Female Genital Tract

Question 1

Embryology female genital tract

Answer 1

unfused upper portions of the müllerian ducts–> fallopian tubes
fused lower portions of the müllerian ducts –> uterus, cervix, and upper vagina
endometriosis is a müllerian-derived lesion
may occur in the vagina and clinically simulate a neoplasm
urogenital sinus –> lower vagina
mesonephric ducts –> normally regress
Gartner duct cysts: when remnants of the mesonephric ducts persist into adult life as epithelial inclusions adjacent to the ovaries, tubes, and uterus; in the cervix and vagina these rests may be cystic and are termed Gartner duct cysts
coelomic epithelium (mesothelium) –> lining of the female genital tract as well as the ovarian surface
morphologically similar lesions arise in various sites within the female genital tract and the adjacent peritoneal surfaces

Question 2

Chlamydia trachomatis

Answer 2

Pelvic inflammatory disease; serous discharge

Question 3

Neisseria gonorrhea

Answer 3

pelvic inflammatory disease (most serious complication of gonorrhea in women); purulent discharge; gram negative diplococci within neutrophils (PMNs

Question 4

Trichomonas vaginalis

Answer 4

large, flagellated ovoid protozoan; yellow, frothy vaginal discharge; “strawberry cervix

Question 5

Gardnerella vaginalis

Answer 5

gram negative bacillus; main cause of bacterial vaginosis; thin, grey-green malodorous (fishy) vaginal discharge; premature labor

Question 6

Ureaplasma urealyticum, mycoplasma hominis

Answer 6

Pre term deliveries

Question 7

Plasma cell morphology

Answer 7

Nucleus placed off to one side

Clearing around the nucleus

Question 8

HSV

Answer 8

Common and involves the cervix > vagina > vulva
By age 40, 30% of females present with antibodies to type 2
HSV-1 → oropharyngeal infection
HSV-2 → genital mucosa + skin infection

Question 9

HSV presentation

Answer 9

1/3 of newly infected females show painful lesions 3-7 days post-infection with fever, malaise, and tender inguinal lymph nodes
Red papules that progress to vesicles and then to painful coalescent ulcers
Cervical or vaginal lesions present with purulent discharge and pelvic pain
Lesions around the urethra may cause painful urination and urinary retention
ALL MALES are symptomatic

Question 10

Viral characteristics

Answer 10

Herpesvirus family; large linear dsDNA, enveloped, icosahedral, derives envelope from nuclear membrane, contains intranuclear inclusion bodies AKA Cowdry bodies

Question 11

HSV lesion

Answer 11

Herpesvirus family; large linear dsDNA, enveloped, icosahedral, derives envelope from nuclear membrane, contains intranuclear inclusion bodies AKA Cowdry bodies
Lesions
Lesions are red papules that progress to vesicles and the coalesce to ulcers that are easily visible on the vulva, but lesions on the cervix or vagina are associated with purulent discharge and pain
Vesicles & ulcers contain viral particles causing ↑ transmission rate with active infection
Lesions heal spontaneously in 1-3 weeks
Easily visible on vulvar skin and mucosa
Near urethra = painful urination (dysuria

Question 12

Latency HSV

Answer 12

infection remains latent in lumbosacral nervous ganglia
Reactivation due to stress, trauma, UV light, hormonal changes (skin & mucosal lesions)
Immunocompromised → meningitis, hepatitis, pneumonitis
detection of anti-HSV antibodies in the serum is indicative of recurrent/latent infection

Question 13

Morphology HSV

Answer 13

Usually biopsy the ulcer phase
Desquamated epithelium with acute inflammation at the ulcer bed
Multinucleated squamous cells with eosinophilic to basophilic viral inclusions with a “ground glass” appearance (viral cytopathic effect

Question 14

Transmission HSV

Answer 14

Transmitted during active infection
May occur during latent phase due to subclinical viral shedding
↓ risk with condoms and antiviral therapy
Never completely prevented!
Females have higher susceptibility
Previous infection with HSV-1 ↓ risk of infection with HSV-2
HSV-2 infection enhances HIV-1 acquisition and transmission
Vertical transmission (mom to baby) warrants C-section if infection is (1° and) active

Question 15

Diagnosis and complications HSV

Answer 15

Diagnosed clinically
Associated with a high mortality rate (2% US women)
Aspiration of exudate shows viral cytopathic effect after 48-72 hrs, and allows serotyping
Primary, acute infections do not have established antibodies in the serum
antibody (Smith antigen) detection = recurrent/latent infection
Use the Tzanck smear

Question 16

Treatment HSV

Answer 16

There is no treatment, but some antivirals (acyclovir) can shorten the active phase

Question 17

Molluscum contagiosum (poxvirus)

Answer 17

Skin or mucosal poxvirus with 4 subtypes
MCV1: most prevalent
MCV2: most often sexually transmitted
6 week incubation period

Question 18

Viral characteristics molluscum contagiosum

Answer 18

dsDNA , can make its own envelope, has complex morphology, only DNA virus that replicates in the cytoplasm and has own RNA polymerase and everything it needs to replicate outside the nucleus
Guarnieri bodies, or inclusion bodies, which are sites of viral replication in the cytoplasm and a dumbbell shaped core

Question 19

Transmission molluscum contagiosum

Answer 19

Transmission
Children (2-12 years old): spread via direct contact or shared items (towels) and is most common on the trunk, arms & legs. Think of sexual abuse if seen in genitals in kids.
Adults: sexually transmitted and seen on genitals, lower abdomen, buttocks, inner thighs

Question 20

Clincial appearance molluscum contagiosum (poxvirus)

Answer 20

Pearly, dome-shaped papules with a dimpled center
The papules measure 1 to 5 mm in diameter, dimpled umbilicated center, and their central waxy core contains cells with cytoplasmic viral inclusion bodies

Question 21

Diagnosis molluscum contagiosum (poxvirus)

Answer 21

1-5mm papules
Pearly, dome shaped with dimpled/umbilicated center
Central waxy core with cytoplasmic viral inclusions

Question 22

Candida (moniliasis)

Answer 22

Yeast are part of many females’ normal vaginal microflora
Opportunistic yeast infection with disturbance of the microbial ecosystem
increased incidence: DM, antibiotics, pregnancy, burn patients, indwelling catheter, immunosuppression (compromise neutrophils or Th17 cells)
Most common cause of opportunistic mycosis

Question 23

Yeast characteristics

Answer 23

Dimorphic: mold in the heat, yeast in the cold

Forms pseudohyphae and budding yeast at 20˚C and germ tubes

Question 24

Presentation candida

Answer 24

Intense vulvovaginal pruritis, erythema, and swelling
Thick white vulvovaginal discharge “curd-like or cottage cheese-like”
If severe → mucosal ulceration

Question 25

Diagnosis candida

Answer 25

Pseudospores or filamentous fungal hyphae in wet KOH mounts of discharge or on Pap smear Not considered an STI

Question 26

Trichmonas vaginalis

Answer 26

``` Definition and transmission Large, flagellated ovoid protozoan Sexual transmission 4-14 days to develop Most common curable STI ```

Question 27

Presentation trichmonas vaginalis

Answer 27

Yellow, frothy vaginal discharge, vulvovaginal discomfort, dysuria, dyspareunia Fiery red mucosa of the vagina and cervix Marked dilation of cervical mucosal vessels → 'strawberry cervix' (colposcopic appearance

Question 28

Diagnose trichmonas vaginalis

Answer 28

Motile trophozoites in methylene blue wet mount, present with corkscrew motility  

Question 29

Gardnerella vaginalis

Answer 29

Gram -ve bacillus Main cause of vaginitis (Bacterial vaginosis) Found normally in the reproductive tract, but lactobacillus keeps it in check

Question 30

Presentation gardnerella vaginalis

Answer 30

Present with thin, green-gray, malodorous (fishy) discharge | Pregnant patients: may cause premature labor

Question 31

Gardnerella vaginalis diagnosis

Answer 31

Pap smear: superficial, intermediate squamous cells covered by a shaggy coating of coccobacilli (clue cells) Cultures: also contain anaerobic pepto-streptococci and aerobic α-hemolytic streptococci Need to differentiate it from candida and trichomonas by examining a slide to look for clue cells Whiff Test: there is a fishy amine odor when KOH is added to it

Question 32

Ureaplasma urealyticum and mycoplasma hominis

Answer 32

May cause some cases of vaginitis and cervicitis Implicated in chorioamnionitis and premature delivery in pregnant patients Ureaplasma: urease positive Mycoplasma: no cell wall Look for the fried egg appearance

Question 33

Chlamydia trachomatis

Answer 33

Most common STI in the world | One of the main causes of pelvic inflammatory disease

Question 34

Bacterial characteristics chlamydia

Answer 34

Small gram - obligate intracellular bacteria

Question 35

Two forms of chlamydia

Answer 35

Elementary bodyL metabolically inactive, infectious form in endosome Reticulate body: metabolically active form

Question 36

Presentation chlamydia

Answer 36

Usually asymptomatic or presents similar to gonorrhea: primary infection is characterized by a mucopurulent discharge containing a predominance of neutrophils chlamydia == mucopurulent ("pus-sy") gonorrhea == serous, thin, watery Most infections cause cervicitis In some patients it may ascend to the uterus and fallopian tubes → endometritis and salpingitis infection of non-ciliated columnar or cuboidal epithelial cells of mucosal surfaces leads to granulomatous response and damage

Question 37

Diagnose chlamydia

Answer 37

Diagnose with Nucleic Acid Amplification Test (NAAT

Question 38

PID

Answer 38

Infection that begins in the vulva or vagina and spreads upward to involve most of the structures of the female genital system Causes pelvic pain, adnexal tenderness, fever, and vaginal discharge Most infections travel via the lymph or venous systems rather than the mucosal route (except Neisseria gonorrhea

Question 39

Causes PID

Answer 39

Neisseria gonorrhea Chlamydia trachomatis (serotypes D-K) puerperal infections: infections after spontaneous or induced abortions and normal or abnormal deliveries polymicrobial: may be caused by staphylococci, streptococci, coliforms, and Clostridium perfringens PID caused by these microbes tends to show less involvement of the mucosa and the tube lumen, and more inflammation within the deeper tissue layers bacteremia is a more frequent complication of streptococcal or staphylococcal PID than gonococcal

Question 40

Acute complications PID

Answer 40

Peritonitis & bacteremia | Endocarditis, meningitis and suppurative arthritis

Question 41

Chronic sequelae PID

Answer 41

hronic sequelae Infertility, tubal obstruction, ectopic pregnancy, pelvic pain, intestinal obstruction due to adhesion between bowel and pelvic organs Fitz-Hugh Curtis syndrome: rare complication involving liver capsule inflammation leading to the creation of adhesions (especially from Neisseria gonorrhea

Question 42

Lymphogranuloma venereum

Answer 42

From Chlamydia serotypes L1-L3 Prevalent in Africa, Asia, and South America Presents first with a painless ulcer at the site of contact then progresses to swollen lymph nodes leading to genital elephantiasis in late stage Tertiary stage presents with ulcers, fistulas, and genital elephantiasis

Question 43

Trachoma

Answer 43

From chlamydia serotypes A, B, Ba, and C – is the leading cause of preventable infectious blindness Follicular conjunctivitis leading to conjunctival scarring; in-turned eyelashes leading to corneal scarring and blindness

Question 44

Treponema pallidus (syphilis)

Answer 44

Thin spirochete, poorly visible on gram stain but has thin gram (-) envelope Outer membrane has endotoxin-like lipids, axial filaments = endoflagella = periplasmic flagella allows for motility, cannot culture in clinical lab so serodiagnosis Obligate pathogen, but not intracellular

Question 45

Transmission treponema

Answer 45

Sexually or across placenta

Question 46

Pathogenesis treponema

Answer 46

Disease is characterized by endarteritis resulting in lesions; strong tendency to chronicity

Question 47

Diagnosis treponema pallidus (syphilis)

Answer 47

Visualized by immunofluorescence or dark-field microscopy Warthin-Starry stain or steiner silver stain Can also use VDRL or RPR

Question 48

Jarisch-herxheimer reaction

Answer 48

Starts generally during the first 24 hours of antibiotic treatment and presents with increase in temperature, decrease in blood pressure, rigors, and leukopenia

Question 49

Primary stage treponema pallidus

Answer 49

Non-tender chancre (wart); clean, indurated edge; contagious; heals spontaneously 3-6 weeks but progresses because painless and is typically left untreated

Question 50

Secondary stage treponema pallidus

Answer 50

Secondary stage Maculopapular (copper-colored) rash that is diffuse, and includes palms and soles, patchy alopecia; condyloma lata: flat wart like perianal and mucous membrane lesions; highly infectious

Question 51

Latent stage treponema

Answer 51

No symptoms

Question 52

Tertiary syphilis

Answer 52

Gummas or syphilitic granulomas that are soft growths with firm necrotic centers Aortitis and aneurysm of ascending aorta with tree-barking appearance; destroys the vasa vasorum that supplies the aorta with blood CNS inflammation: damage to the posterior column of the spinal cord and ocular defect of Argyll Robertson ("prostitutes") pupils which react to accommodation but has no reaction to light

Question 53

Congenital

Answer 53

Desquamating maculopapular rash and tabes dorsalis Can have Saber-shins or anterior bowing of the tibia; saddle nose; Hutchinson’s notched teeth and Mulberry molars with enamel outgrowths; deafness

Question 54

Treat symphysis

Answer 54

Penicillin G

Question 55

Puerperal infection

Answer 55

Infection after spontaneous or induced abortion and normal or abnormal deliveries Polymicrobial with Staph, Strep, coliforms, Clostridium perfringens

Question 56

Neisseria gonorrhea

Answer 56

Most common cause of PID Inflammatory changes appear 2-7 days after inoculation Involves endocervical mucosa (or Bartholin gland, other vestibular or periurethral glands) Spreads cephalad (ascending infection) to fallopian tubes and tuboovarian region via mucosal surfaces; endometrium is usually spared May become disseminated

Question 57

Characteristics of neisseria gonorrhea

Answer 57

Phagocytosed gram -ve diplococci within neutrophils/PMNs (intracellular) Will have pili on electron microscopy

Question 58

Presentation gonorrhea

Answer 58

Females: Often asymptomatic; scarring of tubal lumen and fimbriae can → infertility or ectopic pregnancy Males: Urethral discharge Can lead to Fitz-Hugh Curtis syndrome

Question 59

Morphology gonorrhea

Answer 59

Marked acute inflammation of involved mucosal surfaces Acute suppurative salpingitis Infection of the fallopian tubes Diffusely infiltrated → epithelial injury & sloughing of plicae Salpingo-oophoritis: exudate leaks from fimbriae of the tubal lumen to cause infection of the ovary Tubo-ovarian abscesses: Collections of pus in the ovary and fallopian tube or in the tubal lumen (pyosalpinx) Chronic salpingitis: Scarring of denuded tubal plicae causing gland-like spaces and blind pouches Hydrosalpinx: due to fusion of fimbriae and the accumulation of tubal secretions and tubal distension

Question 60

Diagnosis gonorrhea

Answer 60

Definitive diagnosis Detection of DNA or RNA Culture or NAATS Thayer-Martin agar

Question 61

Treat gonorrhea

Answer 61

antibiotics Penicillin resistant strains have emerged Tubo-ovarian abscesses may require surgical removal as antibiotics may not penetrate Post abortion/postpartum are much more difficult to control due to broad spectrum of potential pathogens

Question 62

Human papillomavirus presentation

Answer 62

Presentation: | Multiple warty lesions on the perineum and around the anus in low-risk types 6 and 11

Question 63

HPV VIRAL CHARCTERISTICS

Answer 63

ral characteristics Non-enveloped, double-stranded, circular DNA virus with an icosahedral capsid. Composed

Question 64

Transmission HPV

Answer 64

HPV enters the target cells by binding to its cellular receptor. This binding is dependent only on capsid protein L1 and does not require the other capsid protein L2. HPVs are generally internalized via a clathrin-dependent endocytic mechanism. After getting internalized, the viral coat is disassembled which allow viral genomes access to the cellular transcription and replication machinery. The virus infects the stem cells basal keratinocytes of the mucosal (genital) epithelium and delivers the genome to the nucleus. Infected epithelial cells are called koliocytes -- have a krinkled nucleus that looks like a raisin

Question 65

Interaction with the immune sysem HPV

Answer 65

The complete virus cycle takes place above the basal layer and without directly triggering cell lysis, limits the interaction of viral antigens (which do not spill out) with the immune cells of the host that keep an active surveillance for pathogens of the basal membrane. Thus the immune system remains largely unaware of the infection that has taken place in the epithelium Together these events help attain a sort of immune anergy that explains the general lack of local inflammation, the poor immune response to the virus, and the long persistence of HPVs even in healthy immunocompetent individuals

Question 66

High risk HPV

Answer 66

16,18,31,45

Question 67

Oncogenic effect HPV

Answer 67

oncogenic potential of HPV can be explained by the activities of the two viral genes encoding E6 and E7

Question 68

E6

Answer 68

E6 == “Cutting the breaks” E6 protein binds to and mediates the degradation of p53 E6 stimulates the expression of TERT, the catalytic subunit of telomerase contributes to the immortalization of cells E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types

Question 69

E7

Answer 69

E7 == “Foot on the gas pedal” The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through the G- S cell cycle checkpoint It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB promoting progression through the cell cycle. E7 proteins from high-risk HPV types have a higher affinity for RB than E7 proteins from low-risk HPV types E7 inactivates the CDK inhibitors p21 and p27 E7 proteins from high-risk HPVs (types 16, 18, and 31) also bind and activate cyclins E and

Question 70

Listeriosis

Answer 70

Listeria monocytogenes can cause stillbirth, neonatal sepsis, or abortion In infants it can lead to widespread disease (granulomatosis infantiseptica) and exudative meningitis Facultative intracellular bacillus Look for gram +ve intracellular bacilli in the CSF Can also look for the bacillus if there are abscesses with alternating greyish or yellow nodules

Question 71

Haemophilus ducreyi

Answer 71

Acute ulcerative infection that leads to painful chancroid (soft chancre) The chancre is tender and erythematous on the external genitalia (penis, vagina/periurethral area) that erodes over a few days to make an irregular non-indurated painful ulcer. There may be multiple ulcers. Regional lymph nodes are enlarged 1-2 weeks later (buboes) and may lead to ulceration of the overlying skin Especially prevalent in tropical areas in Africa and southeast Asia Cofactor in HIV transmission Coccobacci are sometimes found on silver stain  

Question 72

Klebsiella granulomatous

Answer 72

Can cause granuloma inguinale (donovanosis): raised papular lesion on the moist stratified squamous epithelium of the genitalia or the pharynx/oral mucosa There is eventual ulceration and lots of granulation tissue Active lesions have epithelial hyperplasia at the borders of the ulcer Bacterial characteristics: minute encapsulated coccobacillus Endemic in rural developing countries Untreated cases lead to excessive scarring --> lymphatic obstruction and lymphedema == elephantiasis Look for encapsulated coccobacilli in macrophages (Donovan bodies) on Giemsa stain

Question 73

STI with ulcers

Answer 73

