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PATHOLOGY OF FEMALE

REPRODUCTION
SYSTEM
CERVIX
 Normal appearance :
 The portio (ectocervix) :
covered by a stratified nonkeratinizing
squamous epithelium
 Endocervix:
lined by columnar, mucus secreting
epithelium
 The point at which the squamous &
columnar epithelim meet is the
squamocolumnar junction
 The portion of the columnar ept. that
is replaced by squamous ept. is termed
“transformation zone”which is
unstable and susceptible to dysplastic
changes by external factors
ECTOCERVIX
CERVICAL DYSPLASIA &
CARCINOMA
 HPV infection :
 Low risk serotypes ( 6, 11, 42, 43, 44) lead to
condyloma acuminatum and low grade dysplasia

 High risk serotypes (16, 18, 31, 33, 34, 35, 39, 45, 51,
52, 56, 58, 59, 66, and 68 to 70) lead to high grade
dysplasia or even invasive carcinoma
Clinical manifestations HPV type
Plantar warts 1, 2, 4, 63.
Common warts 2, 1, 7, 4, 26, 27, 29, 41, 57, 65, 77, 3,
10, 28.
Flat warts 3, 10, 26, 27, 28, 38, 41, 49, 75, 76.
Other cutaneous lesions (e.g., 6, 11, 16, 30, 33, 36, 37, 38, 41, 48,
epidermoid cysts, laryngeal 60, 72, 73.
carcinoma)
Epidermodysplasia verruciformis 2, 3, 10, 5, 8, 9, 12, 14, 15, 17, 19, 20,
21, 22, 23, 24, 25, 36, 37, 38, 47, 50.
Recurrent respiratory papillomatosis 6, 11.
Focal epithelial hyperplasia de Heck 13, 22.
Conjunctival papillomas/carcinomas 6, 11, 16.
Genital warts (condyloma 6, 11, 30, 42, 43, 45, 51, 54, 55, 70.
acuminatum)
Low-risk cervical intraepithelial 6, 11, 16, 18, 31, 33, 42, 43, 44, 45,
neoplasia 51, 52, 74.
High-risk cervical intraepithelial 16, 18, 6, 11, 31, 34, 33, 35, 39, 42,
neoplasia 44, 45, 51, 52, 56, 58, 66.
Cervical carcinoma 16, 18, 31, 45, 33, 35, 39. 51, 52, 56,
58, 66, 68, 70.
Other genital carcinomas (vagina, 16, 18, 31, 45, 33, 35, 39. 51, 52, 56,
vulva, penis and anus) 58, 66, 68, 70.
Risk factor for cervical neoplasia:
 early stage at first intercourse
 multiple sexual partners
 increased parity
 A male with multiple previous sexual partners
 The presence of a cancer-associated HPV
 The persistent detection of high-risk HPV, particularly in high
concentration
 Exposure to oral contraceptives & nicotine
 Genital infections (chlamydia)
 A long term process, preventable by intercepting the dysplastic
process at early stage  cell cytology screening & monitoring
tools in women population at risk  positive : colposcopy &
biopsy
 Human papillomavirus preferentially infects cells in the
cervical transformation zone, an area of active cell turn-over.

 Basal cells, which feature the HPV receptor, are a natural


target for infection.

 The virus remains in the cell in a latent state until activation


causes viral replication and squamous dysplasia.

 Low-grade squamous intraepithelial lesion/cervical


intraepithelial neoplasia 1 (LSIL/CIN 1) is characterized by
koilocytotic atypia, nuclear enlargement,hyperchromasia,
and perinuclear cytoplasmic clearing.

 These features are the result of viral proteins that affect DNA
synthesis and the structure of intermediate filaments in the
host cell cytoplasm.
 Human papillomavirus gene expression is tightly controlled
in LSILs, which result from productive infections of cells that
have begun the process of differentiation.

