresses neurokinin B (opioid dynorphin B, NKB and Dyn)
* oscillations of NKB and Dyn drive the pulse release of kisspepin, which intern drives the pulse of GnRH
What does FSH from the anterior pituitary stimulate?
Granulosa cells in the ovarian follicles to synthesize aromatase (which converts androgens from the theca interna cells into estradiol)
~ increasing estrogen levels feedback to inhibit FSH release
During the follicular phase of the menstrual cycle, FSH stimulates what?
The maturation of ovarian follicles
What is luteinizing hormone?
• LH stimulates steroid release from the ovaries, ovulation, and the release of progesterone after ovulation by the corpus luteum
• causes theca interna cells to produce androstenedione (androgen)
• at critical concentration of estradiol, negative feedback on LH is shut off and positive feedback of LH creates the LH SURGE, which initiates ovulation
What drugs promote folliculogenesis/cause hyperstimulation of follicles?
• FSH, LH, aromatase inhibitors, estrogen antagonists
• examples: clomiphene (E2 antagonist), and letrozole (aromatase inhibitor)
What drug induces ovulation?
• hCH (analog of LH that binds to the LH/hCG receptor of the granulosa and theca cells of the ovary to cause LH surge)
• examples: ovidrel, pregnyl, novarel, chorex, profasi
What drugs can control the timing of of ovulation OR can be used as uterine fibroid treatment?
• GnRH agonist/antagonists
• examples: leuprolide (GnRH agonist), ganirelix/cetrorelix (GnRH antagonist)
What drugs maintain pregnancy?
• progestins
• example: levonorgestrel
What drugs are used as contraception OR post menopausal symptom relief?
• estrogen/progestins
• examples: ethinyl estradiol + norethindrone or medroxyprogesterone acetate
What drugs are used for endometriosis and PCOS treatment?
• estrogen/progestins, aromatase inhibitors, GnRH agonist/antagonists
• examples: E2/PR (estrogen/progesterone), letrozole/anastraxole/exemestane (aromatase inhibitors), goserelin/leuprolide (GnRH agonists), degarelix (GnRH antagonist)
What are uterine stimulants?
• oxytonics or uterotonics
• mech: increased tone of muscles and induce uterine contractions
• used for: induce/facilitate labor, decrease postpartum hemorrhage, induce abortion
What are uterine relaxants?
• tocolytics
• mech: inhibit uterine contractions
• used to: stop premature labor, by time for fetal lungs to develop
(not used long-term)
What is oxytocin (Pitocin)?
• uterotonic that activates Gq protein coupled receptors and initiates contraction
• used for: labor induction, facilitation of labor, postpartum hemorrhage, milk letdown postpartum
• SE: vasodilation (hypotension, reflex tachycardia), water retention (ADH activation), uterine uterine hyperstimulation (rupture, impaired O2 delivery to baby)
What is ergonivine?
• uterotonic that is an alkaloid from a fungus that grows on cereal grasses such as wheat/rye that prolongs tetany
• used for: postpartum hemorrhage
• SE: vasoconstriction (HTN), vasospasm of arteries (angina), nausea/vomiting, blurred vision, headache
What are prostaglandin drugs used in pregnancy?
• Dinoprostone (PGE2), misoprostol (PGE1)
• activates Gq protein coupled receptors
• used for: facilitation of labor, postpartum hemorrhage, induction of abortion
• SE: N/V/D, uterine pain, uterine hyperstimulation, Dinoprostone can lead to bronco construction
~ fetal SE= PDA cannot close
What are the tocolytics used for uterine relaxation?
• terbutaline (beta2 agonist)
• nephedipine (Ca2+ channel blocker)
• indomethacin (Cox inhibitor)
• atosiban (oxytocin receptor antagonist)
~ all used for the prevention or arrest of preterm labor
Explain Terbutaline as a tocolytic
- selective beta-2 adrenergic receptor agonist that stimulates Gs protein coupled receptor, raising cAMP and interfering with myosin light chain kinase (MLCK)
- SE: stimulates sympathetic system (tachycardia, palpitations, tremor, nervousness)
Explain nephedipine as a tocolytic
- Ca2+ channel blocker (preferentially binds vascular smooth muscle)—> no effective contractions
- SE: vasodilation, flushing, dizziness
Explain indomethacin as a tocolytic
- cyclooxygenase (COX) inhibitor (nonselective COX 1/2)—> inhibits the formation of prostaglandins
- SE: premature closure of ductus arteriosus in fetus, hemorrhages (decreases platelet aggregation)
Explain atosiban as a tocolytic
• oxytocin receptor antagonist with a rapid onset
• not approved in the USA, only in Europe
Explain magnesium sulfate as a pregnancy drug
• historical tocolytic due to decrease of calcium
• used as a neuroprotective for fetus (given to women at risk of preterm birth)
• used to prevent seizures associated with eclampsia
Chromosomal sex
• determined at fertilization (46XX, 46XY)
Gonadal sex
- differentiation based on gene expression cascade kicked off by transcription factor SrY on the Y chromosome (otherwise leads to beta catenin Wnt4 female pathway)
Genital sex is determined by what?
Differentiation due to steroid hormones and other factors produced by differentiated gonads (both internal and external)
What is the pathway of development into a female?
Genital ridge —> bipotential gonad —> XX —> beta-catenin, Wnt4, Rspo1 —> ovary with granulosa/thecal cells—> follicles creating estrogen —> Mullerian duct forming female internal genitalia + female external genitalia
What is the pathway of development into a male?
Genital Ridge —> bipotential gonad —> SrY, Sox9 —> testes with Sertoli and leydig cells —> Sf1 via sertoli and leydig —> AMH, testosterone —> regression of Mullerian duct, DHT + wolffian duct —> Wolffian leads to internal male genitalia, DHT leads to penis, prostate, scrotum
What happens embryogenically at five weeks?
Proliferation of epithelium and underlying mesenchyme medial to the primitive kidney results in a gonadal Ridge and formation of the gonadal cords
What happens embryogenically at week six?
Primordial germ cells have migrated from yolk sack into the genital ridge to become gametes
What does the Wolffian duct become?
Vas deferens, epididymis, seminal vesicle
What does the Mullerian duct become?
Oviduct, uterus, cervix, upper portion of vagina
What is required for testosterone from leydig cells to become dihydrotestosterone required for descent of testes and development of male genitalia?
5-alpha reductase
What is Turner syndrome?
• 45, X genotype (paternal sex chromosome is missing)
• female phenotype but dysfunctional ovaries—> secondary sex characteristics do not develop
• other characteristics: short stature, high arched palate, webbed neck, shield-like chest, inverted nipples, bicuspid aortic valve, renal anomalies
What is Klinefelter syndrome?
- 47, XXY genotype
- male sex and phenotype
- characterized by: infertility, gynecomastia, impaired sexual maturation, atrophic testes, small penis, reduced/lack of secondary male characteristics
What are the three main categories of differences of sex development (DSD)?
- Gonadal dysgenesis
- Undervirilization of 46, XY males
- Overvirilization of 46, XX females
What is ovotesticular DSD (true gonadal intersex, 46,XX)?
• both testicular and ovarian tissue is present
• occurs when both medulla and cortex of gonads develop
• phenotype can be either male or female female but external genitalia is ambiguous
What is overvirilization (46, XX) DSD?
• clitoral enlargement and labial fusion, persistent urogenital sinus
• can be caused by congenital adrenal hyperplasia or exposure to exogenous androgenic agents during pregnancy
What is undervirilization (46, XY) DSD?
• external and internal genitalia variable depending on degree of development
• can be caused from a 5-alpha reductase deficiency (cannot convert testosterone to DHT)
What is androgen insensitivity syndrome (46, XY)?
• genetic basis: loss of function mutation of the X linked androgen receptor gene
• may lead to complete loss of function: female secondary sexual characteristics and external genitalia, vagina ends in blind pouch and uterine structures are rudimentary or absent. testes present
• partial: some masculinization of external genitalia, enlarged clitoris. Testes present
~ testes maybe removed due to high risk of tumor development
Why do anomalies of the female reproductive tract occur?
- arrested development of the uterovaginal primordium during the eighth week of embryogenesis (incomplete/failure of paramesonephric duct or incomplete canalization of the vaginal plate)
What is diethylstilbestrol (DES) known for?
• used as a miscarriage preventative in the 1950s-1970s
• DES alters differentiation of the Mullerian-derived structures and changes the expression patterns of HOX genes
• daughters exposed in utero developed:
1. Vaginal clear cell carcinoma
2. Vaginal adenosis
3. T-shaped uterus (infertile)
What is cryptorchidism?
• undescended testes due to disrupted androgen signaling
• typically resolves within the first year, if not it can result in sterility or germ cell tumors
What is hypospadias?
• external urethral orifice is on the ventral surface of the penis
• caused by inadequate production of androgens or inadequate receptor sites
What can testicular dysgenesis syndrome lead to?
• increase in testicular cancer
• hypospadias
• cryptorchidism
• decrease in sperm count
What can phthalate syndrome lead to in males?
• smaller/malformed penis
• undescended testicles
• shortened anogenital distance
What is endometriosis?
• ectopic endometrial tissue at a site outside of the uterus leading to intrapelvic bleeding and adhesions (most commonly the ovary)
• may cause: infertility, pelvic pain, dysmenorrhea dysuria, pain on defecation/rectal wall involvement
What are some unique histology findings of endometriosis?
• endometrioma: chocolate cyst
• adenomyosis: growth of endometrium into the myometrium
What is the regurgitation theory of endometriosis?
Retrograde flow of endometrial tissue from the fallopian tube with origin from the uterine endometrium
What is the benign metastasis theory of endometriosis?
Vascular/lymphatic spread with origin from the uterine endometrium
What is the metaplastic theory of endometriosis?
Arises directly from coelomic epithelium (pelvic/abdominal peritoneum) or metaplasia of mesonephric rests, with origin from cells outside of the uterus giving rise to endometrial tissue
What is the extrauterine stem/progenitor cell theory of endometriosis?
Stem cells from bone marrow can give rise and differentiate into endometrial tissue, the origin is from cells outside of the uterus
What is a beneficial treatment for endometriosis?
Aromatase inhibitors: estrogen increases survival and persistence of endometriotic tissue
What are common mutations in endometriosis?
