Cervix : Nonneoplastic lesions4 and neoplastic
lesions, specimen handling and grossing,
Effects of Estrogen and Progesterone
The cervical mucus is subject to profound cyclic changes.
immunohistochemistry and updates.
Under estrogenic stimulation, the endocervical secretions
are profuse, watery, and alkaline, facilitating sperm pene-
tration. During the postovulatory phase, secretions are
scant, thick, and acid, containing numerous leukocytes
and act as a barrier to sperm penetration. Endocervical
• Dr Tanushri Mukherjee MD DNB Pathology, Trained in Oncopathology,
secretory activity operates by both the apocrine and the
merocrine type of expulsion of secretory products [24]. In
the former, a portion of apical cytoplasm packed with
Affiliate member of RCPath London
secretory granules is detached whereas, in the latter, secre-
tory products are released from apical granules through
pore-like openings of the surface cytoplasmic membrane.
4
Langerhans Cells and Lymphoid-Derived
Cells
Mucosal immunity is an important component of the host’s
Common iliac
defense mechanism against viral and bacterial pathogens.
lymph nodes
Components of the secretory (IgA antibody mediated),
humoral (IgG antibody mediated) as well as the cellular
immune systems are present in the cervix. A variety of
lymphocyte and dendritic macrophage subsetsExternal are iliac
present
lymph nodes
in both the epithelium of the exo-Uterineandartery
endocervix as well
as the subepithelial
Lymph
nodes
stroma [68]. Dendritic cells include
both mature and immature forms. TheyInternal areiliacprimarily
lymph nodes
. Fig. 4.2
Anatomy of the cervix. The blood supply and lymphatic
drainage of the cervix are demonstrated
the substance and is located mainly in the endocervix, the
portio vaginalis being nearly devoid of smooth muscle
fibers. In contrast, at the isthmus, 50–60% of the supportive
tissue consists of concentrically arranged smooth muscle,
which acts as a sphincter.
Squamous Epithelium
Histology
The mature nonkeratinized squamous epithelium of the
exocervix is similar to the vaginal epithelium but under
normal circumstances lacks the rete pegs seen in the
vagina. It is divided into three zones: the basal/parabasal
or germinal cell layer, which is responsible for continuous
epithelial renewal, the midzone or stratum spinosum,
the dominant portion of the epithelium, and the superfi-
cial zone, containing the most mature cell population
. Fig. 4.9(> Fig. 4.3).
EndocervicalThe basal/parabasal
mucosa. or germinal layercells
When endocervical contains two
engage
types of cells. One type is the true basal cell, which is
apocrine secretion, portions of atypical cytoplasm are
about 10 mm in diameter, with scant cytoplasm and oval
expelled nuclei oriented perpendicularly to the underlying basal
lamina (> Fig. 4.4). The other type of cell is termed the
parabasal cell because of its geographic placement.
Parabasal cells are larger than basal cells and have more
Benign Diseases of the Cervix 161
responsible for antigen recognition and the earliest stage
of cellular immune response.
Large numbers of T lymphocytes are also present in the
cervix under normalConditions [47]. CD3+ T lympho-
cytes are concentrated in a band directly beneath both
the squamous epithelium of the exocervix and the colum-
nar epithelium of the endocervix [47, 72]. These cells
are predominately cytotoxic T-lymphocytes (e.g., CD8+),
although helper T lymphocytes (e.g., CD4+) are also pre-
sent. Variable numbers of B lymphocytes and plasma cells
are also found in the lamina propria of the cervix [47].
Because the presence of lymphocytes as well as lymphoid
follicles (> Fig. 4.10) is a normal finding in the cervix, the
diagnosis of chronic cervicitis should be reserved for spec-
imens showing a marked infiltration of lymphocytes.
Benign Diseases of the Cervix 157
The Transformation Zone
The squamocolumnar junction of the cervix is defined as
the border between the stratified squamous epithelium
and the mucin-secreting columnar epithelium of the
. Fig. 4.3
Normal squamous epithelium. The mature squamous
epithelium of the portio of the cervix shows a gradual
ascending maturation, vacuolization of midzone cells, and
a single layer of basal cells in which the nuclei are
perpendicularly oriented to the basal lamina. The stromal–
epithelial junction contains finger-like, fibrovascular
stromal papilla penetrating the lower portion of the
epithelium
Epithelial regeneration is the major function of
the basal and parabasal layers. Accordingly, epidermal
growth factor receptors including HER-2/neu, and recep-
tors for estrogen and progesterone are found predomi-
nantly in the basal and parabasal cells [8, 54]. The number
of growth factor receptors becomes reduced as the
squamous epithelial cells differentiate into the intermedi-
ate cell layer. Basal cells appear to act as stem cells, whereas
parabasal cells comprise the actively replicating com-
partment. Indeed, mitotic figures are usually found in
parabasal but not basal cells, and other markers for actively
proliferating cells such as Ki-67 antigen, PCN, and other
cyclins are localized to parabasal cells (> Table 4.1)
. Fig. 4.10
[12, 60, 80].
in The midzone
Lymphoid is occupied by cells
follicles. that are undergoing
Occasional lymphoid follicles can be
maturation, characterized by a gradual increase in the
seen in the cervical stroma in the absence of cervicitis
volume of the cytoplasm. Nuclear size, however, remains
stable up to the most superficial cell level. These cells are
referred to as intermediate cells when they exfoliate. They
do not divide. Intermediate cells have abundant periodic-
acid Schiff (PAS)-positive, diatase-labile intracellular gly-
• 1 Anatomy and Development of the Uterine Cervix and Its Implications
for the Pathogenesis of Cervical Cancer
• 2 Human Papillomaviruses (HPVs)
• 3 Benign Lesions of the Cervix
• 4 Cervical Squamous Intraepithelial Lesions
• 5 Squamous Cell Carcinoma of the Cervix
• 6 Endocervical Adenocarcinoma In Situ/Cervical Glandular Intraepithelial
Neoplasia and Adenocarcinoma of the Usual Type
• 7 Non-Human-Papillomavirus (HPV)-Related Adenocarcinomas and
Their Precursors
• 8 Mesenchymal and Mixed Epithelial-Mesenchymal Neoplasms of the
Cervix
• 9 Other Cervical Neoplasms
 Anatomy and Benign lesions
Gross Anatomy .
Histology and Physiology
Squamous Epithelium
Columnar Epithelium
Langerhans Cells and
Lymphoid-Derived Cells .
The Transformation Zone .
Pregnancy and Puerperium .
Pseudodecidual Reaction .
Arias-Stella Reaction .
Metaplasia .
Squamous Metaplasia .
Tubal Metaplasia
Tubo-Endometrioid Metaplasia
Transitional Cell Metaplasia
Inflammatory Diseases .
Atypia of Repair .
Radiation-Induced Atypia Endocervicosis
Hyperkeratosis and Endometriosis
Parakeratosis
BenignTumors
Noninfectious Cervicitis
Endocervical Polyps
Infectious Cervicitis .
Pseudoneoplastic
Mesodermal Stromal Polyp
Glandular Conditions Placental Site Trophoblastic
(Hyperplasias) and Nodule Leiomyoma .Adenomyoma
Endometriosis and Papillary Adenofibroma .
Microglandular Miscellaneous Tumors ,Nabothian
Endocervical Hyperplasia Cyst , Tunnel Clusters , Inclusion
Cyst
Mesonephric Hyperplasia
and Remnants Tumor-Like Lesions ,Decidual
Lobular Endocervical Pseudopolyp , Mullerian Papilloma
Glandular Hyperplasia Postoperative Spindle Cell Nodule
(LEGH) and Inflammatory Pseudotumor ,
Lymphoma-Like Lesions.
Diffuse Laminar
Endocervical Glandular Heterologous Tissue .Glia, Skin,
Hyperplasia (DLEGH) Cartilage .
 Anatomy of Cervix
156 4
The uterus is divided into the corpus, isthmus, and cervix
Benign Diseases of the Cervix

