Diseases of Female Reproductive System

Normal Cervical Epithelium
Cervix-
Ectocervix- external mucosal surface of portio vaginalis.
o Stratified nonkeratinizing squamous epithelium
 Basal cells: deepest layer; dense nuclear chromatin,
uniform oval nuclei oriented perpendicular to basement
membrane, scant cytoplasm
 Parabasal cells: located just above the basal cell layer;
slightly more cytoplasm than basal cells; may be multiple cell
layers thick
 Intermediate cells: abundant cytoplasm which may be
pink or clear due to glycogen accumulation
 Superficial cells: small, round nuclei; abundant pink or
clear cytoplasm; cells flatten and are oriented parallel to
basement membrane
-- Rare melanocytes, Langerhans cells and endocrine cells have
been identified.
Endocervix- mucosa lined cylindrical canal leading from

ectocervix to uterine cavity.
o Single layer of mucinous columnar cells with dense,

uniform, oval, basally oriented nuclei and apical mucin
o Mucin has a pale bluish appearance in H&E preparations;
with PAS-Alcian blue stain, apical mucin stains intense blue / purple
(due to the presence of acid type mucin)
o Ciliated cells can be found (usually in the context of
tuboendometrioid metaplasia)
o Inconspicuous underlying reserve cell layer
o Forms infoldings, clefts and glands of variable shape
 Transformation zone
Columnar cells are constantly changing into squamous cells in an area
of the cervix called the transformation (transitional) zone. It is the
most common place on the cervix for abnormal cells to develop.

o Metaplastic cells: formed by endocervical reserve cells
differentiating toward squamous lineage
 Located at transition between glandular and squamous
epithelia
 Similar appearance to parabasal cells with relatively
scant cytoplasm and dense nuclei
o Endocervical epithelium may overlie metaplastic cells
o Variable nonspecific inflammatory infiltrate consisting of
lymphocytes, plasma cells and even neutrophils is common and is
not necessarily associated with infection.
 Cervical stroma
o Mostly fibrous tissue with some haphazard smooth muscle
fibers
o Blood vessels often numerous and prominent.
 Mesonephric rests / remnants

o Remnants of involuted embryologic mesonephric (Wolffian)
ducts
o Present in lateral cervical wall in ~33% of women
o Microscopic clusters of tubules lined by single layer of
cuboidal cells with eosinophilic luminal secretions.
Dysplastic changes with Cervical Epithelium
- Cervical dysplasia is a precancerous condition in which abnormal cell
growth occurs on the surface lining of the cervix or endocervical canal,
the opening between the uterus and the vagina. It is also
called cervical intraepithelial neoplasia (CIN).
- CIN most commonly occurs at the squamocolumnar junction of the
cervix, a transitional area between the squamous epithelium of the
vagina and the columnar epithelium of the endocervix. It can also occur
in vaginal walls and vulvar epithelium. CIN is graded on a 1-3 scale,
with 3 being the most abnormal, classification described below.
Cellular changes associated with HPV infection, such as koilocytes, are
also commonly seen in CIN.
Classification;
CIN 1 (Grade I)Low-grade squamous intraepithelial lesion (LSIL)
 Mild epithelial dysplasia
 Confined to the basal 1/3 of the epithelium
 Typically corresponds to infection with HPV
 High rate of regression back to normal cells
 Usually managed expectantly
CIN 2/3High-grade squamous intraepithelial lesion (HSIL)

 Represents a mix of low- and high-grade lesions not easily
differentiated by histology
 HSIL+ encompasses HSIL, AGC, and cancer
CIN 2 (Grade II)
 Moderate dysplasia confined to the basal 2/3 of the epithelium

 Represents a mix of low- and high-grade lesions not easily
differentiated by histology
 CIN 2+ encompasses CIN 2, CIN 3, adenocarcinoma in situ (AIS),
and cancer
CIN 3 (Grade III)
 Severe dysplasia with undifferentiated neoplastic cells that span

more than 2/3 of the epithelium
 May involve the full thickness
 May also be referred to as cervical carcinoma in situ
 CIN 3+ encompasses CIN 3, AIS, and cancer
CIN3
A= CIN1; Prominent koilocytotic atypia in the upper epithelial cells, as evidenced

