Materi

praktikum
patologi anatomi
Modul reproduksi

Learning Objectives
1. Define the cervical transformation zone
.2. Review the endometrial and ovarian changes that occur during the
menstrual cycle.3. List three risk factors for the development of
cervical carcinoma.
4. Explain the role of human papilloma viruses in the pathology of
benign and malignant cervical tumors.
5. Recognize the morphologic and biologic spectrum of cervical
intraepithelial neoplasia and the various terminologies used in
describing Pap smears and tissue sections, such as dysplasia,
cervical intraepithelial neoplasia (CIN), and squamous intraepithelial
lesion.
6. Define PID (pelvic inflammatory disease); describe its common
presentation and sequelae.
7. Describe the following genital infections as they affect the female
genital tract:a. syphilisb. gonorrheac. chancroidd. Chlamydiae.
Trichomonasf. herpesg. human papilloma virusList the infections
that can affect fetal outcome.
8. Compare condyloma acuminatum and condyloma latum.

Scenario

A 33-year-old lawyer who postponed pregnancy in her 20s has now been
trying to get pregnant for several years. Her husband had a son during
a prior marriage.
She presents to her gynecologist for workup of her infertility. Pertinent
history includes: menarche, age 12; coitarche, age 15; eight lifetime
sexual partners; cyclic menses regularly every 28 days; no birth control
for 2 years; no pelvic examination in 5 years. No IV drug use. Pertinent
examination and procedure findings include: a friable, vascular lesion on
the anterior uterine cervix, a Pap smear diagnosis of HGSIL (high grade
squamous intraepithelial lesion) (Image 1), an HPV (human papilloma
virus) assay positive for high-risk HPV serotypes, a cervical biopsy
diagnosis of severe dysplasia (CIN III) (Image 2) with flat condyloma
(Image 3), blocked (nonpatent) fallopian tubes on hysterosalpingogram,
and a microimmunofluorescence test on her cervical mucus that is
positive for Chlamydia trachomatis. She is HIV (human
immunodeficiency virus) negative.

Uterine cervical cytology, Papanicolaou stain (Pap smear)

High power
Normal squamus cells

Dysplastic squamous
cells, High grade

Endocervical cells

In comparison to the normal cervical squamous cells, the dysplastic cells have increased
nuclear:cytoplasmic ratios with enlarged nuclei and coarsely granular chromatin. The
presence of endocervical cells indicates that an adequate specimen was obtained

The Pap smear is considered a screening test. Since its

introduction, has it altered the incidence of cervical
carcinoma?
The Pap smear has greatly decreased the incidence of
cervical carcinoma

Uterine cervix, normal

squamocolumnar junction Low power

This image is for orientation. The

squamous epithelium of the ectocervix
is on the left and the columnar
epithelium of the endocervix is on the
right. Note that the squamous
epithelium has a single layer of basal
cells

Uterine cervix, mild

dysplasia (CIN I) - High
power

In the basal 1/3 of this

epithelium, the cells show
disorganization, crowding,
loss of polarity and failure
to differentiate. The cells in
the upper 2/3 are relatively
normal

Uterine cervix, carcinoma in

situ (CIN III) - Medium power
(Glass slide 133)

high-grade squamous
intraepithelial lesion (CIN III) Medium Power
Mitotic figure

Basement membrane

Note loss of cellular polarity and

differentiation. In situ means
that it has not yet invaded
through the basement
membrane and therefore
cannot yet metastasize.
However, an invasive
squamous cell carcinoma
may arise from this precursor
lesion

Virtually the entire thickness of the cervical

epithelium is affected by dysplastic changes.
Note the cellular and nuclear pleomorphism,
failure of normal and orderly differentiation,
hyperchromatic nuclei, and several mitotic
figures extending toward the surface. Only the
very superficial cells appear to differentiate and
flatten. Although most of the basement
membrane is not completely visible in this
image, it is intact

What are the risk factors for the development of cervical

dysplasia?