Gross Anatomy
The cervix (term taken from the Latin, meaning neck) is the most
The uterus is divided into the corpus, isthmus, and cervix
inferior portion of the uterus, protruding[63].
intoThethe
cervixupper vagina.
(term taken from the Latin, meaning
neck) is the most inferior portion of the uterus, protrud-
The transition between the endocervixingand the
into the lower
upper portion
vagina. The transitionof thethe
between
endocervix and the lower portion of the uterine corpus
uterine corpus is termed the isthmus or lower uterine
is termed the isthmus orsegment.
lower uterine segment. The latter is
used for descriptive purposes during gestation and labor Common iliac
The cervix measures 2.5–3 cm in length and in
is anthe adult
important nulligravida,
landmark and
for the pathologist when lymph nodes

describing cancers of the uterine corpus. The muscular

when normally positioned, is angled slightly downward
layer in the and backward.
region of the isthmus is less well developed
than in the corpus, a feature that facilitates effacement and
The vaginal portion (portio vaginalis) of theduring
dilation cervix,labor. also referred
The vagina is fused to as
circumfer-
External iliac
entially and obliquely to the distal part of the cervix and lymph nodes
the exocervix, is delimited by the anterior and posterior vaginal
is divided into an upper, supervaginal, and lower vaginal Uterine artery

fornices; it has a convex elliptical surface.

portion. The cervix measures 2.5–3 cm in length in the
adult nulligravida, and when normally positioned, is
Lymph
nodes

angled slightly downward and backward. The vaginal por- Internal iliac
The portio may be divided into anterior and posterior lips, of which the
tion (portio vaginalis) of the cervix, also referred to as the
lymph nodes

anterior is shorter and projects lower than the posterior lip. In the
exocervix, is delimited by the anterior and posterior vag-
inal fornices; it has a convex elliptical surface. The portio
. Fig. 4.2 .F
center of the exocervix is the external os. may be divided into anterior and posterior lips, of which
Anatomy of the cervix. The blood supply and lymphatic
drainage of the cervix are demonstrated
Norm
the anterior is shorter and projects lower than the poste- epit
asce
The external os is circular in the nulligravida and slit- like in the parous
rior lip. In the center of the exocervix is the external os.
a sin
The external os is circular in the nulligravida and slit-
woman like in the parous woman (> Fig. 4.1a, b). The external
the substance and is located mainly in the endocervix, the
portio vaginalis being nearly devoid of smooth muscle
perp
epit
os is connected to the isthmus of the cervical canal
fibers. In contrast, at the isthmus, 50–60% of the supportive stro
The external os is connected to the isthmus of the cervical canal
(endocervix). The canal is an elliptical cavity, measuring tissue consists of concentrically arranged smooth muscle, epit
8 mm in its greatest diameter and contains longitudinal which acts as a sphincter.
(endocervix). mucosal ridges, the plicae palmatae.
The blood supply of the cervix is provided by the
The canal is an elliptical cavity, measuring 8 mm in its greatest
descending branches of the uterine arteries, reaching the Squamous Epithelium the
lateral walls along the upper margin of the paracervical grow
diameter and contains longitudinal mucosal ridges, the plicae palmatae.
ligaments (cardinal ligaments of Mackenrodt) (> Fig. 4.2).
. Fig. 4.1
Histology tors
Normal cervix uteri. (a) Nulliparous cervix (b) Parous cervix
These ligaments and the uterosacral ligaments, which nan
The blood supply of the cervix is provided by the descending branches
attach the supervaginal portion of the cervix to the second The mature nonkeratinized squamous epithelium of the of
through fourth sacral vertebrae, are the main sources exocervix is similar to the vaginal epithelium but under squa
of the uterine arteries, of fixation, support, and suspension of the organ. The normal circumstances lacks the rete pegs seen in the ate c
venous drainage parallels the arterial system, with com- for the relative insensitivity to pain of the inner two-thirds vagina. It is divided into three zones: the basal/parabasal para
munication between the cervical plexus and neck of the of the portio vaginalis. The cervical nerves are derived or germinal cell layer, which is responsible for continuous part
urinary bladder. The lymphatics of the cervix have a dual from the pelvic autonomic system, the superior, middle, epithelial renewal, the midzone or stratum spinosum, para
origin: coursing beneath the mucosa and deep in the and inferior hypogastric plexuses. the dominant portion of the epithelium, and the superfi- prol
fibrous stroma. Both systems collect into two lateral plex- cial zone, containing the most mature cell population cycl
uses in the region of the isthmus and give origin to four (> Fig. 4.3). [12,
 Reproductive Tract have not been completely resolved. Severa
ries have been proposed [5] , but the most
The majority of the mammalian female reproduc- accepted theory hypothesizes that the uppe
tive tract develops from the Müllerian ducts, thirds of the Müllerian vagina originate fro
Development which form as invaginations of coelomic caudal part of the Müllerian duct, while the

• The majority of the mammalian female

Urogenital sinus (UGS)
reproductive tract develops from the MD
Müllerian ducts, which form as a << 10 W
invaginations of coelomic epithelium WD
into the urogenital ridge mesenchyme,
through which they grow caudally. b Vagina Solid cord 16-20 W

• During early development in females, the

caudal tip of the Müllerian duct, which is c 20-29 W
covered with columnar epithelium,
RC
reaches the urogenital sinus and fuses
with the sinovaginal bulb, a solid d 29-40 W
squamous epithelial cord on the dorsal
wall of the urogenital sinus (Müllerian
TZ, metaplasia
tubercle)
e adult

OSCJ NSCJ EIJ

Fig. 1.1 Embryonic and fetal development of the human squamocolumnar junction is formed, the later
lower female reproductive tract. During early embryonic squamocolumnar junction (OSCJ) (c, d). Vertical
development, the Müllerian duct epithelium (MD), under indicate the mesenchymal signals that influence
 Benign Diseases of the Cervix 4 157

Histology Common iliac

lymph nodes

The mature nonkeratinized squamous epithelium of the External iliac

lymph nodes

exocervix is similar to the vaginal epithelium but under Lymph

Uterine artery

normal circumstances lacks the rete pegs seen in the vagina. nodes

Internal iliac
lymph nodes

It is divided into three zones: the basal/parabasal

. Fig. 4.2
or . Fig. 4.3
germinal cell layer, which is responsible for Anatomy
continuousof the cervix. The blood supply and lymphatic
drainage of the cervix are demonstrated
Normal squamous epithelium. The mature squamous
epithelium of the portio of the cervix shows a gradual
epithelial renewal, the midzone or stratum spinosum, the ascending maturation, vacuolization of midzone cells, and
a single layer of basal cells in which the nuclei are
dominant portion of the epithelium, and the superficial zone,
the substance and is located mainly in the endocervix, the perpendicularly oriented to the basal lamina. The stromal–
portio vaginalis being nearly devoid of smooth muscle
containing the most mature cell population fibers. In contrast, at the isthmus, 50–60% of the supportive
epithelial junction contains finger-like, fibrovascular
stromal papilla penetrating the lower portion of the
tissue consists of concentrically arranged smooth muscle, epithelium
The basal/parabasal or germinal layer contains two whichtypes of
acts as a sphincter.