``` STIs with ulcers HSV Syphilis Chancroid (haemophilus ducreyi) LGV lymphogranuloma venereum (Chlamydia trachomatis (L1-3) Klebsiella granulomatis ```

Question 74

Vulva

Answer 74

Many diseases of the skin elsewhere on the body can also affect this area including psoriasis, eczema, allergic dermatitis Prone to superficial infections due to constant exposure to secretions Immunosuppression: vulvitis Contains modified apocrine sweat glands

Question 75

Bartholin cyst

Answer 75

Acute inflammation (adenitis) than can create an abscess Occur at all ages due to obstruction of the duct by an inflammatory process Lined with transitional or squamous epithelium 3-5 cm in diameter Pain + local discomfort Treatment: excised or opened permanently (marsupialization

Question 76

Leukoplakia

Answer 76

descriptive clinical term for opaque, white, plaque-like epithelial thickening that may produce pruritus and scaling May be due to Inflammatory dermatoses (psoriases, chronic dermatitis) Lichen sclerosis and squamous cell hyperplasia Neoplasia: vulvar intraepithelial neoplasia (VIN), Paget disease, and invasive carcinoma

Question 77

Lichen sclerosis

Answer 77

Smooth, white plaques or macules seen on the vulva May enlarge and coalesce → 'porcelain/parchment' surface paper-thin plaque -- very, very thin Occurs at any age, most common in post-menopausal females labia become atrophic and agglutinated & the vaginal orifice constricts when the entire vulva is involved autoimmune likely presence of activated T cells in the subepithelial inflammatory infiltrate increased frequency of autoimmune disorders in affected women

Question 78

Cancer risk lichen sclerosis

Answer 78

Not a premalignant lesion women with symptomatic lichen sclerosis have a slightly increased risk of developing squamous cell carcinoma of the vulva patients have an ↑ incidence of autoimmune disorders

Question 79

Morphology lichen sclerosis

Answer 79

Marked thinning of the epidermis (parchment paper) Degeneration of the basal cells Excessive keratinization (hyperkeratosis) Sclerotic changes of the superficial dermis Activated T cells are seen in the subepithelial inflammatory infiltrate (band-like infiltrate

Question 80

Squamous cell hyperplastic dystrophy or lichen simplex chronicles

Answer 80

Nonspecific condition resulting from rubbing or scratching of the skin to relieve pruritus Presents as leukoplakia; histology reveals acanthosis (thickening of the epidermis) and hyperkeratosis Not considered premalignant sometimes present at the margins of vulvar cancers

Question 81

Morphology squamous cell hyperplasia

Answer 81

Thickening of the epidermis + hyperkeratosis Hyperplastic epithelium may show mitotic activity but lacks cellular atypia Lymphocytic infiltration of the dermis may occur

Question 82

Condyloma acuminata (benign genital wart)-HPV

Answer 82

inition Benign genital warts due to low oncogenic risk HPV (6 & 11) Usually multifocal Involve vulvar, perineal and perianal areas +/- cervix and vagina Not precancerous lesions

Question 83

Morphology condyloma acuminata

Answer 83

Papillary, exophytic, tree-like cores of stroma covered by thickened squamous epithelium (no mucous inside of them) Surface epithelium: viral cytopathic changes (koilocytic atypia) Nuclear enlargement, hyperchromasia, and a cytoplasmic nuclear halo -- nucleus looks like a raisin

Question 84

Condyloma Latium

Answer 84

Condyloma latum: benign raised lesion due to syphilis == treponema pallidum

Question 85

Fibroepithial polyp

Answer 85

al Polyp: skin tag of the vulva similar to other places on the body

Question 86

Vulvar squamous papilloma

Answer 86

Benign exophytic proliferations covered by nonkeratinized squamous epithelium Develop on vulvar surfaces Single or numerous

Question 87

Vulva carcinoma

Answer 87

``` Most common (still uncommon) 2/3 occur in females > 60 years ```

Question 88

Two types of vulvar carcinoma

Answer 88

Basaloid & warty carcinoma related to HPV 16 (younger age, 50’s) Keratinizing SCC not related to HPV (older age

Question 89

Basaloid carcinoma

Answer 89

Exophytic or indurated and ulcerated Small tightly caked basaloid cells Foci of central necrosis

Question 90

Warty carcinoma

Answer 90

Exophytic, papillary architecture Prominent koilocytic atypia

Question 91

Classic vulvar intraepithelial neoplasia (VIN) carcinoma in situ, bowen disease

Answer 91

Precursor lesion to basaloid & warty carcinoma of the vulva Most common in females of reproductive age HPV16 related

Question 92

Increased risk with increased risk of HPV 16

Answer 92

Young age at first intercourse Multiple sexual partners Male partner with multiple sexual partners

Question 93

Presentation VIN

Answer 93

Multi-centric around the vulva | 10-30% also have vaginal or cervical HPV related lesions

Question 94

Progression to carcinoma

Answer 94

Spontaneous regression may occur | More likely to progresses to invasive carcinoma in females > 45 years old or immunocompromised

Question 95

Morphology VIN

Answer 95

Discrete white (hyperkeratotic) or slightly raised, pigmented lesion Epidermal thickening, nuclear atypia, increased mitoses and lack of cellular maturation May progress to invasive carcinoma that are exophytic or indurated with central ulceration histology: nests and cords of small, tightly packed cells that lack maturation and resemble the basal layer of the normal epithelium

Question 96

Keratinizing squamous cell carcinoma

Answer 96

Occurs in older women with long standing lichen sclerosus or squamous cell hyperplasia Not related to HPV infection precursor lesion is differentiated vulvar intraepithelial neoplasia (differentiated VIN, or VIN simplex

Question 97

Differentiated VIN

Answer 97

Pathogenesis Gradual acquisition may be due to acquisition of driver mutations in oncogenes and tumor suppressors ↑ frequency of TP53 mutations May be associated with chronic epithelial irritation (lichen sclerosus or squamous cell hyperplasia

Question 98

Morphology differentiated VIN

Answer 98

phology Marked atypia of the basal layer of the squamous epithelium Normal differentiation of the superficial layers Invasive keratinizing squamous cell carcinomas Nests and tongues of malignant squamous epithelium Prominent central keratin pearls

Question 99

Progression to carcinoma differentiated VIN

Answer 99

Once invasive lesions develop the prognosis and risk of metastases is related to tumor size, depth of invasion and involvement of lymphatic vessels Initially spreads to inguinal, pelvic, iliac and periaortic lymph nodes Can spread lympho-hematogenously to lungs, liver and other organs

Question 100

Prognosis differentiated VIN

Answer 100

Prognosis Lesions < 2cm = 90% 5 year survival after treatment with vulvectomy + ladectomy Larger lesions with involved lymph nodes have worse prognosis

Question 101

30% of vulvar cancers are caused by infection with high-risk HPVs (HPV-16, 18, 31, and 33) develop from an in situ lesion termed classic VIN 70% of vulvar cancers are not related to HPV and develop in a background of lichen sclerosus or squamous cell hyperplasia premalignant lesion == differentiated VIN

Answer 101

Ok

Question 102

Glandular neoplastic lesions

Answer 102

Ok

Question 103

Papillary hidradenoma

Answer 103

Sharply circumscribed nodule Most common on the labia majora or inter-labial folds Tends to ulcerate = clinically confused with carcinoma Morphology histology is identical to intraductal papilloma of the breast Papillary projections covered with two layers of cells Upper layer: columnar secretory cells Deep layer: flattened myoepithelial cells (characteristic of sweat glands and sweat gland tumors

Question 104

Extramammary paget disease

Answer 104

Pruritic, red, crusted, map-like area, usually on the labia majora Not associated with underlying cancer (unlike the counterpart in the breast) Paget disease of the nipple == 100% of patients have underlying ductal breast carcinoma Extramammary Paget Disease == typically not associated with underlying cancer and is confined to the epidermis of vulvar skin

Question 105

Morphology extramammary paget disease

Answer 105

Intraepithelial proliferation of malignant cells Cells are larger than surrounding keratinocytes May be single or in small clusters within the epidermis Express apocrine, eccrine and keratinocyte differentiation Express cytokeratin 7 likely arise from multipotent cells in the mammary-like gland ducts of the vulvar skin Have pale cytoplasm with mucopolysaccharide that stains with PAS, Alcian blue, or mucicarmine stains

Question 106

Extramammary paget disease location of tumor

Answer 106

``` Location of tumor Intraepithelial malignancy Confined to the epidermis of vulvar skin Cells spread laterally within the epidermis and may be present beyond the borders of the visible lesion treatment is wide local excision ```

