Wall of uterus is made of
- endometrium - lining
- Cervix has the same wall
- Outer portion, exocervix - squamous epithelium
- Inner portion, endocervix - mucinous columnar
- Transformation zone - The part of cervix between the original squamocolumnar junction and the current junction (moves up during a woman’s life); the key area for precancers and cancers, an area squamous and columnar epithelium coexist; target area for pap smear.
Some degree of cervical inflammation may be found in virtually all women, and it is usually of little clinical consequence. However, infections by gonococci, chlamydiae, mycoplasmas, and HSV may produce significant acute or chronic cervicitis.
Mucopurulent cervicitis, need to rule out
gonorrhea and Chlamydia
- Causes of pelvic inflammatory diseases, infertility, ectopic pregnancy.
- Infected female may be asymptomatic, as opposed to affected men.
- Caused by trichomonas vaginalis
- Has frothy yellow discharge
Condyloma acuminatum and cervical pre-invasive and invasive lesions
- Human papilloma virus - about 100 types, over 60 affecting lower genital tract
- 6,11 - Condyloma, low risk, warts
- 16, 18 - high risk, cervical cancer
- The most common STDS - HPV, gonorrhea, chlamydia
- 20-40% of sexually active women have HPV (women tend to by symptomatic)
- 1950s 13/100,000 US women w/warts
- 1970s 106/100,000
- 5.5 million new infections/yr in US
- Estimated total prevalence of 20 million, US
- HPV prevalence in normal pap peaks at mid 20's
- nonproductive infection - Integrated into host DNA, found in most cancers. HPV's viral proteins E6 and E7 interfere with the activity of tumor suppressor.
- productive infection - Episomal, nonintegrated, cause warts and precursor lesions.
- Virtually all HPV infection is nondetectable by PCR within 2 yrs; duration of infection is related to HPV type; on average, high-risk HPV infections last longer
- Latency and re-emergence less well known
Risk factors for HPV genital infection
- Exposure to virus
- Immune status
- Pregnancy - hormonal status? transient immunosuppression?
- Long term OCP use - Increased ER and PR?
- Nutritional status
Condyloma accuminatum - Pathology
- Koliocyte - cells show perinuclear halo
- Nuclear atypia
- Irregular resinoid cells
- Binucleated cells
- DNA viruses, typed based on sequences and grouped into high and low oncogenic risk.
- High-risk HPVs
- - the most important factor in the development of cervical cancer. Still small percentage. Long latency.
- - 15 high risk HPVs identified: HPV-16 accounts for 60% of cervical cancer cases; HPV-18 accounts for 10%
- - Also implicated in squamous cell carcinomas arising at vagina, vulva, penis, anus, tonsil, and other oropharyngeal locations
- Low oncogenic risk HPVs cause sexually transmitted vulvar, perineal, and perianal warts (condyloma acuminatum).
Cervical intraepithelial neoplasia
grade I to III
Squamous intraepithelial lesion
graded low to high
Low-grade squamous intraepithelial lesion (LGSIL) shows marked koilocytic change, seen as perinuclear “halos” in suprabasilar cells.
Outcome of LGSIL
- Reverts to normal 46%
- Persists as LGSIL 37%
- Progresses to HGSIL 16%
Natural History of Squamous Intraepithelial Lesions with Approximate 2-Year Follow-up
- LSIL - 60% regress, 30% persist, 10% go on to HSIL
- HSIL - 30% regress, 60% persist, 10% to carcinoma in 2-10 yrs
Pap smear with ________ to sample the ________.
- Ayre spatula
- transformation zone
In the old pap smears, cancer is indicated by necrosis. Using the liquid cytology process, the debris is removed.
- Good screening
- Not a diagnostic test
- Interval important
- Issues of false positives/negatives
Looks at the transformation zone directly.
Cervical cancer epidemiology
- Worldwide the third most common cancer in women, more than half are fatal.
- Fifty years ago, the leading cause of cancer deaths in women in U.S.
