Gynecology Pathophysiology I- Uterus and Cervix

Sept 29, 2015 9:00 a.m.

Lecturer: Dr Gabriele Medrano MD
Module Director: Luke Newton MD
Textbook:
Hacker & Moores Essentials of Obstetrics and Gynecology 5th edition
Chapter 19 (pages 243-247)
Chapter 25 (pages 298-304)
Chapter 38 (pagers 402-409)
Objectives
1. List the medical treatment for the management of fibroids
a. Uterine leiomyomas (fibroids) are benign tumors derived from the
smooth muscle cells of the myometrium
b. Most common neoplasm of the uterus
c. Most are asymptomatic, but some can cause excessive uterine
bleeding, pelvic pressure and pain, and infertility
d. Risk factors
i. Increasing age during reproductive years
1. Seldom develop or enlarge after menopause. If you
have postmenopausal woman with rapidly growing
fibroids, or has never had enlarged uterus and then
has large fibroids, it is likely the rare instance in which
you get a malignant fibroid (SARCOMA)
ii. Ethnicity (African Americans twice as likely)
iii. Nulliparity
1. Never have given birth to viable offspring
iv. Family History
v. Obesity
1. Fibroids are estrogen dependent, so higher BMI =
higher estrogen levels
e. Pathogenesis of Leiomyomas (Fibroids)
i. Factors that initiate fibroids are unknown
ii. They have increased levels of estrogen and progesterone
receptors than other smooth muscle cells
1. Recall that estrogen is a mitogen which stimulates
proliferation of SM cells
2. Progesterone increases production of proteins that
interfere with apoptosis
iii. Higher levels of growth factor that stimulate production of
fibronectin and collagen which characterizes these lesions
f. Characteristics of Fibroids
i. Well-circumscribed, white, firm lesions with whorled
appearance on cut section

ii. Does not have true cellular capsule though, compressed SM

cells on tumors periphery provide false impression of
capsule
iii. During pregnancy, 5-10% of women with fibroids undergo a
painful red carneous degeneration caused by hemorrhage
into tumor
iv. Fibroids always arise within the myometrium (intramural),
but some migrate toward the serosal surface (subserosal)
or toward the endometrium (submucosal)

Causes bulge into peritoneal cavity

Causes bulge into endometrial

cavity

g. Symptoms of Leiomyomas
i. Most are asymptomatic
ii. Pelvic pressure, congestion, bloating, feeling of heaviness in
lower abdomen, or lower back pain
iii. Prolonged/heavy menstrual bleeding (intramural or
submucosal myoma)
iv. Severe pain with red degeneration (acute infarction) within a
fibroid most commonly during pregnancy
v. Infertility
h. Signs of Leiomyomas
i. In subserosal or intramural myomas on bimanual pelvic
examination, you feel a firm, irregularly enlarged uterus with
smoothly rounded protrusions

This differentiates from endometriosis in which mass is FIXED

ii. If mass moves with the cervix, it is suggestive of fibroid

i. Medical management
i. If small and asymptomatic, do NOT treat
ii. Heavy or prolonged menstruation
1. Progestin-only therapies or combination hormonal
contraceptive methods are usually the first
therapeutic option
2. To reduce menstrual blood loss, use cyclic hormonal
methods
3. To eliminate menses, use extended/continuous
methods
a. GnRH agonist (Leuprolide)
2. List the surgical management options for the treatment of fibroids
a. Preserve fertility
i. Myomectomy
1. Hysteroscopically in submucosal myomas
2. Laparoscopically in pedunculated, subserosal and
some intramural myomas
3. If endometrial cavity is entered during myomectomy,
future delivery must be cesarean birth
4. About 25% of women treated with myomectomy
require a subsequent operation
b. Uterine preservation but not fertility
i. Endometrial ablation
1. Essentially creating Ashermans Syndrome
ii. Uterine artery embolization (UAE)
c. Hysterectomy provides definitive therapy
i. Depends on patients wishes or medical condition
ii. Usually ovarian preservation is encouraged unless >60y/o or
risk factors for ovarian carcinoma
3. List the risk factors for the development of endometrial hyperplasia
a. Endometrial hyperplasia is an overabundant growth of the
endometrium generally caused by persistent levels of estrogen
unopposed by progesterone
b. Most frequently seen at extremes of womans reproductive years
when ovulation is infrequent
c. Situations with unopposed estrogen stimulation (Risk Factors!)
i. PCOS
ii. Estrogen-producing tumors such as granulosa-theca cell
tumors
iii. Obesity due to peripheral conversion of androgens to
estrogen in adipose cells
1. Adipose aromatase
iv. Prolonged use of exogenous estrogens without progestins
Tamoxifen is a SERM which antagonizes/inhibits estrogen
action in ER(+) breast cancer, but it stimulates estrogen receptorsv.
Tamoxifen Used to treat certain breast cancers
in the uterus!
4. List the 4 different types of endometrial hyperplasia

