Pathology of the Uterus, Part 1

Cheryl A. Hanau, M.D.

Click here for Video
• Learning Objectives:
• Describe the normal development and anatomy of the uterus
• Discuss the appearance of endometrium at various phases of the menstrual cycle
• Discuss the epidemiology, classification, clinical consequences, gross and microscopic
appearance and clinical course (including staging, where applicable) of:
– Benign disorders of the uterus:
• Dysfunctional Uterine Bleeding, congenital anomalies, inflammation, drug
effects, IUD effects, adenomyosis and endometriosis
• Discuss the epidemiology, classification, clinical consequences, gross and microscopic
appearance and clinical course (including staging, where applicable) of:
– Premalignant disorders of the uterus:
• Hyperplasia of the endometrium (simple and complex, +/- atypia)
– Tumors of the uterus:
• Benign, premalignant, and malignant tumors of the endometrial glands
(Type 1 and Type 2), endometrial stroma, and myometrium

Proliferative Endometrium Proliferative Endometrium-

Note Mitoses

Day 17 – Subnuclear Vacuoles Day 17 – Subnuclear Vacuoles

Day 21 Stromal Edema – Day 26- Entire Stroma Day 26- Entire Stroma
Secretory! Decidualized Decidualized

Menstrual Endometrium Day 23 – Pre-decidua

around vessels

‘ Pregnancy – Hypersecretory Endometrium

• Dysfunctional Uterine Bleeding – Why is there no Photo of the

Endometrial Pathology????
• Abnormal bleeding in the absence of an organic lesion of
the endometrium
• Very common – seen most often around menarche and
menopause
• Anovulatory Bleeding
• Most common cause of DUB
• Excess estrogen stimulation and no progesterone since no corpus luteum; then estrogen
declines and get bleeding
• Bleeding is variable in amount and erratic
 •Some cases are secondary to obesity, malnutrition, chronic systemic disease,
endocrine disorders, polycystic ovaries, etc, but most are due to subtle hormonal
imbalances
• Additional Causes of DUB
• Inadequate luteal phase
• Inadequate progesterone secretion from corpus luteum; see menstruation 6-9 days
after LH surge
• Irregular shedding
o Heavy bleeding due to extended secretion of progesterone from corpus
luteum, see secretory and proliferative phases together on biopsy

Irregular Shedding Fusion Defects and Atresias Bifid Uterus

• Inflammatory Conditions
• Acute endometritis- usually near time of
delivery or miscarriage
• Caused by retained products of conception (POC)
• Infection by Strep or Staph
• Chronic endometritis
• See plasma cells in endometrium
• Risk factors include IUD, PID, retained POC
• Special forms of endometritis – TB, Mycoplasma, Chlamydia, fungi, Herpes simples, CMV,
Parasites, sarcoid
• Drug Effects
• Estrogens stimulate the endometrium
• Duration of exposure more important than dose
• Can get hyperplasia or carcinoma from prolonged administration
• Oral Contraceptives
• Shortens proliferative phase, secretory changes develop
• slowly
• After a few cycles, atrophied endometrium with
• decidualized stroma
• Known adverse reactions due to oral contraceptives include
thromboembolism with sudden death, hepatic adenoma that
 can present as sudden intraperitoneal bleeding, jaundice and
intimal fibrosis and luminal narrowing of small arteries.

• Intrauterine Device - IUD IUD

• Induce acute and chronic inflammation and decidual reaction
• Can see increased incidence of infections, particularly
actinomycosis
• Endometriosis
• Endometrial glands and stroma outside the uterus –
i.e. ‘ectopic endometrial tissue’
• Sites of occurrence listed in descending order of frequency:
• Ovary
• Uterine ligaments
• Rectovaginal septum
• Cul de sac and pelvic peritoneum
• Intestine and appendix
• Mucosa of cervix, vagina, fallopian tubes
• Laparotomy scars
• Seen in women of reproductive age - 6-10%