- The death rate has declined by two thirds (the thirteenth cause right now) due to effective screening, early diagnosis, and curative therapy.
Cervical cancer risk factors
- Number of partners
- Early intercourse
- Early 1st pregnancy
- Socioeconomic status
- Vitamin deficiencies
- Interval since last pap
- Most squamous cell carcinoma
- Adenocarcinoma increasing
- Endophytic or exophytic (burrowing or fungating)
- Signs - none, Postcoital bleeding
- Spreads by regional lymphatics
Staging of cervical carcinoma
- Stage 0 - Carcinoma in situ (CIN III, HSIL)
- Stage I - confined to the cervix
- Ia - Preclinical, diagnosed only by microscopy
- Ia1 - Stromal invasion no deeper than 3 mm and no wider than 7 mm (microinvasive carcinoma)
- Ia2 - Maximum depth of invasion between 3-5mm; horizontal invasion not more than 7 mm
- Ib - Histologically invasive carcinoma, confined to the cervix and greater than stage Ia2
- Stage II - extends beyond the cervix but not to the pelvic wall. involves the vagina but not the lower third.
- Stage III - extends to the pelvic wall. No cancer-free space between the tumor and the pelvic wall on rectal examination. Involves the lower third of the vagina.
- Stage IV - extends beyond the true pelvis or involves the mucosa of the bladder or rectum. Also includes cancers with metastatic dissemination.
- Paired Mullerian ducts fuse, give rise to tubes and uterus and upper vagina
- mucosal layer, or endometrium
- - stratum functionalis - expands and vascularizes and is subsequently sloughed off during the process of menstruation
- - stratum basalis - remains relatively constant.
- muscularis layer, or myometrium - allows for the expansion and contraction of the uterine cavity and is responsive to oxytocin.
- serosal layer, or perimetrium
Evaluation of the endometrium
- Hormonal status of patient
- Documentation of ovulation
- Causes of abnormal bleeding
- Workup of infertility
- Proliferative - Estrogen effect
- Secretory - Estrogen/progesterone effect
Endometrium through the cycle
- Proliferative endometrium - first half of ovarian cycle (d1-14), estrogen effect only. "donuts"
- Secretory endometrium - after ovulation (d15-28), estrogen and progesterone effect. "piano keys". Glands with glycogen for nourishment if implantation happens. Saw toothed glands.
- The “ideal” menstrual cycle is 28 days. Day 1 is day 1 of menses and ovulation occurs on day 14.
- Happens in Stratum Functionalis
If no implantation, functionalis breaks down due to lack of hormones
Abnormal uterine bleeding
- Systemic disease - eg hyper thyroid
- Organic causes - intrinsic uterine disease such as endometritis, polyps, submucous leiomyomata
- Dysfunctional uterine bleeding - hormonal imbalance, most common
- Hyperplasia and carcinoma
Organic causes of uterine bleeding
- Endometritis - acute, chronic (if plasma cell is present), nonspecific, specific etiologies such as TB, actinomyces
- Endometrial polyps - common
- Submucous leiomyomata - fibroid impinging on the endometrium, which results in bleeding
Dysfunctional uterine bleeding
- Usually but not always anovulatory (not ovulating properly)
- Etiology varies with age
- - adolescent - Immaturity of HPO axis
- - reproductive age - PCO/stress/obesity
- - perimenopausal - ovarian failure
- Excess unopposed estrogen - Needs to prevent carcinoma. Estrogen grows endometrium, progesterone stabilizes it. When regulation is lost, hyperplasia happens. Polycystic disease is treated with progesterone.