 High grade squamous intraepithelial lesions/cervical


intraepithelial neoplasia 2 to 3 (HSILs/CIN 2–3) do not
support HPV genomic replication and, therefore, do not
usually have the nuclear or cytoplasmic characteristics of an
active viral infection.

 Studies have shown that HSIL may also develop


independently without progression or transformation from
LSIL; instead, they likely arise de novo from epithelium
adjacent to LSIL
PAP SMEAR
PAP SMEAR
Colposcopic view of the cervix :
A. in the reproductive age woman
B. the postmenopausal cervix
MULTIPAROUS
NORMAL TO DYSPLASTIC
NORMAL TO DYSPLASTIC
 Figure 1. A, Benign squamous mucosa with glycogenization
of cytoplasm forming pseudokoilocytes. The process involves
the entire epithelium (hematoxylin-eosin, original magnification
×40).

 B, Low-grade squamous intraepithelial lesion (cervical


intraepithelial neoplasia 1) with true cytologic atypia,
koilocytosis, and parabasal proliferation (hematoxylin-eosin,
original magnification ×400).
 Figure 6. Stratified mucin-producing intraepithelial lesion
(hematoxylin-eosin, original magnification ×200).

 Figure 7. Superficial invasive squamous carcinoma arising


from endocervical gland involved by high-grade squamous
intraepithelial lesion (cervical intraepithelial neoplasia 3)
(hematoxylin-eosin, original magnification ×100).

 Figure 8. A, High-grade squamous intraepithelial lesion


(cervical intraepithelial neoplasia 2 [CIN 2]) (hematoxylin-
eosin, original magnification ×40). B, p16
immunohistochemical stain of CIN 2 (original magnification
×40).
GRADING
 For CIN there must be nuclear abnormalities all the way to the
surface epithelium for all grades 1–3

 Grading CIN: grades 1–3 show nuclear atypia (= enlargement,


pleom., ↑NCR, variable hyperchromasia, irregular nuclear
membranes, coarse chromatin and usu. lack of prominent
nucleoli) & evidence of maturation lack occupying no more
than the 1st, 2nd or 3rd thirds of the epithelial thickness
respectively. Full thickness atypia (± slight surface flattening)
is CIS (a subtype of CIN3)
 CIN I or flat condyloma. characterized by koilocytotic changes
mostly in the superficial layers of the epithelium. Koilocytosis, is
composed of nuclear hyperchromasia and angulation with
perinuclear vacuolization produced by cytopathic effect of HPV.
 CIN II the dysplasia is more severe, with maturation of keratinocytes
delayed into the middle third of the epithelium. It is associated with
some variation in cell and nuclear size, heterogeneity of nuclear
chromatin and mitoses above the basal layer, extending in to the
middle third of the epithelium. The superficial layer of cells shows
some differentiation, and in some cases it shows the koilocytotic
changes described.
 CIN III, marked by even greater variation in cell and nuclear size,
marked chromatin heterogeneity, disorderly orientation of the cells,
and normal or abnormal mitoses; these changes affect virtually all
layers of the epithelium and are characterized by loss of maturation.
Differentiation of surface cells and koilocytotic changes have usually
disappeared
BETHESDA CLASSIFICATION SYSTEM 2011

Epithelial cell abnormalities:


 Squamous cell :
Atypical squamous cell (ASC)
 Of undetermined significance (ASC-US)
 Cannot exclude HSIL (ASC-H)
 Low-grade squamous intraepithelial lesion (LSIL)
 Encompassing :Human papillomavirus, Mild dysplasia,
Cervical intraepithelial neoplasia 1(CIN 1)
 High-grade squamous intraepithelial neoplasia (HSIL) :
Encompassing moderate and severe dysplasia, carcinoma
in situ, CIN 2 and CIN 3
 Squamous cell carcinoma
CERVICAL CARCINOMA
 80% to 85% are of squamous cell histology
 15% to 20% are mostly adenocarcinomas or
adenosquamous carcinomas.
FIGO Staging of Cervical Carcinoma (Old = 1988; New = 1995) :