Multiple lifetime sexual partners (five or

more), high-risk sex partners (those with:
condyloma, penile carcinoma, multiple
sexual partners, partners who have
condyloma, dysplasia, or cervical
carcinoma), early coitarche

Cervix, low-grade squamous intraepithelial lesion (flat

condyloma) - Low power
koilocytes
Basement membrane
Which human papilloma virus
(HPV) serotypes are associated
with high-grade dysplasia and
carcinoma? HPV serotypes 16, 18,
31, 33, and 35

Flat condyloma, or human papilloma virus infection, is characterized

by the presence of koilocytes, which are squamous cells with
enlarged, wrinkled, dark ("raisinoid") nuclei surrounded by a halo.
The cells are usually found in the superficial half of the epithelium

Cervix, carcinoma Gross

This pink-tan, friable, fungating lesion

on the anterior cervical lip is
characteristic of cervical
carcinoma.
Why can we consider squamous cell
carcinoma (SCCA) of the cervix a
sexually transmitted disease

Uterine cervix, squamous

carcinoma - Very low power

Nodules of tumor have

invaded the wall of the
uterine cervix.

Squamous carcinoma of the cervix is the end point of a progression

of lesions that begins with infection by human papilloma virus
(HPV), probably in tandem with environmental cofactors. Women
who are sexually active can become infected; women who are not
sexually active generally don't get SCCA of the cervix. The risk
factors that predispose sexually active women to develop SCCA are:
young age at first sexual intercourse, especially before age 16 (the
hormonal interactions on the changing cervix of menarche render it
susceptible to infection); multiple lifetime sexual partners (the more
partners, the higher the probability of infection); male sexual
partners who are high risk themselves (they have had condyloma or
penile cancer, other partners with cervical cancer or dysplasia, or
multiple sexual partners); and cigarette smoking.

Cervix, squamous cell carcinoma Low power

Normal squamous cell
epithelium

In situ and invasive scc

At low power, the abrupt transition between the

normal squamous epithelium and the squamous
cell carcinoma (in situ and invasive) can be
appreciated

Carcinoma in situ is confined to the

epithelium, while invasive carcinoma infiltrates
the underlying stroma.
This young woman had two disease
processes: infertility as a sequela of
Chlamydia trachomatis infection, untreated
and asymptomatic for a long time, and
squamous cell carcinoma in situ of the cervix,
a sequela of HPV infection.

How does it transform cells?

The transforming ability is linked to the viral

oncoproteins E6 and E7. Oncoprotein E6 binds to
the product of tumor suppressor gene TP53 and
inactivates it. With loss of TP53 function, cells with
damaged DNA are allowed to progress through the
cell cycle, and ultimately enough mutations
accumulate to give rise to cancer. E7 binds to the
retinoblastoma gene (RB) protein and, in doing so,
displaces the transcription factors that are normally
sequestered by RB; the released transcription
factors drive the cell cycle without restraint.

Uterine cervix, squamous

carcinoma - Medium power
Invasive border

A higher power view shows a nest of malignant squamous cells

(note pleomorphism and invasive border) with little keratin
formation. This squamous carcinoma is not so well differentiated

Uterus, fallopian tubes and ovaries, pelvic inflammatory

disease with tubo-ovarian complexes - Gross

The inflamed fallopian tubes and ovaries have coalesced to form huge tuboovarian complexes in this typical example of pelvic inflammatory disease. The
tubo-ovarian complex on the patient's right has undergone torsion, resulting in
hemorrhagic infarction Which organisms are commonly associated with pelvic
inflammatory disease?
Gonococcus (Neisseria gonorrhoeae), Chlamydia, and enteric bacteria.