PTEN, ARID1A
(Seen in endometriosis cysts, atypical endometriosis, and associated cancers)
What does disordered proliferative/non-menstrual shedding look look like on histology?
What is the most common cause of dysfunctional uterine bleeding?
Anovulatory cycle: failed ovulation results in prolonged to unopposed estrogen driven proliferation phase causing dilated glands and stromal condensation
What is acute endometritis?
• an ascending infection from the lower genital tract (commonly group A hemolytic streptococci, staphylococci)
• symptoms: fever, elevated WBC count, pelvic pain
• PMN rich stromal infiltrate
• curettage and antibiotics are curative
What is chronic endometritis?
• abnormal bleeding, pain, discharge, infertility
• may be due to chlamydia, many with no identifiable cause
What is the histology of chronic endometritis?
- presence of plasma cells
- sarcoidosis or TB may show granulomas
What are endometrial polyps?
- exophytic benign masses of varying size projecting into the endometrial cavity
- may be asymptomatic or cause abnormal bleeding
- association with tamoxifen (breast cancer drug that causes weak proestrogenic affect in the endometrium)
Why is endometrial hyperplasia important?
- it is a cause of abnormal uterine bleeding and a precursor to the most common type of endometrial cancer (hypertrophic, endometrioid)
- defined as: increase in gland compared to stroma and increased gland to stroma ratio > 1:1
What are the causes of endometrial hyperplasia?
prolonged estrogen stimulation
* anovulation
* obesity
* estrogen replacement therapy/tamoxifen for breast cancer
* ovarian stromal hyperplasia
* ovarian granulosis cell tumor
* PCOS
What are the common gene mutations of endometrial hyperplasia?
• inactivation of PTEN—> overactive PI3K/AKT growth pathway
• Cowden syndrome may develop endometrial carcinoma (germline PTEN mutation)
Type 1 endometrial carcinoma (endometrioid)
• age of onset: 55-65
• clinical: unopposed estrogen, obesity, hypertension, diabetes
• morphology: endometrioid
• precursor: hyperplasia
• gene mutation: PTEN, ARID1A, PIK3CA, KRAS, FGF2, MSI, WNT signaling, TP53
• spread: lymphatics, indolent
Type 2 endometrial carcinoma (atrophic, serous)
- age of onset: 65-75
- clinical: atrophy, thin physique
- morphology: serous, clear cell, mixed Mullerian tumor, with psammoma body formation and papillary formation
- precursor: serous endometrial intraepithelial carcinoma
- genetic mutations: TP 53, aneuploidy, PIK3CA, FBXW7, CHD4, PPP2R1A
- spread: aggressive intraperitoneal and lymphatic spread
Endometrial carcinoma pathways
• type 1: hyperplasia (unopposed estrogen) endometrioid, non-atypical hyperplasia via PTEN, MLH1, KRAS, etc.
• type 2: sporadic atrophic endometrium via TP53/aneuploidy, etc.
Endometrial carcinoma staging
• stage 1: confined to corpus uteri
• stage 2: involves corpus and cervix
• stage 3: extends outside the uterus, but not outside the true pelvis
• stage 4: extends outside true pelvis and involves mucosa of the bladder or rectum
What is a malignant mixed Mullerian tumor?
- endometrial adenocarcinoma with component of malignant mesenchymal tissue
- homologous stroma: resembles normal uterine stroma (leiomyosarcoma, endometrial stromal sarcoma)
- heterologous stroma: resembles stroma not present in the uterus (skeletal= rhabdomyosarcoma, cartilage= Chondrosarcoma, bone= osteosarcoma)
What is a uterine leiomyoma (also known as fibroids)?
- benign smooth muscle neoplasm occurring singly or with multiple nodules
- sharply circumscribed, round nodules with myometrial location
- micro: uniform spindle cells, rare mitotic figures,White, tan and whorled
What is uterine leiomyosarcoma?
• malignant mesenchymal neoplasm with different differentiation towards smooth muscle
• arises from myometrial or endometrial stromal precursor cells
• genetic mutation: MED12
Fungal/yeast infection of the vagina/cervix
- Candida: normal vaginal flora, symptomatic overgrowth due to disturbance in microenvironment
- diabetes, antibiotics, pregnancy, altered immunity may cause infection
- pseudohyphae/yeast on KOH prep or Pap smear
Herpes simplex two
- genital mucosa and skin infection leading to red papules/vesicles/painful ulcers on the vulvar surface and cervix/vagina
- systemic symptoms include fever, malaise, tender inguinal nodes
- latent in the lumbosacral nerve ganglia
What are the three M’s of herpes simplex 2 virus infection?
- Multinucleation
- Margination
- Molding
Molluscum contagiosum: pox virus
• typically an STI in adults: genitals, inner thigh, lower abdomen, buttocks
• pearly dome shaped papules with center depression/dimple
• six week incubation period, can last month to a year
What does molluscum contagiosum look like on histology?
• distinctive cup shaped lesion composed of molluscum bodies in the epidermis above the stratum basale
What is trichomonas vaginalis?
- flagellated protozoan transmitted sexually
- 4 days-4 weeks: develops yellow frothy discharge, discomfort, dysuria, painful intercourse
- red vagina and cervical mucus with dilated vessel (strawberry cervix)
What is bacterial vaginosis?
• infection with gardnerella vaginalis (coccibaccilli covered squamous cells on Pap smear)
• thin gray/green odorous discharge
What is primary syphilis (Treponema pallidum)?
• chancre: perineal or vulvar shallow ulcer 3 to 4 weeks post infection
• lymphocytic and plasma cell rich infiltrate, perivascular epithelial hyperplasia
What is secondary syphilis?
- 4-8 weeks post chancre constitutional symptoms
- mucocutaneous lesions, moist papules (condyloma lata), and a scaly rash of the palms and soles
- latency can last many years
What is tertiary syphilis?
• characterized by gumma (granulomatous lesions)
• multiple disseminated lesions that show granulomas, lymphocytes, histocytosis cells microscopically
What are the most common causes of pelvic inflammatory disease?
- Neisseria gonorrhea: a sense along mucosal surfaces beginning in the endocervix
- Chlamydia: ascends through lymphatics, deeper infection
What are the acute complications of pelvic inflammatory disease?
• peritonitis
• bacteremia leading to endocarditis, meningitis, suppurative arthritis
What are the chronic complications of pelvic inflammatory disease?
• infertility
• tubal obstruction
• ectopic pregnancy
• pelvic pain
• adhesions and intestinal obstruction
What is a Bartholin cyst?
• inflammation of the Bartholin gland duct leading to obstruction and cyst formation (transitional or squamous lining)
What is lichen sclerosus of the vulva?
• smooth white plaques or macules which may coalesce
• thinning of the epithelium, labia becomes atrophic, and the vaginal orifice constricts
• due to activated T cells in the subepithelial infiltrate, an autoimmune disorder
What is lichen simplex chronicus (squamous cell hyperplasia) of the vulva?
- non-specific condition from rubbing or scratching to relieve pruritus
- thickened epidermis and hyperkeratosis with variable dermal lymphocytes, no cytologic atypia
What is condyloma acuminatum?
- genital wart: exophytic and verrucoid
- can be vulvar, perineal, perianal, vaginal, or cervical
- typically caused by HPV 6 or 11
- micro: papillary tree-like branching stromal cores, koilocytosis with perinuclear halo, wrinkled nuclear membrane, binucleation
Squamous cell carcinoma: Basaloid and warty
• related to HPV 16
• younger age, peaks at 50
• arises from VIN, multicentric
Squamous cell carcinoma of the vulva: keratinizing
- related to long-standing lichen sclerosis or squamous hyperplasia
- more common, peaks in 70+
- high frequency of TP53 mutations
Vulvar carcinoma staging
What is extramammary paget disease (vulva glandular neoplasia)?
• pruritic, red crusted map-like area on labia minora
• IHC: cytokeratin 7+, CEA and mucicarmine +
What is vaginal adenosis?
• vagina initially covered by endocervical type glandular epithelium and a small patches remain following normal squamous replacement during development
• seen more commonly in women exposed in utero to DES
Vaginal intraepithelial neoplasia (VaIN)
- almost all associated with HPV 16, 18
- greatest risk factor is prior cervical or vulvar carcinoma
- upper vagina more commonly involved (spreads to iliac nodes)
- lower 2/3 of vagina less commonly involved (spread to inguinal nodes)
What is sarcoma bottyoides (embryo rhabdomyosarcoma)?
• vaginal neoplasia seen in infants and children under five
• polypoid grape-like masses protruding from the vagina
• mesenchymal tumor with different differentiation towards skeletal muscle
• can mimic and inflammatory polyp
• local invasion of peritoneal cavity and urinary tract
What is polycystic ovarian syndrome?
• a complex endocrine disorder characterized by hyperandrogenism, menstrual abnormalities, polycystic ovaries, chronic anovulation, and decreased fertility
• presents with obesity, hirsutism, type two diabetes, premature atherosclerosis
• multiple cystic follicles with luteinizing theca layer hyperplasia
What is ovarian carcinoma?
• a malignant lesion with bilateral spread and nodal metastasis (and liver/lung)
• cytologically positive ascites fluid with orangeophilic psammoma bodies
What seromarker can be used to monitor disease progression and recurrence for ovarian carcinoma?
CA-125
What are the three classifications of ovarian neoplasia?
- Surface epithelial: fallopian tube epithelium and endometriosis (older ages)
- Germ cell: Pluripotent cells from the yolk sack (younger ages)
- Sex cord/Stromal
What are the types of surface epithelial ovarian neoplasia?
- Serous
- Mucus
- Endometrioid
~ all can have benign, borderline, or malignant forms
What gene mutations increase the risk for surface epithelial/stromal ovarian neoplasia?
Type 1: low-grade, arise in borderline tumors, KRAS, BRAF, ERB2, wild type TP53
Type 2: high-grade, arise from serous intra-epithelial carcinoma, BRCA1, BRCA2, TP53, wild type KRAS and BRAF
What is a malignant serous tumor type 1?
• low-grade micropapillary serous carcinoma
• micro: more complex testing, micropapillary pattern, moderate cytologic atypia
What is an ovarian benign serous cystadenoma?
• thin-walled cyst with variable solid tissue and smooth inner lining
• micro: simple layer of psychologically bland serous epithelium
What is an ovarian malignant serous tumor type 2?
