Test 1 Flashcards
WT-1
Wilms tumor related gene
Expressed in the developing genital ridge, kidney, and gonads
Deletions/mutations a/w gonadal dysgenesis and predilection for Wilms tumor and nephropathy
Wilms tumor
Most common renal malignancy of early childhood (ages 2-4)
Contains embryonic glomerular structures
P/w large, palpable unilateral flank mass and/or hematuria
Loss of function mutations of tumor suppressor genes WT1 or WT2 on Chr 11
SF-1
Steroidogenic factor
Regulates genes involved in gonadal & adrenal development, steroidogenesis, and reproduction –> HELPS MAKE THE TESTES
SF-1 deletions can cause gonadal dysgenesis, adrenal failure, and persistent Müllerian structures
SOX-9
Target of SRY
With SF-1, elevates levels of anti-Mullerian hormone
Deletions or mutations –> severe skeletal dysplasia; gonadal dysgenesis in 75%
WNT-4
Inhibits SOX-9 = anti-testes
β-catenin
In females
- directly binds transcription factors
- regulated by Wnt
- regulates the formation of different body regions during development
Double DAX-1
On the X Chr. If there’s just one gene (XY karyotype), doesn’t do anything. If 2 (= XX), inhibits SRY activation of SOX9.
What hormones are being produced in a male fetus at 8 weeks, and by what cells?
Testosterone, by the Leydig cells
AMH, by the Sertoli cells
What do the Mullerian ducts become?
Fallopian tubes, midline uterus, & upper portion of the vagina
What do the Wolffian ducts become?
Epididymis, vas deferens, & seminal vesicles
Hypospadias indicate lack of what hormone?
Testosterone & particularly DHT - you need normal amounts to form the penile urethra
What stimulates Leydig cell production of testosterone during gestation?
1st trimester: hCG (acts like LH)
Rest: hypothalamic-pituitary-gonadal axis - baby’s own LH stimulates Leydig cells
What happens with exposure of female infants to androgen before 13 weeks gestation? After 13 weeks?
Before 13 weeks: can get urogenital sinus, vagina attached to urethra & without separate opening
After 13 weeks: only clitoromegaly
21-hydroxylase deficiency - clinical features
CAH, leads to virilization of females
Get hyperpigmentation, hyponatremia/hyperkalemia (can be life-threatening in first 2-3 weeks of life)
Uterine didelphys
Failure of fusion of ducts
Defects at level of vagina = longitudinal vaginal septum, which may or may not be obstructive.
Failure of fusion at level of cervix = two uterine horns (didelpys) and two cervices.
Failure of fusion above cervix = two uterine horns (didelpys).
Fetal survival >55%
Unicornuate uterus
Unilateral elongation of duct
Renal agenesis on the same side as the missing duct occurs in about 40% of
cases.
Probably because of poor vascularity, reproductive potential is poor with a
spontaneous abortion rate of about 50%.
What structures form the vagina?
Upper 2/3: Mullerian ducts
Lower 1/3: urogenital sinus
Failure of fusion: transverse vaginal septum
What’s another name for Mullerian ducts?
Paramesonephric ducts
What is a rudimentary horn?
Partial ductal elongation defect - thus, a rudimentary horn is on one side of the uterus. Defined by whether they contain endometrial tissue & whether they communicate w/ uterus or not
Cavitary rudimentary horn
Defined by the presence of functional endometrial tissue. Pregnancies can implant in this tissue, and if they do not communicate with the rest of the uterus, catastrophic results can ensue (rupture, maternal death). They should thus be surgically removed.
Bicornuate uterus
A uterus composed of two horns separated by a septum (“heart-shaped”)
Communicating endometrial cavities
Fetal survival 60%
Sertoli cells produce what hormone?
Estrogen
What are the four phases of spermiogenesis?
- Golgi phase
- Cap phase
- Acrosomal phase
- Maturational phase
Golgi phase
First stage of spermiogenesis
Large acrosomal vesicles are created by the Golgi apparatus.
Cap phase
Second stage of spermiogenesis
Acrosomal vesicles migrate to one pole of the cell; centrioles to the opposite end of the cell. Acrosomal vesicles become the acrosomal cap of the sperm.
What type of embryonal carcinoma is most common?
Mixed (85%)
What are markers for embryonal carcinoma?