a. There are two categories

i. Simple hyperplasia
ii. Complex hyperplasia
b. Two subcategories
i. With atypia
ii. Without atypia
c. 4 different types
i. Simple hyperplasia (without atypia) (B)
ii. Simple atypical hyperplasia
iii. Complex hyperplasia
iv. Complex atypical hyperplasia (C)
1. Greatest malignant potential w/ about 20-30%
progressing to endometrial carcinoma if untreated
Normal proliferative endometrium

d. Diagnosis
i. Suspect when woman develops intermenstrual bleeding or
when high-risk woman develops unexplained heavy or
prolonged bleeding
ii. Endometrial sampling is necessary to obtain a histologic
diagnosis
5. Understand the different medical and surgical treatments for the treatment
of endometrial hyperplasia
a. Simple hyperplasia
i. In reproductive-aged women without atypia, treatment
consists of a thorough, coordinated sloughing of the
hyperplastic endometrium
ii. Progestin- 10 days each month for 3 months then biopsy to
confirm normalization of endometrium
b. Complex hyperplasia
i. Evaluated with fractional D&C and initially treated with daily
progestin for 3-6 months then biopsy
c. Complex atypical hyperplasia
i. Best treated with hysterectomy after carcinoma has been
excluded
d. Endometrial ablation is absolutely contraindicated in any of these
situations until endometrium normalizes
6. Describe the different proposed theories to explain the pathogenesis of
endometriosis
a. Endometriosis is a benign condition in which endometrial glands

and stroma are present outside the uterine cavity and walls
i. Even though it is a benign process, it shared many
characteristics with malignancy (locally infiltrative, invasive,
and widely disseminated)
b. Typical patient is in her 30s, nulliparous, and infertile
c. Pathogenesis is not completely understood. 3 hypothesis:
i. Retrograde menstruation theory
1. Endometrial fragments transported through fallopian
tubes during menses implant and grow in various
intraabdominal sites
2. Endometrial tissue from menses is capable of growth
in vivo or in vitro
ii. Mllerian metaplasia theory
1. Metaplastic transformation of peritoneal mesothelium
into endometrium under influence of unidentified
stimuli
iii. Lymphatic spread theory
1. Endometrial tissues are taken up into lymphatics
draining uterus and are transported to various pelvic
sites where tissue grows ectopically
2. Endometrial tissue has been found in pelvic lymphatics
of up to 20% of patients with disease
7. Describe the most common sites of occurrence for endometrial implants
a. Occurs most commonly in the dependent portions of the pelvis
i. Ovaries (1) (2/3 women have ovarian involvement)
ii. Broad ligament (4)
iii. Peritoneal surfaces of cul-de-sac(2) (uterosacral ligaments
(3) and posterior cervix)
iv. Rectovaginal septum (10)
b. Frequent involvement of
i. Rectosigmoid colon (11)
ii. Appendix (8)
iii. Vesicouterine fold of peritoneum (6)
c. Occasionally seen in laparotomy scars (15) (cesarean delivery or
myomectomy probably due to seeding)

Numbers in order
from most common
(1) to least common
(20) site

8. Describe the most common symptoms associated with endometriosis

a. Dysmenorrhea (painful menstruation)
i. Early in clinical course women tend to have cyclic pelvic pain
starting 1-2 days before period and ending after menses
ii. It is secondary dysmenorrhea due to premenstrual swelling
and extravasation of blood and debris inducing intense
inflammatory reaction mediated by prostaglandins and
cytokines
iii. Over time, pain becomes more chronic with exacerbations at
menses
iv. No clear relationship b/w stage of endometriosis and
frequency/severity of pain
b. Dyspareunia (painful intercourse)
i. Associated with deep thrust penetration
ii. Occurs mainly when cul-de-sac, uterosacral ligaments, and
posterior fornix are involved or uterine immobility due to
internal scarring
c. Dyschezia (painful defecation)
i. Experienced with uterosacral, cul-de-sac, and retrosigmoid
colon involvement
d. Premenstrual and postmenstrual spotting is characteristic
symptom
e. Infertility
9. Describe the gold standard diagnostic tool to diagnose endometriosis
a. Endometriosis presents with a wide variety of signs.
Characteristically, a tender, fixed adnexal mass is appreciated on
bimanual examination. Occasionally, no signs at all are appreciated
on PhEx.
b. Definitive gold standard diagnosis is made by characteristic gross
and histologic findings obtained at laparoscopy or laparotomy
i. Unfortunately it is very difficult to identify endometriotic
implants
10. Describe when is surgical management indicated and also describe the
types of surgical management for endometriosis
a. When endometriosis implants in ovaries, it can form
endometrioma (cysts w/ endometrial walls filled with thick,
chocolate-colored fluid and tarry consistency of crankcase oil which
represents aged, hemolyzed blood and desquamated
endometrium). They can cause acute and chronic pain and may
sometimes require surgery.
i. When cysts burst they leave behind fibrotic cyst wall
infiltrated with hemosiderin-laden macrophages leading to
significant scarring of ovary
b. Surgical intervention is required for an endometrioma larger than
3cm, gross distortion of pelvic anatomy, involvement of bowel or