Endometriosis Sites Endometriosis – Endometrial Glands and Stroma outside of

the uterus

• Endometriosis
• Clinical:
o Pelvic pain, dysmenorrhea, infertility, dysuria, rectal pain
• Morphology
• Can see dark, ‘powder burns’ on laparoscopy, undergoes cyclic bleeding
• Ovaries can contain large cysts containing degenerated bloody material (chocolate
cysts)
• Uterus does not enlarge (in contrast to adenomyosis)
Endometriosis
• Pathogenesis - Theories
• Regurgitation theory (but 90% of women have this and most don’t have
endometriosis)
• Benign metastasis theory - spread by vessels or lymphatics
 • Extrauterine stem/progenitor cell theory
• Molecular findings - Endometriotic implants show:
• Release of proinflammatory and other factors
• Endometriotic stromal cells contain aromatase (not in normal endometrial stromal
cells) which increases estrogen production
• Conveys a survival advantage
• Some studies show association between endometriosis and ovarian CA of endometrioid
and clear cell types
Laparoscopy Laparoscopic view of Endometriosis Endometriotic Cyst (Chocolate
endometriosis Cyst)

• Endometriosis
• Microscopic findings:
• Endometrial glands and stroma, may be difficult to identify due to surrounding
hemorrhage and fibrosis
• Sometimes just see hemosiderin-laden macrophages – this plus the correct
clinical presentation is enough for a diagnosis of ‘presumptive endometriosis’
• Atypical endometriosis shows cytologic atypia and/or glandular crowding – looks
like atypical endometrial hyperplasia – may be precursor to endometriosis-
related ovarian carcinoma
Adenomyosis – Endometrial
Lining of Endometriotic Cyst Adenomyosis Adenomyosis Glands and Stroma within
the myometrium

• Adenomyosis
• Presence of endometrial glands and stroma within the myometrium
• Common, benign, most often seen in peri-menopausal women who present with
bleeding and dysmenorrhea
• Uterus can become enlarged with thickened myometrium
• Can respond to hormones and cycle
• Treatment: hysterectomy
• Does not have malignant potential
• Tumors of the Uterus Endometrial Polyp
• Endometrial Polyp
• Common cause of abnormal bleeding
• Seen in women in 40s and 50s
• Can be sessile or on a stalk, polypoid fragments of
tissue with epithelium on three sides
• Cytogenetic studies show that the stromal
cells contain chromosomal rearrangements
similar to those seen in other benign mesenchymal Endometrial Polyp
tumors – glands are ‘along for the ride’
• Glands can become hyperplastic but very rarely become malignant

Endometrial Hyperplasia
• Another cause of abnormal bleeding
• Frequent precursor to the most common type of endometrial cancer
• Morphologically:
• Increased gland to stroma ratio
• Abnormalities in epithelial growth relative to normal endometrium
• Can progress from simple (non-atypical) to atypical to carcinoma

Endometrial Hyperplasia
• Linked to prolonged estrogen stimulation of the endometrium by anovulation or
increased estrogen production or exogenous estrogen
• Conditions promoting hyperplasia include:
• Obesity – peripheral conversion of androgen to estrogen
• Menopause
• Polycystic ovarian disease (including Stein-Leventhal syndrome)
• Functioning granulosa cell tumors of the ovary
• Excessive cortical function (cortical stroma hyperplasia)
• Prolonged administration of estrogenic substances (estrogen replacement therapy)
• These are the same influences postulated to be of pathogenetic significance in some
endometrial carcinomas, discussed later

Endometrial Hyperplasia
• Traditionally subdivided into low grade (simple, not atypical) and high grade (atypical)
subgroups
• Low-grade hyperplasia shows either no atypia or only a very mild degree of cellular
abnormality
• In contrast, high-grade hyperplasia, also termed atypical hyperplasia, typically has the
morphologic features (gland crowding and cytologic atypia) and genetic characteristics
(mutations that inactivate the tumor suppressor gene, PTEN) of intraepithelial
neoplasia.
Endometrial Hyperplasia
• Inactivation of the PTEN tumor suppressor gene through deletion and/or inactivation
appears to play a role in the development of hyperplasia and of endometrial carcinoma
• Seen in 20% of hyperplasia, and 30-80% of endometrial carcinomas

Loss of PTEN gene expression in intraepithelial neoplasia

(lack of staining in glands w/out arrows).

\]
Grading of Endometrial Hyperplasia
• Historically used 4 categories – based on simple vs. complex architecture with vs.
without atypia
• Now WHO uses only two categories:
• Non-atypical hyperplasia
• Atypical hyperplasia – AKA Endometrial Intraepithelial Neoplasia (EIN)
o Vary in size and shape
• Rarely becomes malignant (1%)
• Caused by persistent estrogen stimulation; usually just becomes ‘cystic
atrophy’ if estrogen is withdrawn

END OF PART 1