 Istage
 confined to the uterus (corpus extension does not change the
but worsens the prognosis)

 II extracervical but not to the pelvic walls/lower third vagina (IIB =
parametrial involvement)

 III  confined to pelvis but extends to walls/lower vagina or causes


hydronephrosis/non-functioning kidney

 IV  mucosa of bladder/rectum involved or extrapelvic spread (IVB


= distant mets)
CIN I & MILD KOILOCYTOSIS
CIN I & MITOTIC ABNORMALITY
CIN II & KOILOCYTOSIS
CIN III & SUPERFICIAL
PARAKERATOSIS
CIN III & GLANDULAR
ENVOLVEMENT
CIN III VAGINAL VIEW
CERVICAL CA
CERVICAL CA
CERVICAL CA
ENDOMETRIAL HYPERPLASIA

 An excess of estrogen relative to progestin, prolonged or


marked  induce exaggerated endometrial proliferation
(hyperplasia), can be preneoplastic.

 The severity of hyperplasia is classified based on


architectural crowding and cytologic atypia, ranging from
simple hyperplasia to complex hyperplasia, and finally
atypical hyperplasia

 Complex architecture associated with cytologic atypia


has a 20% risk of developing carcinoma
 The hyperplastic process may not involve the entire
endometrium

 Subdivided:
– Simple hyperplasia vs complex hyperplasia
– Atypical hyperplasia vs hyperplasia without atypia

 Atypia based on cytologic features; simple versus complex


based on extent of glandular complexity and crowding

 ~23% of atypical hyperplasias progress to carcinoma,


whereas <2% of hyperplasias without cytologic atypia
progress to carcinoma
 Risk factors :
1. anovulatory cycles
2. polycystic ovary syndrome
3. estrogen-producing ovarian tumor
4. obesity
5. hormone intake
 Anovulatory cycles consist of persistence of the Graafian follicle without
ovulation.

 This results in continued and excess estrogen production without the normal
postovulatory rise in progesterone levels. With no progesterone production, no
secretory endometrium is formed.

 Instead, biopsies reveal nonsecretory (proliferative) endometrium with mild


hyperplasia.

 The mucosa becomes too thick and is sloughed off, resulting in the abnormal
bleeding. Anovulatory cycles characteristically occur at menarche and
menopause. They are also associated with polycystic ovary (Stein-Leventhal)
syndrome.

 It is important to note that other causes of unopposed estrogen effect can lead
to this appearance of a proliferative endometrium with mild hyperplasia.

 These causes include exogenous estrogen administration or estrogen-


secreting neoplasms, such as a granulosa cell tumor of the ovary or an
adrenal cortical neoplasm.
 Endometrial hyperplasia, related to excess estrogens, is important clinically
because of its relation to the development of endometrial adenocarcinoma. The
types of endometrial hyperplasia include simple hyperplasia, complex
hyperplasia, and atypical hyperplasia.

 Simple hyperplasia, which histologically resembles proliferative-type


endometrium, was previously classified as mild hyperplasia or cystic
hyperplasia. In cystic hyperplasia, some glands become dilated or form cysts.

 Complex hyperplasia consists of crowded endometrial glands having budding,


but no cytologic atypia, while atypical hyperplasia is characterized by complex
glandular crowding with cellular atypia.

 The most important prognostic feature is the presence of cytologic atypia.


