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Gynecologic Pathology II

Pathology of the Uterus

Carey Z. August, M.D. UIC College of Medicine

Attending Pathologist, Advocate Illinois Masonic Medical M2 Pathology Course
Center Lecture #54
Clinical Assistant Professor of Pathology, UIC Monday, January 26, 2004
Phone: 773-296-7900 9:30-10:20

Reading: Robbins Pathologic Basis of Disease, 6th edition, 1999, pp.1054-1065

Summary: This lecture will cover diseases of the endometrium, myometrium, and
endometrial stroma, as well as endometriosis. The concept of hormonal imbalance in the
pathogenesis of abnormal uterine bleeding and infertility will be explored in conjunction
with the demonstration of morphologic findings in the endometrium in infertility,
hyperplasia, and adenocarcinoma of the endometrium. Mesenchymal tumors of the
uterus and their classifications both in terms of cell of origin and biologic behavior will
be presented. We will study the morphology and clinical significance of endometriosis,
as well as theories of its genesis.

Keywords: Endometrium, Myometrium, Uterus, Endometriosis, Smooth muscle tumors,

Hyperplasia, Adenocarcinoma.

Goals and objectives:

The student should know the information in the reading and hand-out. In particular:
1.Understand how morphologic findings of the endometrial glands and stroma are altered
by hormonal status in normal and abnormal conditions.
2.Explain the pathogenesis and categories of endometrial hyperplasia.
3.Distinguish between the two main types of endometrial adenocarcinoma in terms of
morphology, clinical findings, and prognosis.
4.Describe the morphologic distinctions amongst uterine smooth muscle tumors, and
explain their biologic significance.
5.Relate the clinical implications of and pathogenetic theories of endometriosis.

I.Endometrial Dating-one parameter studied in cases of infertility

Gynecologic Pathology II
Pathology of the Uterus

A.Evaulation of endometrial biopsies can reveal whether or not an appropriate response

to ovulation has occurred.

B.Proliferative phase-before ovulation; stimulation of estrogen.

Glandular cells replicate-increased mitotic rate, increased tortuosity of glands.

C.Secretory phase-after ovulation; combined stimulation of progesterone and estrogen.

Glandular cells gain and subsequently deplete vacuoles containing secretions.
Stroma becomes edematous and then demonstrates predecidualization of cells.
Culminates in the lytic changes of menstruation.

D.Correlation of LMP date with histologic findings to look for “luteal phase defect”.

II.Abnormal Uterine Bleeding

Bleeding between menstrual periods (metrorrhagia) or excessive bleeding during
menstrual periods (menorrhagia) or bleeding after menopause (postmenopausal
A.Most likely causes are different in different age groups.

B.Bleeding dyscrasias, lesions of lower genital tract, complications of pregnancy,

infection, adenomyosis, benign and malignant tumors, polyps, hyperplasia,
exogenous hormone effect, dysfunctional uterine bleeding.

C.Dysfunctional uterine bleeding-abnormal bleeding secondary to a functional dis-

turbance rather than a specific organic lesion.
1.Generally seen in setting of anovulation, which leads to unopposed estrogen
stimulation (i.e., no progesterone)-architectural derangements of the endometrial
glands (persistent proliferative or disordered proliferative patterns) which may
be followed by stromal breakdown or progression to hyperplasia and carcinoma.
2.Cause of anovulation is not always discernible, but may be from:
a.endocrine disorder (pituitary, adrenal, thyroid disease)
b. functioning ovarian tumor (such as granulosa cell tumor)or abnormality (such as
polycystic ovarian disease) producing estrogen
c.metabolic (obesity, chronic disease, malnutrition)
3.May also see dysfunctional bleeding secondary to menopause, exogenous
hormones, and luteal phase defect.

D.Clinical evaluation and biopsy used to exclude malignancy and hyperplasia and
determine if the patient requires either surgical or medical therapy.

E.Endometritis-causes bleeding, pain, discharge, and ultimately, infertility.

1.Acute-generally limited to bacterial infections after delivery or miscarriage. This
is why retained products of conception must be removed.
2.Chronic-characterized by plasma cells in the endometrium. Most common causes:
Chronic pelvic inflammatory disease (PID)

Gynecologic Pathology II
Pathology of the Uterus

Postpartal or postabortal, generally with retained products of conception

F.Adenomyosis-nonneoplastic, can cause pain uterine enlargement, bleeding

Endometrial glands and stroma extend deeply into myometrium
“Globular” uterus with visble small cysts in myometrium.