cells. One type is the true basal cell, which is about 10 mm
Squamous Epithelium
in diameter, with scant cytoplasm and oval nuclei oriented
Histology
perpendicularly to the underlying basal lamina .
The mature nonkeratinized squamous epithelium of the
The other type of cell is termed the parabasal cellexocervix
because of to the vaginal epithelium but under
is similar
normal circumstances lacks the rete pegs seen in the
its geographic placement. Parabasal cells are larger
vagina. It is than
divided into three zones: the basal/parabasal
or germinal cell layer, which is responsible for continuous
basal cells and have more cytoplasm. Parabasal cells the midzone or stratum spinosum,
epithelial renewal,
the dominant portion of the epithelium, and the superfi-
typically form a layer that is one-to-two-cells thick overcontaining
cial zone, the the most mature cell population
( Fig. 4.3). > [12, 60, 80].
basal layer. The basal/parabasal or germinal layer contains two
types of cells. One type is the true basal cell, which is
about 10 mm in diameter, with scant cytoplasm and oval
nuclei oriented perpendicularly to the underlying basal
lamina (> Fig. 4.4). The other type of cell is termed the
parabasal cell because of its geographic placement.
Parabasal cells are larger than basal cells and have more
cytoplasm. Parabasal cells typically form a layer that is
Epithelial regeneration is the major function of
the basal and parabasal layers. Accordingly, epidermal
growth factor receptors including HER-2/neu, and recep-
tors for estrogen and progesterone are found predomi-
nantly in the basal and parabasal cells [8, 54]. The number
of growth factor receptors becomes reduced as the
squamous epithelial cells differentiate into the intermedi-
ate cell layer. Basal cells appear to act as stem cells, whereas
parabasal cells comprise the actively replicating com-
partment. Indeed, mitotic figures are usually found in
parabasal but not basal cells, and other markers for actively
proliferating cells such as Ki-67 antigen, PCN, and other
cyclins are localized to parabasal cells (> Table 4.1)
The midzone is occupied by cells that are undergoing
maturation, characterized by a gradual increase in the
volume of the cytoplasm. Nuclear size, however, remains
stable up to the most superficial cell level. These cells are
referred to as intermediate cells when they exfoliate. They
do not divide. Intermediate cells have abundant periodic-
acid Schiff (PAS)-positive, diatase-labile intracellular gly-
cogen, which is responsible for the clear, vacuolated
 Benign Diseases of the Cervix 4 157

Histology 158 4 Benign Diseases of the Cervix

w
ce
Common iliac co
• Normal squamous epithelium. The mature
lymph nodes va
le
squamous epithelium of the portio of the cervix
shows a gradual ascending maturation, E
vacuolization of midzone cells, and a single layer T
of basal cells in which the nuclei are at
d
External iliac
perpendicularly oriented to the basal lamina. a
lymph nodes sq
3
• The stromal– epithelial junction
Uterine arterycontains finger- [6
th
like, fibrovascular stromal papilla penetrating the
Lymph C
nodes in
lower portion of the epithelium

• Under normal conditions the basal layer acts as a

Internal iliac
lymph nodes 160 4 Benign Diseases of the Cervix
fo
p
am
le
to
reserve cell layer, and mitoses are only identified in fence. Occasionally, nonsecretory ce fo
. Fig. 4.2 . Fig. 4.3 . Fig. 4.4
parabasal cells observed ( > Fig. 4.9), the main funct
Normal squamous epithelium. Under normal conditions the
th
re
Anatomy of the cervix. The blood supply and lymphatic basal layer actsdistribute
Normal squamous epithelium. The mature squamous andlayer,
as a reserve cell mobilize the endocervic
and mitoses are only
es
lated cells
identified in parabasal neuroendocrine, argyrophil an
drainage of thesquamous
• Atrophic cervix are demonstrated
epithelium. The epithelium is epithelium of the portio of the cervix shows a gradualtypes also are identified within the en st
st
devoid of glycogen-rich vacuolated cells. The ascending maturation, vacuolization of midzoneThecells, andby histochemical stains [26].at
lium
superficial zone forms the most differentiated
positive cells often contain serotonin
normal cellular orientation is disrupted, but cellular a single layer of basal cells in which the nucleicompartment
are of the squamous epithelium. These cells
purpose of these rare endocrine
o
are flattened and have a larger area of cytoplasm (50 mm en
ep
thecohesion
substanceisand is located
normal and mainly in the
cytologic endocervix,
atypia the perpendicularly oriented to the basal lamina.inThe
is absent. stromal–
diameter) obscure.
and Biochemically
smaller pyknotic nuclei thanand immunoh
the under- p
lying intermediate cells. The pink, eosinophilic cytoplasm am
portio vaginalis being nearly devoid of smooth muscle epithelial junction contains finger-like, fibrovascular columnar cells of the endocervix have
has abundant intermediate filaments, which provide rigid- st
epithelia, characterized by the presence
fibers. In contrast, at the isthmus, 50–60% of the supportive stromal papilla penetrating the lower portionity membrane-bound keratinosomes by electron micros-
of the ular weight cytokeratins, including cy
copy ( Fig. 4.5).>
ap
re
tissue consists of concentrically arranged smooth muscle, epithelium andepithelium
The squamous 19 [29]. of the portio is supported u
by fibrous connective tissue,in devoid
Mitoses of endocervical
the normal columnar rae
which acts as a sphincter. glands. It has occasional finger-like extensions into the n
rarely observed. It is not known wh
epithelium, the stromal papillae (> Fig. 4.3). The pene- ce
occurs
trating vessels within thefrom
papillaethe underlying
supply the epithelialsubcolu
cells
with nutrients which under
and oxygen. normal
Occasional circumstances
free nerve endings
Epithelial regeneration is the major function of are seen entering the stromal
even ultrastructural level, or Cf
at the papilla.
Squamous Epithelium the basal and parabasal layers. Accordingly, epidermal In postmenopausal women, who no longer produce
mature
ovarian hormones, endocervical
the squamous cells is[35].
epithelium UnlikeH
atrophic
growth factor receptors including HER-2/neu, and recep- cular
with little or no stromal papillae
intracytoplasmic glycogen of
(> the origina
Fig. 4.6).
 Mitoses in the normal columnar epithelium are very
rarely observed. It is not known whether regeneration
occurs from the underlying subcolumnar reserve cells,
which under normal circumstances are seldom seen

. Fig. 4.6
even at the ultrastructural level, or from the persisting
mature endocervical cellsBenign[35].Diseases
Unlike the attenuated vas-
of the Cervix
cular stromal papillae of the original squamous portio
4 161