by the prominent perinuclear halos
B= CIN1; Nuclei acid in situ hybridization of the same lesion shown in A for HPV
nucleic acids, the blue staining denotes HPV DNA, which is typically most
abundant in the koilocytes.
C= CIN2; Diffuse immunostaining for Ki-67; illustrating widespread deregulation of
cell cycle controls.
D= CIN3; Up-regulation of p161NK4 (seen as intense immunostaining)
characterizes high-risk HPV infections.
The cytology of cervical intraepithelial neoplasia as seen on the Papanicolaou
smear.
Cytoplasmic staining in superficial cells (A&B) may be either red or blue.
A= Normal exfoliated superficial squamous epithelial cells.
B= CIN I.
C= CIN II.
D= CIN III.
Here, the reduction in cytoplasm and the increase in the nucleus to cytoplasm
ratio, occurs as the grade of the lesion increases. This reflects the progressive loss
of cellular differentiation on the surface of the lesions from which these cells are
exfoliated.
HPV Immunization
Cervical cancer and HPV types- HPV types 16 and 18 are responsible for
about 70% of all cervical cancer cases worldwide. After HPV16/18, the
six most common cervical cancer-causing HPV types are 31,33,35,45,52
and 58.
HPV vaccines that protect against HPV infections theoretically prevent

women from developing pre-cancerous lesions and cervical cancer
(Prophylactic vaccine).;
HPV vaccine that control the HPV infected cells theoretically treat
women with active disease or act as adjuvant (Therapeutic vaccine).
HPV vaccine target antigens- capsid proteins L1 and L2, replication
proteins E1 and E2, oncoproteins E6 and E7
Ideal HPV vaccine-

- Safe and effective.
- Both prophylactic and therapeutic
- Single inoculation with long term protection.
- Cheap and easy to handle and administer.
Vaccine types; virus Like particles (VLPs), recombinant live vector

vaccine, protein and peptide vaccines, “naked” DNA vaccines, edible
vaccines.
There are two VLPs vaccines commonly licensed in many countries

around world.
- Gardasil (Bivalent): HP16 and HP18
{0,1,6}
AS04 Adjuvant (MPL+ Alum)
- Cervarix (Quadrivalent): HPV 16, HP18,
HPV 6, HPV 11
{0,2,6}
Aluminium as adjuvant
IM injections at 0,1 or 2, 6 months.
Vaccination, when and whom?
Recommended; at age 11-12

-before sexual exposure.
-high probability of HPV acquisition within several yrs of sexual

exposure.
-immune system ‘ages’ after puberty.
===Ab level after vaccination 9-10y> 13-15y>16-23y
Vaccination <9 yrs and >26yrs- not licensed for use or not so in use due
to less effectiveness in these ages.
Vaccination in sexually active female
- May have less benefit since may have already been affected.
- Unlikely that they acquired all 4 types.
- Even if the patient has been infected, vaccination would

provide protection against infection with HPV vaccine types
not already acquired.
Vaccine schedule
Two doses of the HPV vaccine are recommended at ages 11–12; the
vaccine can be given as early as age 9. If waited until they’re older, they
may need three doses instead of two.
Children who start the vaccine series on or after their 15th birthday
need three shots given over 6 months.
- Dosing schedules with the vaccines are at 0,1 to 2 months

and 6 months.
- Minimum intervals are 4 weeks between doses 1 and 2, 12
weeks between 2 and 3(if), and 24 weeks between the first
and third doses.
Some Ovarian Tumors with Morphology
Serous tumors
-cysts lined by tall columnar, ciliated epithelial cells and filled with
serous fluid.
Types;
A. Benign serous tumors

-Cystadenomas
- Columnar cells seen lining wall of cysts and papillae in better

differentiated tumors, abundant cilia found.
Cystadenofibroma—well differentiated glands embedded within a

dense fibrous stroma.
B. Borderline tumors
- Serous Borderline tumors
- entirely increased complexity of stromal papilla with stratification

and nuclear atypia.
- But there is no infiltrative growth into stroma.
- Epithelial stratification (2-3 Layers)

C. Malignant Serous Tumors
== Serous Cystadenocarcinoma
- Complex papillary architecture.

- Malignant cells in glandular pattern.
- Nuclear Atypia.
- High mitotic activity.
- Stratification
- Stromal invasion.
*Thus, Papillary serous cystadenocarcinoma; microscopic features

include stratification of low columnar epithelium lining the inner
surface of the cyst and a few psammoma bodies. The stroma shows
invasion by cluster of anaplastic tumor cells.
Mucinous tumors
A. Benign tumors;
===Cystadenoma, cystadenofibroma
Cystadenoma- benign cysts lined by a single layer of tall columnar

mucinous epithelium without cilia, basally placed nuclei and large
apical mucinous vacuoles. Glisening mucin.
B. Borderline Mucinous tumors;

Two types- intestinal and endocervical type
Endocervical type
- Associated with endometrosis

- Lining of tall non-ciliated cells
- Basally located nuclei
- Abundant intracellular mucin
Intestinal type
- Epithelial lining with “picket fence appearance.”