Question 107

Extramammary paget disease metastasis

Answer 107

Metastasis May remain intraepidermal for years and not invade or metastasize Invasion = poor prognosis

Question 108

Vagina

Answer 108

_________VAGINA Remarkably free from primary disease squamous cell carcinoma is the most serious primary disease In adults, inflammation often affects the vulva and perivulvar structures and spreads to the cervix without significant involvement of the vagina  

Question 109

Developmental anomalies vagina

Answer 109

Septate (double) Vagina due to failure of Müllerian duct fusion and is accompanied by a double uterus (uterus didelphys) Causes Genetic syndromes In utero exposure to DES (diethylstilbestrol) used to prevent threatened abortions (vaginal bleeding during the first 20 weeks) Disturbed epistromal signaling during fetal development

Question 110

Vaginal adenosis

Answer 110

Embryonal epithelium: columnar, endocervical type epithelium Replaced with squamous epithelium ascending from the urogenital sinus small patches of residual glandular epithelium which persists into adult life == vaginal adenosis Red, granular areas that stand out from a normal, pale-pink vaginal mucosa Micro: columnar mucinous epithelium indistinguishable from endocervical epithelium Most common in females exposed to DES in utero Rarely: clear cell carcinoma can arise from DES-related adenosis stopped using DES in the 1980s

Question 111

Gardner duct cyst

Answer 111

Common lesions found along the lateral vaginal walls Derived from Wolffian (mesonephric) duct rests cysts In the proximal vagina are derived from müllerian epithelium 1-2cm fluid filled cysts found in the submucosa

Question 112

Benign vaginal tumors

Answer 112

Occur in females of reproductive age Stromal tumors (stromal polyps) Leiomyomas Hemangiomas

Question 113

Squamous cell carcinoma of the vagina

Answer 113

Virtually all primary carcinomas of the vagina are squamous cell carcinomas associated with high-risk HPVs (16, 18, 31, and 33) ↑ risk: previous carcinoma of the cervix or vulva Arises in 1-2% of females with previous invasive cervical carcinoma premalignant lesion == vaginal intraepithelial neoplasia (VIN) analogous to cervical squamous intraepithelial lesions Most invasive tumors affect the posterior wall of the upper vagina at the junction of the ectocervix Lesions of the upper 1/3 metastasize to iliac lymph nodes Lesions in the lower 2/3 metastasize to inguinal lymph nodes

Question 114

Embryonal rhabdomyosarcoma

Answer 114

Definition Rare tumor of malignant embryonal rhabdomyoblasts Infants and children < 5 years Tumors invade locally and cause death via penetration into the peritoneal cavity or obstruction of the urinary tract

Question 115

Morphology embryonal rhabdomyosarcoma

Answer 115

Cells are small with oval nuclei and cytoplasmic protrusions (tennis racket shape) Striations may be seen in the cytoplasm Tumor cells may be crowded in a cambium layer beneath vaginal epithelium Or the tumor cells can be within an edematous, loose fibromyxomatous stroma in the deep regions with inflammatory cells (often mistaken for inflammatory polyps) Grow as polypoid, rounded, bulky masses Appear as grapelike clusters tend to invade locally and cause death by penetration into the peritoneal cavity or by obstruction of the urinary tract

Question 116

Treatment embryonal rhabdomyosarcoma

Answer 116

Conservative surgery + chemotherapy | Best if diagnosed early

Question 117

Cervix external vaginal portion

Answer 117

External vaginal portion (ectocervix) Visible on vaginal exam Covered with mature squamous epithelium continuous with the vaginal wall that converges at the external os

Question 118

Cervix endocervical canal

Answer 118

Columnar, mucus secreting epithelium that converges at the external os Ectocervix and endocervical come together at the squamocolumnar junction

Question 119

Squamocolumnar junction==transformation zone

Answer 119

Location where squamous and columnar epithelium meet Variable position based on age and hormonal influence Typically moves upward into the endocervical canal with time squamous metaplasia == the replacement of the glandular epithelium by advancing squamous epithelium

Question 120

Transformation zone—this matters

Answer 120

Area of the cervix where the columnar epithelium abuts the squamous epithelium Immature squamous metaplastic epithelial cells in this zone are the most susceptible to HPV infection The unique epithelium of the cervix makes it highly susceptible to HPV infections HPV == leading cause of cervical cancer so this matters MOST susceptible area this is where cervical precursor lesions and cancers will develop

Question 121

Lactobacilli in vagina

Answer 121

Gram +ve non-spore forming bacillus Dominant microbial species of the normal vagina Produces lactic acid --> maintains pH < 4.5 that suppresses growth of other saprophytic and pathogenic organisms At low pH they produce H2O2, which is bacteriotoxic pH becomes alkaline (> 7) due to bleeding, sexual intercourse, antibiotics, or vaginal douching Leads to ↓ H2O2 production by lactobacilli Promotes overgrowth of other microorganisms that can lead to cervicitis or vaginitis Receives nutrients from intracellular glycogen vacuoles of squamous cells which start being shed at puberty

Question 122

Cervicitis or vaginitis

Answer 122

(acute or chronic) May be due to gonococci, chlamydia, mycoplasmas, HSV Important to identify because of associations with upper genital tract disease, pregnancy complications, sexual transmission, and pelvic inflammatory disease (PID) --> Fitz-Hugh-Curtis Syndrome (violin string adhesions) Marked cervical inflammation can cause reparative and reactive changes of the epithelium + shedding of atypical squamous cells → abnormal Pap smear due to infection, not neoplasm -- don't want to do a hysterectomy because of an infection, give antibiotics

Question 123

Endocervical polyps

Answer 123

Common, benign exophytic growths within the endocervical canal Loose, fibromyxomatous stroma covered by mucus secreting endocervical glands +/- inflammation Vary from small, sessile 'bumps' to large, polypoid masses that protrude through the cervical os may be the source of irregular vaginal "spotting" (bleeding) that arouses suspicion for ominous disease

Question 124

Treat endocervical polyps

Answer 124

Curettage or surgical excision=curative

Question 125

Cervical carcinoma

Answer 125

3rd most common cause of cancer in women worldwide Typically progresses slowly, allowing screening, detection and treatment 50% are fatal Significant benefits from early diagnosis & curative treatment Pap smears detects precursor lesions and low-stage, highly curable cancers Strong association with HPV

Question 126

High risk HPV strains

Answer 126

15 high risk HPVs, but HPV-16 accounts for 60% of cervical cancer cases (the most high-risk/prevalent == HPV-16) HPV18 accounts for 10%

Question 127

High risk HPV on cancer

Answer 127

15 high risk HPVs, but HPV-16 accounts for 60% of cervical cancer cases (the most high-risk/prevalent == HPV-16) HPV18 accounts for 10% High Risk HPVs on cancer Most important factor in the development of cervical cancer Also implicated in squamous cell carcinoma at other sites (vagina, vulva, penis, anus, tonsils, oropharynx) HPV is a DNA virus Viral DNA remains extrachromosomal (episomal) Alone, it is not sufficient to cause cervical cancer Progression to carcinoma is influenced by exposure to cocarcinogens and host immune status Cause 80% of LSIL and 100% of HSIL

Question 128

Low risk HPV on cancer

Answer 128

Cause of condyloma acuminata Sexually transmitted infections of the vulvar, perineal and perianal regions E6: Fails to bind p53, but dysregulates growth & survival via the Notch pathway E7: Bind RB with low affinity Viral DNA remains extrachromosomal (episomal

Question 129

HPV infections

Answer 129

V Infections genital HPV infections are extremely common; most of them are asymptomatic, do not cause any tissue changes, and therefore are not detected on Pap test

Question 130

Prognosis HPV infections

Answer 130

50% of HPV infections are cleared within 8 months, and 90% of infections are cleared within 2 years high-risk type infections last longer --> more time to develop a precursor lesion --> increased risk

Question 131

HPV infection

Answer 131

May infect immature basal cells of the squamous epithelium in areas of epithelial breaks or immature metaplastic squamous cells at the squamocolumnar junction Cannot infect mature superficial squamous cells covering the ectocervix, vagina or vulva unless there is damage to the surface epithelium allowing access to immature cells in the basal layer of the epithelium cervix = large area of immature squamous metaplastic epithelium = particularly vulnerable to HPV infection **Infects immature squamous cells **Replicates in mature squamous cells

Question 132

Epithelial susceptibility to HPV increased risk

Answer 132

↑ risk == Cervix and Anus (homosexual men

Question 133

Epithelial susceptibility to HPV decreased risk

Answer 133

↓ risk == Vulva and Penis (barring any epithelial breaks

Question 134

Mature squamous cells and HPV

Answer 134

Cannot be infected by HPV, but are the site of HPV replication Normally arrested in G1 phase of cell cycle -- "senescent" If infected, actively progress through the cell cycle as the virus uses the host cell DNA synthesis machinery to replicate its genome

Question 135

E7

Answer 135

Enhanced cell cycle progression and impaired ability to repair DNA damage due to: viral E7 binds the hypophosphorylated (active) from of RB and promotes its degradation via proteasomes this allows E2F to dissociate and ??? viral E7 binds & inhibiting p21 & p27 (cyclin dependent kinase inhibitors, CKIs

Question 136

E6

Answer 136

net effect: increased proliferation of cells that are prone to acquire additional mutations viral E6 exacerbates the defective DNA repair via binding to p53 (tumor suppressor) and promoting proteasomal degradation of p53 viral E6 upregulates telomerase expression via TERT → cellular immortalization

Question 137

E6 and E7

Answer 137

↑ proliferation of cells that are prone to acquire new mutations that can lead to cancer development Expression is increased via integration into the host genome Oncogenes near viral insertion may be dysregulated These oncogenic proteins inactivate tumor suppressors, activate cyclins, inhibit, apoptosis, and combat cellular senescence E6 and E7 proteins from low-risk HPV types E7: binds to RB with lower affinity E6: does not bind to p53 at all dysregulates growth and survival by interfering with the Notch signaling pathway instead

Question 138

Squamous intraepithelial lesions

Answer 138

Classification | Classified into a two tier system, all are most commonly caused by HPV16

Question 139

Low grade squamous intraepithelial lesion

Answer 139

Previously CIN I (mild cervical intraepithelial neoplasia) | 80% of LSILs are associated with high-risk HPV types

Question 140

High grade squamous intraepithelial lesion

Answer 140

Previously CIN II (moderate dysplasia), CIN III (severe dysplasia) & CIS (carcinoma in situ) 100% of HSILs are associated with high risk HPV types

Question 141

LSIL

Answer 141

Associated with a productive HPV infection High level of viral replication only mild alteration in growth of host cells Does NOT progress directly to invasive carcinoma Most (60%) regress spontaneously, small portion (10%) → HSIL Not treated as a premalignant lesion 10x more common than HSIL

Question 142

HSIL

Answer 142

progressive deregulation of the cell cycle by HPV --> increased cellular proliferation decreased/arrested epithelial maturation lower rate of viral replication derangement of the cell cycle in HSIL may become irreversible and lead to a fully transformed malignant phenotype 80% of HSILs develop from LSILs; 20% of HSILs develop de novo all HSILs are considered to be at high risk for progression to carcinoma

Question 143

Diagnose SIL

Answer 143

Diagnosed based on identification of nuclear atypia with: Nuclear enlargement Hyperchromasia (dark staining) Coarse chromatin granules Variation in nuclear size & shape May be accompanied with cytoplasmic 'halos' Halos: perinuclear vacuoles due to E5 protein localization to the endoplasmic reticulum= koilocytic atypia

Question 144

AIDS in diagnosis SIL

Answer 144

Highest viral loads in upper ½ of the epithelium Ki-67 (marker of actively dividing cells) usually restricted to basal layer viral E6 and E7 prevent cell cycle arrest --> Ki-67 seen in upper levels (where it shouldn't be) Overexpression of p16 (increased CDK4) [cyclin dependent kinase inhibitor] "Both Ki-67 and p16 staining are highly correlated with HPV infection and are useful for confirmation of the diagnosis in equivocal cases of SIL

Question 145

Grading SIL

Answer 145

Grading Based on expansion of immature cell layer from its normal, basal location Confined to lower 1/3 = LSIL Expansion into upper 2/3 = HSIL

Question 146

LSIL

Answer 146

60% regress 30% persist 10% progress to HSIL

Question 147

HSIL

Answer 147

30% regress 60% persist 10% progress to carcinoma within 2-10 years Most develop from LSIL, though 20% develop de novo

Question 148

Cervical carcinoma

Answer 148

Average Age: 45 years due to high risk HPVs (16, 18, 31, 33, and 45) 80% of cervical carcinomas are squamous cell carcinomas 15% of cervical carcinomas are adenocarcinoma (precursor lesion == adenocarcinoma in situ) 5% of cervical carcinomas are adenosquamos or neuroendocrine carcinomas have a shorter progression time than squamous cell carcinoma patients often present with advanced disease and less favorable prognosis

Question 149

Squamous cell carcinoma morphology

Answer 149

Nests and tongues of malignant squamous epithelium Keratinizing or nonkeratinizing Invade the underlying cervical stroma -- makes it a carcinoma (i.e. malignant

Question 150

Adenocarcinoma morphology

Answer 150

Proliferation of glandular epithelium composed of malignant endocervical cells with large, hyperchromatic nuclei and mucin depleted cytoplasm = dark appearance of glands (vs. normal endocervical epithelium

Question 151

Adenosquamous morphology

Answer 151

Adenosquamous Morphology | Intermixed malignant glandular and squamous epithelium

Question 152

Neuroendocrine morphology

Answer 152

Appears similar to small cell carcinoma of the lung but is +ve for high risk HPV (16, 18, 31, 33, and 45) Very poor prognosis

Question 153

Advanced cervical carcinoma morphology

Answer 153

Spreads via direct extension to contiguous tissues Paracervical soft tissue Urinary bladder Ureters (→ hydronephrosis) Rectum Vagina Lymphovascular invasion --> local and distant lymph node metastases (liver, lungs, bone marrow