epithelium, the subepithelial capillary network in the

Effects
Atrophic of Estrogen
squamous andThe
epithelium. Progesterone
epithelium is devoid of responsiblemucosa
endocervical for antigen
is wellrecognition
developed.and the earliest stage
glycogen-rich vacuolated cells. The normal cellular ofThe
cellular immune
stroma of theresponse.
endocervix is comparatively better
The cervical mucus is subject to profoundiscyclic
orientation is disrupted, but cellular cohesion normalchanges.
and Largethan
innervated numbers
that ofofthe
T lymphocytes are also
exocervix. Fibers runpresent
parallelintothe
Under atypia
cytologic estrogenic stimulation, the endocervical secretions
is absent cervixbundles,
muscle under normalConditions [47]. CD3+
but sensory free endings T lympho-
have not been
are profuse, watery, and alkaline, facilitating sperm pene- cytesdemonstrated.
clearly are concentrated in a bandfollicles,
True lymphoid directlywith
beneath
or with-both
tration. During the postovulatory phase, secretions are outthe squamous
germinal epithelium
centers, of the exocervix
are encountered in the and the colum-
subepithelial
scant, thick, and acid, containing numerous leukocytes nar epithelium
stroma of the endocervix
of both the exocervix [47, 72]. These cells
and the endocervix.
and act as a barrier to sperm penetration. Endocervical are predominately cytotoxic T-lymphocytes (e.g., CD8+),
secretory activity operates by both the apocrine and the although helper T lymphocytes (e.g., CD4+) are also pre-
merocrine type of expulsion of secretory products [24]. In sent. Variable numbers of B lymphocytes and plasma cells
the former, a portion of apical cytoplasm packed with are also found in the lamina propria of the cervix [47].
secretory granules is detached whereas, in the latter, secre- Because the presence of lymphocytes as well as lymphoid
tory products are released from apical granules through
pore-like openings of the surface cytoplasmic membrane.
follicles (> Fig. 4.10) is a normal finding in the cervix, the
diagnosis of chronic cervicitis should be reserved for spec-
• Endocervical mucosa. There are cleft-like
imens showing a marked infiltration of lymphocytes.
infoldings and tunnel-like collaterals. The
Langerhans Cells and Lymphoid-Derived
Cells
The Transformation Zone neighboring gland-like structures represent
Mucosal immunity is an important component of the host’s
defense mechanism against viral and bacterial pathogens.
The squamocolumnar junction of the cervix is defined as
the border between the stratified squamous epithelium
tangentially sectioned cleft-tunnel complexes
and the mucin-secreting columnar epithelium of the
Components of the secretory (IgA antibody mediated),
humoral (IgG antibody mediated) as well as the cellular
immune systems are present in the cervix. A variety of • Endocervical mucosa. Tall columnar mucin-
lymphocyte and dendritic macrophage subsets are present
in both the epithelium of the exo- and endocervix as well
. Fig. 4.7
as the subepithelial stroma [68]. Dendritic cells include
. Fig. 4.8
filled endocervical cells with basal nuclei
Endocervical mucosa. There are cleft-like infoldings and Endocervical mucosa. Tall columnar mucin-filled
both mature and immature forms. They are primarily
tunnel-like collaterals. The neighboring gland-like endocervical cells with basal nuclei
structures represent tangentially sectioned cleft-tunnel
complexes
• Endocervical mucosa. When endocervical cells
engage in apocrine secretion, portions of
atypical cytoplasm are expelled .
• Lymphoid follicles. Occasional lymphoid
follicles can be seen in the cervical stroma in
the absence of cervicitis

. Fig. 4.9 . Fig. 4.10

Endocervical mucosa. When endocervical cells engage in Lymphoid follicles. Occasional lymphoid follicles can be
apocrine secretion, portions of atypical cytoplasm are seen in the cervical stroma in the absence of cervicitis
expelled
it histologically
accompanied can be confused
by alterations in with adenocarcinoma
its shape, which resultinin misinterpreted
The conceptas ofrepresenting adenocarcinoma
the transformation in situ.
zone is extremely
situ. Differentiation from adenocarcinoma in situ is based As with tubal metaplasia, the features that indicate a
onmore of an
of ‘‘eversion’’
significant or rollingactivity,
outwardtheof endocervical important forasunderstanding
opposed to athe pathogenesis of squamous
a lack
columnar epithelium
architectural abnormalities
mitotic
onto Transformation zone
theasportio
such cribiforming
absence of
(> Fig.and
4.11).
pap-
illary projections, and the failure of cells to stain for p16ink.
a result, in most women during the reproductive period,
However, one should be cautioned that atypical tubal
As
metaplastic,
cell carcinomas
location of ofthethecervix
and shape
or edematous stromal response.
glands
neoplastic,
and
anditslack
process
precursors,
are the
since vir-
of a desmoplastic
tually all cervical squamous neoplasia begins at the new
cervical ectopy
metaplasia is present,
can occur and the size
in association withofadenocarcinoma
the ectopy is most squamocolumnar junction and because the extension and
in situ of the cervix, including both tubal and non-tubal limits of cervical cancer precursors coincide with the distri-
types (> Chap. 5, Precancerous Lesions of the Cervix).
bution of the transformation zone. It is also important to
I I I
rememberThe thatregion
duringbetween the original
the childbearing squamocolumnar
years and during junction and
Tubo-Endometrioid Metaplasia the postpubertal functional squamocolumnar junction is termed
pregnancy,thethe transformationzone.
transformation zone is located, in almost all
Tubo-endometrioid
C metaplasiaC of the cervix is a Ctype of instances, on the exposed portion of the cervix. Conse-
metaplasia that is S
histologically similar S
to the tubal meta-S quently, The transformation
the vast majority ofzone is histologically
cervical neoplasias cancharacterized
be by the
plasia that can develop in the endometrium in patients with presence of metaplastic epithelium (Squamous Metaplasia.
unopposed estrogenic stimulation. Endocervical glands
removed for histologic diagnosis by punch biopsy. Move-
demonstrating tubo-endometrioid metaplasia are lined ment of Thethe concept
functionalof squamocolumnar
the transformationjunction
zone is con-
extremely important
by a pseudostratified epithelium composed of columnar
“Original” squamocolumnar Endocervical eversion (ectopy) Transformation zone
tinues throughout the reproductive years. Therefore, in cell carcinomas
for understanding the pathogenesis of squamous
cells with a high nuclear:cytoplasmic ratio (> Fig. 4.23). of the cervix and its precursors, since virtually all cervical
junction with “original” squamocolumnar with “functional” older and postmenopausal women, the functional
junction squamocolumnar junction squamous neoplasia begins at the new squamocolumnar junction
squamocolumnar
and becausejunction is nearly always
the extension located
and limits within cancer precursors
of cervical
. Fig. 4.11 coincide
the external with4.12c).
os (> Fig. the distribution of the transformation zone.
The transformation zone. Schematic representation of
It is also important to remember that during the childbearing
original and functional squamocolumnar junctions and years and during pregnancy, the transformation zone is located, in
three basic types of portios. Left: Diagram of a portio Pregnancy
almostand Puerperium
all instances, on the exposed portion of the cervix.
completely covered with native squamous epithelium. The
Consequently, the vast majority of cervical neoplasias can be
squamocolumnar junction is at the external os. Middle: The morphologic
removedalterations that diagnosis
for histologic occur in thebyantepartum
punch biopsy. Movement of
Denotes cervical ectopy, with the squamocolumnar or postpartum cervix are
the functional not pathognomonic
squamocolumnar of con-
junction preg-tinues throughout
junction being located on the exocervix below the external nancy ortheparturition
reproductive
but years.
are seen more commonly at
os. Right: Indicates areas of cervical ectopy that have these times than in intheolder
Therefore, nonpregnant postpartumwomen,
and postmenopausal state. the functional
become covered with squamous epithelium. This area is the They aresquamocolumnar
related to the stimulatory
junction is effects
nearly of elevated
always located within the
cervical transformation zone. The new, or functional, external os
steroid hormones. The spongy enlargement of the preg-
. Fig. 4.20 . Fig. 4.21
squamocolumnar
Transformation zonejunction of theOntransformation
epithelium. zone is at
the left, the native nant metaplasia.
Tubal cervix is caused by columnar,
(a) The increased mucus-producing
vascularity and edema
the external
portio os. S,
epithelium squamous
is present epithelium;
with C, endocervical
full maturation. On the of the stroma
epithelium accompanied
has been replaced by by aacute
tubalinflammation.
type epithelium The
right, metaplastic squamous epithelium is present. Note the with ciliated, secretory and intercalated cells. (b) At higher
columnar epithelium; I, uterine isthmus massive destruction of collagen fibers and accumulation
sharp boundary. Metaplasia has extended into the magnification the resemblance to the epithelium of the
 Effects of Estrogen and Progesterone

The cervical mucus is subject to profound cyclic changes.