• either cystadenocarcinoma or adenocarcinoma, with increased solid tissue and complex papillations, necrosis commonly present
• Increased cytologic atypia, destructive stromal invasion with desmoplastic reaction
What is a unique feature of borderline ovarian tumors?
They can spread to peritoneal services with non-invasive implants and slow progression
What genetic mutation is consistently present in ovarian mucinous neoplasia?
KRAS
Ovarian benign mucinous tumors:
• cystadenoma, cystadenofibroma
• intact, surface rarely involved
• can be large (25kg)
• often multiloculated cystic filled with thick mucin
What are the cell types of an ovarian benign mucinous tumor?
• tall columnar epithelium with basal nuclei and apical mucin vacuole vs goblet cell
• minimal nuclear stratification
What changes as an ovarian mucinous tumor becomes borderline from benign?
• increased complexity of gland contours and pilling/tufting of epithelium
What are the unique features of ovarian mucinous carcinoma?
- more solid, less cystic. Necrosis common
- metastasis from G.I. tract is common (appendix)
- if bilateral, typically metastatic
- confluent glandular growth, destructive stromal invasion and desmoplasia (marked cytologic atypia)
What is pseudomyxoma peritonei?
- mucinous ascites and cystic epithelial implants on peritoneal surfaces
- commonly from the appendix or G.I. origin, may be ovarian/ovarian involvement
Ovarian tumors typically metastasize to where?
• uterus, fallopian tube, contralateral ovary, pelvic peritoneum (Mullerian origin)
• breast and G.I. tract
What is a Kruckenberg tumor?
Bilateral metastatic mucinous signet ring carcinoma of the ovaries, often gastric origin (diffuse carcinoma)
What are the mutations seen in ovarian endometrioid neoplasia (and ovarian clear cell carcinoma)?
• increased PI3K/AKT pathway
• PTEN, PIK3CA, ARD1A, KRAS
• mismatch DNA repair genes (HPCC)
• TP53 mutations
What does ovarian endometrioid carcinoma look like microscopically?
• low-grade
• well formed endometrial type glands with confluent growth
What does ovarian clear cell carcinoma look like?
What is a Brenner tumor?
- benign surface epithelial tumor composed of bladder-like epithelium
- ovarian transitional cell neoplasia
- sharply demarcated nests of transitional cells in ovary stroma
- Usually solid, can have cystic transitional component
What is the most common ovarian germ cell neoplasia?
Benign cystic teratoma (dermoid cyst)
• young women in active reproductive years
• lined with squamous, skin, hair, sebaceous glands, teeth (calcification)
What are the monodermal variants of an ovarian mature cystic teratoma?
- Stroma ovarii: all thyroid
- Carcinoid: all neuroendocrine
- Stromal carcinoid: thyroid and neuroendocrine
What is an ovarian dysgerminoma?
- ovarian counterpart of testicular seminoma, malignant ovarian germ cell tumor
- elevated hCG, KIT mutations
- large vascular cells with clear cytoplasm (fried egg) and lymphoid infiltrates
- very chemo responsive
What is an ovarian yolk sac tumor?
- extraembryonic differentiation of malignant germ cells seen in children/young women
- elevated AFP, alpha-fetoprotein
- rapid growing pelvic mass, unilateral
- schiller duval bodies: central vessel surrounded by epithelium in a space led by epithelium
What is an ovarian choriocarcinoma?
• malignant mixed germ cell tumor that secretes high levels of hCG
• chemo resistant, fatal
What are unique features of ovarian granulosa cell tumors (seen in older women)?
- Call-exner bodies (gland like structures with central acidophilic material)
- Coffee bean nuclei (longitudinal groove in the nuclei)
What is the most common genetic mutation for an adult granulosis cell tumor?
FOXL2
~ serum inhibin stain can be a biomarker for identification/monitoring
What are the tumors arising in ovarian stroma that are composed of fibroblasts, plump spindle cells with a lipid droplets or a mixture of the two?
Fibroma, thecoma, fibrothecoma
- present with ascites, Meig’s syndrome
- association with basal cell Nevus syndrome
- presents at younger age
What is Meig’s syndrome?
ovarian fibroma + ascites + hydrothorax on the right side
What do ovarian fibroma/thecoma/fibrothecomas look like microscopically?
• spindle cells with scant cytoplasm
• variable lipid vacuoles and luteinization
• varying collagen bands
Over 50% of Sertoli/Leydig tumors have mutations of what?
DICER1: encoding an endonuclease involved in proper processing of micro-RNAs
• these tumors are typically benign, hormonally active, and produce masculinization or defeminization
What is seen microscopically in sertoli leydig tumor?
Sertoli:
• tubules of well differentiated columnar cells
• basal nuclei, uniform
Leydig:
• plump polygonal cells
• pink cytoplasm/round nucleus
• crystalloid of Reinke
Ovarian pure Leydig cell tumors
Natural birth control methods require what?
• female with regular, predictable cycles
• both partners dedicated
What are the best birth control methods for STI protection?
Male/external and female/internal condoms
What is unique about the diaphragm as a form of birth control?
It must be left in for at least six hours (max 48) post intercourse in order to not disturb the barrier and allow sperm through
The sponge birth control method has what side effects?
Increased rate of yeast infections, UTIs, and toxic shock syndrome if left in place for extended period
What are the absolute contraindications for an estrogen/progesterone birth control?
• previous thromboembolic event/stroke
• hx of CAD or 2+ risk factors for ASCVD
• hx of estrogen dependent tumor
• liver disease
• pregnancy
• undiagnosed abnormal uterine bleeding
• smoker over age 35 and >15cigs/day
• migraine headaches with neurological symptoms
• uncontrolled hypertension
• diabetes > 20 years with nephropathy, retinopathy or neuropathy
What are the non-contraceptive benefits of combined estrogen/progesterone birth control?
• reduction in dysmenorrhea, heavy menstrual bleeding, and ovarian/endometrial cancers
• improves acne, hirsutism, benign breast disease, osteopenia, and osteoporosis
• decreases functional ovarian cysts
What are the formulation options for the combined estrogen/progesterone birth control?
• oral
• vaginal ring
• transdermal patch
What is drospirenone?
• a spironolactone analog with anti-mineralocorticoid and lower endogenic effects
• improves weight stability and water retention in individuals taking contraceptives
• SE: may increase serum potassium, increase in VTE risk
What is a monophasic estrogen/progesterone pill?
Same fixed dose for 21/7-24/4 days
What is a biphasic, triphasic estrogen/progesterone pill?
• varying doses through the first three weeks + a placebo week
What are extended cycle estrogen/progesterone pills?
84 or 365 days of fixed dose hormones (breakthrough bleeds more common initially)
When using the vaginal ring, when do you need a back up contraception?
If it has been outside of the vagina for longer than three hours
Transdermal estrogen/progesterone patches are contraindicated in what patients?
BMI > 30
What are the formulations for progesterone only birth control?
• oral (minipill)
• injectable
• implant
• IUD
What are the issues to consider when talking about progesterone only birth control?
- irregular bleeding
- potential androgenicity side effects
- Slow return to fertility
- breakthrough ovulation if pills are missed
- effects on bone health
Timing is the most critical with what birth-control formulation?
Progesterone only mini pill (must be within three hours otherwise backup contraception is needed)
What is levonorgestrel?
• plan B
• one step, take within 72 hours of unproductive intercourse
What is ulipristal acetate?
• Ella, morning after pill
• can use up to 120 hours, five days post unprotected intercourse
• progesterone agonist/antagonist
• side effects of headache, nausea/dizziness more common than Plan B
IUD comparison graph:
What are the major contraindications of IUDs?
• pregnancy
• congenital or acquired uterine cavity malformation
• acute pelvic infection
• uterine bleeding of unknown cause
• breast cancer (for hormone based)
• Wilson’s disease/copper allergy (for copper IUD)
What post procedure follow-up must be done following vasectomy?
Semen analysis to assure no motile sperm (three months following vasectomy, approximately 20 ejaculations)
~ other form of contraception is needed until this follow up
What is the primary cause of cervicitis or vaginitis?
Anything that causes the pH to rise and disrupts the balance of lactobacilli which can lead to overgrowth of organisms
What is the difference between chronic cervicitis and acute?
Chronic: lymphocyte rich, germinal centers form (follicular cervicitis)
Acute: neutrophilic infiltrate, sometimes purulent
What are cervical polyps?
• benign lesions (small bumps to large masses protruding through the cervical os) that may cause bleeding
• micro: loose fibrovascular stroma covered by benign endocervical epithelium
• removal is curative
What is a cervix Nabothian cyst?
- most common cervical cyst, forms when squamous metaplasia obstructs gland outlets leading to dilation with mucus
- patients typically have multiple, they are typically superficial but can extend through the cervix wall
What is cervical microglandular hyperplasia?
- benign proliferation of endocervical glands with polypoids
- micro: tightly packed glandular units, small lumens, flattened epithelium, squamous metaplasia common
What’s the difference between low risk and high risk HPV causing cervical malignant/pre-malignant disease?
Low risk: condylomata (6 and 11)
High risk: dysplasia, progression to cervical cancer (16, 18, 31, 33)
Where does HPV typically infect in the cervix?
Basal squamous cells where exposure occurred, immature squamous metaplasia at the transformation zone (squamocolumnar junction)
What is the pathogenesis of high-risk HPV causing cervical cancer?
HPV viral proteins E6 and E7
• E7 binds RB and promotes its degradation, inhibits p21 and p27, cyclin dependent kindness inhibitors
• E6 binds p53 promoting its degradation, up regulating telomerase
Where is the viral DNA when considering low risk condyloma versus high-risk cancer?
Low risk: viral DNA is extrachromosomal
High risk: viral DNA is integrated into the host genome, increasing E6 and E7 expression and dysregulating oncogenes
What is the progression of cervical pre-malignant disease?
CIN1 (LSIL) —> CIN2-3b (HSIL)
What is the most common cervical carcinoma?
Squamous cell carcinoma (80%), adenocarcinoma (15%), adenosquamous or neuroendocrine (5%)
How is early micro-invasive cervical carcinoma treated?
Cone biopsy
(invasive disease treated with hysterectomy and regional node dissection/radiation and chemotherapy)
How does microinvasive versus invasive squamous cell carcinoma of the cervix look microscopically?
How does adenocarcinoma in situ versus invasive adenocarcinoma of the cervix look microscopically?
What do the Pap smear cells look like for an LSIL-CIN1?