bladder, and adhesive disease; other symptomatic women are

treated with medical therapy as first line
c. The most comprehensive surgery includes total abdominal
hysterectomy, bilateral salpingo-oophorectomy with
destruction of all peritoneal implants, and dissection of all
adhesions. Appendectomy usually also done.
d. If she wants future fertility, then laparoscopic or open surgery is
performed instead
11. List the different medical treatments available for endometriosis
a. Islands of endometriosis respond cyclically to ovarian steroidal
hormone production
i. Estrogen stimulates proliferation of implants
ii. When support form estrogen and progesterone is removed
(involution of corpus luteum), the implants slough leading to
PAIN (acutely) and FIBROSIS in the long term
b. Continuous hormonal exposure, especially in high doses, generally
induces significant regression
c. Treatment (both surgical and medical) is indicated for
endometriosis when quality of life is affected. No need to treat
asymptomatic patient
d. For relief of non-cyclic pelvic pain, short-term medical treatment
may be considered first-line treatment
i. NSAIDs
ii. Oral contraceptives
1. Treat endometriosis related pelvic pain
iii. Progestins (medroxyprogesterone acetate)
1. Treat endometriosis related pelvic pain
e. Second-line medical treatment
i. GnRH agonist
1. Cause temporary medical castration bringing about
marked (temporary) regression of endometriosis
2. Relief of pain and involution of implants
3. Side effects include:
a. Hot flashes
Pretty much all Sx of low estrogen!
b. Vaginal dryness
c. Calcium loss from bone
d. Unfavorable lipid profile
ii. Higher-dose progestins
iii. Danazol
1. Androgenic derivative used if fertility is not present
concern
2. Decreases plasma levels of SHBG leading to increase
in free testosterone. Obviously, side effects include:
a. Hirsutism
b. Acne
c. Deepening of voice, hoarseness, sore throat

12. List the most common types of High Risk HPV

a. There are 15 high risk HPV types and types 16 and 18 are
responsible for 70% of cervical cancers
b. Types 6 and 11 are associated with cervical condylomas and lowgrade cervical intraepithelial neoplasia (CIN)
13. List the risk factors for cervical cancer
a. Regular screening with Papanicolaou (Pap) smears has markedly
decreased the incidence of the disease, and most cases now occur
in women who have not had regular Pap smears
b. Persistent infection with high-risk HPV is the cause of virtually all
cervical cancers
c. Risk factors (increased likelihood of exposure to a high-risk HPV
type:
i. Young age at first coitus (<20)
ii. Multiple sex partners
iii. Sexual partner with multiple sex partners
iv. Young age at first pregnancy
v. High parity
vi. Lower socioeconomic status
vii. Smoking
d. ACOG recommends that all women undergo annual physical
examination and have a Pap smear by age 21
14. List the symptoms associated with cervical cancer
Bleeding when your not a. Invasive cancer usually presents with postcoital, intermenstrual,
or postmenopausal vaginal bleeding
supposed to:
b. Non-sexually active females dont have bleeding until disease is
After sex
quite advanced
Between periods
c. Advanced disease symptoms:
After menopause
i. Persistent vaginal discharge
ii. Pelvic pain
iii. Leg swelling
iv. Urinary frequency
15. List the most common signs of cervical cancer
a. On pelvic exam, cervix may be ulcerative or exophytic and it
usually bleeds on palpation, and there is associated serous
purulent or bloody discharge

b. Usually have normal general physical exam

c. Advanced disease signs:
i. Weight loss
ii. Enlarged inguinal or supraclavicular lymph nodes, edema of
legs, or hepatomegaly
d. Cervical cancer is staged CLINICALLY!
16. Know the most common type of cervical cancer
Squamous cell carcinoma
a. Most uterine cervical cancers are squamous in origin
17. List the treatments of cervical cancer
a. Primary prevention with HPV vaccination most effective if
performed before the onset of sexual activity
b. Stage 1a1 (microinvasive carcinoma)
i. Extrafascial abdominal or vaginal hysterectomy if depth
invasion on cone biopsy is 3mm or less, horizontal
dimension 7mm or less, and no lymphatic or vascular space
involvement
ii. Cervical conization alone if patient wants to maintain
fertility
c. Stage 1a2
i. Modified radical hysterectomy and pelvic lymph node
dissection
ii. If fertility wants to be kept then large-cone biopsy or radical
trachelectomy combined with pelvic lymphadenectomy
d. Stages 1b1 and 1b2
i. Primary surgery
1. Radical hysterectomy and bilateral pelvic
lymphadenectomy
2. Ovaries may be spared
3. Treatment of choice for 1b1
ii. Primary chemoradiation therapy
1. Treatment of choice for 1b2
e. Radical hysterectomy
i. Uterus is removed along with adjacent portions of vagina,
cardinal ligaments, uterosacral ligaments, and bladder pillars
ii. Most common complication is bladder dysfunction
iii. Most serious complication is ureteric fistula
f. Radical trachelectomy Surgical resection of uterine cervix
i. For young women with early cancer (<2cm diameter)
ii. May allow fertility preservation
g. Radiation therapy