Therefore, both simple hyperplasia and complex hyperplasia are lower- grade
hyperplasias, while atypical hyperplasia, which used to be called adenomatous
hyperplasia with atypia, is a higher-grade hyperplasia. Adenocarcinoma is
characterized by stromal invasion. Endometrial polyps are benign sessile
masses that are found within the uterine cavity.
Morphology
 Glands:stroma ratio usu. ≥ 3:1 (may be very high in complex
hyperplasia or ≈ normal is simple)

 Gland architecture:
simple (dilated glands ± occ. buds/infolds);
branches,
complex (more crowding and irregular shapes with
r
‘hand-in-glove’, etc. but still with stroma between
glands); characteristically have back-to-back glands with
papillary intraluminal infoldings

 Nuclear cytology: non-atypical/atypical (↑size, rounding,


vesicular, irregular membrane, prominent nucleoli, coarse
r
chromatin, normal mitoses, ± marked stratification) –
compared to uninvolved glands
ENDOMETRIAL HYPERPLASIA
ENDOMETRIUM
PROLIFERATIVE PHASE
ECTOPIC PREGNANCY
 Implantation of the fetus in any site other than a normal
uterine location
 90% is within the tube, the other site are the ovary,
abdominal cavity, & intrauterine portion of fallopian tube
 Majority (75–80%) occur in the ampulla, 10–15% isthmic, 5%
at the fimbriae
 Previous history of pelvic inflammatory disease in 35– 45%
of all cases
If not recognized, rupture typically occurs around the
eighth gestational week
ECTOPIC PREGNANCY
ECTOPIC PREGNANCY
 Right: muscular wall of
the tube
 Lumen:contains blood
clot & chorionic villi,
sheets of trophoblast
 The epithelial lining of
the tube has been
replaced by well-
developed decidua
HYDATIDIFORM MOLE
 Fertilization of 2 spermatozoa  blunted or normal egg
 Characterized by cystic swelling of the chorionic villi,
accompanied by variable trophoblastic proliferation
 Two types:
- complete mole: all or most villi are edematous, diffuse
trophoblast hyperplasia, > 90% have a 46,XX diploid
pattern
- partial mole: some of the villi are edematous, the
trophoblasic proliferation is focal, the karyotype is
triploid (e.g 69,XXY)
Feature Complete Partial mole
mole

Karyotype 46,XX (46,XY) Triploid


Villous All villi Some villi
edema
Trophoblast Diffuse, Focal, slight
proliferation circumferential
Atypia Often present Absent
Serum hCG Elevated Less elevated
hCG in tissue ++++ +
Behavior 2% choriocarc. Rare chorioca.
HYDATIDIFORM MOLE
HYDATIDIFORM MOLE
OVARIAN CANCER
 The fifth leading cause of cancer deaths in
women
 The leading cause of death from
gynecological malignancy
 The second most commonly diagnosed
gynecologic malignancy.
 The “silent killer”: asymptomatic in early
stages
PATHOLOGY OF OVARIAN TUMOR
A. Epithelial (over 90% of ovarian tumor)
 Serous:
 Cystadenoma, papillary cystadenoma, or cystandenofibroma
 adenocarcinoma
 Mucinous
− Cystadenoma, Rupture pseudomyxoma peritonei
− Cystadenocarconoma (solid)
 Endometrioid (rare)
 Clear cell (mesonephroid).
− Mullarian in origin and usually aggrisive
 Transitional cell (Brenner) tumor
 Mixed mesodermal/carcinosarcoma
 Mixed epithelial and undifferentiated epithelial tumors

 Borderline tumors (low malignant potential) good prognosis (97% 5-


yrs survival)
B. Non-epithelial (10% of ovarian malignancies)
(BHCG, AFP, LDH)

1. Germ cell tumors:


Peak incidence in early 20s

 Dysgerminoma
 is the most common
 If diagnosed early they are potentially curable
 Radio and chemo-sensitive
 Treated by chemotherapy to preserve ovarian function
 Good prognosis (90% survival)
2. Sex cord-stromal tumors
 Majority are granulosa cell tumors
 Occur at any age
 surgery is treatment of choice