Learning Objectives

1. List four settings that may lead to chronic endometritis.

2. Define adenomyosis.
3. Describe the incidence, common locations, three major pathogenetic
potential origins, and the clinical features of endometriosis.
4. Define dysfunctional uterine bleeding (DUB), and describe the
pathogenesis of anovulatory cycles.
5. Explain the relationship between endometrial hyperplasia and
endometrial adenocarcinoma.
6. Describe the risk factors, pathogenesis, clinical features, and spread of
endometrial carcinoma.
7. Describe the typical clinical presentation, possible sequelae, and
microscopic features of uterine leiomyomas. Compare with
leiomyosarcoma.
8. Define malignant mixed Mullerian tumor and endometrial stromal tumor.

A massively obese (5'3", 275 pounds), 55-year-old, sexually active

woman, nulligravida (no pregnancies), presented to her
gynecologist because of vaginal spotting for 1 year. Her medical
history included non-insulin-dependent diabetes mellitus and
medically controlled hypertension, both diagnosed at age 43. Her
gynecologic history included: menarche, age 11; coitarche, age 20;
lifetime sexual partners, 2; 6 menses/year until age 51 when she
became menopausal and her menstrual periods stopped. An
endometrial biopsy yielded abundant tissue (Image 1). Following
the biopsy, the patient was lost to follow-up for 8 years. She is now
brought to the ER after fainting at home. Her hemoglobin is 5 g/dL.
Endometrial biopsy is repeated, followed by a simple hysterectomy
with bilateral salpingo-oophorectomy (Images 2-4).

Uterus, endometrioid
adenocarcinoma - Low power

The endometrium has been replaced by the coalesced malignant

glands of endometrioid adenocarcinoma. Note the superficial
myometrial invasion

What are risk factors for the development of endometrial

adenocarcinoma?

Obesity, diabetes, hypertension, and infertility with

anovulatory cycles. The most likely common thread in
these conditions is unopposed estrogenic stimulation.
Obesity, because of increased peripheral conversion (in
adipose tissue) of steroids to estrogen, increases overall
estrogen levels. Nulligravidity (no pregnancies) can imply
nonovulation, due to lack of cycling (ie, high estrogen
levels). The mechanism of association of diabetes and
hypertension to endometrial adenocarcinoma is less
clear, but we do know that insulin stimulates production
of androgen in the ovary, which is then converted
peripherally to estrogen.

Ovary and fallopian tube,

endometriosis - Gross, cut surface

Endometriosis is often cystic and contains dark blood and debris resembling
chocolate - thus, these lesions are often described as "chocolate cysts."
Questions:
What are other common locations for endometriosis? Uterine ligaments,
rectovaginal septum, and pelvic peritoneum

Colon, endometriosis - Low power

This is a section of colonic wall in which the submucosa and mucosa are involved by
endometriosis. Histologically, endometriosis is composed of endometrial glands and stroma, often
associated with evidence of hemorrhage (hemosiderin). Questions:
What are the potential origins of the development of endometriosis?
Regurgitation through the fallopian tubes; metaplasia of the peritoneum; vascular or lymphatic
invasion.What is a possible complication of endometriosis of the intestines? Obstruction.

Uterus, leiomyomata - Gross

The normal pear shape of the uterus in this image is markedly distorted by
numerous leiomyomata. Leiomyomata are the most common tumors in females.
Although often asymptomatic, they can cause abnormal uterine bleeding and
impaired fertility. Review: Neoplasia Introductory Images Part 1, Image 20 (uterus,
leiomyomata, gross, cut surface)
Questions:
What is the risk of malignant transformation of uterine leiomyomata?
Malignant transformation, if it occurs, is extremely rare.