PLAP (placental-like alk phos), placental lactogen, hCG
What composes 40% of testis tumors in infants?
Teratoma
With a teratoma in men, which is worse - mature or immature?
Immature
The more immature it is, the more likely to progress to metastasis
What composes 80% of testicular tumors in children?
Yolk sac tumor
Pure variety common in children
What is the marker for a yolk sac tumor?
AFP
Schiller-Duval bodies
Seen in yolk sac tumors
Glomeruloid structure with central blood vessel surrounded by neoplastic cells
What is the marker for a choriocarcinoma?
hCG
What is the most common testicular cancer in men >60 yo?
Lymphoma
Bowen’s Disease
Carcinoma in situ (SCC) of penile shaft
Presents as leukoplakia
Erythroplasia of Queyrat
Carcinoma in situ (SCC) of glans of penis - specifically, the mucosa of uncircumcised males
Presents as erythroplakia
Kallman’s is due to what genetic mutation?
KAL1
What do undetectable levels of LH & FSH, and low levels of T, tell you?
Supplements
What do narcotics do to hormone levels?
They wipe out the GnRH pulse –> low T
What is the most common cause in CO of low T? Why?
Undiagnosed OSA
At night, O2 levels drop —> cortisol levels go up + catecholamines go up —> cause central weight gain, insulin resistance, dec. NO in penis, slight impairment in GnRH pulse generator
* T worsens undiagnosed OSA!!!!! **
Lymphocytic hypophysitis
AI destruction of the pituitary gland
Can be caused by IPI, a melanoma chemotx
What does a high FSH:LH ratio in a post-pubertal man indicate?
Indicates loss of inhibin / Sertoli cell dysfunction
What are the hormone levels in hypergonadotrophic hypogonadism?
High GnRH, FSH +/- LH
Low T
What is the zona pellucida? When does it appear?
A glycoprotein coat that occurs during the primary follicle stage
Facilitates sperm attachment to and entry of the oocyte
What is the corona radiata? When does it appear?
Corona radiata = internal halo of granulosa cells, surrounded by antral fluid
Appears during the Graafian follicle (antral) stage
Cumulus oophorus
The stalk that attaches the oocyte + corona radiata to the remaining granulosa cells through the antral fluid collection
Parakeratosis
Intact nuclei in the keratin layer
Seen in condyloma acuminatum
Extramammary Paget Disease
Specialized form of adenocarcinoma
Marked hyperkeratosis & “pale” basal epidermis
“Pagetoid” pattern of growth: pale nests are malignant cells. Paget cells = large cells in epidermis with clear halo
Lichen sclerosis
Dermal fibrosis (solid pink on top) w/ perivascular monocellular infiltrate
Grossly: white papules/plaques that look like parchment; painful intercourse
Sarcoma botryoides
Rhabdomyosarcoma variant
Affects girls
Embryonal rhabdomyosarcoma
Cambium layer: Dense zone of rhabdomyoblast present beneath the surface epithelium
Small, spindle-shaped cells w/ abundant mitoses
DES-associated clear cell carcinoma
“Barrel-like” cervix
Anterior upper 1/3 of vagina often with discontinuous lesions - “kissing lesion”
Tubulocystic pattern of growth w/ dense hyaline stroma; clear cytoplasm w/ bland nuclei
Metrorrhagia
Irregular periods
Menorrhagia
Heavy or prolonged periods
What is the most common uterine sarcoma, and at what age does it typically appear?
Leiomyosarcoma
40-60 yo
What are the two types of endometrial cancer?
Type I: Endometrioid adenocarcinoma
Type II: Serous (adeno)carcinoma
Type I endometrial cancer
Pre-menopausal
Risk factors: unopposed estrogen, genetics (Lynch Syndrome)
Background hyperplasia; minimal invasion/spread
Generally good prognosis
What are the mutated MMR genes that are implicated in HNPCC/Lynch Syndrome?
MLH1, MSH2
What are the other genes implicated in Type I endometrial cancer?
PTEN, KRAS + MI, b-catenin + PIK3CA
What effect does progesterone have on the endometrial lining?
Thins it
What effect does estrogen have on the endometrial lining?