What do the Pap smear cells look like for an HSIL-CIN2-3?
How is HPV testing compared to Pap smear for cervical carcinoma screening and prevention?
HPV test is more sensitive but less specific than the Pap smear.
What are the order of actions for cervical carcinoma screening?
- Pap smear. If atypical squamous cells:
- HPV screening. If 16 or 18:
- Reflex testing (colposcopy with acetic acid). If positive:
- Biopsy (cone if malignant)
What are the two layers of the embryonic disc?
1.Epiblast: the thicker layer, consisting of high columnar cells that forms the floor of the amniotic cavity and is continuous with the amnion
2. Hypoblast: consisting of small cuboid cells forming the roof of the exocoelomic cavity
What is an important characteristic of the second week of embryo development?
The appearance of the primary chorionic villi
What is an extrauterine implantation?
• ectopic pregnancy
• blastocyst implants outside of the uterus and may cause rupture of the uterine tube and hemorrhage into the peritoneal cavity in the first eight weeks
• may be confused with appendicitis due to similar pain symptoms
What is placenta previa?
• Implantation of the blastocyst in the inferior segment of the uterus near the internal os of the cervix
• may cause bleeding, and C-section requirement
Relatively large doses of progestin/estrogen prevent what?
Implantation of the blastocyst
What is gastrulation?
Occurs in the third week of development, giving rise to the three germ layers (ectoderm, mesoderm, endoderm)
The ectoderm gives rise to what?
Epidermis, CNS, PNS, eyes, internal ears, neural crest cells, connective tissues of the head
The mesoderm gives rise to what?
Skeletal muscles, blood cells, lining of blood vessels, visceral smooth muscular coats, serosal lining of body cavities, ducts and organs of the reproductive and excretory systems, majority of the cardiovascular system
The endoderm gives rise to what?
Epithelial linings of the respiratory and digestive tracts, glandular cells of organs such as liver and pancreas
What is the primitive streak?
• appears on the surface of the epiblast of the bilaminar embryonic disc
• marks the beginning of an embryo patterning of craniocaudal axis
What functions as the primary inductor (signaling center) in the early embryo?
The notochord
What is neurulation?
• neural plate invagination forming neural grooves which can then become neural tubes
What do the neural crest cells give rise to?
The sensory ganglia of the spinal and cranial nerves
What are somites?
•Cells derived from the primitive node forming the Paraxial mesoderm.
• Responsible for the craniocaudal patterning of the body
• found on either side of the neural tube
What are the two major folds in embryological development?
1. Craniocaudal fold: creates cylindric embryo, cranial and caudal regions ventrally as the embryo elongates
2. Lateral towards the medial: folding of the sides of the developing embryo produces right and left lateral faults resulting in an Omphaloenteric duct
What forms in week five of embryogenesis?
• enlargement of head: growth of brain/face
• cervical sinus forms
• kidneys
What happens in week six of embryogenesis?
• movement of trunk and limbs
• external ear development
• intestinal growth (herniation allowing for proliferation)
What happens in week seven of embryogenesis?
• differentiation of digits
• upper limb ossification
When does substantial weight gain occur in embryogenesis?
Weeks 21 to 25
When do slow and fast eye movements occur in embryogenesis?
Slow: weeks 13 to 16
Fast: weeks 21 to 25
When do the lungs and pulmonary vasculature develops efficiently enough to provide adequate gas exchange?
Weeks 26 to 29
When can the CNS direct rhythmic breathing movements and control body temperature?
Weeks 26 to 29
What contributes to the differentiation of outer cells to trophoblast and inner cells to the pluripotent inner cell mass in the pre-implantation embryo?
- asymmetric daughter cell inheritance of transcriptional regulators among outer and inner cells during cleavage
- environmental signals/cell polarization suppressing hippo signaling in the outer cells
- a double negative feedback loop of transcription regulator expression between inner and outer cells
The left-right asymmetry of the human body is a result of what event during embryonic development?
Directional pattern of ciliary beating at the primitive note
When do the two major global demethylation events that occur in the human life cycle take place?
- In blastomeres during cleavage
- In primary germ cells at the time of embryonic gonad formation
In which cells are chromosome parent of origins specific imprints erased during a global DNA methylation event?
Primordial germ cells
What mechanism best explains cell fate decisions occurring in the germ layers (ectoderm, mesoderm, endoderm)?
Combinatorial patterns of transcription factor and signaling molecule activity
During the process of fertilization, what causes critically important events (exocytosis of cortical granules, resumption and completion of meiosis 2, activation of the first cell cycle and development program of the zygote)?
A rise cytoplasmic calcium in the oocyte
What is the difference between oogonia and spermatogonia entering meiosis?
Oogonia: enter meiosis before birth, arrest at prophase 1
Spermatogonia: enter meiosis beginning at puberty
What persists in adult men but is absent in adult women, leading to adult men producing sperm throughout their life but the amount of eggs a woman has is finite?
- Spermatogonia persist in adult men (men can make more sperm cells)
- Oogonia are absent in adult women (women cannot make any more eggs)
Left to right assymmetry in embryogenesis arises from what?
The ability of primitive node cilia to concentrate Nodal on the left side of the embryo, resulting in regional activation of Ptx2
Dorsal-ventral neural cell identities in the neural tube are instructed by what?
Opposing gradient of BMP and SHH
~ also opposing gradients of transcription factors such as Pax6, Pax7, and NKx6.1
What transcription factors are involved in the cranial-caudal axis determination?
FGF, Wnt3, retinoic acid (RA), clusters of HOX genes
Different gradients of what transcription factors lead to gastrulation decisions (endoderm, endoderm, or mesoderm)?
BMP4 and Oct4
Gata6 promotes what type of differentiation: epiblast or hypoblast?
Hypoblast
NANOG promotes what type of differentiation: epiblast or hypoblast?
NANOG helps maintain pluripotency and an inner cell mass/embryoblast (future epiblast fate)
CDX2 promotes what type of differentiation: inner cell mass or trophoblast?
Trophoblast
Oct4/Nanog/Sox2 promotes what type of differentiation: inner cell mass or trophoblast?
Intercell mass and the maintenance of pluripotency
Cranial-caudal axis patterning in the LIMB is dependent on what?
SHH expressed in the ZPA (zone of polarizing activity)
Deletion of 15q13-q15 in the male homolog leads to what?
Prader-Willi syndrome: characterized by hypotonia, hypogonadism, short stature, hyperphagia, cognitive impairment
Deletion of 15q13-q15 in the female homolog leads to what?
Angleman syndrome: characterized by developmental delay, stiff/a toxic movements, hyperactivity, severe cognitive impairment, a happy disposition
What is secreted by the embryo shortly after fertilization to allow for implantation preparation?
Pre-implantation factor (PIF)
What is a morula?
Cell mass > 4 cells (blastomeres)
What happens to the cells of a blastocyst?
- inner cell mass: becomes embryoblast which forms the tissues of the embryo proper
- outer cell mass: becomes trophoblast which forms the placenta
The trophoblast differentiates into what two layers?
- Cytotrophoblast: mitotically active and proliferative
- Syncytiotrophoblast: multinucleated cell mass that is invasive and erode into the epithelium/stroma. Secrete progesterone, estrogen, hCG, lactogens
What is the decidua?
• all but the deepest portion of the endometrium becomes transformed into the decidua graviditatis which is shed with the placenta at parturition (birth)
• decidualization is stimulated by progesterone
What makes up the Chorion?
• syncytiotrophoblast, cytotrophoblast, extraembryonic somatic mesoderm
What is the difference between the primary/secondary/tertiary chorionic villi?
• Their components:
1. Primary is only Syncytiotrophoblast and Cytotrophoblast
2. Secondary contains connective tissue (mesenchyme)
3. Tertiary contains blood vessels
What are the three components of the placenta?
- Decidua basalis
- Decidua capsularis
- Decidua parietalis
What is the decidua basalis?
• Placental area that underlies the implantation site between the conceptus and myometrium.
• Constitutes maternal portion of the placenta
• sight of decidual reaction: most extensive villar invasion
What is the decidual capsularis?
• area of the placenta between the conceptus and the uterine lumen
• becomes attenuated as the embryo grows, eventually fusing with the decidua parietalis and eliminating the uterine cavity
What is the decidua parietalis?
Remainder of the endometrium where there is no implantation or connection to the fetus
What are the TORCH pathogens that can cross the placenta barrier?
T: toxoplasmosis/toxoplasma gondii
O: other
R: rubella
C: CMV
H: herpes simplex
~ other: hip B, Coxsackie virus, syphilis, varicella zoster, HIV, Parvo B19
What is hCG?
- human chorionic gonadotropin, a peptide produced by syncytiotrophoblasts
- helps maintain corpus luteum and its production of progesterone/estrogen during the first trimester
What takes over the secretion of progesterone from the corpus luteum in pregnancy?
Syncytiotrophoblasts
What is human placental lactogen (hPL)?
- peptide produced by syncytiotrophoblasts that affect growth, lactation, lipid and carbohydrate metabolism
- mimics prolactin and growth hormone to provide glucose and ketones for fetal nutrition
Why and how is prolactin, prostaglandins, and relaxin produced in pregnancy?
Produced by the decidual cells derived from the stromal connective tissue of the mother— softens pubic symphysis prior to parturition
What is spontaneous abortion?
• loss of pregnancy before 20 weeks gestation (most occur before 12 weeks)
• fetal causes: chromosomal abnormalities such as aneuploidy, polyploidy, translations, mutations
• maternal causes: endocrine factors, uterine defects, systemic vascular disorders, infections
What is an early medicinal treatment for ectopic pregnancy?
Methotrexate
What are the types of twins?
• mono or dizygotic
• mono or dichorionic
• mono or diamniotic
What is twin-twin transfusion syndrome (monochorionic complication)?
• vascular anastomosis from one side to the other, sometimes an AV shunt occurs leading to preferential blood flow to one twin at the expense of the other (one under perfused, one fluid overloaded)
What is placenta accreta?
Absent decidua, abnormal adherence of villous tissue to myometrium
What is placenta increta?
Absent decidua, placental villa invade into the myometrium
What is placenta percreta?
Absent decidua, placental villa invade through the myometrium
What is placenta abruption?