Question 154

Stage 0

Answer 154

Staged as carcinoma in situ (CIS) = CIN III, HSIL

Question 155

Stage I

Answer 155

I: Carcinoma confined to the cervix I-A: preclinical carcinoma (diagnosed only with microscopy) I-A1: stromal invasion < 3mm deep & < 7mm wide (microinvasive carcinoma) I-A2: 3mm < max stromal invasion < 5mm from the base of the epi; horizontal < 7mm I-B: Confined to the cervix and > stage

Question 156

Stage II

Answer 156

Stage II: Carcinoma extends beyond the cervix but not to the pelvic wall Involves the upper 2/3 of the vagina No involvement of the lower 1/3

Question 157

Stage III

Answer 157

Stage III: Carcinoma is extended beyond the pelvic wall Rectal exam: no cancer free space between the tumor and pelvic wall Involvement of the lower 1/3 of the vagina

Question 158

Stage IV

Answer 158

Stage IV: Carcinoma has extended beyond the true pelvis or involves the mucosa of the bladder or rectum Also includes cancers with metastatic dissemination

Question 159

Treat

Answer 159

Early invasive: cervical cone excision Invasive cancer: hysterectomy + lymph node dissection Advanced cancer: + radiation + chemotherapy

Question 160

Prognosis

Answer 160

patients tend to die from consequences of local tumor invasion (ureteral obstruction, pyelonephritis, uremia) 100% 5 year survival for microinvasive carcinomas < 50% 5 year survival for tumors extending beyond the pelvis 50% are detected in females without regular screenings most patients with advanced cervical cancer die of the consequences of local tumor invasion (e.g. ureteral obstruction, pyelonephritis, and uremia) rather than distant metastases

Question 161

Cytologic cancer screening

Answer 161

Cytologic Cancer Screening Pap Smear: transformation zone is scraped and smeared onto a slide, fixed and stained with Papanicolaou method Significantly ↓ mortality of cervical cancer because most cancers arise from precursor lesions over many years Lesions shed abnormal cells HPV DNA testing (↑ sensitivity, ↓ specificity) can also be added for females < 30 years > 30 not recommended due to ↑ incidence of infection and low specificity of test results

Question 162

Pap smear recommendations

Answer 162

Recommended at age 21 or within 3 years of the onset of sexual activity, then every three years After age 30 Normal cytology, (-) for HPV, every 5 years Normal cytology, (+) for high risk HPV, every 6-12 months

Question 163

Abnormal pap

Answer 163

Follow up should include colposcopic exam of the cervix and vagina to identify the lesion Examine mucosa after application of acetic acid, and abnormal epithelium = white spots Abnormal areas should be biopsied LSIL: followed in conservative fashion can do a local ablation if there is concern about the reliability of patient follow-up HSIL: cervical conization

Question 164

HPV vaccine

Answer 164

Recommended for all girls and boys 11-12 years old, up to age 26 Provide nearly complete protection vs strains 16 & 18 One also provides protection vs 6 & 11 (genital warts) Protects up to 10 years Cervical screenings should still continue as not all strains are protected against Gardasil: 6, 11, 16, 18

Question 165

Myometrium

Answer 165

myometrium == tightly interwoven bundles of smooth muscle that form the wall of the uterus hormonally responsive to oxytocin during parturition

Question 166

Endometrium

Answer 166

endometrium == lining of the internal cavity of the uterus; composed of glands embedded in a cellular stroma hormonally responsive to sex steroid hormones

Question 167

Menses

Answer 167

Beginning of the menstrual cycle this is Day 0 Shedding of the functionalis (superficial portion of the endometrium) Day 15: Corpus luteum involutes if no fertilized egg Progesterone drops → functionalis layer degenerates/sheds Normal stroma breakdown (bleeding into stroma with fibrin, RBCs, and inflammatory cells) Stem cells in basal layer regenerate after menses

Question 168

Proliferative phase

Answer 168

rapid growth of glands & stroma from the basalis (deeper portion of the endometrium) → new functionalis Glands are straight, tubular structures lined with regular, tall, pseudostratified columnar cells Numerous mitotic figures No evidence of mucus secretion or vacuolization Endometrial stroma: actively proliferating spindle cells with scant cytoplasm Phase ceases at ovulation estrogen drives the proliferation of both glands and stroma

Question 169

Ovulation

Answer 169

Endometrial proliferation ceases | Differentiation occurs in response to progesterone produced by the corpus luteum in the ovary

Question 170

Post ovulation

Answer 170

Marked appearance of secretory vacuoles beneath the nuclei in the glandular epithelium Week 3: prominent secretory activity Basal vacuoles move towards apical surface Glands are dilated between days 18-24 due to max secretion Week 4: Tortuous glands with a serrated/sawtooth (secretory phase) appearance accentuated by secretory exhaustion and shrinkage of the glands

Question 171

Secretory phase

Answer 171

Tortuous and serrated or saw toothed Stromal changes during the late secretory phase are important for dating the endometrium Progesterone down regulates the expression of estrogen receptors in the glands and stroma Endometrial proliferation is suppressed promotes the differentiation of the glands and causes functional changes in the stromal cells Early secretory: secretory subnuclear vacuoles (day 16-17) 3rd week of cycle: vacuoles become supranuclear and are most prominent Tortuous and serrated or saw toothed Stromal changes during the Late Secretory Phase are important

Question 172

Day 21-22

Answer 172

Day 21-22: Appearance of prominent spiral arterioles + ↑ in ground substance & edema between stromal cells normal placenta: maternal blood enters the intervillous space through endometrial arteries (spiral arteries) and circulates around the villi to allow gas and nutrient exchange

Question 173

Day 23-24

Answer 173

Day 23-24: Stromal cell hypertrophy, ↑ cytoplasmic eosinophilia (predecidual change), resurgence of stromal mitoses

Question 174

Day 24-28

Answer 174

Days 24-28: Pre-decidual changes occur + a normal, sparse infiltrate of neutrophils + lymphocytes Decidualized cells high in glycogen and lipid

Question 175

Dissolution of corpus luteum

Answer 175

Leads to ↓ progesterone Functionalis degeneration + bleeding into the stroma occurs Stromal breakdown → onset of the next menstrual cycle

Question 176

Estrogen

Answer 176

Estrogen == drives proliferation of glands & stroma during the proliferative phase "Crosstalk" between the cells may occur Hormonal effects on glandular proliferation occur via stromal cells Stromal cells → growth factors (IGF1, epidermal GF) that bind to receptors on epithelial cells

Question 177

Endometrial stem cells

Answer 177

Endometrial Stem Cells Play a central role in the regeneration of endometrium after menses May contribute to the development of ectopic endometrial tissue and endometrial cancer

Question 178

Functional endometrial disorders

Answer 178

Uterine bleeding that lacks an underlying (structural) abnormality Most commonly due to hormonal disturbances Any alteration of the hypothalamic-pituitary-ovarian system can alter release (timing or amount) of hormones

Question 179

Causes of functional endometrial disorders

Answer 179

Most commonly due to hormonal disturbances May also be due to pathologies such as chronic endometritis, endometrial polyps, submucosal leiomyomas, endometrial neoplasms

Question 180

Anovulatory cycle

Answer 180

Most frequent cause of dysfunctional bleeding is anovulation (failure to ovulate) due to subtle hormonal imbalances most common at menarche and perimenopausal periods failure of ovulation --> excessive endometrial stimulation by estrogens that is unopposed by progesterone

Question 181

Causes anovulatory cycle

Answer 181

most commonly due to subtle hormonal imbalances Endocrine disorders: thyroid, adrenal, or pituitary tumors/etiology Ovarian lesions: granulosa cell tumors or polycystic ovaries Generalized metabolic disturbances: obesity, malnutrition or chronic systemic disease

Question 182

Morphology anovulatory phase

Answer 182

repeated anovulation may result in bleeding that may prompt endometrial biopsy (sometimes) Stromal condensation Eosinophilic epithelial metaplasia similar to menstrual epithelium BUT lacks progesterone dependent morphologic features (glandular secretory changes, stromal predecidualization) because the source of progesterone (corpus luteum) does not develop without ovulation Endometrium exhibits pseudostratified glands with scattered mitotic figures

Question 183

Inadequate leutal phase

Answer 183

manifests clinically as infertility and increased bleeding or amenorrhea due to inadequate progesterone production during postovulatory period Secretory endometrium with features lagging behind those expected for the estimated date

Question 184

Inflammatory disorders

Answer 184

Endometrium & myometrium are relatively resistant to infection endocervix forms a barrier to ascending infection Chronic inflammation of the endometrium (not associated with menstrual phase) is of concern

Question 185

Acute endometriosis

Answer 185

Uncommon; limited to bacterial infections that arise after delivery or miscarriage Predisposed by retained products of conception due to group A hemolytic streptoocci, staphylococci, etc. Nonspecific inflammation of the stroma treatment: curettage of fragments and antibiotics (beta-lactams for strep and staph) == curative

Question 186

Chronic endometriosis

Answer 186

Most common form of endometritis Typically caused by an ascending infection (especially chlamydia), sometimes idiopathic if organisms are not detected on culture, proceed with antibiotic therapy to prevent sequelae If you see one plasma cell on biopsy then it is chronic endometritis until proven otherwise diagnosis is made on the identification of plasma cells in the stroma plasma cells not normally seen in the normal endometrium

Question 187

What is chronic endometriosis associated with

Answer 187

PID (mostly chlamydia) Retained gestational tissue, post-partum or post-abortion IUD TB (miliary or from drainage of TB salpingitis) [rare in Western countries] Chlamydia No identified cause (15%)

Question 188

Presentation chronic endometriosis

Answer 188

Abnormal bleeding Pain Discharge Infertility

Question 189

Pelvic TB

Answer 189

Both fallopian tubes are involved Infects the endometrium 50% of the time Rarely infects the cervix, vagina, or vulva If the ovaries are infected, then there is only surface infection Mucosa of the tube may not be involved 1/3 of patients will have had TB somewhere else in the body before

Question 190

Morphology pelvic TB

Answer 190

Multinucleated giant cells Histiocytes Can see the bugs with a Kinyoun or Ziehl-Neelsen acid fast stain

Question 191

Endometriosis

Answer 191

Ectopic endometrial tissue seen outside of the uterus Tissue typically includes stroma + endometrial glands (which may be absent) Causes infertility, dysmenorrhea, and pelvic pain Complications can occur if invasion/spread occurs Most common in females 3-4th decade

Question 192

Locations endometriosis

Answer 192

``` Ovaries Uterine ligaments Rectovaginal septum Cul de sac Pelvic peritoneum Large & small bowel, appendix, Mucosa of cervix, vagina, fallopian tubes Laparotomy scars ```

Question 193

Pathogenesis endometriosis

Answer 193

Regurgitation theory: endometrial tissue implants at ectopic sites via retrograde flow of menstrual endometrium through the fallopian tubes this occurs regularly even in normal women Most likely theory to explain endometriosis; though not perfect

Question 194

Molecular analyses endometriosis

Answer 194

Release of proinflammatory & other factors: VEGF (need blood supply), PGE2, IL1β, TNFα, IL6, IL8, NGF, MCP1, MMPS, TIMP ↑ estrogen production by endometriotic stromal cells (↑ aromatase, which is absent in normal stroma) inhibitors of aromatase are beneficial in the treatment of endometriosis These contribute to invasion and establishment of neurovascular networks + decreased immune clearance = survival of ectopic tissue ↑ responsiveness to estrogen ↓ responsiveness to progesterone

Question 195

Risk of carcinoma from endometriosis

Answer 195

patients have a 3x ↑ risk of ovarian cancer of the endometrioid and clear cell types PTEN, ARID1A mutations Mutations are also found in endometriotic cysts, atypical endometriosis & associated carcinomas

Question 196

Atypical endometriosis morphology

Answer 196

Precursor to endometriosis-related ovarian carcinoma Cytologic atypia of epithelium lining the endometriotic cyst without major architectural changes OR Glandular crowding due to excess epithelial proliferation +/- cytologic atypia → appearance similar to complex atypical endometrial hyperplasia

Question 197

Clincial endometriosis

Answer 197

Active reproductive/childbearing years, 3-4th decade, 6-10% of women affected Severe dysmenorrhea, Dyspareunia, and Pelvic pain due to intrapelvic bleeding & periuterine adhesions Menstrual irregularities Infertility == presenting complaint in 30-40% of patients pain with defecation if rectal wall is involved dysuria if bladder serosa involvement

Question 198

Diagnose endometriosis

Answer 198

``` Diagnosis via presence of endometrial glands and stroma +/- hemosiderin May be obscured by secondary fibrosis Rarely only stroma is identified treatment Aromatase inhibitors or surgical ```

Question 199

Treat endometriosis

Answer 199

Aromatase inhibitors or surgical

Question 200

Adeno Yoshi’s

Answer 200

Related to endometriosis Presence of endometrial tissue within the uterine wall (myometrium) Down growth of endometrial tissue into & between smooth muscle fascicles of the myometrium Occurs in 20% of females (uteri) Irregular nests of endometrial stroma +/- glands Separated from basalis by 2-3mm menometrorrhagia, colicky dysmenorrhea, dyspareunia, pelvic pain (premenstrual) May coexist with endometriosis

Question 201

Endometrial polyps

Answer 201

Exophytic masses of variable sizes that project into the endometrial cavity Single or multiple, sessile polyps Occasionally: large and pedunculated (attached by a stalk) May be asymptomatic or cause abnormal bleeding Seen in reproductive age, peri and postmenopausal females May (rarely) give rise to adenocarcinoma

Question 202

Morphology endometrial polyps

Answer 202

Possess chromosomal rearrangements seen in other benign mesenchymal tumors Stroma appear neoplastic, while the glands appear reactive Glands may be hyperplastic, atrophic or functional (demonstrate secretory changes) May become hyperplastic with generalized endometrial hyperplasia