Uterus, leiomyoma - Medium power

This tumor is composed of interlacing fascicles of bland, spindle-shaped, smooth muscle cells. Review: Neoplasia Introductory
Images Part 1, Image 21 (uterus, leiomyoma)
Questions:
How would the cells in a leiomyosarcoma differ?
Do leiomyosarcomas arise from leiomyomas?
Leiomyosarcomas are more cellular and have pleomorphic nuclei with multiple mitotic figures. Review: Neoplasia Introductory
Images Part 1, Images 23 and 24 (uterus, leiomyosarcoma)

Only very rarely

Uterus, leiomyosarcoma and several leiomyomata - Gross,

cut surface

Compared with several leiomyomata that are also present,

the leiomyosarcoma has a more irregular border and has a
variegated cut surface with areas of necrosis/hemorrhage

Uterus, adenomyosis - Gross, cut

surface

Adenomyosis causes thickening of the myometrium, leading to globular enlargement

of the uterus. Occasionally, small cysts may be seen in the affected myometrium,
which are represented by endometrial glands histologically. Microscopically, benign
endometrial glands and stroma within the myometrium characterize this lesion. :
What symptoms may be associated with this lesion?
QuestionsMenorrhagia, dysmenorrhea, and dyspareunia

Learning Objectives

1. Describe the pathogenesis and clinical features of

polycystic ovarian disease.
2. List the three classifications of ovarian tumors, and cite
the relative incidence of ovarian tumors.
3. Describe and contrast the pathologic and clinical features
of ovarian serous and mucinous cystadenomas, borderline
tumors, and carcinomas.
4. Describe the usual clinical presentation and pathologic
features of mature cystic teratomas.
5. Describe the two most common types of sex cord-stromal
tumors: granulosa-theca cell tumors and fibrothecomas.
6. Define Krukenberg tumor

A 52-year-old, fit, slim former dancer goes to her internist because of vague
abdominal pain and a feeling of fullness. Her medical history is
noncontributory. Her gynecologic history includes: menarche, age 13; coitarche,
age 18; lifetime sexual partners, 3; no IV drug use or transfusions. Her internist
examines her, but can find no problems, so he sends her to a gastroenterologist.
The GI specialist examines her, finds no problems, and orders upper and lower
GI studies, which are negative.
The woman continues to see these physicians, with worsening symptoms, over
five months; it is decided that, because no disease has been found, she needs a
psychiatric consultation to aid with her developing anxiety and depression. The
psychiatrist knows he needs to exclude organic disease before he treats
emotional symptoms, so he performs a physical examination. He notes abdominal
fullness with a fluid wave, consistent with ascites. He also performs a pelvic
examination. A 10-cm left adnexal mass is easily felt. Cytologic examination of
the ascitic fluid is performed (Image 1). At laparotomy, a tumor is diagnosed by
the pathologist by doing a frozen section (Images 2-4). Tumor is found to have
spread to her other ovary, omentum, and numerous sites on her peritoneum. She
receives chemotherapy, but dies one year after diagnosis.

Ascitic fluid cytology, papillary serous

carcinoma - High power

Cluster of neoplastic cell

Cytologic examination of
ascitic fluid often can
provide the diagnosis in
patients with unexplained
ascites. Note the papillary
arrangement of the tumor
cells. Although simple in this
case, differentiation of tumor
cells from benign
mesothelial cells in cytologic
preparations can be
extremely difficult

Why is ovarian carcinoma often discovered at an advanced stage? The relatively hidden location of the ovaries
allows tumors to spread before becoming clinically apparent

Ovary, serous cystadenocarcinoma - Gross, cut

surfaces

This ovarian tumor has both solid and cystic portions. Note the friable, tan-pink papillary
excrescences filling the bisected cystic structure. Other portions of the tumor have a firm,
white, desmoplastic stroma, likely representing invasive tumor. Could this be a mature cystic
teratoma of the ovary?
No. Mature cystic teratomas tend to be cysts filled with hair and sebaceous material. This
ovarian tumor is composed of complex papillary structures with occasional psammoma bodies
Serous cystadenocarcinomas are considered ovarian tumors of surface epithelial origin; what
are the origins of the other two groups of ovarian tumors? Germ cells and ovarian sex cordstromal cells. 65-70% of ovarian tumors arise from surface epithelial cells.