 Granulosa cell tumor


 Adult:
 the mean age 52 yrs.
 secretes oestradiol  endometrial hyperplasia or carcinoma
 Some are androgenic,
 inhibin is the tumor marker
 Most are stage one and unilatral
 Requires long term follow up
 Often good prognosis, poor prognosis with advanced stage
and recurrence.
 Juvenile:
 Unilateral and large
 5% malignant and aggressive, treated by chemotherapy
 Sertoli stromal cell tumor:
 Tumor contains: sertoli cells, leydig cells.
 Occur at any age
 May secrete estrogen, androgen, AFP
 Commonly present with menstrual disturbance in
premenopausal woman.
 Treatment usually surgery then chemotherapy
3. Metastatic tumor:
 10% are secondary tumors
 Commonly from endrometrium then stomach
(Krukenburg)), colon, breast, lung, and pancreas.
Risk factors
 The majority of women with
ovarian cancer have no known
risk factors
( >90% spontaneous)
 Most significant risk factor is
genetic predisposition
Risk factors: Heredity
 Up to 10% of epithelial ovarian cancer
cases are familial

 Familial breast-ovarian cancer syndrome:


BRCA1 BRCA2 are suppressor gene;
account for 90% of familial ovarian cancers
Additional Risk Factors
 Age
 Women over age 55
(postmenopausal )  Personal history of
breast cancer
 Reproductive history
 early menarche, late
 Family History of breast
menopause, nulliparity or
or ovarian cancer
first child at age >30

 Fertility drugs  Talcum powder


 prolonged use of Clomid, ◦ Some studies have shown
especially without slightly increased risk in
achieving pregnancy women who use talc
(controversy) powder on genital area
Protective factors
 Multiparity: First pregnancy before age 30
 Oral contraceptives: 5 years of use cuts risk
nearly in half
 Breast feeding
 Tubal ligation
 Hysterectomy
 Lactation
 Bilateral oopherectomy
PAPILLARY CYSTADENOCARCINOMA
SEROSUM OVARIUM
 This was a large tumor with
many cystic cavities filled with
watery fluid. One cystic cavity is
shown
 It is lined by deeply basophilic
epithelium which forms long
papilliferous processes.
 The epth. grown outwards,
penetrating the fibrous wall of
the cyst to reach the serosa
FIBROADENOMA MAMMAE
 Tend to be found in younger woman (20-35 years)
 Very rarely become malignant
 Forms a firm well-defined mass, up to about 3 cm in
diameter

 Are mixed tumours, in having both epithelial &


connective tissue components

 Clinically, fibroadenomas are rubbery, freely movable,


oval nodules that usually measure 2 to 4 cm in
diameter.
Morphology
 Two main histological features : intracanalicular and
pericanalicular  often both types are found in the
same tumor

 A) Intracanalicular fibroadenoma : stromal proliferation


predominates and compresses the ducts, which are
irregular, reduced to slits.

 B) Pericanalicular fibroadenoma : fibrous stroma


proliferates around the ductal spaces, so that they
remain round or oval, on cross section. The basement
membrane is intact.
FIBROADENOMA MAMMAE
FIBROADENOMA MAMAE
FIBROADENOMA MAMAE
 The tumor consist of
both stromal &
glandular hyperplasia
 The stromal
underwent a
myxomatous
degeneration
 The duct dilatated, &
the epithelial nuclei
normal
 The nodules are
surrounded by bands
of denser fibrous
tissue
Risk Factors for Breast Cancer
in Women
 History of breast cancerBRCA1 or BRCA2 mutations
 Increasing age
 Early menarche
 Late menopause
 Nulliparity
 First birth after the age of 30
 Atypical lobular hyperplasia or atypical ductal hyperplasia
 Prior breast biopsies
 Long-term postmenopausal estrogen replacement
 Early exposure to ionizing radiation
INVASIVE DUCTAL CARC. MAMAE

 The tumor cell are polygonal hyperplastis, some give a ductuli appearance
with central necrosis

 The stromal is fully invaded by the tumor cells