G.Endometrial polyps-sessile or pedunculated mass projecting into endometrial cavity

May cause bleeding
May be associated with hyperplasia
Rarely adenocarcinoma may arise in them
May be associated with use of tamoxifen

H.Endometrial hyperplasia
1.Architectural and sometimes cytologic disturbances of the endometrial glands
2.Potential for development of endometrial adenocarcinoma increases with higher
degrees of abnormality (especially cytologic abnormality)
3.Associated with sustained levels of unopposed estrogen stimulation:
polycystic ovarian disease, estrogen-secreting ovarian tumors, menopause, estrogen
replacement therapy, persistent anovulation, obesity.
4.Architectural abnormalities-simple vs. complex hyperplasia; if there is cytologic
atypia, it is called atypical hyperplasia
a.Simple hyperplasia-glands are cystically dilated while maintaining cellular
stratification and are crowded.
b.Complex hyperplasia-glands show greater crowding, greater variation in size and
shape, complex budding patterns
c.Cytologic atypia of the glandular cells-loss of polarity, nuclear irregularity,
increased N/C ration, prominent nucleoli, more frequent mitoses.
Atypical hyperplasia-may progress to endometrial adenocarcinoma in 25%.
d.It may be nearly impossible to distinguish atypical hyperplasia from adeno-
carcinoma on endometrial biopsies.

III.Endometrial Carcinoma
A.Virtually always presents with abnormal bleeding.

B.Most patients are peri- or postmenopausal-rare under 40 yo.

C.Two types: Type I and Type II

Type I: Generally associated with unopposed estrogen stimulation and hence with
Patient profile: diabetes, obesity, nulliparous, hypertension, infertility.
May also be associated with PCOD, estrogen-secreting ovarian tumors
Usually present at an early stage

Gynecologic Pathology II
Pathology of the Uterus

Histologic types: endometrioid adenocarcinoma and variants, including

endometrioid adenocarcinoma with squamous metaplasia (“adenoacanthoma”)

Type II:Generally occur in older patients than Type I, unassociated with the factors
noted for Type I, unassociated with hyperplasia
More aggressive disease, likely to present at a more advanced stage
Most common histologic type: papillary serous carcinoma;
others include clear cell
Much greater likelihood of dying of disease than Type I

D.Malignant Mixed Mesodermal (Mullerian) Tumor –“MMMT”-carcinosarcoma

Highly aggressive tumor which most likely represents a poorly-differentiated
adenocarcinoma which shows areas that have dedifferentiated into mesenchymal
(“sarcomatous”) components-cartilage, skeletal muscle (“rhabdomyoblastic”),
bone (these are “heterologous”-not native to the uterus) or smooth muscle,
fibroblastic (these are “homologous”-native to the uterus)

E.Staging of endometrial carcinoma (applies to all types)-based on surgical findings

I.Tumor confined to the uterus (depth of invasion important)
II.Tumor involves the cervix
III. Tumor involves uterine serosa, peritoneum, or vagina.
IV.Distant metastases

IV.Mesenchymal tumors of the uterus

A.Leiomyoma (“Fibroid”)-benign smooth muscle tumor
1.Most common tumor in women-25% of women in active reproductive life have
2.Estrogen-responsive: may grow rapidly in pregnancy, may shrink after meno-
3.May be asymptomatic, but symptoms may arise in relation to location:
a.submucosal-abnormal bleeding
b.intramural-abnormal bleeding, pain, bladder compression, infertility
c.subserosal-pain, bladder compression, mass
4.Circumscribed whorled bundles of smooth muscle. Cell nuclei are uniform.
Mitoses are rare.
5.Uncommon variants which may mimic malignancy:
“bizarre” or “symplastic”; “benign metastasizing”; “mitotically active”

B.Leiomyosarcoma-malignant smooth muscle tumor

1.In general, do not arise from benign leiomyomas-arise de novo.
2.In general, mitotic rate is >10/10 high power fields.
3.Usually also see atypia, necrosis, invasive border

C. Smooth Muscle Tumor of Uncertain Malignant Potential

Gynecologic Pathology II
Pathology of the Uterus

Term used when it is difficult to classify as benign or malignant.

D.Endometrial Stromal Tumors

1.Endometrial stromal nodule-well-circumscribed nodule of cells that look like the
endometrial stroma-don’t invade-benign.
2.Low-grade stromal sarcoma (“endolymphatic stromal myosis”)-infiltrative
nodule of cells that look like endometrial stroma, but invade myometrium, blood
vessels, and can spread beyond the uterus and metastasize-low-grade malignancy.
3.Endometrial stromal sarcoma-high grade spindle cell tumor with lots of mitoses,
cytologic atypia, infiltration. Very aggressive malignancy.

V.Endometriosis-endometrial tissue (need to see 2 out of 3 of glands, stroma,

hemosiderin-laden macrophages) outside the uterus.
A.Most common sites: ovaries, uterine ligaments, rectovaginal septum, pelvic
pelvic peritoneum,laparotomy scars.

B.Pain, infertility, dysmenorrhea, ovarian malfunction-symptoms depend on location.

C.Generally seen in reproductive years, may regress.

D.Theories of origin: Tubal regurgitation, coelomic metaplasia, vascular/lymphatic


E.The foci may cycle and bleed, which leads to scarring and, in the ovary, cyst
formation (“endometrioma”).

F.NOT a premalignant condition, but rare malignancies (especially in ovary) may

develop in endometriosis.