Ovary, serous cystadenocarcinoma

- Medium power
This invasive, high-grade,
papillary serous
carcinoma inciting a
desmoplastic reaction is
best appreciated at this
higher power

How does this tumor differ histologically from a serous tumor of low
malignant potential . In serous cystadenocarcinoma, the epithelium
destructively invades the stroma. They are the most common
malignant ovarian tumor, comprising 40% of all ovarian cancers.

Ovary, serous cystadenoma

Ovary, serous tumor of low malignant

potential (serous borderline tumor

Ovarian serous cystadenomas are typically

unilocular and have a smooth inner surface.
Occasional serous cystadenomas may have
several locules, as in this example. Note the lack
of friable papillae. Friable papillae are
characteristically seen in serous
cystadenocarcinomas or serous tumors of low
malignant potential

In contrast to serous
cystadenomas, serous borderline
tumors have numerous friable
papillae, often covering the inner
cyst surface

the prognosis for a serous

cystadenoma? Excellent;
excision is curative

Ovary, serous tumor of low malignant potential (serous borderline

tumor) - Low power ?

What histologic
characteristic
distinguishes serous
tumors of low malignant
potential from serous
cystadenomas
Serous tumors of low
malignant potential are
lined by complex papillary
structures covered by
epithelium with nuclear
atypia and mitotic activity,
while serous
cystadenomas are lined
by a flat, bland epithelium.

The papillae of serous borderline

tumors are covered by a complex,
atypical epithelium similar to that
seen in serous
cystadenocarcinomas. However,
serous borderline tumors lack the
destructive invasion of the cyst wall
seen in serous
cystadenocarcinomas

Ovary, multilocular mucinous

cystadenoma

Bisected ovarion tumor

High power
Endocervical-like
musinous epithelium

The outside surface of this tumor is smooth, similar to a serous

cystadenoma; however, upon bisection, the typical multilocular
pattern of a mucinous cystadenoma can be seen. Benign,
endocervical-like, mucinous epithelium lines the locules.
Questions:
How does a typical mucinous cystadenoma differ in gross
appearance from a typical serous cystadenoma?
Serous cystadenomas are typically unilocular, whereas
mucinous cystadenomas are typically multilocularA serous
cystadenocarcinoma?
Serous cystadenocarcinomas typically have solid and cystic
components filled with friable papillae.

Ovary, benign cystic teratoma

piamater
(dermoid cyst)
brain

This teratoma has a cystic space

from which hair and keratin debris
(on the right) have been removed. In
the wall of the cyst is a structure
resembling a tooth. Germ cell
tumors can form tissues
representing all three germ cell
layers

Neural tissue resembling a

portion of brain surrounded
by meninges is seen. The
brown pigment is
reminiscent of retina

Ovary, mature cystic teratoma Gross, cut surfaces and contents

Protuberant nodul
with teeth
Hair and sebaceaous
material

These cystic tumors contain hair and sebaceous material and often have a protuberant nodule
(Rokitansky protuberance) that contains numerous types of tissues, including brain, bone, and
even teeth. Where else in the body do teratomas arise?
They occur in testis and, rarely, in the mediastinum, pineal gland, and sacrococcygeal region

Signet ring cells

Ovary, Krukenberg tumor
(metastatic gastric carcinoma)

Mucin stain

Krukenberg tumors are characteristically bilateral, markedly enlarged

ovaries infiltrated with metastatic signet-ring cell carcinoma from the
stomach. The intracytoplasmic mucin of the signet-ring cells stains
pink with a mucin stain.
Other tumors commonly metastasize to the ovariesare endometrial
carcinoma, breast carcinoma, and other gastrointestinal carcinomas.

Ovary, fibrothecoma - Gross, cut

surface
These benign tumors are
firm and scar-like and
may be hormonally active
if the thecoma
component predominates
.
Meigs syndrome is hydrothorax, ascites, and an ovarian
tumor. Fibrothecomas are discovered in middle-aged to
elderly women.
Which of the three groups of ovarian tumors is represented by
this tumor? Sex cord-stromal tumors

Ovary, granulosa cell tumor Gross, cut surfaces

cysts
Intervening solids region

These tumors may be solid, cystic, or partially cystic, as the above example. They are
potentially malignant; however, only 10% behave in a malignant fashion. Questions:
They may also be associated with endometrial hyperplasia or carcinoma. Why?