Question 203

Hormone sensitivity endometrial polyps

Answer 203

Responsive to estrogen Little to no response to progesterone Associated with tamoxifen therapy (for estrogen receptor positive breast cancer) tamoxifen has weak pro-estrogenic effects in the endometrium (anti-estrogenic effects in breast

Question 204

Atrophic polyps

Answer 204

Remnants of previously hyperplastic polyps | Seen mostly in postmenopausal females

Question 205

Endometrial hyperplasia

Answer 205

↑ proliferation of the endometrial glands relative to the stroma that leads to ↑ gland:stroma ratio Associated with prolonged estrogenic stimulation of the endometrium anovulation increased estrogen production from endogenous sources exogenous sources of estrogen (hormone replacement therapy) Important cause of abnormal bleeding Frequent precursor to the most common type of endometrial carcinoma

Question 206

What is endometrial hyperplasia associated with

Answer 206

Obesity (peripheral conversion of androgens → estrogens) Menopause Poly-Cystic Ovarian Syndrome (PCOS) Functioning granulosa cell tumors of the ovary Excessive ovarian cortical function (cortical stromal hyperplasia) Prolonged administration of estrogenic substances

Question 207

Genetics endometrial hyperplasia

Answer 207

PTEN inactivating mutation

Question 208

PTEN inactivating mutation

Answer 208

tumor suppressor gene seen in both endometrial hyperplasia (20%) and endometrial carcinomas (30-80%) Causes overactive PI3K/AKT growth regulatory pathway which enhances ability of estrogen to stimulate gene expression (i.e. endometrial and mammary epithelial cells) loss of PTEN function --> overactive estrogen dependent gene expression not predictive of progression to carcinoma germline mutation == Cowden syndrome Cowden patients have an ↑ incidence of endometrial + breast cancer

Question 209

Classification endometrial hyperplasia

Answer 209

Nonatypical hyperplasia Atypical hyperplasia (endometrial intraepithelial neoplasia) Differ in appearance and their propensity to progress to carcinoma

Question 210

Nonatypical hyperplasia morphology

Answer 210

↑ gland:stroma ratio Glands vary in size & shape May be dilated May be back-to-back, but some intervening stroma is typically retained due to endometrial response to persistent estrogen stimulation may evolve to cystic atrophy if estrogen is withdrawn Rarely progresses to adenocarcinoma

Question 211

Atypical hyperplasia morphology (endometrial intraepithelial neoplasia )

Answer 211

Complex patterns of proliferating glands with nuclear atypia Nuclei have open/vesicular chromatin + conspicuous nucleoli Glands are back-to-back and branch Cells: rounded, losing perpendicular orientation to basement membrane Overlaps with well-differentiated endometrioid adenocarcinoma Differentiation may require hysterectomy

Question 212

Treat endometrial hyperplasia

Answer 212

Hysterectomy Up to half of patients are found to have carcinoma after hysterectomy In patients who wish to remain fertile, progesterone therapy and close follow up may be trialed Lack of regression usually prompts hysterectomy (hopefully after successful pregnancy

Question 213

Carcinoma of the endometrium

Answer 213

Most common invasive cancer of the female’s genital tract earlier detection and eradication of the precursor lesions of cervical carcinoma 7% of all invasive cancer in women, excluding skin cancer Bleeding is an early sign two types: Type 1 (endometrioid) and Type II (serous) Type I (endometrioid) == low-grade, indolent, preceded by atypical hyperplasia Type II (serous) == high-grade, aggressive, poor prognosis, preceded by serous endometrial intraepithelial carcinoma

Question 214

Type I (endometriod) carcinoma of endometrium

Answer 214

most common type accounting for 80% of all endometrial carcinomas Most are well differentiated & mimic proliferative endometrial glands (endometrioid morphology) Age 55-65 Comes from hyperplasia

Question 215

Type I arise in setting of endometrial hyperplasia and associated with

Answer 215

``` Arise in the setting of endometrial hyperplasia & associated with: Obesity Diabetes HTN Infertility Unopposed estrogen stimulation ```

Question 216

Mutations type I

Answer 216

most common (hallmark) == ↑ signaling via PI3K/AKT pathway via multiple mutations increasing sensitivity to estrogen as more mutations occur PTEN, PIK3CA, KRAS PIK3CA mutations rarely occur in atypical hyperplasias (mutations in PIK3CA have a role in invasion) loss-of-function mutations of ARID1A enhances PI3K/AKT signaling seen in ovarian endometrioid and clear cell carcinomas that arise within endometriosis Other mutations include: @MLH1, CTNNB1, FGFR2 & DNA mismatch repair defects TP53 mutations are seen in 50% of the poorly differentiated carcinomas thought to be a late event in tumor progression

Question 217

Type I DNA mismatch repair genes

Answer 217

Defects of DNA mismatch repair genes are prevalent in carcinomas in females from families with HNPCC (hereditary nonpolyposis colorectal carcinoma). This is Lynch syndrome Often due to epigenetic silencing (hypermethylation

Question 218

Spread type I

Answer 218

Localized polypoid tumor or diffuse infiltration of the endometrial lining Spread via myometrial invasion, then direct extension Invasion of broad ligament → palpable mass Late metastases via lymphatics to lungs, liver, bone, etc Chemotherapy is given to these patients if the cancer has spread beyond the uterus

Question 219

Grade 1

Answer 219

Grade 1: Well differentiated, well-formed glands | distinguished from hyperplasias by lack of intervening stroma

Question 220

Grade 2

Answer 220

Grade 2: Moderately differentiated, well-formed glands mixed with solid sheets of cells (50% or less or tumor mass

Question 221

Grade 3

Answer 221

Grade 3: Poorly differentiated greater than 50% solid growth

Question 222

Grading

Answer 222

Lack of intervening stroma will differentiate well differentiated tumors from hyperplasia There can be squamous elements too, but these are ignored in the grading

Question 223

Staging

Answer 223

Also applies to Malignant Mixed Mullerian Tumors

Question 224

Stage I

Answer 224

Stage I: carcinoma is confined to the corpus uteri (body of the uterus

Question 225

Stage II

Answer 225

Stage II: carcinoma involves the copus + cervix

Question 226

Stage III

Answer 226

Stage III: carcinoma extends outside the uterus but not out of the true pelvis

Question 227

Stage IV

Answer 227

Stage IV: carcinoma extends outside the true pelvis or involves the mucosa of the bladder or rectum

Question 228

Type II carcinoma of the endometrium (serous )

Answer 228

Arise in the setting of endometrial atrophy in women 10 years older than type I (age 65-75) uncommon <40 years olds More common in African Americans Poorly differentiated (grade 3) tumors with poor prognosis due to cell exfoliation, travel through fallopian tubes & implantation on peritoneal surfaces Often already spread out of the uterus at presentation

Question 229

Subtypes of type II

Answer 229

``` Subtypes Serous (most common), clear cell carcinoma, malignant mixed mullerian tumor ```

Question 230

Pathogenesis type II

Answer 230

90% have TP53 missense mutations == accumulation of altered protein Precursor lesion: serous endometrial intraepithelial carcinoma (also has altered TP53) Identical cells, but lack stromal invasion (i.e. are not malignant; confined to epithelial surfaces) Likely begins as a surface epithelial neoplasm that extends to adjacent glands, then invades stroma Other mutations: PI3K, PP2A which are also seen in the precursor lesions (early events

Question 231

Morphology type II

Answer 231

Seen in small, atrophic uteri Tumors are large and bulky or invasive into the myometrium Papillary growth pattern ↑ nuclear: cytoplasmic ratio, atypical mitotic figures, hyperchromasia, prominent nucleoli May also have a glandular growth pattern, but can differentiate by looking for the nuclear atypia

Question 232

Clinical type II

Answer 232

No screening test available Asymptomatic or with irregular or post-menopausal bleeding with excessive leukorrhea No uterine enlargement in early stages Diagnosis requires histological exam of tissue from biopsy or curettage Most patients are cured if there is postmenopausal bleeding as this leads to early detection

Question 233

Prognosis type II

Answer 233

Prognosis is based on stage at presentation Most (in USA) are stage I and well-moderately differentiated Stage I (grade 1 or 2): 90% 5 year survival treatment with surgery +/- irradiation Stage I (grade 3): 75% 5 year survival Stage II or III: < 50% 5 year survival

Question 234

Prognosis for type II serous subtype

Answer 234

Propensity for extrauterine spread More frequent in African American females 2x mortality for African Americans 18-27% 5 year survival even if confined to the uterus, 80% recurrence Adjuvant radiation may reduce local recurrence Chemotherapy may be given, even in the absence of detectable extrauterine spread

Question 235

Malignant mixed mullerian tumors

Answer 235

Endometrial adenocarcinomas with a malignant mesenchymal component Mesenchymal component may be tumor cells resembling uterine mesenchymal elements (stromal sarcoma, leiomyosarcoma) or contain heterologous malignant cell types (rhabdomyosarcoma, chondrosarcoma). Epithelial & stromal components are from the same founding cell Majority are carcinomas with sarcomatous differentiation

Question 236

Mutations malignant mixed mullerian tumors (carcinosarcomas)

Answer 236

Mutations PTEN, TP53, PIK3CA (similar to endometrial carcinoma) Alterations typical of those in sarcomas are absent mechanism of sarcomatous transformation is unknown

Question 237

Morphology malignant mixed mullerian tumros

Answer 237

Bulky, polypoid, and may protrude through the cervical os Usually consist of adenocarcinoma (glandular) mixed with malignant mesenchymal elements (sarcomatous) The metastases typically only have the epithelial components

Question 238

Clinical malignant mixed mullerian tumors

Answer 238

Seen in postmenopausal women Present with bleeding resemble endometrial carcinoma genetically poor outcomes with current therapies

Question 239

Prognosis malignant mixed mullerian tumors

Answer 239

Prognosis based on depth of invasion and stage Also based on differentiation of the mesenchymal component patients with tumors that have a heterologous mesenchymal component do worse than those who do not 25-30% 5 year survival for high-stage disease

Question 240

Tumors of the endometrial stroma are __-

Answer 240

Rare

Question 241

Adenosarcoma

Answer 241

stromal neoplasm admixed with benign glands Large, broad based endometrial polypoid growths May prolapse through the cervical os Females in 4-5th decade Low grade malignancy 25% recur and are confined to the pelvis

Question 242

Diagnosis adenosarcoma

Answer 242

Based on malignant appearing stroma and coexistent benign but abnormally shaped endometrial glands need to distinguish adenosarcomas from large benign polyps adenosarcomas are estrogen-sensitive and responds to oophorectomy

Question 243

Stromal tumors

Answer 243

stromal nodules == benign, well-circumscribed tumors low-grade endometrial tumor sarcoma == infiltrate into the surrounding myometrium high-grade endometrial tumor sarcoma == marked atypia associated with chromosomal translocations that create fusion genes

Question 244

Low grade endometrial tumor sarcoma

Answer 244

JAZF1 (transcription repressor)/SUZ12 (polycomb gene family)

Question 245

High grade endometrial tumor sarcoma

Answer 245

"other gene fusions," function of which is currently unknown

Question 246

Uterine leiomyoma

Answer 246

Most common tumor in women Benign, smooth muscle neoplasms Multiple > single

Question 247

Genetics uterine leiomyoma

Answer 247

Commonly have normal karyotypes 40% have a simple chromosome abnormality T(12q14;6p): HMGIC, HMGIY -- genes that regulate chromatin structure ^^ also implicated in a variety of other benign neoplasms MED12 mutations seen in 70% of tumors

Question 248

Location of the tumor uterine leiomyoma

Answer 248

Found in the myometrium of the corpus | Infrequently involve uterine ligaments, lower uterine segment or cervix

Question 249

Morphology uterine leiomyoma

Answer 249

Sharply circumscribed, discrete, round, firm, gray-white tumors that vary in size Characteristic whorled pattern of smooth muscle bundles resembling the uninvolved myometrium Individual muscle cells are uniform in size and shape Characteristic oval nucleus & long, slender bipolar cytoplasmic processes Scarce mitotic figures (helps to differentiate from leiomyosarcoma) Large: develop yellow-brown-red areas of softening

Question 250

Clinical uterine leiomyoma (fibroids)

Answer 250

Often asymptomatic, but may have: Abnormal bleeding Urinary frequency (bladder compression) Sudden pain due to infarction of a large or pedunculated tumor Impaired fertility Malignant transformation → leiomyosarcoma is extremely rare