- acute clinical syndrome characterized by pain, uterine tetany, fetal distress, and sometimes DIC
- acute abruption has no morphological placental abnormality, chronic has some organization of indents in the placenta or adherens
What correlates with increased morbidity and mortality in acute chorioamnionitis?
Villous edema due to decreased blood flow
What is wrong with this placenta?
• acute chorioamnionitis
• featuring green discoloration of surface membranes, opaque membranes, cloudy amniotic fluid due to neutrophils and bacteria
Neutrophilic acute inflammation of basalis, chorion, and amnion along with funisitis of the cord indicates what?
Acute chorioamnionitis
What will histology show of a placenta infection due to hematogenous bacterial spread (such as listeria)?
• acute necrotizing villitis/intervillositis
• subtrophoblastic acute inflammation and necrosis of villi
• may cause fetal demise
What is preeclampsia?
• a systemic syndrome characterized by widespread maternal endothelial dysfunction that present during pregnancy with hypertension, edema, and proteinuria
What is eclampsia?
A severe form of preeclampsia including CNS involvement leading to seizures, coma, death
Severe preeclampsia can develop what syndrome?
HELLP syndrome (hemolytic anemia, elevated liver enzymes, and low platelets)
What is the pathogenesis of preeclampsia and eclampsia?
• trophoblasts failed to remove the smooth muscle of the spiral artery leading to abnormal placenta vascular and malignant hypertension
What uterine vessel pathology is seen in preeclampsia and eclampsia?
- Fibroid necrosis of vessel walls
- Subendothelial lipid/macrophages
- Luminal thrombi
Poorly controlled gestational diabetes can lead to what?
A baby with increased birthweight (macrosomia), and long-term complications including obesity and diabetes later later in life. Mother can also develop over diabetes 10-20 years post-delivery
What is a hydatidiform mole?
- cystic swelling of the chorionic villi and variable trophoblastic proliferation resulting from the fertilization of an empty egg (complete, commonly 46XX) or fertilization of an egg with two sperm (incomplete)
What is a common ultrasound pattern seen with hydatidiform moles?
“Snowstorm pattern”
How does a hydatidiform mole present clinically?
• with spontaneous miscarriage or curettage due to abnormal ultrasound showing villous enlargement
• complete moles have extraordinarily high hCG levels
What is an invasive hydatidiform mole?
- molar pregnancy that invades into or even perforates the uterine wall
- villi may embolize to lung or brain (but do not grow at those sites)
- presents with vaginal bleeding, uterine enlargement, persistently elevated hCG
- Tx: responds to chemotherapy, hysterectomy may be required with rupture
What is choriocarcinoma?
• malignant neoplasm of the trophoblastic cells derived from a previously normal or abnormal pregnancy (predominantly cytotrophoblasts and syncytiotrophoblasts)
• pts with hx of complete moles have a strong risk of choriocarcinoma
What does choriocarcinoma look like grossly/microscopically?
• fleshy tan tumors with extensive red hemorrhagic look, deep invasion of myometrium is typical
• proliferating cytotropho/syncytiotrophoblasts with abnormal forms
• abundant blood and necrosis
What is more chemo responsive: gestational or non-gestational choriocarcinoma?
Gestational (100% chemo response rate). Non-gestational is much more resistant to chemotherapy
What are some COVID-19 related fetal demise placental findings?
• necrotizing vasculitis/endothelialitis
• acute necrotizing villitis
• villous infarction
• intervillous fibrin deposition
• intervillous histiocytic/neutrophilic inflammation
What type of gland is a mammary gland?
Exocrine:
- merocrine (eccrine) release of protein
- apocrine release of lipids
What hormones are required for the development of the mammary gland?
• estrogen
• growth hormone/IGF-1
What is witch’s milk?
The production of milk from a newborn of either sex due to the passing of maternal hormones before birth and during breast-feeding
Postnatal mammary gland development: picture/image
How do the development of mammary glands/breast change during pregnancy?
• rapid epithelial growth increasing fat and blood flow
• alveoli form
• continuous high levels of prolactin
• colostrum and milk secreted by luminal epithelial cells
• suckling releases oxytocin to cause contraction of epithelial cells to eject milk
• weaning: luminal epithelial cells complete a ptosis and evolution occurs (returning to inactive/puberty state)
Mammary gland: inactive, pregnant, lactating picture/graph
What is the milk flow secretion (apocrine secretion of fats)?
Intralobular duct —> interlobular duct —> lactiferous duct —> lactiferous sinus —> lactiferous duct —> nipple
What is the TDLU?
• terminal duct lobular unit consisting of the terminal ductules/acini, intralobular collecting duct, and intralobular stroma (loose CT)
What is the skin make up of the nipple?
• stratified squamous keratinized epithelial— no sweat glands/hair follicles
• melanin increases during pregnancy
• sensory: tall connective tissue papillae with Meissner’s corpuscles
• smooth muscle arrangements: circumferential and longitudinal
Describe the Areola
• gland of Montgomery (tubercles) on surface
• sweat and sebaceous glands present, produces oily secretions that keep the areola and nibble lubricated and protected
• produces all factory substance that encourages babies to latch on and breast-feed
What are the alveoli of the mammary gland?
• secretory units formed during pregnancy at the distal ends of the intralobular ducts
• cuboidal and squamous epithelium
• secrete lipids (apocrine) and protein (merocrine/eccrine)
What are the cells of the mammary alveoli?
- Epithelium:
• luminal epithelial cells (cuboidal, milk secretion)
• myoepithelial cells (contraction for oxytocin letdown reflex) - Connective tissue:
• adipose, fibroblasts, immune cells
What does an inactive mammary gland look like?
- higher visualization of loose connective tissue, small compressed ducts
What does an active/late pregnancy mammary gland look like?
• MANY alveoli, filling with milk
• less visualization of loose connective tissue (compressed)
• plasma cell infiltrates
What does a lactating mammary gland look like?
- active and resting alveoli depending on milk holding/milk release
What are the postmenopausal changes of mammary glands?
• atrophy of gland and stroma
• cyst formation is common
• connective tissue has fewer fiber blasts, fewer collagen fibers, fewer elastic fibers (droopy appearance)
What does estrogen do to mammary glands?
Stimulates the ductal cell proliferation
What does progesterone do to mammary glands?
• stimulates alveolar growth
• high levels inhibit milk production
• causes breast tenderness and increased size during luteal phase of menstrual cycle
What does prolactin do to mammary glands?
- pre-parturition: promotes maturation of ducts and alveoli
- post-parturition: promotes milk production, modifies lipid metabolism, stimulates casein and lactose production
Milk ejection, letdown reflex
Suckling stimulates hypothalamus—> oxytocin release + increased prolactin and production of milk at the alveolus —> myoepithelial contraction to eject milk from filled alveoli
When is a clinical breast exam performed?
When signs and symptoms are actively present
How is a clinical breast exam performed?
1. Visualize: arms down, arms up, hands on hips, leaning forward
2. Palpate: using finger pads, move in a vertical strip palpating in small concentric circles. Apply light, medium, and deep pressure at each examining point
What are concerning clinical findings of the breast?
• lump/contour change
• skin tethering
• new/changing nipple inversion
• surface ulceration or nipple scaling
• edema or peau d’orange (skin of an orange)
• erythema, warmth
What is a dominant mass in breast tissue?
A palpable breast mass that is three-dimensional, distinct from surrounding tissues, and a symmetrical relative to the other breast. It persists throughout the menstrual cycle
What is an indeterminate mass of the breast?
An area of vague or indiscrete nodularity or thickening that differs from the surrounding tissue. The finding is not matched in a mirror image location in the opposite breast
What’s in an important history finding for breast masses?
The relationship to menses
What are the best evaluations of a dominant breast mass in someone older than 40 years old?
1. Mammography
2. Ultrasound
3. MRI
What are the best evaluations of a dominant breast mass in someone older than 40 years old with a suspicious mammogram?
- Ultrasound
- MRI breast
- Image guided core biopsy
- Mammography short interval follow up
What are the best evaluations of a dominant breast mass in someone older than 40 years old and a non-suspicious mammogram?
- Mammography short interval follow up
- Ultrasound of the breast
What is the best evaluation of a dominant breast mass in someone younger than 30 years old?
1. Ultrasound (due to the young, highly fibrotic breast tissue making mammography indeterminant)
2. Mammography
3. MRI
What is a method used to further identify lesions on mammography?
Spot compression of the mass mammography
When is fine needle aspiration of a breast mass indicated?
• palpable lesion
• cystic structures
~ cannot use with implants, or lesions near the chest wall
If a patient comes in for unknown nipple discharge, what is the work up?
• urine pregnancy test
• thyroid testing
• serum prolactin level
• check medication list (OCPs, anti-hypertensive/ACEis, and medication can cause discharge)
• if >30, imaging with mammogram/ultrasound
Flowchart for nipple discharge with no mass:
What is acyclic breast tenderness?
- diffuse, typically bilateral tenderness often occurring in the luteal phase of the menstrual cycle
- predominantly women during their 30s/40s (uncommon in postmenopausal)
- pain is described as heaviness/soreness
What is non-cyclic breast tenderness?
• sharp, burning, unilateral pain
• tends to affect older populations of women 40+ in postmenopausal state
• cause is unknown, work is recommended
What is polythelia and why does it occur?
Additional supernumerary nipple anywhere on the milk lines
What is polymastia?
More than two breasts
What is athelia?
Absence of one/both nipples
What is amastia?
The absence of breast and nipple (and potentially the pectoralis muscle-Poland syndrome)
What are the most common UTIs seen in pregnancy?
E. coli, staph aureus, kpebsiella, proteus
~ can progress to pylonephritis, screen with UA, UC, leukocyte esterase and nitrate positive in G- specimen
What are the most common UTIs seen in pregnancy?
E. coli, staph aureus, klebsiella, proteus
~ can progress to pylonephritis, screen with UA, UC, leukocyte esterase and nitrate positive in G- specimen
Is there complication to pregnancy with vaginal candidiasis?
No— but treat with climatrozole or miconazole
Bacterial vaginosis in pregnancy
• increases risk for preterm premature rupture of membranes (PPROM), preterm delivery, and puerperal infections
• Tx: oral or vaginal metronidazole, vaginal clindamycin
• diagnosis: wet prep, clue cells, fishy odor (whiff test with KOH), and a gray vaginal discharge
Group B streptococcus infection during pregnancy
• can lead to UTI, choriamnionitis, endometriosis, neonatal sepsis
• treat with IV penicillin G when in labor or if prolonged rupture of membranes
Chorioamnionitis in pregnancy
• infection of the membranes leading to maternal fever, elevated maternal white blood count, uterine tenderness and fetal tachycardia (> 160 BPM)
• can cause PPROM, indication for delivery
• Tx: ampicillin and gentamycin
What infections affect fetuses in pregnancy?