Stabilizes it = less bleeding
Type II endometrial carcinoma
Post-menopausal
Molecular hallmark: p53 mutations
Aggressive; 10-20% of endometrial Cas
Generally poor prognosis
Serous carcinoma
Type II
Papillary growth; atypia
Disseminated at presentation - even w/out invasion of myometrium, can be in LN
What are the genes that put you at risk for ovarian cancer?
BRCA1 and BRCA2
What is one (not so great) screening test for ovarian cancer?
CA-125
Any woman, with any ovarian tumor (benign or malignant), can have this elevated. Or other causes!
What are the four types of ovarian cancer?
- Surface epithelial cells
- Germ cells
- Sex cord-stroma
- Metastatic from other locations
The origin of most epithelial cell ovarian tumors is now believed to be…?
Fimbriated end of Fallopian tubes
What are the four types of surface-epithelial ovarian tumors?
- Serous
- Mucinous
- Endometrioid
- Clear cell
(Seers Make Everything Clear)
Serous ovarian carcinoma
- Most frequent subtype
- Tubal-type epithelium w/ cilia
- 1+ thin-walled cysts
- HIERARCHICAL BRANCHING
- No stromal invasion
- Psammoma bodies
Clear cell carcinoma
- Tubulocystic growth pattern
- “Hobnail cells”: nuclei bulging into cystic space without apparent cytoplasm
- A/w endometriosis
Immature teratoma
ALWAYS malignant in a woman
Immature neuroepithelium - tightly packed small dark cells w/ lots of mitoses
Grading is based on amount of immature neural tissue (more is worse)
Dysgerminoma
50% of malignant germ cell tumors
Excellent prognosis - highly responsive to chemotx. 10 yr survival >90%
“Squared off” nuclear contour
Adult granulosa cell tumor
3% of primary ovarian tumors
A/w endometrial neoplasia, b/c they make estrogen
Serum marker to monitor recurrence: inhibin
Call-Exner bodies
Granulosa cell tumors
Resembles primitive follicle; central space w/ secretions
Meig’s Syndrome
Fibroma + ascites + hydrothorax
Krukenberg tumor
Metastatic gastric carcinoma to ovaries
Signet ring morphology
What effects does estrogen have on bone? The liver?
Bone: decreases resorption (antagonizes effect of PTH)
Liver: increases levels of SHBG, TBG, transferrin, and fibrinogen. Increases HDL, lowers LDL. Increases coag factors (2, 7, 9, 10) and decreases AT3 (thrombogenic).
Menopausal hormone therapy
Systemic estrogen remains the most effective treatment for vasomotor sx (hot flashes, etc.) and vulvovaginal and urogenital complaints (pruritis, etc.).
Use lowest effective dose and for shortest duration possible. Risk of endometrial cancer is reduced if estrogen given first 1-25 days of month, then a progestin for the last 10-14 days.
Ospemifene
SERM approved for painful sexual intercourse
SERMs (selective estrogen receptor modulators)
Agonist (estrogen-like) activity on bone receptors (increase bone mineral density) and liver receptors (decrease LDL and total cholesterol) but lack agonist activity (growth promotor) in uterine and breast tissue.
However, retain increased risk of thromboembolic d/o via increase in hepatic synthesis of clotting proteins.
Tamoxifen
Treatment and prevention of breast cancer
A/w increased risk of endometrial cancer.
Induces hot flashes
Raloxifene
Approved for prevention of breast cancer. Also approved for prevention and treatment of postmenopausal osteoporosis.
Does not appear to have endometrial agonist effects.
Induces hot flashes
Clomiphene
Blocks negative feedback of estrogen at pituitary –> increases LH/FSH release –> stimulation of ovulation in anovulatory women
Mifepristone
Competitive antagonist of progesterone receptor
Used to terminate early pregnancies (abortion pill)
Misoprostol
Prostaglandin analog
Given 36-72 hours after mifepristone for synergistic effect on endometrium
First gen. progestin
Norethindrone
Potent and well-tolerated. Lower progestin activity, so higher risk of spotting.
2nd gen progestin
Levonorgestrel
Increased progestin activity. Androgenic and anabolic effects. Lessened risk of VTE.
3rd generation progestin
Desogestrel
Lower androgenic activity; higher risk of thrombosis
4th gen progestin
Drospirenone (in Yasmin)
Spironolactone analog w/ similar antimineralocorticoid and antiandrogenic activity –> may result in temporary weight loss (due to aldo ant)
Concerns with increased risk of thromboembolism