Question 251

Pregnancy and uterine leiomyoma

Answer 251

``` ↑ frequency of: Spontaneous abortion Fetal malpresentation Uterine inertia (failure to contract with sufficient force) Postpartum hemorrhage ```

Question 252

Benign metastasizing leiomyoma

Answer 252

Uterine leiomyoma that extends into vessels and spreads hematogenously to other sites Most commonly the lung

Question 253

Disseminated peritoneal leiomyomatosis

Answer 253

Multiple, small peritoneal nodules | Benign

Question 254

Leiomyosasrcoma

Answer 254

Uncommon, malignant neoplasm Arise from myometrium or endometrial stromal precursor cells, rarely from leiomyomas (i.e. de novo) Peak 40-60 years (before & after menopause

Question 255

Genetics leiomyosarcoma

Answer 255

Complex, highly variable karyotypes, often with deletions | MED12 mutations -- virtually unique to uterine smooth muscle tumors

Question 256

Morphology leiomyosarcoma

Answer 256

Bulky, fleshy masses that invade the uterine wall OR Polypoid masses that project into the uterine lumen

Question 257

Spread and prognosis leiomyosarcoma

Answer 257

50% metastasize hematogenously to lungs, bone, and brain Local spread to abdominal cavity can also happen 40% 5 year survival Anaplastic lesions: 10-15% 5 year survival Often recur after surgery

Question 258

Diagnose leiomyosarcoma

Answer 258

Distinguished from benign counterpart via nuclear atypia, mitotic index, zonal necrosis; malignant if: 10 mitoses per high powered field 5 mitoses per high powered field with nuclear atypia or large cells

Question 259

Fallopian tubes

Answer 259

Formed from upper unfused Mullerian duct Most commonly affected by infections and associated inflammatory conditions Also affected by ectopic (tubal) pregnancy and endometriosis

Question 260

Inflammation Fallopian tubes

Answer 260

60% of suppurative salpingitis == neisseria gonorrhea | many of the remaining cases == chlamydia trachomatis

Question 261

Paratubal cysts Fallopian tubes

Answer 261

Most common primary lesion of the fallopian tubes, excluding endometriosis Small translucent cysts filled with clear, serous fluid Hydatids of Morgagni: Larger cysts near the fimbriated end of the tube or in the broad ligaments that arise from remnants of the mullerian duct and are lined with benign, serous (tubal type) epithelium Relatively insignificant

Question 262

Adenomatoid tumors of the Fallopian tubes (mesotheliomas)

Answer 262

benign, uncommon Occur sub-serosally on the tube or in the mesosalpinx Counterpart to the same tumor of the testes or epididymis

Question 263

Primary adenocarcinoma of the Fallopian tubes

Answer 263

Rare tubal mass that may be detected by pelvic exam. Others may come to attention due to abnormal discharge, bleeding, or abnormal cells on Pap smear ~ 50% are stage 1 at diagnosis, but only have a 60% 5 year survival Higher grade tumors are more aggressive treatment: ovarian cancer chemotherapy protocols at least a subset of "serous ovarian cancers" actually arise from the epithelium of the Fallopian tube

Question 264

Ovarian functional or benign ovarian cysts

Answer 264

Most common lesion encountered in the ovary

Question 265

Neoplastic disorders can be grouped according to their origin

Answer 265

müllerian epithelium germ cells sex cord-stromal cells

Question 266

Primary inflammations of the ovary (oophoritis) are uncommon

Answer 266

may have an autoimmune component --> autoimmune oophoritis --> may lead to infertility

Question 267

Cystic ovarian follicles

Answer 267

very common in the ovary | Originate from unruptured graafian follicles or in follicles that ruptured and then immediately sealed

Question 268

Morphology cystic ovarian follicles

Answer 268

Multiple cysts < 2cm in diameter Larger may cause pelvic pain or be palpable, if >2cm then called Follicle Cyst Filled with a clear, serous fluid Lined by gray, glistening membrane Granulosa cells if not atrophied due to intraluminal pressure Conspicuous outer theca cells due to ↑ amounts of pale cytoplasm (leutinization)

Question 269

Cystic ovarian follicles hyperthecosis==pronounced leutinization

Answer 269

Hyperthecosis == pronounced leutinization | Often associated with ↑ estrogen production and endometrial abnormalities

Question 270

Lateral cysts (corpora lutea)

Answer 270

Seen in the normal ovaries of reproductive age females Lined with a rim of bright yellow tissue containing leutinizing granulosa cells May rupture → peritoneal reaction May be mistaken for endometriotic cysts due to old hemorrhage and fibrosis

Question 271

Polycystic ovarian syndrome

Answer 271

Complex endocrine disorder characterized by hyperandrogenism (hirsutism, acne, deep voice), menstrual abnormalities (amenorrhea), polycystic ovaries, chronic anovulation, and decreased fertility affects 6-10% of reproductive age women worldwide (common?)

Question 272

What is PCOS associated with

Answer 272

underlying metabolic disorder Obesity (altered adipose tissue metabolism) T2DM (insulin resistance, Acanthosis Nigricans) Premature atherosclerosis Dysregulation of enzymes for androgen biosynthesis (excess androgen production) Endometrial hyperplasia and carcinoma due to ↑ free estrone (E1) levels

Question 273

E2 estradiol

Answer 273

Predominates in reproductive years | Most potent estrogen produced by aromatization of testosterone in Graafian follicle

Question 274

E3 estriol

Answer 274

Placental estrogen that originates in fetal adrenal gland as DHEA and converted in placenta Least potent

Question 275

Stromal hyperthecosis (cortisol stromal hyperplasia)

Answer 275

Uniform enlargement of the ovary; usually bilateral White-tan appearance Hypercellular stroma & leutinization of stromal cells Seen as nests of cells with vacuolated cytoplasm Most common in post-menopausal females; overlaps with PCOS in younger females similar presentation to PCOS virilization may be even more striking

Question 276

Theca lutein hyperplasia of pregnancy

Answer 276

Theca cells proliferate and the perifollicular zone expands in response to gonadotropins released during pregnancy Concentric theca-lutein hyperplasia Regression of follicles → nodular appearance Do not confuse with true luteomas of pregnancy

Question 277

Ovarian tumors

Answer 277

80% are benign; occur mostly in females 20-45 years old Borderline tumors appear at a slightly older age Malignant tumors are more common in older females 45-65 Most have spread beyond the ovary by the time of diagnosis --> disproportionate number of deaths from cancers of the female genital tract

Question 278

Tissue sources ovarian tumros

Answer 278

``` Surface/fallopian tube epithelium and endometriosis Pluripotent germ cells that migrate to the ovary from the yolk sac Stromal cells (including sex cords) which are forerunners of the endocrine apparatus of the postnatal ovary ```

Question 279

Signs and symptoms ovarian tumors

Answer 279

Abdominal pain and distention Urinary and GI tract symptoms due to compression or invasion Vaginal bleeding

Question 280

Ovarian epithelial tumors

Answer 280

Most primary ovarian neoplasms arise from the Müllerian epithelium

Question 281

Types of epithelial ovarian tumros

Answer 281

Serous Mucinous Endometrioid

Question 282

Classification of epithelial tumors of ovary

Answer 282

Cystic or fibrous, and may be: Benign (classified by tumor components) Borderline Malignant (cystadenocarcinomas

Question 283

Clinical epithelial tumors or ovary

Answer 283

Type I: Low-grade with variable histology, often associated with borderline tumors or endometriosis Type II: High-grade, most often serous, arise from serous intraepithelial carcinoma

Question 284

Type I epithelial ovarian tumor

Answer 284

Type I: Low-grade with variable histology, often associated with borderline tumors or endometriosis

Question 285

Type II

Answer 285

Type II: High-grade, most often serous, arise from serous intraepithelial carcinoma

Question 286

Mullerian epithelium: serous tumors

Answer 286

Cystic, with tubal-like epithelium most common malignant ovarian tumor; ~40% of all cancers of the ovary 70% are benign or borderline that happen 20-45 years old 30% are malignant, occur later in life (early if familial) All serous tumors have psammoma bodies (concentric calcifications)

Question 287

Risk factors of malignant serous tumors

Answer 287

``` Nullparity Family history of breast/ovarian cancer Heritable mutations in BRCA1, BRCA2 20-60% risk of cancer by age 70 ↓ risk 40-59 year old that took oral contraceptive therapy or had tubal ligation ```

Question 288

Low grade pathogenesis mullerian epithelial serous tumors

Answer 288

Arise in serous borderline tumors KRAS, BRAF, ERBB2 mutations Wildtype TP53 Responds better to chemotherapy

Question 289

High grade pathogenesis mullerian epithelium: serous tumors

Answer 289

↑ frequency of TP53 mutations BRCA1/2 mutations are rare (but if present always result in this class of tumor) No KRAS, BRAF mutations Mutations: TP53, amplification in PIK3CA, RB deletions ↑ frequency of genomic imbalances Amplification of oncogenes Deletion of tumor suppressors

Question 290

Genetics mullerian epithelium serous tumour

Answer 290

low-grade tumors arising in serous borderline tumors have mutations in the KRAS, BRAF, or ERBB2 oncogenes, and usually have a wild-type tp53 high-grade tumors have a high frequency of tp53 mutations and lack mutations in either KRAS or BRAF

Question 291

What is mullerian epithelium serous tumors associated with

Answer 291

Larger areas of solid or papillary tumor mass, irregularity, and fixation/nodularity of the capsule are features associated with malignancy

Question 292

Associated features with malignancy serous tumors of mullerian epithelium

Answer 292

Larger areas of solid or papillary tumor mass, irregularity, and fixation/nodularity of the capsule are features associated with malignancy

Question 293

Benign morphology serous of mullerian

Answer 293

Smooth glistening cyst wall with no epithelial thickening or with small papillary projections 20% are bilateral Cysts are lined with columnar epithelium with lots of cilia

Question 294

Borderline tumor morphology mullerian serous

Answer 294

↑ # of papillary projections 30% are bilateral Often involve the surface of the ovary Increased complexity of the stromal papillae, stratification of the epithelium, and mild nuclear atypia, but stromal invasion is not seen Epithelial proliferation occurs in a 'micropapillary carcinoma' pattern that is a precursor to low grade serous carcinoma

Question 295

High grade mullerian serous morphology

Answer 295

Complex patterns of growth Widespread infiltration of underlying stroma Marked nuclear atypia, pleomorphism, and multinucleation Increased mitotic activity with atypical mitosis Cysts are lined with columnar epithelium 66% are bilateral Often involve the surface of the ovary

Question 296

Serous tubal intraepithelial carcinoma

Answer 296

Cells identical to high grade, but there is no invasion "But there is also an invasive type? WTF is going on in this section?" - SD/OMM Fellow Marc Larsen-Hallock Marked epithelial atypia in the fallopian tubes Indicates a fallopian tube origin for high grade serous carcinomas females are BRCA1/2 Germline mutations Often seen at the time of prophylactic salpingo-oophorectomy Associated with sporadic, high grade serous ovarian cancer

Question 297

Tumor spread mullerian serous

Answer 297

Propensity to spread to the peritoneal surfaces & omentum Tumors are more likely to spread to the peritoneum if they are not encapsulated Borderline tumors can arise or extend to the peritoneum and remain fixed or spread leading to intestinal obstruction after many years Low grade may spread in this manner but survival is still good High grade are often highly metastatic throughout the abdomen at presentation and are commonly associated with ascites Extent of spread outside the ovaries determines the staging

Question 298

Prognosis and treatment mullerian serous

Answer 298

Prognosis and treatment depend on pathologic classification as both low & high grade may extend to the peritoneum Borderline & malignant, confined to the ovary: 100% & 70% 5 year survival Borderline & malignant, spread to the peritoneum: 90%, 25% 5 year survival Borderline tumors may recur and 5-year survival is not synonymous with cure

Question 299

Mullerian epithelium: mucinous tumor

Answer 299

20-25% of all ovarian neoplasms Most are benign or borderline tumors Common in middle adult life, rare before puberty or after menopause

Question 300

Pathogenesis mullerian mucinous

Answer 300

Most have KRAS mutation, more likely if the tumor is malignant

Question 301

Main differences between mucinous and serous

Answer 301

Rarely involve the surface of the ovary Rarely bilateral, if bilateral, think non-ovarian origin (appendix) Produce larger cystic masses

Question 302

General morphology mullerian mucinous

Answer 302

Multi-loculated tumors willed with sticky, gelatinous fluid rich in glycoproteins May grow very large (up to 25kg) Lined by tall, columnar epithelium with apical mucin, lacking cilia Most show gastric or intestinal type differentiation

Question 303

Borderline tumor morphology mullerian epithelium

Answer 303

Epithelial stratification, tufting +/- papillary growth (vs. Cystadenomas) Papillary growth looks very similar to tubular adenomas or villous adenomas of the intestine

Question 304

Mucinous carcinoma morphology/prognosis mullerian mucinous

Answer 304

Confluent glandular growth “expansile” invasion 95% 5 year survival for stage I, noninvasive. 90% 5 year survival for invasive malignant tumors. Fatal if spread beyond the ovary Distinguish from metastatic mucinous adenocarcinoma

Question 305

Pseudomyxoma peritonei

Answer 305

Extensive mucinous ascites, cystic epithelium implants on peritoneal surfaces, adhesions, and frequent involvement of the ovaries May result in intestinal obstruction and death source most commonly extraovarian (appendiceal) as most ovarian tumors do not spread away from the ovary bilateral presentation requires exclusion of nonovarian origin most primary mucinous ovarian tumors are unilateral

Question 306

Endometrial tumors

Answer 306

``` Endometrioid carcinomas comprise 10-15% of all ovarian cancers Benign endometrioid (adenofibromas) and borderline tumors may occur but are rare Relatively good prognosis May arise in the setting of endometriosis and borderline tumors 15-20% of cases with endometrioid carcinoma coexist with endometriosis ```

Question 307

Associations of endometriod tumors

Answer 307

Can be associated with ovarian endometriosis or uterine endometrial carcinoma

Question 308

Main difference of endometrioid vs serous/mucinous

Answer 308

Presence of tubular glands resembling benign or malignant endometrium

Question 309

Pathogenesis endometrioid tumors

Answer 309

When associated with endometriosis, occurs in patients, on average, 10 years younger Shared features with endometrial counterpart mutations that increase PI3K/AKT signaling pathway (PTEN, PIK3CA, ARID1A, and KRAS) Mutations of mismatch DNA repair and CTNNB1 (β-catenin) TP53 mutations seen in poorly differentiated tumors

Question 310

Morphology endometrioid tumors

Answer 310

Solid + cystic areas of growth Epithelium consists of tubular glands resembling endometrium 40% are bilateral, implies extension beyond the genital tract Low grade tumors 75% 5 year survival (stage I)

Question 311

Clear cell carcinoma

Answer 311

Benign and borderline types are very rare and the carcinoma subtype is still uncommon. Large epithelial cells with abundant clear cell cytoplasm -- (resembles hypersecretory gestational endometrium) Variant of endometrioid adenocarcinoma