• herpes Symplex virus
• varicella zoster
• parvo B19
• CMV
• rubella
• HIV
• Neisseria gonorrhea
• chlamydia trachomatis
• hepatitis B
• syphilis
• toxoplasmosis
What is done for pregnant patients with herpes simplex virus?
• suppressive antiviral therapy starting at 36 weeks (valtrex, acyclovir)
• c-section if active lesions in order to avoid vertical transmission to the baby
• no routine screen recommended
What are the complications of varicella zoster pregnancy?
- teratogen: congenital varicella syndrome
- live virus vaccine: cannot give pregnancy
What is congenital varicella syndrome?
Cutaneous scars, CNS abnormalities, ocular abnormalities, limb abnormalities
What is a major complication of parvovirus B19 (fifth disease) and pregnant patients?
Fetal hydrops: fetal hemolytic anemia
How does HIV in infection impact delivery in pregnant patients?
• c-section has shown to lower transmission rates if viral load >1000
• HRT treatment in labor, full anti-retrovirals
• treat neonate post delivery
What are the risks of Neisseria gonorrhea in childbirth and what are the treatments?
- transmission during delivery, newborn conjunctivitis= most common cause of blindness
- tx: erythromycin ointment at birth, treatment with ceftriaxone
Can a hepatitis B vaccination be given during pregnancy?
Yes
Complications of syphilis and pregnancy
• routine screening at first visit and 28 weeks, re-screen at delivery in high-risk populations
• risk of congenital syphilis
• Tx: maternal penicillin treatment
Explain congenital syphilis newborn appearance
• saber shins
• saddle nose
• deafness
• Hutchinson teeth
How can toxoplasmosis be avoided in pregnant patients?
• avoidance of gardening, soil, unfiltered drinking water, raw/undercooked or cured meats/meat products
• infected, Tx: sulfadiazine-pyrimethamine, <18wks Tx with spiramycin
What complications does listeria cause in pregnant patients?
• listeria can lead to fetal death, premature birth, or infected newborn
• avoid unpasteurized products and soft cheeses, avoid hotdog/deli meat unless he did to 165°
How does fetal surveillance change for gestational diabetes patients?
• diet controlled: normal routine OB care
• medication: NST or BPP weekly after 32 weeks, twice weekly if uncontrolled
• all: growth ultrasound at 36-37 weeks delivery recommended induction at 39 weeks, discuss C-section if baby >4500g for concern of dystocia
What is preterm labor?
• cervical change associated with uterine contractions prior to 37 weeks
• in nulliparous women, uterine contractions with at least 2 cm dilation and 80% or greater effacement (multiparous women may have 2-4 centimeter dilations without preterm labor)
What are the treatments for preterm labor (typically due to irritable uterus)?
• cortical steroids to improve fetal outcomes
• antibiotics for prophylaxis of GBS infection/unknown
• limited tocolysis: nifedipine or indomethacin
• magnesium for mild tocolytic and neuroprotective
What are the common antenatal cortical steroids for lung maturation of a fetus?
- Betamethasone (two 12 mg intramuscular doses 24 hours apart)
- Dexamethasone (6 mg intramuscular doses every 12 hours for four doses)
What evaluation should be done first with an antepartum bleeding pt?
ULTRASOUND
What is vasa previa?
• umbilical cord vessels that insert in the membranes with the vessels overloading the internal cervical os, vulnerable to fetal exanguination upon rupture of the membranes
Placenta 1. Accreta, 2. Increta, 3. Percreta
- Placenta accreta: invasion of the placenta attaching to the myometrium of the uterus
- Placenta increta: penetrates into the myometrium
- Placenta percreta: penetrates through the myometrium, potentially invading other organs (bladder, bowel)
What is a placenta abruption and what is the treatment?
- vaginal bleeding and abdominal pain due to detachment of the placenta from the endometrial lining. Typically accompanied by hypertonic uterine contractions, uterine tenderness, and non-reassuring fetal heart rate pattern
- TX: stabilize, prepare for preterm delivery, prepare for hemorrhage, determine RH status
What are the fetal risks of hypertension in pregnancy?
• intrauterine growth restriction
• pre-term delivery
• placenta insufficiency
What are the potential treatments of chronic hypertension and pregnant patients?
• BP > 140/90
• beta blocker, calcium channel blocker, methyldopa, diuretic
What drug is contraindicated in chronic hypertension of pregnant patients?
Ace inhibitors: associated with hydramnios and neonatal renal failure
What is the definition of gestational hypertension?
Hypertension without proteinuria at > 20 weeks gestation (BP> 140/90). No hx of hypertension
What medications can reduce risk for preeclampsia?
- calcium supplementation if low dietary Calcium (uncommon in the USA)
- Low dose aspirin from 12-36 weeks
What are the severe features of preeclampsia?
• blood pressure > 160/110
• pulmonary edema/cyanosis
• impairment of liver function
• visual or cerebral disturbances
• pain in the epigastric area or RUQ not responsive to treatment
• decreased platelet count < 100,000
• renal insufficiency, creatinine doubled or >1.1
What is eclampsia?
• pre-eclampsia with new onset grand mal seizures (death due to stroke, intracranial hemorrhage, ARDS)
• tx: magnesium sulfate (anticonvulsant), and hypertensive, immediate delivery removal of placenta
What are the blood pressure treatments used in patients with eclampsia?
• hydralazine
• labetalol
• nifedipine
• alpha-methyldopa
• additional: magnesium sulfate to prevent seizures
What is a reactive result of a non-stress test of a fetus?
2 accelerations in 20 minutes (this is good). If non-reactive, considered juice/stimulation/BPP
What is oxytocin stress testing?
- completed when a non-stress test is non-reassuring, IV oxytocin to induce contractions and assess FHT with the contractions
- desired result: FHT variability without decelerations during contractions
What are the five categories on a biophysical profile (BPP)?
- Amniotic fluid volume
- Fetal tone
- Fetal activity
- Fetal breathing movements
- Fetal heart rate reactivity (nonstress test)
~ score of 0 (bad) or 2 if normal, desired score: 8 to 10
What are the complications of multifetal gestation?
• ALL: growth restriction, PDT, chromosomal anomalies
• Mono/Di: twin to Twin transfusion syndrome, single fetal growth restriction, increased chromosomal anomalies, single fetal demise
• mono/mono: cord entanglement
What are the maternal complications of multifetal gestation?
• hypertension, preeclampsia
• anemia
• hyperemesis, increased N/V
• gestational diabetes
• cholestasis of pregnancy (itchy palms/soles)
• dematoses of pregnancy
• need c-section
What is the first line antidepressant drug used during pregnancy?
SSRIs: most commonly sertraline (but also citalopram, fluoxetine)
Others: SNRIs (venlafaxine, duloxetine) bupropion
What does the bishop’s score for induction measure?
• position
• consistency
• effacement
• dilation
• fetal station
What are the ways to cause cervical ripening?
• membrane stripping/ mechanical ripening with balloon catheter
• prostaglandins (Dinoprostone, misoprostol)
• amniotomy (manual water break)
• oxytocin/pitocin
When are serum hCG level detected?
8-11 days post-conception
What functions to support the pregnancy with progesterone production during the first 6 to 7 weeks gestation?
A single corpus luteum
What are some MSK findings of pregnant woman?
- striae gravidarum (stretch marks)
- diastasis recti (abdominal wall midline separation)
- linea nigra (midline of the abdominal skin becomes darker)
- melasma gravidarum (mask of pregnancy, brownish patches on the skin of the face/neck)
Why does physiological anemia of pregnancy occur?
The plasma volume increases by 40 to 50% and the red cell mass increases only by 25%, causing a decrease in the hemoglobin concentration
What are the three main factors that contribute to respiratory changes in pregnancy?
- The mechanical effects of the enlarging uterus on other body structures
- The increased total body oxygen consumption
- The stimulant effects of progesterone long-term
How does renal/endocrine physiology change during pregnancy?
- Renal plasma flow and the GFR increase by 40% leading to lower levels of creatinine and urea in the serum
- insulin response is increased early and pregnancy, potentially leading to insulin resistance and just additional diabetes
How much weight should a woman with a normal BMI gain during pregnancy?
25 to 35 pounds
What is the equation to determine due date of pregnancy?
LMP -3 months +7 days
How early must a physical exam be performed in pregnancy in order to get an accurate assessment of uterine size and dating of pregnancy?
Before 12 weeks gestation
What are the screening tests, and what are the diagnostic tests for genetics in the prenatal period?
screening: cfDNA, first trimester screening, quad screening, SMA, cystic fibrosis testing
diagnostic: chorionic villi sampling and a genetic amniocentesis
What is cfDNA (NIPT) testing?
Non-invasive prenatal testing: genetic test using fetal cells in maternal circulation. Can be done as early as 10 weeks.
What is done during first trimester screening (between 11 and 14 weeks)?
• blood to measure PAPP-A and hCG
• ultrasound to measure the nuchal translucency
• trisomy 13, 18, 21
What are common second trimester screenings?
• quad screening: AFP, estriol, hCG, inhibin-A
• Trisomy 18, 21, and neural tube defects
When is the anatomy screen ultrasound done in during prenatal care?
20 weeks
When do glucose screenings and syphilis testing occur during the prenatal period?
Around 28 weeks
When is Group B strep testing done in a pregnant person?
36 weeks
What are the three stages of labor?
1.) begins with the onset of regular contractions and lasts until the cervix is completely dilated
2.) begins with complete dilation and ends with the delivery of the baby
3.) delivery of placenta and inspection/repair of the vagina, cervix, and perineum
Cervical examination: what is dilation?
The degree of potency, expressed in centimeters, of the internal os of the cervix
Cervical examination: what is effacement?
A process by which the cervix is drawn intra-abdominally by the uterine corpus, resulting in shortening and thinning of the intravaginal portion of the cervix. It is expressed in percentages or centimeters of cervical length
What are the cardinal movements of labor?