Under estrogenic stimulation, the endocervical secretions are profuse, watery, and alkaline, facilitating sperm
penetration. During the postovulatory phase, secretions are scant, thick, and acid, containing numerous leukocytes
and act as a barrier to sperm penetration.
Endocervical secretory activity operates by both the apocrine and the merocrine type of expulsion of secretory
products. In the former, a portion of apical cytoplasm packed with secretory granules is detached whereas, in the
latter, secretory products are released from apical granules through pore-like openings of the surface cytoplasmic
membrane.
Langerhans Cells and Lymphoid-Derived Cells
Mucosal immunity is an important component of the host’s defense mechanism against viral and bacterial
pathogens.
Components of the secretory (IgA antibody mediated), humoral (IgG antibody mediated) as well as the cellular
immune systems are present in the cervix. A variety of lymphocyte and dendritic macrophage subsets are present in
both the epithelium of the exo- and endocervix as well as the subepithelial stroma [68]. Dendritic cells include both
mature and immature forms.
 4
IHC of normal cervical tissues Benign Diseases of the Cervix 159

. Table 4.1
1 Development of the Uterine Cervix and Its Implications for the Pathogenesis of Cervical Cancer 7
Immunohistochemical staining patterns of normal cervical tissues

Cells of stratified squamous epithelium Reserve cells/squamous Endocervical

Antibody Basal Parabasal Intermediate Superficial metaplasia columnar cells
Growth factors/receptors a b

Her 2/neu [8] + + ! ! + +

EGF receptor [8] + + ! ! + !
Estrogen receptor [31, 54, " + + ! + + c d

84]
Progesterone receptor ! +a ! ! + +
[31, 54, 84]
Cell cycle proteins e f g

PCN [6, 55, 80, 90] ! + ! ! NA +

MIB-1 (Ki-67) [70, 97] ! " ! ! ! !
bcl-2 [84, 97] + ! ! + "
Cyclin B1 [54] ! + ! ! unknown unknown h i j

Cyclin D1 [12] + + ! ! + +
Other proteins
CD44 [45] + + ! ! + !
k l m
CEA ! ! ! ! ! +
Fig. 1.4 Expression of p63; (cyto)keratins k5, k7, k8, positive for k17 (i), and BCL2 occurs in the nonprolifer-
a
Expressed during luteal phase of menstrual cycle and during pregnancy and k17; BCL2; and Ki67 in normal adult endocervix ating basal cells (k), while the parabasal cells are Ki67
and ectocervix. In the normal endocervix, p63, k7, k17, positive (l). The arrow in (e) refers to a remnant of a
 WHO Classification of tumours of the uterine cervixa,b
Epithelial tumours Other epithelial tumours
Squamous cell tumours and precursors Adenosquamous carcinoma 8560/3
Squamous intraepithelial lesions Glassy cell carcinoma 8015/3
Low-grade squamous intraepithelial lesion 8077/0 Adenoid basal carcinoma 8098/3
High-grade squamous intraepithelial lesion 8077/2 Adenoid cystic carcinoma 8200/3
Squamous cell carcinoma, NOS 8070/3 Undifferentiated carcinoma 8020/3
Keratinizing 8071/3 Neuroendocrine tumours
Non-keratinizing 8072/3 Low-grade neuroendocrine tumour
Papillary 8052/3 Carcinoid tumour 8240/3
Basaloid 8083/3 Atypical carcinoid tumour 8249/3
Warty 8051/3 High-grade neuroendocrine carcinoma
Verrucous 8051/3 Small cell neuroendocrine carcinoma 8041/3
Squamotransitional 8120/3 Large cell neuroendocrine carcinoma 8013/3
Lymphoepithelioma-like 8082/3
Benign squamous cell lesions Mesenchymal tumours and tumour-like lesions
CHAPTER 7 Squamous metaplasia Benign
Tumours of the uterine cervix Condyloma acuminatum Leiomyoma 8890/0
Squamous papilloma 8052/0 Rhabdomyoma 8905/0
Squamous cell tumours and precursors Transitional metaplasia Others
Glandular tumours and precursors Malignant
Glandular tumours and precursors Adenocarcinoma in situ 8140/2 Leiomyosarcoma 8890/3
Adenocarcinoma 8140/3 Rhabdomyosarcoma 8910/3
Benign glandular tumours and tumour-like lesions Endocervical adenocarcinoma, usual type 8140/3 Alveolar soft-part sarcoma 9581/3
Mucinous carcinoma, NOS 8480/3 Angiosarcoma 9120/3
Other epithelial tumours Gastric type 8482/3 Malignant peripheral nerve sheath tumour 9540/3
Intestinal type 8144/3 Other sarcomas
Neuroendocrine tumours Signet-ring cell type 8490/3 Liposarcoma 8850/3
Villoglandular carcinoma 8263/3 Undifferentiated endocervical sarcoma 8805/3
Mesenchymal tumours and tumour-like lesions Endometrioid carcinoma 8380/3 Ewing sarcoma 9364/3
Clear cell carcinoma 8310/3 Tumour-like lesions
Mixed epithelial and mesenchymal tumours Serous carcinoma 8441/3 Postoperative spindle-cell nodule
Mesonephric carcinoma 9110/3 Lymphoma-like lesion
Melanocytic tumours Adenocarcinoma admixed with
neuroendocrine carcinoma 8574/3 Mixed epithelial and mesenchymal tumours
Germ cell, lymphoid and myeloid tumours Benign glandular tumours and tumour-like lesions Adenomyoma 8932/0
Endocervical polyp Adenosarcoma 8933/3
Secondary tumours Müllerian papilloma Carcinosarcoma 8980/3
Nabothian cyst
Tunnel clusters Melanocytic tumours
Microglandular hyperplasia Blue naevus 8780/0
Lobular endocervical glandular hyperplasia Malignant melanoma 8720/3
Diffuse laminar endocervical hyperplasia
Mesonephric remnants and hyperplasia Germ cell tumours
Arias Stella reaction Yolk sac tumour
Endocervicosis
Endometriosis Lymphoid and myeloid tumours
Tuboendometrioid metaplasia Lymphomas
Ectopic prostate tissue Myeloid neoplasms