- Intestinal type lining may be several layers thick.
- Mild to moderate nuclear atypia no stromal invasion.
- Goblet cells
C. Malignant tumors;
==Malignant adenocarcinoma
- Cell atypia
- Increased layering
- Gland complexity
- Papillae
- Areas of stromal invasion
Teratoma
- Immature
- Mature; solid, cystic (dermoid cyst)
- Monodermal (e.g. struma ovarii, carcinoid)
Immature teratoma
- Varies from small foci to a predominant component and is

composed primarily of neuroectodermal elements;
neuroepithelial rosettes and tubules, cellular foci of
mitotically active glia, and, occasionally small areas
resembling glioblastoma multiforme or neuroblastoma.
- Mature components of varying amounts may also be seen.
Dermoid Cyst
- Adult-type tissues, usually representing all 3 germ layers,
sometimes arranged in an organoid fashion. Small foci of
fetal-type tissues may occur.
- Ectodermal(predominate)>mesodermal>endodermal
- Neuroectodermal elements can incite a florid vascular
proliferation.
- Escaped cyst contents elicit a characteristic
lipogranulomatous response in the wall of the cyst or the
surrounding.
Carcinoid teratoma
 Resembles carcinoid tumors elsewhere; nuclear features of

neuroendocrine tumor such as salt and pepper chromatin may be
helpful but are also seen in follicular cells of strumal carcinoid
 Patterns are insular (resembles appendix or small bowel tumors),
trabecular (resembles stomach or rectal tumors), strumal (below),
mucinous
o All have a gastrointestinal counterpart except strumal
carcinoid
o Mixed primary ovarian carcinoids, such as insular and
trabecular or strumal and goblet cell do exist
 May have abundant fibrous stroma rich vessels
 Rarely has prominent pleomorphism, mucinous features or signet
ring pattern
REFERENCES
Robbins and Cotran Pathologic Basis of Disease
Wikipedia
Various sources on internet
SUBMITTED BY
Salon Lamichhane
BDS (2018)
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Diseases of Female Reproductive System

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Normal Cervical Epithelium

Endocervix- mucosa lined cylindrical canal leading from

o Single layer of mucinous columnar cells with dense,

 Mesonephric rests / remnants

CIN 2/3High-grade squamous intraepithelial lesion (HSIL)

CIN 2 (Grade II)

 Moderate dysplasia confined to the basal 2/3 of the epithelium

CIN 3 (Grade III)

 Severe dysplasia with undifferentiated neoplastic cells that span

A= CIN1; Prominent koilocytotic atypia in the upper epithelial cells, as evidenced

HPV vaccines that protect against HPV infections theoretically prevent

Ideal HPV vaccine-

Vaccine types; virus Like particles (VLPs), recombinant live vector

There are two VLPs vaccines commonly licensed in many countries

- Cervarix (Quadrivalent): HPV 16, HP18,

Vaccination, when and whom?

Recommended; at age 11-12

-high probability of HPV acquisition within several yrs of sexual

-immune system ‘ages’ after puberty.

===Ab level after vaccination 9-10y> 13-15y>16-23y

Vaccination in sexually active female

- Unlikely that they acquired all 4 types.

- Even if the patient has been infected, vaccination would

- Dosing schedules with the vaccines are at 0,1 to 2 months

A. Benign serous tumors

- Columnar cells seen lining wall of cysts and papillae in better

Cystadenofibroma—well differentiated glands embedded within a

- Serous Borderline tumors

- entirely increased complexity of stromal papilla with stratification

- But there is no infiltrative growth into stroma.

- Epithelial stratification (2-3 Layers)

- Complex papillary architecture.

*Thus, Papillary serous cystadenocarcinoma; microscopic features

Cystadenoma- benign cysts lined by a single layer of tall columnar

B. Borderline Mucinous tumors;

- Associated with endometrosis

- Epithelial lining with “picket fence appearance.”

- Varies from small foci to a predominant component and is

 Resembles carcinoid tumors elsewhere; nuclear features of

Various sources on internet

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