The mechanisms of labor that allow the baby to adapt to the pelvis during the second stage of labor: descent, flexion, internal rotation, extension, external rotation, expulsion
What are some common fetal presentations?
• Vertex presentation is normal
• face, brow, breach, shoulder are not normal
How are the 4 degrees of perineal lacerations classified?
First-degree: involving the mucosa/skin
Second-degree: extending into the submucosal tissues (most common)
Third-degree: involving the anal sphincter
Fourth- degree: involving the rectal mucosa
What is the most common indication for a C-section?
Dystocia: wrong presentation or the baby doesn’t fit
What is epigenetics?
The study of heritable changes in gene expression
Excess weight during pregnancy is associated with what pregnancy/childbirth complications?
• high blood pressure
• Preeclampsia
• preterm birth
• gestational diabetes
• macrosomia
• Birth injury/C-section required
• neural tube defects or other birth defects
Maternal deficiency of folate could result in what?
Neural tube defects of the fetus. Mother should start folate supplementation one month before conception and at least during the first 12 weeks of pregnancy (the neural tube closes by 28 days post conception)
Maternal deficiency of iron could lead to what?
• poor physical growth (low birthweight/premature) neurological development (impaired cognitive/behavioral development), cellular functioning, and synthesis of hormones in the fetus
• anemia in the mother
Maternal deficiency of iodine could result in what?
- adverse effects of the infant brain: spectrum of low IQ to severe mental delay (cretinism)
- hypothyroidism
Maternal deficiency of calcium/vitamin D could result in what?
- poor development of fetal bones and teeth (rickets)
- vitamin D is also important for reduction of inflammation, modulation of cell growth, neuromuscular/immune function, and glucose metabolism of the infant
Maternal deficiency of omega-3 fatty acids result in what?
• poor fetal brain and retina development
• neurodevelopmental delay
What are some man-made toxins to avoid during pregnancy?
• PFAS
• DES
• pthalates
• EDCs including plastics
Infants who are breast-fed have a reduced risk of what?
• asthma/severe lower respiratory disease
• obesity/type one diabetes
• acute otitis media
• SIDS
• gastrointestinal infections
• (preterm) necrotizing enterocolitis
Mothers who breast-feed have a lower risk of what?
• high blood pressure
• type two diabetes
• ovarian cancer
• breast cancer
What is infertility?
The inability to get saved after 12 months of regular intercourse without using contraception in women less than 35, or after six months and a woman older than 35
What tests are used as an assessment of ovarian reserve?
Day three FSH, estradiol, AMH
What are the indications for an operative vaginal delivery?
Maternal exhaustion, inability to push effectively, maternal cardiac disease, non-reassuring fetal heart tracing
Why is cephalohematoma of the newborn a complication of operative delivery?
Prolonged application of the vacuum
What are the most common indications for a C-section in the United States?
• failure to progress
• non-reassuring FHTs
• malpresentation
• cord prolapse
What pregnancies must be assumed to be ectopic until proven otherwise?
Post sterilization (salpingectomy)
What are the three approaches to treatment of ectopic pregnancy?
- Hemodynamically stable patient: methotrexate
- Surgery (salpingectomy, or salpingostomy)
- Expectant Management (absorbed miscarriage)
What is considered a threatened abortion?
First trimester bleeding
When is RhoGAM (anti-D immunoglobulin) given in pregnancy?
• in the third trimester to prevent the formation of antibodies
• given after the baby is born if the baby is Rh positive, and mom is Rh negative
What is the definition of primary amenorrhea?
No spontaneous uterine bleeding by age 15 in the presence of normal sex characteristics, or by the age of 13 in the absence of any secondary sexual characteristics
What is the definition of secondary amenorrhea?
The absence of menstrual bleeding for >3 months in women with previously normal menses, or >6 months in women with irregular menses
What are the causes of amenorrhea due to disorders of outflow tract?
- Imperforate hymen
- Transverse vaginal septum
- Mullerian agenesis
- Androgen insensitivity syndrome
- Asherman’s syndrome (intrauterine scars/tissue adhesions due to trauma/surgery)
What are the causes of amenorrhea due to disorders of the ovary?
- Turner syndrome (45, XO)
- 46XX gonadal dysgenesis
- 46XY gonadal dysgenesis
- PCOS
- 17 Alpha hydroxylase deficiency
What are the causes of amenorrhea due to disorders of the anterior pituitary?
- Hyperprolactinemia (prolactinoma)
- Sellar masses: cyst, meningioma
- Sheehan syndrome: necrosis of pituitary postpartum
- Damage to pituitary: radiation, hemochromatosis, sarcoidosis
- Thyroid disease
What is functional hypothalamic amenorrhea?
Abnormal GnRH secretion causing a decrease in LH surges, no follicular development, and low estradiol. Typically seen from eating disorders, exercise, and stressO
What is an isolated GnRH deficiency, also known as idiopathic hypogonadotropic hypogonadism?
Kallman Syndrome: genetic
What are common systemic illnesses resulting in amenorrhea due to decreased GnRH secretion?
Celiac, type one diabetes, IBS, juvenile rheumatoid arthritis, syphilis, tuberculosis
Evaluation of primary amenorrhea flow chart
What is oligomenorrhea?
Menses at intervals greater than 35 days
What’s the difference between intermenstrual and midcycle spotting bleeding?
Intermenstrual: bleeding between regular periods
Midcycle spotting: just prior to ovulation, from declining estrogen
PALM-COEIN system of abnormal uterine bleeding:
PALM indicates structural causes, COEIN indicates non-structural causes
P-polyp
A- adenomyosis
L- leiomyoma/fibroid
M- malignancy and hyperplasia
C- coagulopathy
O- ovulatory dysfunction
E- endometrial (hyperplasia/carcinoma/sarcoma/infection/inflammatory/PID)
I- iatrogenic (meds)
N- not yet classified
What medications can lead to ovulatory dysfunction unintentionally?
Steroids, thyroid hormones, hormones, anticoagulants, SSRI, herbs such as ginkgo, ginseng, soy, IUDs
What is the Rotterdam criteria for diagnosis of PCOS?
Need two of three:
1. Oligo-ovulation or anovulation
2. Clinical or lab evidence of hyperandrogenism
3. Positive ultrasound for polycystic ovaries
What is the American embryological society (AES) criteria for the diagnosis of PCOS?
Need all three:
1. Clinical or lab evidence of hyperandrogenism
2. Oligo-ovulation or anovulation and/or ultrasound changes
3. Exclusion of other androgen excess of ovulatory disorders
What is the treatment of acute, heavy bleeding from the vagina leading to a hemodynamically unstable patient?
• high dose IV estrogen to help regrow the endometrium
• IV fluids
• blood products
• consider D&C
• follow with progesterone withdrawal bleed
What is the medical management of a patient who is hemodynamically stable, but has acute heavy bleeding from the vagina?
• oral contraceptives
• NSAIDs
• anti-fibrinolytics
• GnRH agonist
What are common treatments for long-term, prolonged, heavy menstrual bleeding?
- Mirena IUD (progesterone only)
- Endometrial ablation
- Hysterectomy
If you have a woman patient with right or left lower quadrant abdominal pain, what is the first evaluation that should be done?
• Beta hCG and a transvaginal ultrasound to evaluate pregnancy, complications of pregnancy, and/or reproductive tract pathology
Explain the serum hCG levels of a pregnant patient:
The hCG doubles every 29 to 53 hours during the first 30 days after implantation of a viable IUP. Slower rise indicates abnormal pregnancy
What are the most prevalent and penetrant breast cancer genetic mutations?
BRCA1, BRCA2
What is the three step process of BRCA mutation leading to cancer?
- Inheritance of genetuc mutation in BRCA1 or BRCA2 in one allele
- Increased somatic mutations because BRCA1 and BRCA2 are DNA repair proteins
- By random chance this process often causes somatic genetic alteration in the second allele of the BRCA gene, extreme genetic alterations can lead to cancer
BRCA1 is often inactivated how?
sporadic tumors by epigenetic mechanism: promoter methylation
What do BRCA1 and BRCA2 do in the body?
They are essential components of homologous recombination arm of DNA repair machinery
~ BRCA1 is required for differentiation, at the luminal progenitor site
What kind of tumors are created by BRCA1 mutations?
• progenitor luminal cells accumulate
• basal-like sporadic tumors
• often triple negative
BRCA mutations leading to inactivation of DNA repair creates what new drug targets for breast cancers?
1. PARP inhibitors (olaparib)
2. Immune checkpoint blockade therapy (PD 1/PD 1L inhibition- Pembrolizumab)
What is PARP?
Poly (ADP-ribose) polymerase: recognizes DNA breaks, adds an ADP ribose unit to the site of breaks allowing for recruitment of repair factors
What are the two most prevalent types of sporadic breast cancer, and what are their signaling pathways?
- Estrogen receptor alpha positive (estrogen/ER alpha)
- HER2 overexpression (EGF/EGFR family)
What controls proliferation of normal luminal cells of the breast tissue indirectly?
Extracellular estrogen via:
• estrogen binding ER alpha receptor
• ER alpha promotes transcription of secreted growth factors (amphiregulin)
• growth factors act on nearby cells (paracrine) to promote proliferation
How do tumor cells regulate growth?
Directly via estrogen promoting transcription of cell cell cycle regulators such as cyclin D1, and cells expressing ER undergo proliferation
How does ER promote transcription of a different set of genes in patients with breast cancer?
Overexpression of FOXA1, where chromatin becomes tonically open, allowing for ER to bind and promote cyclin D1 (a key regulator of the G1/S transition in the cell cycle)
What is tamoxifen?
• an ER antagonist cancer therapy used in breast cancer
• synthetic estrogen molecule, binds ER receptor and inhibits it/encourages interaction with co-prepressors and not coactivators
What are aromatase inhibitors and why are they used in breast cancer?
• block synthesis of estrogen in non-ovarian tissues (adipose, adrenal) in order to remove estrogen from the equation
• in pre-menopausal women, GnRH depression (leuprolide) is required to inhibit estrogen from the ovaries
What is the HER2/ERBB2/Neu overexpression breast cancer?
• HER2 is a member of the EGFR family (receptor tyrosine kinase) —> when activated, they initiate signaling pathways that promote proliferation and survival
Why is overexpression of ERBB2/HER2 oncogenic?
- the ERBB2/HER2 dimerization domain is constitutively open
- it does not require ligand binding for activation and dimerization and therefore the cell cycle can proceed independently of external growth factors
What are the drugs at target ERBB2/HER2?