They often produce large amounts of estrogen, resulting

in unopposed estrogen stimulation of the endometrium.

Learning Objectives

Define ectopic pregnancy and know:

a. the most common site of implantation
b. predisposing factors
c. possible outcomes
d. methods of detection
2. Explain the symptom complex of toxemia of pregnancy, the difference between
preeclampsia and eclampsia, and clinical and pathologic features of toxemia. Explain
the pathogenesis of toxemia.
3. List the lesions included in gestational trophoblastic disease and their relative
malignant potential.
4. Compare and contrast complete and incomplete hydatidiform moles with regard to:
a. histology
b. cytogenetics
c. clinical behavior
5. Identify the most common precursor lesions of gestational trophoblastic disease.
Explain how serum HCG is used to follow patients with choriocarcinoma

A 19-year-old female in the 18th week of pregnancy presents to the emergency

room complaining of vaginal bleeding. Additional history reveals 2 previous
pregnancies, both of which ended in spontaneous abortions.
By physical examination, her uterine size is more consistent with the 24th week of
gestation. Her vagina contains blood, and a few grape-like vesicles are noted
protruding from the cervical os. By ultrasound examination, her endometrial cavity is
filled with vesicles. A fetus is not identified. Serum beta-HCG (human chorionic
gonadotropin) is 500,000 mU/mL.
Dilatation and curettage is productive of abundant bloody, grape-like vesicles
(Images 1-3).
The patient does well following the curettage, is discharged 2 days later, and is lost
to follow-up. However, 4 months following the discharge, she has a grand mal
seizure and is rushed to the emergency room, where she begins to cough up
blood. A chest x-ray reveals multiple pulmonary nodules bilaterally, and a
transbronchial biopsy is performed (Image 4). Her serum beta-HCG is 600,000
mU/mL.

Complete hydatidiform mole - Low

power
Large hydrophilic villi
Exuberant trophoblastic proliferation

Enlarged, hydropic, avascular villi, some with a central cistern (not seen here), surrounded
by an exuberant trophoblastic proliferation are characteristic of a complete mole.
karyotypic analysis of a complete mole reveal 46,XX or XY. All of the chromosomes are
paternal. Karyotypic analysis of a partial mole 69,XXY or XXX. Two sets of chromosomes
are paternal, one maternal

Complete hydatidiform mole sitotrophoblast

Medium power
villus
sinsytiothrophoblast

Higher power displays the exuberant trophoblastic proliferation with cytotrophoblasts

and syncytiotrophoblasts surrounding a villus.
What is the subsequent risk for development of gestational choriocarcinoma following
evacuation of a complete mole? 2.5%.
...a partial mole? Very low.
How does one monitor patients after removal of the molar pregnancy? By serial HCG
(human chorionic gonadotropin) measurement; serum HCG should steadily decline
and disappear by approximately 100 days.

Placenta, normal villi

Uterus, Choriocarsinoma

These are normal third-trimester

chorionic villi. Note the small
size, prominent vasculature, and
lining of cytotrophoblasts and
syncytiotrophoblasts. Compare
this image to the previous three
images.

Choriocarcinoma is also characterized

by an exuberant proliferation of
cytotrophoblasts and
syncytiotrophoblasts; however, no villi
are present.

A common complication of metastatic

choriocarcinoma is Hemorrhage.

Fallopian tube, ectopic pregnancy Gross

An incised, swollen fallopian tube segment reveals a fetus and the adjacent placental
tissues.
Disorder leads to an increased incidence of ectopic pregnancy is Pelvic inflammatory
disease
the typical symptoms of an ectopic tubal pregnancy are Severe abdominal pain, possibly
followed by shock, if there is rupture of the fallopian tube with hemorrhage.