Question 312

Mutations clear cell carcinoma

Answer 312

PIK3CA, ARID1A, KRAS, PTEN, TP53 mutations

Question 313

Morphology CCC solid and cystic

Answer 313

Solid: cells are arranged in sheets or tubules Cystic: cells line the spaces

Question 314

Prognosis CCC

Answer 314

90% 5 year survival if confined to the ovaries | Poor outcome if advanced

Question 315

Cystadenofibroma

Answer 315

Small, multilocular tumors with simple papillary processes Epithelium is variable more pronounced proliferation of the fibrous stroma under the columnar epithelium Benign Borderline tumors or carcinoma rarely occur and metastatic spread is extremely uncommon

Question 316

Transitional cell tumors (brenner tumors)

Answer 316

Can be solid or cystic, typically unilateral Normal stroma with nests of neoplastic epithelial cells resemble urothelium with mucinous glands in the center Usually benign, even when large Incidental detection

Question 317

Clincial nature of benign tumors

Answer 317

Lower abdominal pain + abdominal enlargement GI complaints, urinary frequency, dysuria, pelvic pressure may occur Benign tumors are easily resected and cured

Question 318

Clincila nature of malignant tumors

Answer 318

Progressive weakness, weight loss, cachexia Massive ascites (exfoliated tumor cells) if extending through the tumor capsule to seed the peritoneal cavity Serosal surfaces seeded with small nodules that rarely invade the parenchyma Regional lymph nodes involved; liver, lung, GI, etc. involvement 50% cross midline to opposite ovary and indicate downhill course with death in months-years most women with ovarian carcinoma present with high stage disease relatively poor 5- and 10-year survival rates when compared to cervical or endometrial carcinomas CA-125 or HE4 are biomarkers that can be used to monitor disease recurrence & progression

Question 319

Germ cell tumors

Answer 319

15-20% of all ovarian tumors; majority are benign cystic (mature) teratomas (aka dermoid cysts) Some may have malignant behavior Similar to germ cell tumors in the male testis

Question 320

Teratoma types

Answer 320

Mature (benign): majority Immature (malignant) Monodermal/highly specialized

Question 321

Mature teratoma benign

Answer 321

Most are cystic (referred to as dermoid cysts) and almost always lined with skin-like structures Young women during active reproductive years Discovered incidentally or associated with paraneoplastic syndromes (inflammatory limbic encephalitis) almost all are 46,XX majority arise from an ovum after first meiotic division minority arise from an ovum before first meiotic division

Question 322

Mature teratoma benign morphology

Answer 322

10-15% are bilateral Unilocular cysts with hair + sebaceous material Tooth structures (Rokitansky tubercle) + calcification within the walls (& other germ layers: cartilage, thyroid, neural tissue, etc.) Walls = stratified squamous epithelium 1% undergo malignant transformation (usually the skin component) → squamous cell carcinoma

Question 323

Monodermal or specialized teratoma

Answer 323

``` struma ovarii and carcinoid tumors Rare: strumal carcinoid, a combo of the previously mentioned tumors in the same ovary always unilateral May see a contralateral teratoma Only 2% metastasize ```

Question 324

Stroma ovarii

Answer 324

Composed entirely of mature thyroid tissue that may by functional → hyperthyroidism Always unilateral

Question 325

Ovarian carcinoid

Answer 325

``` Arises from intestinal tissue in teratomas and may be functional >7cm = 5HT (5-HIAA) production --> carcinoid syndrome even in absence of hepatic metastases because ovarian veins are connected directly to systemic circulation always unilateral (metastatic intestinal carcinoid is virtually always bilateral ```

Question 326

Immature malignant eratomas

Answer 326

Tumor tissue resembles embryonal and immature fetal tissue | Seen in prepubertal patients and young women (average age: 18 at presentation)

Question 327

Morphology immature malignant teratoma

Answer 327

Solid, bulky tumors with a smooth external surface May see hair, sebaceous material, cartilage, bone, calcification +/- necrosis & hemorrhage

Question 328

Growth and spread immature malignant teratomas

Answer 328

Grow rapidly, frequently penetrate the capsule, and spread locally or distantly Risk of spread is proportional to amount of tissue containing immature neuroepithelium

Question 329

Prognosis immature malignant teratomas

Answer 329

Stage I, grade 1 = excellent prognosis Prophylactic chemotherapy if higher grade yet confined to the ovary Recurrences occur in first two years absence of disease beyond two years == excellent chance of cure

Question 330

Dysgerminoma

Answer 330

50% of all malignant ovarian germ cell tumors Ovarian counterpart of testicular seminoma (which is the most common male germ cell tumor). 2% of all ovarian cancers Most have no endocrine function, but may produce hCG (if syncytiotrophoblasts are present) 75% in patients in 2nd-3rd decade, but may occur in childhood May occur in patients with gonadal dysgenesis (Pseudohermaphroditism) all dysgerminomas are malignant

Question 331

Mutations dysgerminoma

Answer 331

OCT3, OCT4, NANOG (as seen in seminomas) which maintain pluripotency 33% have mutations of KIT (may target for therapy

Question 332

Morphology dysgerminoma

Answer 332

Unilateral tumors that vary in size Large vesicular cells with clear cytoplasm (like seminoma) Well defined borders Central nuclei Grow in sheets or cords Scant fibrous stroma infiltrated by mature lymphocytes +/- granulomas

Question 333

Treatment and prognosis dysgerminoma

Answer 333

``` all are malignant only ∼ 1/3 are aggressive unilateral, non-invasive, no metastasis == 96% cure rate (excellent prognosis) after salpingo-oophorectomy responsive to chemotherapy overall survival is >80% ```

Question 334

Yolk sac tumor

Answer 334

Rare tumor derived from malignant germ cells differentiating along the extraembryonic yolk sac lineage rare, but the second most common malignant tumor of germ cell origin Produce α-fetoprotein (AFP) that can be stained for in hyaline droplets

Question 335

Morphology yolk sac tumor

Answer 335

Glomerulus-like structure with a central blood vessel enveloped by tumor cells in a space lined by tumor cells (Schiller-Duval body) -- characteristic histologic feature

Question 336

Clinical yolk sac tumor

Answer 336

Seen in children or young females Abdominal pain and rapidly growing pelvic mass (usually involving a single ovary) 80% survival with chemotherapy regardless of disease stage

Question 337

Choriocarcinoma

Answer 337

Extraembryonic differentiation of malignant germ cells of placental origin germ cell origin can only be confirmed in prepubertal females after puberty, ovarian ectopic pregnancy cannot be excluded Exist in combination with other tumors (pure choriocarcinoma is extremely rare) ovarian tumors are aggressive and have usually metastasized by presentation (lungs, liver, bone) Elaborate high levels of chorionic gonadotropins (β-hCG) which is used for diagnosis and detecting recurrence When found in the ovary: unresponsive to chemotherapy and often fatal In placental tissue: responsive

Question 338

Embryonal carcinoma: highly malignant germ cell tumor of primitive embryonal elements

Answer 338

histologically similar to embryonal carcinoma in the testes

Question 339

Polyembryoma

Answer 339

malignant germ cell tumor containing so-called 'embryoid bodies'

Question 340

Mixed germ celll tumors

Answer 340

germ cell tumors containing various combinations of dysgerminoma, teratoma, yolk sac tumor, and choriocarcinoma

Question 341

Sex cord stroma tumors

Answer 341

Ovarian neoplasms are derived from ovarian stroma which came from the sex cords of embryonic gonad Undifferentiated gonadal mesenchyme: Males: Sertoli + Leydig cells (+ fibroblasts) Females: granulosa + theca cells (+ fibroblasts) Tumors of all these cell types may secrete estrogens or androgens and may be feminizing or masculinizing granulosa/theca cell tumors secrete estrogen and are feminizing Leydig and Sertoli cells secrete androgens and are masculinizing

Question 342

Granulosa cell tumors

Answer 342

Composed of cells that look like granulosa cells of a developing ovarian follicle 5% of all ovarian tumors and most are adult granulosa cell tumors 2/3 occur in post-menopausal females May elaborate large amounts of estrogen (some produce androgens) May behave like low grade malignancies

Question 343

Morphology granulosa cell tumors

Answer 343

Typically unilateral and vary from microscopic foci to large, solid, and cystic encapsulated masses If they are hormonally active, they are yellow from stored lipids often are hormonally active and associated with endometrial hyperplasia/cancer The small cuboidal/polygonal cells may grow in anastomosing cords, sheets, or strands Call-Exner bodies: small, distinct, gland-like structures filled with acidophilic material Occasionally there is a predominant thecoma component (clusters/sheets of cuboidal/polygonal cells

Question 344

Clincial granulosa

Answer 344

Precocious puberty if the tumor is functionally active in a juvenile patient Adult females may have proliferative breast disease, endometrial hyperplasia, and endometrial carcinoma, and/or bleeding Masculinization or Pseudohermaphroditism if androgens are produced (most only produce estrogen though) Some tumors elaborating hormone can lead to endometrial carcinoma

Question 345

Diagnosis granulosa

Answer 345

↑ serum inhibin (produced by granulosa cells) that inhibits FSH Allows diagnosis and monitoring treatment Most of the adult type have FOXL2 mutations (important in granulosa cell development

Question 346

Prognosis granulosa

Answer 346

All are potentially malignant tumors composed predominantly of theca cells are unlikely to be malignant Malignant tumors are usually indolent and local recurrences are treated with surgery can recur in the pelvis or abdomen 2=10-20 years after resection of the primary tumor Histology does not predict tumor behavior 85% 10 year survival

Question 347

Fibroma

Answer 347

Tumor arising in the ovarian stroma composed of well differentiated fibroblasts with scant interspersed collagenous stroma by definition, hormonally inactive 90% are unilateral Solid, spherical or slightly lobulated, encapsulated masses covered with a glistening, intact ovarian serosa benign Mitotic activity + ↑ nuclear:cytoplasmic ratio = Fibrosarcoma and a malignant course

Question 348

Thecoma

Answer 348

Tumor arising in the ovarian stroma composed of plump spindle cells with lipid droplets Pure = rare If the predominant cell in a tumor, may be hormonally active benign

Question 349

Fibrothecoma

Answer 349

Fibrothecoma Tumor arising in the ovarian stroma composed of both fibroblasts & plump spindle cells with lipid droplets benign

Question 350

Meigs syndrome

Answer 350

Meigs Syndrome == ovarian tumor, hydrothorax, and ascites (Fibroma, Thecoma, Fibrothecoma) == benign Ovarian tumor present as a pelvic mass +/- pain Ascites if the tumor > 6cm Hydrothorax, usually only on the right side

Question 351

Sertoli leydig cell tumors

Answer 351

Functional tumors that often lead to masculinization or defeminization Some may have estrogenic effects Cells are in various stages of development Females of all ages, peak in 2nd-3rd decade

Question 352

Mutation Sertoli leydig cell tumor

Answer 352

DICER1 mutation in > 50% | Endonuclease essential for micro-RNA processing

Question 353

Morphology sertoli leydig cell tumors

Answer 353

Unilateral tumors Solid grey to golden brown Grossly resemble granulosa cell tumors Well-differentiated: Sertoli or Leydig cells interspersed with stroma Poorly-differentiated: sarcomatous pattern with disorderly disposition of epithelial cell cords; Leydig cells may be absent There may be heterologous elements in some tumors (mucinous glands, bone, cartilage

Question 354

Sertoli leydig cell tumors

Answer 354

functional and commonly produce masculinization or defeminization a few have estrogenic effects Neoplasms can block normal female sexual development in children In adults there may be atrophy of breasts amenorrhea, sterility, loss of hair May progress to virilization with male distribution of hair (hirsutism), hypertrophy of the clitoris, voice changes < 5% recur or metastasize

Question 355

Hilo’s cell tumors (pure leydig cell tumors)

Answer 355

Rare, unilateral, (predominantly) testosterone producing tumors Ovarian tumor of sex cord or stromal origin Benign tumor with clusters of polygonal cells around hilar vessels

Question 356

Morphology hilum cell tumors

Answer 356

unilateral tumors with large, lipid laden Leydig cells Distinct borders Reinke crystalloids: characteristic cytoplasmic structures

Question 357

Clincial Hilus cell tumors

Answer 357

Present with evidence of masculinization: hirsutism, voice changes, clitoral enlargement Mild vs. Sertoli-Leydig cell tumors

Question 358

Treatment Hilus cell tumor

Answer 358

Surgery Almost always benign

Question 359

Pregnancy luteoma

Answer 359

Ovarian tumor of sex cord or stromal origin Rare tumor that closely resembles the corpus luteum of pregnancy Produce virilization in pregnant patients and their female infants/progeny

Question 360

Gonadoblastoma

Answer 360

Uncommon ovarian tumor of sex cord or stromal origin Resembles immature Sertoli & granulosa cells Seen in patients with abnormal sexual development and in patients with indeterminate gonads 80% are phenotypic females 20% are phenotypic males with undescended testicles and female internal secondary organs coexistent dysgerminoma occurs in 50% of the cases Excellent prognosis if tumor is completely excised

Question 361

Metastatic tumors

Answer 361

Derived from tumors of mullerian origin (most common) Uterus Fallopian tube Contralateral ovary Pelvic peritoneum Extra-mullerian: carcinoma of the breast or GI tract Pseudomyxoma peritonei (appendiceal tumor

Question 362

Kurek Berg tumor

Answer 362

Metastatic GI tumor involving the ovaries -- when gastric carcinoma metastasizes to the ovaries bilateral metastases composed of mucin producing, signet ring cancer cells usually of gastric origin

Question 363

Ovarian torsion causes

Answer 363

Children – congenitally malformed or long fallopian tubes, or absent mesosalpinx Pregnancy (20%) – enlarged corpus luteum, laxity in ligaments Pregnancy induction – multiple enlarging follicles Ovarian tumors – benign and malignant, dermoid most common

Question 364

Etiology ovarian torsion

Answer 364

Children Congenitally malformed or long fallopian tubes, or absent mesosalpinx Pregnancy (20%) Enlarged corpus luteum, laxity in ligaments Pregnancy induction Multiple enlarging follicles Ovarian tumors Benign and malignant, dermoid most common

Question 365

Spontaneous abortion

Answer 365

Pregnancy loss before 20 weeks gestation, usually before 12 weeks Occurs in 10-15% of recognized pregnancies, occurs in another 20% which are not recognized by women 70% of pregnancies terminate within 14 days of fertilization with passage of some abnormal tissue

Question 366

Fetal chromosomal abnormalities

Answer 366

Aneuploid, polyploid, translocation

Question 367

Maternal endocrine factors spontaneous abortion

Answer 367

Luteal phase defect, poorly controlled diabetes, thyroid dysfunction

Question 368

Systemic disorders affecting maternal vasculature spontaneous abortion

Answer 368

Systemic disorders affecting maternal vasculature Antiphospholipid antibody syndrome, coagulopathy, HTN APS gives a false positive test for syphilis

Question 369

Infections spontaneous abortion

Answer 369

Protozoa (toxoplasma), bacterial (mycoplasma, listeria), viral (CMV, HSV2, Parvovirus, Rubella) Ascending infection is particularly common in second trimester losses CMV: common, intranuclear inclusions

Question 370

Ectopic pregnancy

Answer 370

Fetal implantation outside the normal intrauterine location Most common: fallopian tube (90%) 2% of confirmed pregnancies and for 4-10% of pregnancy related deaths

Question 371

Who has increased risk of ectopic pregnancy

Answer 371

PID → chronic salpingitis Peritubal scarring and adhesions (due to appendicitis, endometriosis, prior surgery) use of an IUD is associated with a twofold increase of ectopic pregnancy if you get pregnant with an IUD, it's most likely a tubal pregnancy Smoking

Question 372

Tubal pregnancy pathogenesis

Answer 372

Embryonal sac implants in the lumen and is surrounded by immature chorionic villi Chorionic villi + trophoblastic cells invade the wall Eventually produced distention → thinning of the wall and rupture Rupture → massive intraperitoneal hemorrhage that can be fatal, which is a medical emergency tubal abortion == when the conceptus is extruded through the fimbriated end of the tube into the abdominal cavity

Question 373

Tubal pregnancy clinical

Answer 373

tubal pregnancy is the most common cause of hematosalpinx (blood filled fallopian tube), should always be suspected when a tubal hematoma is present Moderate to severe abdominal pain + bleeding 6-8 weeks after the last normal menstrual period this is when the conceptus is large enough to rupture the fallopian tube Hemorrhagic shock and acute abdomen (sudden severe pain of less than 24hrs) if there is rupture

Question 374

Diagnose tubal pregnancy

Answer 374