Secondary tumours

a
The morphology codes are from the International Classification of Diseases for Oncology (ICD-O) {575A}. Behaviour is coded /0 for benign
tumours, /1 for unspecified, borderline or uncertain behaviour, /2 for carcinoma in situ and grade III intraepithelial neoplasia and /3 for
malignant tumours; b The classification is modified from the previous WHO classification of tumours {1906A}, taking into account changes in
our understanding of these lesions; *These new codes were approved by the IARC/WHO Committee for ICD-O in 2013.
 Predecidual reaction and Arias Stella
Reaction
hs postpartum [49].
vels of progesterone
• Pseudodecidual Reaction - Pseudodecidualization of the stroma, either patchy or diffuse,
pseudodecidualized
roma at other sites. occurs in about one-third of the cervices histologically and disappears by 2 months
oplasm, with well- postpartum
b).
• It is presumably mediated by the high levels of progesterone during pregnancy. The
appearance of pseudodecidualized cervical is identical to decidualized stroma at other
sites. The cells develop abundant pink cytoplasm, with well- defined cellular borders .
rias-Stella reaction • Arias-Stella Reaction -During pregnancy, the gestational Arias-Stella reaction can
nds and in ectopic
In one study of 191
develop in both endocervical glands and in ectopic endometrial glands within the cervix.
as-Stella reaction of
ocally, in 9% of the • The Arias-Stella reaction of the endocervix is usually focal and is more commonly
of the endocervix is present in the proximal portion of the endocervix involving superficial as opposed to
present in the prox- deeply situated glands. Microscopically, the Arias-Stella reaction that occurs in the
lving superficial as endocervical glands during pregnancy is identical to that which occurs in the
s. Microscopically,
endometrium. The cells within the affected glands are markedly enlarged with irregular,
in the endocervical
o that which occurs frequently hyperchromatic nuclei that can project into the glandular lumen in a hobnail
ithin the affected pattern. The cells are pseudostratified and have hypersecretory cytoplasmic features with
rregular, frequently abundant vacuolated cytoplasm . Papillary processes with fibrovascular cores, lined by
t into the glandular enlarged epithelial cells can project into the endocervical gland lumen.
are pseudostratified
features with abun- • The Arias-Stella reaction can occasionally be mistaken for clear cell carcinoma or
14). Papillary pro-
y enlarged epithelial
adenocarcinoma in situ of the cervix. Differentiation from clear cell carcinoma is made
gland lumen. by the lack of a mass lesion and clear-cut stromal invasion as well as by the absence of
ionally be mistaken the classic tubular and papillary areas typical of clear cell carcinoma.
noma in situ of the
carcinoma is made • The cells in adeno- carcinoma in situ have more uniform nuclei and less cytoplasmic
ut stromal invasion vacuolization. The Arias-Stella reaction lacks mitotic activity, whereas both clear cell
ubular and papillary
carcinoma and adenocarcinoma in situ are mitotically active.
The cells in adeno-
m nuclei and less
Stella reaction lacks
cell carcinoma and
y active. Because of . Fig. 4.13
 . Fig. 4.14
Arias-Stella reaction. The Arias-Stella reaction should not be
Squamous Metaplasia
. Fig. 4.16
Squamous epithelialization. During squamous
confused with clear cell adenocarcinoma of the cervix epithelialization a narrow tongue of squamous epithelium
•Squamous metaplasia
from the portio grows under theis everted
the replacement
endocervical of the mucin-producing columnar
epithelium by stratified squamous epithelium and appears to occur by two different
mucosa and lifts it off the basement membrane. The
endocervical cells then degenerate and are sloughed
mechanisms.
“Epithelialization” • mature, immature or atypical
Direct Ingrowth of
Endocervical squamous epithelium
ectropion from portio •OneDuring
mechanism
squamousconsists of direct
epithelialization, ingrowth
tongues of native from the native portio epithelium
Low pH of vagina bordering
squamous the columnar
epithelium epithelium,
of the portio growabeneath
processthefrequently referred to as ‘‘squamous
hormones
Original trauma adjacent columnar
epithelialization.’’ epithelium and expand between the
squamocolumnar infection
junction mucinous epithelium and its basement membrane. As
Transformaion zone
“Squamous metaplasia” •The second mechanism
the squamous cells expand andinvolves a proliferation
mature, the endocervical of undifferentiated subcolumnar
cells are cells
reserve gradually
of thedisplaced upward, degenerate,
endocervical epithelium,and which differentiate into squamous
Subcolumnar eventually are sloughed (> Fig. 4.16). The progression of
reserve cell Maturation of epithelium. This process has been termed squamous metaplasia.
•
proliferation squamous epithelium
Benign Diseases of the Cervix 4 • All
squamous transformation of the endocervical ectropion
167

forms
has been of squamous
hypothesized metaplasia
to be primarily as aondiagnosis
dependent local imply that the lesion is not a
. Fig. 4.15
(vaginal)
form environmental
of squamous factors initiatedlesion
intraepithelial by the low (acid)
(SIL) or one that carries neoplastic risk
Squamous metaplasia. There are two histogenic
pH of the vagina after puberty [16]. Trauma, chronic
mechanisms by which the endocervical mucosa is replaced
• Prior to orpuberty
irritation, the original
cervical infection also playsquamocolumnar
a role in develop- junction is distinct, joining the
by squamous epithelium. The first is the direct ingrowth of
squamous epithelium from the portio, which is referred to prepubescent, native, squamous mucosa with the endocervix and there is little if
ment and maturation of the transformation zone by stim-
ulating
any repair andmetaplasia.
squamous remodeling; eventually
At puberty,the ectocervix
hormonal is and other biochemical factors are
as squamous epithelialization (top). The other is through
covered by a protective surface of mature squamous epi-
proliferation of subcolumnar reserve cells and their thought
thelium (to induce changes such that there is eversion of the columnar epithelium,
> Fig. 4.17). The process of squamous epitheli-
subsequent maturation into a squamous epithelium, which
which
alizationthen undergoes
is thought squamous
to be responsible for metaplasia
the obliterationthrough a microscopic sequence of
is called squamous metaplasia (bottom). Both result in
a mature squamous epithelium overlying endocervical reserve cell hyperplasia, immatureectopy.
of the outer two-thirds of endocervical squamous
Rapid metaplasia and mature squamous
squamous re-epithelialization
metaplasia, with the formation of the columnar
of a newepithelium
squamocolumnar junction
mucus-producing glands (right)
of the transformation zone may also be produced iatro-
• Metaplastic squamouscryosurgery
genically by electrocautery, cells has orbeen
laser described
surgery. that may be even more uniquely
bordering the columnar epithelium, a process frequently The second mechanism involved in replacement of
susceptible to high-risk HPV infection p16 immunostaining is negative in
referred to as ‘‘squamous epithelialization.’’ The second columnar epithelium by a squamous epithelium and the
squamous metaplasia; this can be useful for distin- guishing between immature
mechanism involves a proliferation of undifferentiated function of the transformation zone is squamous meta-
subcolumnar reserve cells of the endocervical epithelium, squamous
plasia. The metaplasia
first stage ofand high-grade
squamous SIL in
metaplasia is problematic
the cases
which
. Fig. 4.19 differentiate into squamous epithelium. This pro-
Squamous metaplasia. (a) Reserve cells proliferate and are stratified under the columnar epithelium.
appearance ofsquamous
• Immature small cuboidal cells beneathshares
metaplasia the columnar
features of both the mature squamous
cess(b)cells.Columnar
has been termed squamous metaplasia.
differentiation is lost, resulting in a multilayered squamous epithelium composed of immature metaplastic mucinous epithelium, the so-called subcolumnar reserve
Note occasional mucinous endocervical cells at the surface. (c) The immature metaplastic epithelium begins to
differentiate
epithelium and the columnar mucinous epithelium.
from a neoplastic lesion. Other features that can aid in variation in size and shape. Moreover, the stroma-
 rm of tubal metapla-
by ciliated and non-
d have larger, more
Many of these cells are ciliated or have secretory features
with apical snouts, but the glands lack an associated endo-
metrial stroma. Tubo-endometrioid metaplasia occurs
Tubal Metaplasia
observed in typical commonly after cervical conization and has been inter-
cells of atypical tubal preted as a form of aberrant differentiation following
atified. Atypical tubal cervical injury [46]. Because of the pseudostratification
gnostic problem since and high nuclear:cytoplasmic ratio, these glands can be
h adenocarcinoma in misinterpreted as representing adenocarcinoma in situ.
inoma in situ is based As with tubal metaplasia, the features that indicate a
tivity, the absence of metaplastic, as opposed to a neoplastic, process are the
ribiforming and pap- location and shape of the glands and lack of a desmoplastic
ells to stain for p16ink. or edematous stromal response.
d that atypical tubal
with adenocarcinoma
tubal and non-tubal
ons of the Cervix).
Tubal metaplasia refers to endocervical glands that are lined by a
Mullerian-type epithelium that closely resembles that of the
asia

he cervix is a type of
fallopian tube. In pure tubal metaplasia, the endocervical glands are
lar to the tubal meta-
etrium in patients with lined by an epithelium that more closely resembles that of the
Endocervical glands
metaplasia are lined
mposed of columnar
fallopian tube and con- tains many more ciliated cells than are
ic ratio (> Fig. 4.23).
normally present in the endocervical epithelium as well as tubal type
secretory cells and reserve or intercalary cells

Tubal metaplasia can be found in up to 31% of patients and does not

. Fig. 4.21
Benign Diseases of the Cervix 4 169
appear to be related to the phase of menstrual cycle, the presence of
inflammatory changes, or low-grade SIL (CIN 1)

• Tubal metaplasia can be quite extensive and can occasionally be

the left, the native Tubal metaplasia. (a) The columnar, mucus-producing
maturation. On the
um is present. Note the
epithelium has been replaced by a tubal type epithelium
with ciliated, secretory and intercalated cells. (b) At higher
mistaken for endocervical glandular neoplasia. However, the bland
nded into the
eplaced the columnar
magnification the resemblance to the epithelium of the
fallopian tube is obvious
cytological features, lack of mitotic activity, and prominent cilia
seen at the apical surfaces of tubal metaplasia.