1. Trastuzumab monoclonal antibody: binds at extracellular domain of ERBB2
2. Lapatinib: small molecule inhibitor binds and blocks kindness active site (therefore EGFR/ERBB2 heterodimer activity)
When is chemotherapy used in breast cancer?
• ER positive, estrogen dependent only
• premenopausal: SERMs- tamoxifen
• postmenopausal: SERMs + aromatase inhibitors
When is an aromatase inhibitor used in breast cancer (letrozole/anastraxole/exemestane)?
Post menopausal women. You cannot use in pre-menopausal women unless combined with ovarian suppression such as GnRH agonist (continuous)
What is a PI3K inhibitor drug used in breast cancer?
Alpelisib
How is male breast cancer treated?
• identical to female breast cancer:
- Tamoxifen
- Chemotherapy if needed (doxirubicin, cyclophosphamide, paclitaxel)
- aromatase inhibitor, + GnRH agonist
If a patient possesses a deleterious BRCA mutation, what drug is available for the treatment of breast cancer?
PARP inhibitor (olaparib)
The GAIL model of risk measurement and breast cancer can NOT be used in what patients?
• women with prior breast cancer
• women age < 35
• women with history of chest irradiation
• women possessing BRCA gene mutations
• men
What are the absolute contract indications to breast-feeding?
• maternal HIV or human T cell lymphotrophic virus
• infant with galactosemia
• mother using street drugs such as meth, cocaine, or PCP (not including MAT/MOUD pts)
• mother with confirmed/suspected Ebola virus
What are the contraindications to breast-feeding calling for a temporary cessation?
• untreated brucellosis
• mother is taking certain medication/DI with radiopharmaceuticals
• mother has active Herpes simplex virus infection with lesions on breast
• active tuberculosis or varicella at delivery (expressed milk is OK)
What is lactogenesis 1?
• Secretory differentiation occurring during pregnancy
• first trimester: estrogen and progesterone cause lobular proliferation and ductal growth
• second trimester: alveoli multiply and nipple/areolar changes due to human placenta lactogen (HPL) and prolactin
• third trimester: final stage of mammary growth and development due to progesterone
What is lactogenesis 2?
• Secretory activation in days 3-8 postpartum find as the onset of copious milk production/milk coming in
• under neuroendocrine control
• progesterone levels drop after delivery
• prolactin increases due to nipple stimulation
• oxytocin is released by infant cues/stimulation
• cortisol decreases (can be inhibitory of milk production if High)
What is lactogenesis 3?
- galactopoesis: day 9 and onward, maintenance of established milk supply
- supplied by control and demand: feedback inhibitor of lactation, increase release with prolactin
What are the common bacterial causes of mastitis, and what is the treatment?
Causes: staph aureus, strep group A or B, e. Coli, coag negative negative staph
Tx: dicloxacillin, cephalosporin (cephalexin, first gen), or clindamycin for allergic reactions to penicillin
What are the treatment options for MRSA mastitis?
• Trimethoprim Sulfamethoxazole (TMP-SMX)
• vancomycin
Explain causes, diagnosis, and treatment of breast abscesses
• risk factor: delayed or in adequate treatment of mastitis, commonly MRSA
• diagnosis: ultrasound, microbio
• Tx: drainage and antibiotics (serial breast aspirations)
What drug gets into breastmilk 100%?
Alcohol: milk alcohol levels are equal to blood alcohol levels.
~ advisory: waiting two hours for every 8 ounces of wine/2 beers to resume breast-feeding
What are the differences in appearance of acute mastitis with staph vs strep?
Staph: may form abscesses
Strep: more diffuse cellulitis spread
Both: neutrophilic inflammation in the breast duct, usually in the first month of breast-feeding. Treated antibiotic, surgical draining occasionally needed
What is duct ectasia?
• palpable periaerolar mass often associated with thick whitish secretions and skin retraction
• presents in the 5th to 6th decade in multiparous women
• rupture results in chronic inflammation (lymphocytes, macrophages, plasma cells) and granulomatous reaction
What is lymphocytic mastopathy (sclerosing lymphocytic lobulitis)?
• single or multiple hard palpable masses or mammographic densities due to fibrosis (keloid like)
• atrophic ducts and lobules with thick basement membranes and prominent lymphocytic infiltrate
• most common with type one diabetes or autoimmune thyroid disease
What characteristics make breast fat necrosis mimic cancer?
- painless palpable mass
- skin thickening or retraction
- mammographic density
- calcifications
What is the morphology of breast fat necrosis?
- acute hemorrhage and liquefactive necrosis with PMN (neutrophil) and macrophages
- fibroblasts and chronic inflammatory cells
- giant cells, calcifications, hemosiderin
What are the complications of silicone implants in the breast?
• capsular contraction producing distortion
• leakage causing foreign body reaction, infection, hematoma
• breast implant associated anaplastic large cell lymphoma (rare)
Breast benign epithelial lesions that are fibrocystic and nonproliferative commonly have what type of metaplasia?
Apocrine
What is ductal hyperplasia without atypia of the breast?
- increase number of luminal and myoepithelial cells fill and distend the lumen of a duct or lobule
What is sclerosing adenosis of the breast?
• increase number of acini in the lobule causing compression and distortion
• fibrosis creating infiltrative appearing nests and cords of cells mimicking carcinoma
• IHC reveals presence of myoepithelium
What is a papilloma of the breast?
• proliferative, without atypic hyperplasia and multiple branching fibrovascular cores covered by benign epithelium with a dilated duct
• 80% have nipple discharge
• may have atypical papilloma or DCS association
What is a complex sclerosing lesion of the breast?
- sclerosing adenosis, papillomas, and epithelial hyperplasia with a radial scar
- myoepithelial layer present on immunoperoxidase
What is atypical ductal hyperplasia of the breast?
• monomorphic cell population expanding in the duct resembling DCIS
• cribiform-like spaces, partial filling of involved duct
What is atypical lobular hyperplasia of the breast?
- lesion with cells identical to LCIS (lobular carcinoma in situ)
- Fill and distends less than 50% of the acini within a lobule
- loss of E-cadherin
What are the intralobular stroma tumors?
• fibroadenoma: benign
• Phyllodes tumor: malignant
What are the interlobar stromal tumors?
• lipoma
• myofibroblastoma
• fibromatosis
• hemangioma
• angiosarcoma
• rhabdomyosarcoma
• liposarcoma
What is a fibroadenoma?
• most common benign tumor of the breast peeking between ages 20-30
• palpable mass or mammographic nodule that is well circumscribed and rubbery
• estrogen responsive: changes size with pregnancy and age
What is a phyllodes tumor?
• malignant tumor of the sixth decade consisting of stromal overgrowth and leaf-like features
• high cellularity, mitotic rate, and pleomorphism
• hematogenous spread in 1/3 of high-grade cases
What does a phyllodes breast tumor look like under the microscope?
Low grade: left
High grade: right
What benign lesions contain calcifications that can be seen on mammography?
- Apocrine cysts
- Hyalinized fibroadenomas
- Sclerosing adenosis
How do malignancy associated calcifications look on mammogram?
- Small, irregular, numerous, clustered, pleomorphic
- Associated stellate density
- Ductal pattern (DCIS): linear calcifications
95% of breast malignancy is what type of tumor?
Adenocarcinoma arising from the terminal duct lobular unit (TDLU): either ductal or lobular
What is ductal carcinoma in situ?
- malignant clonal proliferation of epithelial cells limited to ducts by the basement membrane
- myoepithelial cells are present in ducts and lobules as well as intact basement membrane
- two subtypes: comedo with necrosis and non-comedo without
What are the subtypes of DCIS?
• Comedo
• cribiform
• micropapillary
What is breast DCIS Paget disease of the nipple?
• rare manifestation of breast cancer leading to unilateral erythematous eruption involving the nipple with a scaly crust. Pruritus is common
• Typically poorly differentiated, ER- , HER2+
• mucicarmine stain and CEA/CK7 highlight the Paget cells
What is lobular carcinoma in situ of the breast?
LCIS is a clonal proliferation of cells within ducts and lobules that grow in a dyscohesive fashion, usually due to an acquired loss of the tumor suppressive adhesion protein: E-cadherin
What do the cells of breast LCIS look like?
• rounded discohesive shape due to lack of e-cadherin, CDH1
• mucin positive signet ring cells are common
• typically ER+, PR+, HER2-
What is invasive mucinous (colloid) carcinoma?
• soft, gelatinous mass that is often well circumscribed
• island of tumor cells in pools of mucin
• usually ER+, HER2-
What does invasive tubular carcinoma look like?
• well formed tubules around a central scar and characteristic teardrop or tadpole shapes
• apocrine snouts on the luminal side
• low-grade DCIS often present
• No myoepithelial present— differentiates from noninvasive radial scar)
• always Nottingham grade 1
What is papillary carcinoma of the breast?
• true papillae with fibrovascular cores
• columnar cells= low-grade
• intracystic and non-invasive or invasive
What is invasive apocrine carcinoma?
• abundant pink granular cytoplasm, vesicular chromatin with prominent nucleolus cells that resemble those lining cutaneous apocrine glands/apocrine metaplasia seen in FCC
• often HER2+
What are the features of invasive micropapillary carcinoma of the breast?
• no fibrovascular core
• hollow balls of cells with peripheral space
• mimic papillae
• common lymphatic invasion
• often HER2+
What are the features of invasive medullary carcinoma of the breast?
• pushing border, no desmoplasia
• syncytial cell growth with lymphoid infiltrates
• pleomorphic/prominent nuclei
• minimal or absent DCIS
• common pattern in BRCA tumors
• often ER- and HER2-
• medullary carcinoma features
Breast cancer and men is typically associated with what?
• Klinefelter’s syndrome (XXY)
• BRCA2 mutations
• ER+
• ductal (NST)
How does rubella virus impact pregnancy?
• congenital rubella syndrome: deafness, cardiac anomalies, cataracts, mental retardation
• vaccination cannot be given in pregnancy due to live attenuation
How does cytomegalovirus or CMV impact pregnancy?
• congenital CMV: hearing loss is common, potential growth restriction
What is the discriminatory zone of hCG levels?
> 2000, or >3500 at some clinics. This indicates at approximately what hCG level a gestational sac should be able to be seen on imaging