``` hCG titers (should show that you are pregnant) Pelvic sonography (look for donut sign) -- nothing in the uterus (uh oh moment) Endometrial biopsy: decidua without chorionic villi or implantation site Laparoscopy to take a look ```

Question 375

Twin placenta

Answer 375

``` Dizygotic: fertilization of two ova Monozygotic: division of one fertilized ovum three types Diamnionic dichorionic: May be fused Diamnionic monochorionic Monoamnionic monochorionic Monochorionic = monozygotic (identical) Dichorionic = nonspecific (may be mono/di zygotic ```

Question 376

Twin twin transfusion syndrome

Answer 376

Complication of monochorionic/monozygotic/identical twin pregnancy Vascular anastomoses connect the circulations and may include 1 or more AV shunts Can lead to fluid overload for one & under perfusion for the other May lead to death of one or both fetuses

Question 377

Placenta prevails

Answer 377

a -- "get a preview of the placenta" Placenta implants in the lower uterine segment or cervix → serious 3rd trimester bleeding Complete: covers the internal cervical os and requires c-section to avoid placental rupture and fatal maternal hemorrhage

Question 378

Placenta accretion

Answer 378

Placenta Accreta -- "abnormal attachment of the placenta" Partial or complete absence of the decidua, thus direct attachment to myometrium Placental villous tissue adheres directly to the myometrium = failure of placental separation at birth Severe, life threatening postpartum bleeding can occur Predisposed by placenta previa or history of cesarean section Can be placenta increta or percreta too depending on the depth of invasion

Question 379

Placenta infection

Answer 379

Develop via Ascending infection through the birth canal (most common, usually bacterial) Hematogenous (transplacental) infection

Question 380

Placenta infection

Answer 380

Can cause premature rupture of membranes → preterm delivery Amniotic fluid: cloudy with purulent exudate Chorionamnion: infiltrate of neutrophils + edema & congestion of vessels Fetal 'vasculitis' of umbilical and fetal chorionic plate vessels may occur Acute villitis due to hematogenous spread is uncommon

Question 381

TORCH infection

Answer 381

Affect the placenta and can cause chronic villitis Toxoplasmosis Others (To Light Passing hovering Zambonis: TB, listeria, parvovirus, HIV, Zika) Rubella CMV Herpes simplex virus Syphilis

Question 382

Gestational HTN

Answer 382

Develops during pregnancy No proteinuria Must be distinguished from preeclampsia

Question 383

Preeclampsia

Answer 383

Systemic syndrome with widespread maternal endothelial dysfunction Presents during pregnancy with HTN, edema, proteinuria (nephrotic range?) Most common in the 3rd trimester & primiparas (first pregnancies) Can lead to eclampsia

Question 384

Eclampsia

Answer 384

Severe manifestation of eclampsia. Women are very ill. Convulsions occur (seizures) Can progress to coma

Question 385

HELLP syndrome

Answer 385

Occurs in 10% of women with severe preeclampsia Microangiopathic hemolytic anemia Elevated liver enzymes Low platelets

Question 386

Pathogenesis preeclampsia

Answer 386

Placenta plays a central role in pathogenesis symptoms rapidly disappear after delivery of the placenta Potentially due to factors released from the placenta into maternal circulation Diffuse endothelial dysfunction Vasoconstriction → HTN ↑ vascular permeability = proteinura + edema

Question 387

Abnormal placental vasculature preeclampsia

Answer 387

Abnormal trophoblastic implantation + lack of physiologic remodeling of maternal vessels Failure leaves the placenta ill equipped to meet the ↑ circulatory demands of late gestation Placental ischemia may occur

Question 388

Endothelial dysfunction preeclampsia

Answer 388

Imbalance of Angiogenic/Anti-angiogenic Factors Ischemic placenta → factors that antagonize VEGF & TGFβ released into maternal circulation FMS-like tyrosine kinase (sFltl) antagonizes VEGF Endoglin antagonizes TGFβ Factors are higher in women with this condition and cause defective placental vascular development and vasoconstriction (due to TGFβ inhibition of NO) Maternal vessels remain small caliber high resistance vessels that leads to HTN and tissue hypoperfusion

Question 389

Coagulation abnormalities preeclampsia

Answer 389

Hypercoagulable state Likely due to ↓ PGI2 which is normally stimulated by VEGF (which these women lack) Normally PGI2 is a potent antithrombotic factor and the deficiency leads to formation of thrombi in arterioles and capillaries especially in the Liver, kidneys, brain, and pituitary

Question 390

Placenta morphology preeclampsia

Answer 390

Placental infarcts that are larger and more numerous Exaggerated ischemic changes of chorionic villi & trophoblasts → syncytial knots Frequent retroplacental hematomas Abnormal decidual vessels

Question 391

Kidney and liver morphology preeclampsia

Answer 391

Liver: irregular, focal, subcapsular + intraparenchymal hemorrhages Variable kidney lesions

Question 392

Brain and heart morphology preeclampsia

Answer 392

Brain: foci of hemorrhage +/- thromboses | Similar changes in heart & anterior pituitary

Question 393

When preeclampsia presents

Answer 393

Usually occurs > 34 weeks of gestation | Earlier in women with hydatidiform mole, pre-existing kidney disease, HTN or coagulopathy

Question 394

Risk factors preeclampsia

Answer 394

``` Risk factors age> 40 African American renal disease HTN DM clotting disorders first pregnancy family history ```

Question 395

Clincial preeclampsia

Answer 395

Insidious onset of HTN, edema, and proteinuria in several days headache + visual disturbances indicate severe manifestations that may require delivery eclampsia == seizures --> coma

Question 396

Treat preeclampsia preterm

Answer 396

Mild: close monitoring of mom + baby. Delivery is indicated with end organ damage, eclampsia, fetal compromise or HELLP syndrome regardless of age Term: Delivery (regardless of severity) HTN is not amenable to antihypertensive therapy HTN & proteinuria disappear 12 weeks after delivery (unless they were present prior to pregnancy

Question 397

Complications preeclampsia

Answer 397

20% of patients develop HTN and microalbuminuria within 7 years of a pregnancy complicated by this disease 2x ↑ risk of vascular disease of the heart and brain

Question 398

Hydatidiform mole

Answer 398

Cystic swelling of the chorionic villi and trophoblastic proliferation Diagnosed at ~ 9 weeks via sonogram increased risk of persistent trophoblastic disease (invasive mole) or choriocarcinoma

Question 399

Risk for hydatidiform mole

Answer 399

Bimodal distribution: teenagers or females > 40 | 2X more likely in Southeast Asia

Question 400

Complete mole genetics

Answer 400

Fertilization of an egg that has lost its females chromosomes and genetic material is completely paternal 90% are 46,XX: One sperm duplicates its genetic material (androgenesis) 10% are 46,XX or 46,XY: Empty egg is fertilized by two sperm Embryo dies early and is not identified NO fetal tissue -- complete absence of fetal tissue 2.5% risk of choriocarcinoma 15% risk of persistent or invasive mole

Question 401

Partial mole genetics

Answer 401

due to fertilization of an egg by two sperm -- polyspermy 69,XXY (usually triploid); 92,XXXY (can be tetraploid) Fetal tissue IS present ↑ risk of persistent molar disease Not associated with choriocarcinoma Only some villi are enlarged and edematous Trophoblastic hyperplasia is focal and less marked

Question 402

General morphology hydatidiform mole

Answer 402

Delicate, friable mass of thin walled, translucent, cystic, grapelike structures with swollen, edematous (hydropic) villi

Question 403

Complete mole morphology

Answer 403

All/most chorionic villi are enlarged Scalloped in shape with central cavitation (cisterns) Covered by extensive trophoblastic proliferation of the entire/complete villi circumference

Question 404

Partial mole morphology

Answer 404

Only a fraction/partial of the villi are enlarged and edematous Trophoblastic hyperplasia is focal and less marked than in complete moles

Question 405

Clinical partial mole

Answer 405

Partial or early complete Spontaneous miscarriage or curettage due to abnormal villous findings on ultrasound (will see snowstorm pattern on ultrasound

Question 406

Clincial complete mole

Answer 406

HCG rate of rise is markedly increased and rises more than in normal single or multiple pregnancies Removed via curettage patients are monitored for 6-12m to ensure HCG levels return to normal persistent/invasive moles = when HCG levels remain high; happens in 15% of molar pregnancies

Question 407

Invasive mole

Answer 407

Mole that penetrates or perforates the uterine wall (i.e. it invades) there is invasion of the myometrium by hydropic chorionic villi, accompanied by proliferation of both cytotrophoblasts and syncytiotrophoblasts (produce β-hCG

Question 408

Pathogenesis invasive moles

Answer 408

Hydropic chorionic villi penetrate the myometrium May embolize to lungs or brain but do not grow at these sites (will regress without chemotherapy) Cytotrophoblasts & syncytiotrophoblasts proliferate Tumor is locally destructive Invasion of parametrial tissue or blood vessels

Question 409

Presentation invasive moles

Answer 409

Presents as vaginal bleeding + irregular uterine enlargement | Persistently ↑ HCG

Question 410

Treat invasive mole

Answer 410

responds well to chemotherapy | may result in uterine rupture requiring hysterectomy

Question 411

Choriocarcinoma

Answer 411

Uncommon malignant neoplasm of trophoblastic cells derived from a previously normal or abnormal pregnancy (e.g. extrauterine ectopic pregnancy) Rapidly invasive, metastasizes widely == very aggressive Responds well to chemotherapy

Question 412

Preceding factors choriocarcinoma

Answer 412

``` Complete hydatidiform mole (50%) Previous abortion (25%) Normal pregnancy (22%) Ectopic pregnancy (3%) Germ cells of the ovaries or mediastinum (rare ```

Question 413

Morphology choriocarcinoma

Answer 413

Soft, fleshy, yellow-white tumor Large, pale areas of necrosis + extensive hemorrhage Invades underlying myometrium, often penetrating blood vessels Abundant (possibly abnormal) mitoses May extend to uterine serosa and adjacent structures Does not produce chorionic villi, comprised only of proliferating syncytiotrophoblasts and cytotrophoblasts

Question 414

Clincial choriocarcinoma

Answer 414

Irregular vaginal spotting of a bloody, brown fluid May occur months after pregnancy, abortion, etc Larger than expected uterus high propensity for hematogenous spread (widespread): Lungs (50%) vagina (30-40%) brain liver bones kidney ↑ HCG, but may be low in some tumors (especially if tumor is necrotic

Question 415

Treat choriocarcinom

Answer 415

Evacuation of uterine contents + chemotherapy chemotherapy results in nearly 100% remission and a high rate of cures Cured patients can have normal subsequent pregnancies and deliveries Non-gestational tumors that arise outside the uterus are more resistant to therapy

Question 416

Placental size trophoblastic tumor

Answer 416

Neoplastic proliferation of extra-villous trophoblasts (intermediate trophoblasts) Normal to be found in non-villous sites like the placental parenchyma and placental membranes Polygonal mononuclear cells with abundant cytoplasm Produce increased human placental lactogen (hPL) Malignant trophoblastic cells diffusely infiltrating the endomyometrium Presentation: uterine mass and abnormal uterine bleeding/amenorrhea, moderately ↑ HCG May follow normal pregnancy (50%), spontaneous abortion, or hydatidiform mole Localized disease = excellent prognosis Disseminated disease = 10-15% mortality