• Atypical tubal metaplasia is a form of tubal metaplasia in which

the glands are lined by ciliated and non- ciliated cells that are
crowded and have larger, more hyperchromatic nuclei than that
observed in typical tubal metaplasia .

Tubo-endometrioid metaplasia of the cervix is a type of metaplasia

that is histologically similar to the tubal meta- plasia that can
develop in the endometrium in patients with unopposed estrogenic
stimulation. Endocervical glands demonstrating tubo-endometrioid
metaplasia are lined by a pseudostratified epithelium composed of
columnar cells with a high nuclear:cytoplasmic ratio

. Fig. 4.22 . Fig. 4.23

Atypical tubal metaplasia. The epithelium is more crowded Tubo-endometrioid metaplasia. Typical endocervical
and pseudostratified than in typical tubal metaplasia. The epithelium on the left. On the right columnar, mucus-
the cervix to injury is limited and reflects the basic mech-
lium is often infiltrated with migrating inflammatory cells.
anisms of inflammation and repair. Two types of morpho-
Mitotic figures are normal and are confined to the prolif-
logic changes, however, that are often encountered in
erative basal and parabasal cell populations. Characteris-
association with a variety of inflammatory diseases deserve
tically, the cells in the upper half of the epithelium are
specific attention. These are atypia of repair and hyper-

keratosis and parakeratosis.
Atypia of Repair
In cases of severe, acute, long-standing chronic inflamma-
tion or infection with epithelial injury of any kind –
Atypia
normal, and maturation occurs in an orderly fashion.
When reparative changes affect endocervical columnar
cells, the morphological alterations include nuclear enlarge-
ment and hyperchromasia with irregularity of nuclear size
and shape and smudgy chromatin. There can also be cyto-
plasmic eosinophilia and loss of mucinous droplets
(> Fig. 4.26a, b). The combination of endocervical cell

•Squamous reparative atypia. (a) When reparative changes

develop in mature squamous epithelium, there is usually basal
cell hyperplasia that involves the lower one-third of the
epithelium. The nuclei contain prominent chromocenters but
lack nuclear abnormalities associated with neoplasia.
Intermediate and superficial epithelial cells continue to show
maturation but often develop perinuclear halos and some
degree of nuclear enlargement. However, the superficial cells
lack the nuclear atypia characteristic of HPV-infected cells.
•(b) When reparative changes develop in immature metaplastic

Benign Diseases of the Cervix 4 squamous epithelium, the epithelium exhibits intercellular
edema,
171 and acute and chronic inflammatory cells often infiltrate
. Fig. 4.25 both the epithelium and stroma. The nuclei of the metaplastic
Squamous reparative atypia. (a) When reparative changes develop in mature squamous epithelium, there is usually basal
cell hyperplasia that involves the lower one-third of the epithelium. The nuclei contain prominent chromocenters but lack
cells become hyperchromatic and enlarged and typically have
nuclear abnormalities associated with neoplasia. Intermediate and superficial epithelial cells continue to show maturation prominent chromocenters. Microabsesses are frequently seen
but often develop perinuclear halos and some degree of nuclear enlargement. However, the superficial cells lack the nuclear
atypia characteristic of HPV-infected cells. (b) When reparative changes develop in immature metaplastic squamous •Endocervical reparative atypia. The endocervical epithelium
epithelium, the epithelium exhibits intercellular edema, and acute and chronic inflammatory cells often infiltrate both the
epithelium and stroma. The nuclei of the metaplastic cells become hyperchromatic and enlarged and typically have
develops nuclear enlargement, mitosis, microabscesses, and
prominent chromocenters. Microabsesses are frequently seen inconspicuous intracellular mucus. Note the diffuse distribution
of nuclear chromatin, the cytoplasmic eosinophilia, and the
absence of abnormal mitoses, features distinguishing
endocervical atypia of inflammation from in situ
adenocarcinoma of the cervix
•Papillary endocervical reparative change. The marked
. Fig. 4.26 . Fig. 4.27
Endocervical reparative atypia. The endocervical Papillary endocervical reparative change. The marked
inflammation of the stroma results in the endocervical
epithelium develops nuclear enlargement, mitosis, inflammation of the stroma results in the endocervical epithelium being raised into papillary projection
microabscesses, and inconspicuous intracellular mucus. epithelium being raised into papillary projections
Note the diffuse distribution of nuclear chromatin, the
cytoplasmic eosinophilia, and the absence of abnormal
and glandular epithelium. The atypical squamous cells
mitoses, features distinguishing endocervical atypia of
that develop post radiation have nuclear enlargement
inflammation from in situ adenocarcinoma of the cervix
and can be multinucleated. The cells can have abundant
 evidence that parakeratosis represents precursor lesions to rogenic causes of cervical tissue injury and inflammation.
as that seen in essary in neoplasia,
cervical such women both[48]. It should beand
hyperkeratosis emphasized,
parakeratosis Stromal edema, vascular congestion, and neutrophilic
y and in women however,
can occurthat
insince hyperkeratosis
association may occasionally
with HSIL and invasive over-
cervical infiltration of the stroma and epithelium characterize
cases there is no cancer.
lie Because
HSIL and of carcinomas,
invasive this association, some
all grossly experts
visible whitehave
suggested that all women with otherwise negative Pap
plaques on the portio vaginalis or vaginal epithelium
smears but demonstrating these findings need colposcopy.
orresponds to the should
However,biopsied.
be several studies have reported that less than 4%
keratosis), which of women with hyperkeratosis or parakeratosis without
i (parakeratosis) nuclear atypia on an otherwise negative Pap smear had SIL
helium is often Noninfectious Cervicitis
granular layer,
ngated rete pegs. Noninfectious cervicitis is, for the most part, chemical or
ntain sparse gly- mechanical in nature, and the inflammatory response is
Frequently, there
inflammation.
nonspecific. Common causes include chemical irritation
secondary to douching or local trauma produced by for-
Hyperkeratosis of the cervix. A
associated with eign bodies, including tampons, diaphragms, pessaries,
and intrauterine contraceptive devices. Surgical instru- superficial layer of anucleated,
gical nor clinical mentation and therapeutic intervention are common iat-
cursor lesions to
nd parakeratosis
rogenic causes of cervical tissue injury and inflammation.
Stromal edema, vascular congestion, and neutrophilic
keratinized squamous cells,
invasive cervical
me experts have
infiltration of the stroma and epithelium characterize
which is frequently
se negative Pap
need colposcopy.
hat less than 4%
accompanied by a thickened
. Fig. 4.28 . Fig. 4.29
eratosis without
ap smear had SIL
Hyperkeratosis of the cervix. A superficial layer of
anucleated, keratinized squamous cells, which is frequently
accompanied by a thickened granular layer is present
granular layer is present
Parakeratosis of the cervix. Pyknotic nuclei are retained in
the superficial cell layer. Parakeratosis is frequently
accompanied by hyperkeratosis

Parakeratosis of the cervix.