- Endometrium (glands and stroma) implanted outside
- the uterus
- May be asymptomatic, or may cause dysmenorrhea,
- infertility (etiology unknown), dyspareunia
- Symptoms do not correspond to extent of disease
- May have powder burn lesions, endometriomas
- CA-125 (marker for ovarian cancers)
- Need to see both glandular and stromal epithelium to confirm the diagnosis
Theories of endometriosis
- Sampson-retrograde menses
- Still undertermined
Sites of endometriosis
- [Peritoneal surfaces on the pelvic surfaces]
- Uterine ligaments
- Fallopian tubes
- Occasionally Vulva, vagina, appendix
Myometrium is made of
- Most common pelvic tumor
- 20% of women over 30, mostly asymptomatic
- Intramural, subserosal (can be felt), submucosal (abnormal bleeding), well-circumscribed.
- Often outgrow blood supply with degeneration
- Malignant change < .5% (leiomyosarcoma)
- May be clonal proliferation of single cell
- Estrogen responsive. Shrink with menopause.
- Symptoms - none, or may relate to location-pain, bleeding, pressure, bladder/rectal symptoms
- Lack of circumscription
- Mitosis and atypia
- Coagulative apoptosis
- Thickening of endometrium is characteristic
- Complex (risk factor for developing carcinoma)
- Atypia (strong indicator of developing into carcinoma)
- Risk of developing or concurrently harboring a cancer around 25% with atypical
Any spot after becoming amenorrheic for at least a year
Post/peri-menopausal bleeding or polycystic ovaries due to unopposed estrogen may indicate endometrial hyperplasia, need to be inspected for thickening.
- Most common gyn cancer in US
- Ages 50-70 peak (postmenopausal)
- Most often estrogen-related
- Risks: estrogen-related - Obesity, infertility hx, early menarche, late menopause, polycystic ovaries, estrogen meds without progesterone - markers of estrogen
- Other risks, maybe - radiation, Diabetes, hypertension, obesity
- Previous history of breast/ovary cancer (genetic factor)
- Significance of postmenopausal bleeding (has to be investigated)
- Other abnormal bleeding (between menses, post-coital [the latter is more related to cervical cancer])
- Diagnosis by sampling. Sonogram as additional study. Pap rarely useful.
- With early diagnosis, prognosis excellent.
- Graded based on how solid it is (less gland, endometrial looking, higher grade)
Two types of endometrial cancer
- estrogen sensitive - 1: yes vs. 2: no
- occurence - 1: more common vs. 2: less common
- important gene mutation - 1: PTEN vs 2: p53
- time - 1: pre/peri-menopause vs 2: post-menopause
- hyperplasia - 1: yes vs 2: no
- Race - 1: caucasian vs. 2: black
- common grade - 1: low vs. 2: high
- myometrium invasion - 1: minimum vs. 2: deep
- Typical types - 1: usual vs. 2: uterine serous carcinoma (aka papillary serous carcinoma)
- Prognosis - 1: better vs. 2: poorer
- Unless specified, endometrial cancer always referred to type 1
Prognostic factors of endometrial cancer
- Grade - % solid
- Depth of invasion into myometrium
- Current staging surgical/pathologic
- 5 year survival - stage I >85%, stage IV 10%
Simplified Staging of endometrial cancer
- I - Corpus
- II - Corpus/cervix
- III - Outside uterus in true pelvis
- IV - Outside true pelvis, or bladder/rectal mucosa
Functions of Ovaries
- Sex hormone production - Estrogen and progesterone
- Control of ovarian - pituitary via FSH and LH.
- Surface epithelium
- Nonspecialized Stroma - plump spindle cells.
- Specialized stroma - granulosa and theca cells
- Germ cells
Fertilization occurs in
the fallopian tubes
- growing follicle
- preovulatory follicle
- corpus luteum
Theca cells surround the follicle, in which granulosa cells surround the oocyte.
If pregnancy doesn't happen, corpus luteum becomes corpus albicans
- Menstrual irregularity
- Benign conditions
- Malignant conditions
- G I C, germinal inclusion cyst
- Follicle cysts
- Corpus luteum cysts
- Common, usually benign, but should always be evaluated.
- Most common related to menstrual cycle - follicle cyst, corpus luteum cyst. These can be watched or treated with oral contraceptives. Surgery is uncommon.
- Benign non-functional cysts often come to cystectomy. Sometimes laparoscopic.
- May have no symptoms, may cause pain/pressure.
Benign cyst has smooth inside surface, and only contains fluid inside, no bumps.
- Cyst closed off in the ovary, "chocolate cyst"
- For diagnosis, must see endometrial glands and stroma.
- Epithelial 75% - more in older women
- Germ Cell 20% - most common in younger women
- Stromal 5%
Epithelial neoplasms of ovary.
- Multipotential Müllerian epithelium.
- Can mimic variety of epithelial types.
- Can be benign, low malignant potential (“borderline”) or malignant.
- Many types of tumors - serous, mucinous, endometrioid, clear cell, others.
Germ cell Neoplasms of ovary
- Most Benign Cystic teratoma (dermoid)
- Variety of malignancies
- - Immature teratoma
- - Yolk sac tumor (endodermal sinus)
- - Dysgerminoma
- - Choriocarcinoma
- - Embryonal
- - Mixed
- Specialized - Granulosa cell tumors, fibrothecomas, Sertoli-Leydig cell tumors, Steroid cell tumors; more likely to cause problems.
- Various occasional nonspecialized
- 70% benign
- 5-10% last menstrual period
- 20-25% Malignant
- bag of fluid
- not many lobules
- smooth surface
- When borderline, contains both smooth area and papilla
- When malignant, has fibrovascular cores, Psammoma bodies, epithelium on the surface
- Papillary serous carcinoma
- Less common, but more serious
- Screening - no good method
- CA-125 - not specific
- Exam - late diagnosis
- Ultrasound + BRCA positive can be good, but impractical
- Symptoms - often none or nonspecific until advanced stage. Cranky midlife women with heartburn.
Ovarian cancer - Simplified staging
- I - Ovaries
- II - Pelvic extension
- III - Peritoneal implants/regional nodes
- IV - Distant mets
- usually diagnosed late.
Etiology of ovarian cancer
- Genetics small % cases
- “incessant ovulation”
- Increased risk with nulliparity
- Decreased risk with oral contraceptives
Germ cell tumors
- Most of them are benign, teratomas
- Everything else is malignant
Dermoids (benign cystic teratomas)
- Very common
- Can be very heavy, all three germ layers, all kinds of tissues
- May occasionally twist or rupture
- May have no symptoms
- Treated with cystectomy
can be hormonally active
Granulosa Cell tumor - stromal tumor
- Low grade malignancy
- Usually unilateral
- Can produce E2 and overstimulate endometrium
- Usually unilateral
- More frequent in menopause
- Can produce estrogen
- Meig’s syndrome - fibroma, right hydrothorax, ascites
- Pointed nuclei
Metastatic tumors to ovary
- rich blood and lymphatic supply
- can get metastatic from everywhere
- signet ring cells
- comes from the breast, stomach, and colon
Evaluating an ovarian mass
- Role of Frozen sections
- Epithelium - Ciliated, nonciliated columnar, intercalated
- Muscular wall - Inner circular, outer longitudinal
Conditions of the Fallopian tubes
- Pelvic inflammatory disease - G&C
- Ectopic pregnancy
- Neoplasia - rare
Pelvic inflammatory disease
- Depends on the location
- Usually ascending
- Cervicitis -> endometritis -> tubal infections (salpingitis) -> intra-abdominal comlications
- Erythema, edema, exudate (pus, neutrophils, dead bacteria and cells)
- Low bilateral abdominal pain
- Adnexal swelling, tenderness
- Filled with clear fluid, no pus
- May have scarring
- Can cause infertility
- Classic signs - early suggestion of pregnancy with amenorrhea, other symptoms, then bleeding, then pain.
- Most cases atypical in presentation. A diagnostic challenge.
- Critical to suspect
- Therapy - salpingostomy vs salpingectomy
- Used to be staged with ovarian cancer, similar in histology and treatment
- Now rare, and staged differently