Pyknotic nuclei are retained in
the superficial cell layer.
Parakeratosis is frequently
accompanied by
hyperkeratosis

. Fig. 4.29
layer of Parakeratosis of the cervix. Pyknotic nuclei are retained in
hich is frequently the superficial cell layer. Parakeratosis is frequently
a histological diagnosis based on the presence of scattered pelvic inflammatory disease, infectious cervicitis is the
ters are found beneath the epithelium in noninfectious postpartum and postabortal endometritis. Spontaneous
lymphocytes has no clinical significance and is meaning- initial event of the pelvic inflammatory disease. It is also
cervicitis ( Fig. 4.30). The presence of lymphoid follicles abortion, premature delivery, chorioamnionitis, stillbirth,
>
less. Occasionally, lymphoid follicles with germinal cen- the primary infectious focus in related syndromes such as
beneath the cervical epithelium is frequently referred to and neonatal pneumonia and septicemia have been
ters are found beneath the epithelium in noninfectious postpartum and postabortal endometritis. Spontaneous

Infectious Cervicitis
as follicular cervicitis. In some instances, the lymphoid directly related to concurrent bacterial infection of the
cervicitis (> Fig. 4.30). The presence of lymphoid follicles abortion, premature delivery, chorioamnionitis, stillbirth,
cervix. Even when asymptomatic, infectious cervicitis
beneath the cervical epithelium is frequently referred to and neonatal pneumonia and septicemia have been
as follicular cervicitis. In some instances, the lymphoid directly related to concurrent bacterial infection of the
cervix. Even when asymptomatic, infectious cervicitis

. Table 4.2
Microorganisms causing infectious cervicitis

. Table 4.2
Bacteria, chlamydia, mycobacteria, polymicrobial,
Microorganisms
endogenous vaginalcausing
aerobes infectious
and anaerobescervicitis
Chlamydia
Bacteria, trachomatis mycobacteria, polymicrobial,
chlamydia,
endogenous vaginal aerobes and anaerobes
Neisseria gonorrhoeae
Mycoplasma trachomatis
Chlamydia hominis
Group B Streptococcus
Neisseria gonorrhoeae
Ureaplasma ureolyticum
Mycoplasma hominis
Gardnerella
Group vaginalis
B Streptococcus
Actinomyces israelii
Ureaplasma ureolyticum
Mycobacteriumvaginalis
Gardnerella tuberculosis
Treponema pallidum
Actinomyces israelii
Viruses
Mycobacterium tuberculosis
Treponema pallidum
Herpes simplex virus
Viruses
Human papillomavirus
Herpes simplex virus
Fungi
Human
Candida papillomavirus
Fungi
Aspergillus
. Fig. 4.30 Candida
Protozoa and parasites
Chronic cervicitis. A subepithelial lymphoid follicle with Aspergillus
Trichomonas vaginalis
. Fig. 4.30 a prominent germinal center is present. When lymphoid
Protozoa
Ameba and parasites
Chronic cervicitis. Afollicles are numerous,
subepithelial the condition
lymphoid is referred
follicle with to as
Trichomonas
Schistosomes vaginalis
a prominent germinal follicular
centercervicitis
is present. When lymphoid
Ameba
follicles are numerous, the condition is referred to as
Schistosomes
follicular cervicitis
 Condyloma acuminata-LSIL CIN1(condylomatous variant)

•A benign proliferation characterized by papillary fronds

. Fig. 4.32
Exophytic condyloma acuminata. The lesions are multifocal
and form raised white projections on both the vagina and
cervix
. Fig. 4.33
Exophytic condyloma acuminata. The classic histological
features are papillomatosis with acanthosis, parakeratosis,
hyperkeratosis, as well as cytological alterations including
multinucleation, koilocytosis and nuclear atypia
containing fibrovascular cores and lined by stratified
squamous epithelium with definite evidence of HPV
infection.
•Epidemiology LSILs architecturally resembling
condylomata acuminata are much more common in
external genital sites than in the cervix
•Condylomata acuminata are associate most strongly with
low-risk HPV types particularly HPV types 6 and 11.

condylomas include myriad of minute, maculopapular,

only slightly raised, condylomas involving the vagina and
the cervix.
Microscopically, the histological features of exophytic
cervical condyloma acuminata include architectural alter-
ations such as papillomatosis, acanthosis, parakeratosis,
and hyperkeratosisaswellascytologicalterationsincluding
koilocytosis (manifested by perinuclear cytoplasmic cavita-
tion), nuclear enlargement and atypia. Multinucleation is
also frequently observed (> Fig. 4.33) (> Chap. 1, Benign
Diseases of the Vulva, > Chap. 5, Precancerous Lesions of
the Cervix).
The natural history of exophytic cervical condyloma
accuminata is one of the spontaneous regressions, good
response to conservative therapy, unpredictable recur-
rence, and sometimes persistence. Lesion regression or
apparent cure following biopsy is fairly common. The
natural history of genital condylomata in general may be
modified by host factors, notably immunosuppression
Macroscopy
involving the vagina and vulva. Antibiotic therapy, poorly
controlled diabetes mellitus, and immunosuppression all
The lesion looks like a genital wart on mucosal surface if
favor fungal overgrowth [93]. Cervical candidal infections large enough to see Colposcopy enhances visualization.
can be associated with increased numbers of polymorpho-
leukocytespresentintheupperlayersoftheepitheliumand Histopathology
fungal hyphae that can be identified by periodic acid-Schiff
(PAS) stains, both at the surface of the epithelium and The squamous epithelium covering the knuckle-like
within the superficial layers of the epithelium.
fronds of the lesion exhibit acanthosis, papillomatosis and
Protozoal and Parasitic Diseases koilocytosis as defined in the section on LSIL. less mature
variant with a metaplastic appearance (immature papillary
Cervical infestation by Trichomonas vaginalis is quite
frequent and most often associated with concurrent tricho- squamous metaplasia) .
monal vaginitis. Acute trichomonal cervicitis may provoke
an intense inflammatory response with prominent repara-
tive atypia in exfoliated squamous and endocervical cells,
with corresponding gross and colposcopic abnormalities.
Rare instances of parasitic infestations such as
Pseudoneoplastic Glandular Conditions (Hyperplasias) and Endometriosis
178 4 Benign Diseases of the Cervix

round an
tures. The
trated wit
nuclei of
• -Microglandular endocervical hyperplasia is a benign sional ple
proliferation of endocervical glands. Microglandular activity is
high-pow
hyperplasia is frequently detected as an incidental finding on a and subc
cervical biopsy, cone biopsy or a hysterectomy specimen. If a large nu
cells, inclu
clinically apparent, it most often resembles a cervical polyp, more flor
measuring 1–2 cm in size. glandular
pattern w
morphism
• These patients may complain of postcoital bleeding or microglan
glands can
spotting. Microglandular hyperplasia is most common in be mistak
adenocarc
women of reproductive ages areas, esp
or when s
• Histologically, microglandular hyperplasia may pre- sent in a distinguis
nature of
single focus or be distributed in multiple foci. It may involve by a lack o
activity o
the surface and/or deeper portions of endocervical clefts. The endocervi
most common form consists of tightly packed varying-sized of micro
areas wit
glandular or tubular units, lined by flattened to cuboidal cells microglan
with eosinophilic granular cytoplasm containing small
quantities of mucin The glands vary in size . Mesone

The vestig
• There is an adenomatous pattern with cuboidal lining cells and focal ric ducts a
squamous metaplasia. (b) At higher magnification the cells appear 40% of th
wide vari
uniform and form a reticular pattern. Note the extensive vacuolization nants app
of the lesion that is caused by cystic dilation of intercellular spaces. cervix is
There is a paucity of intracellular mucin nephric re
eral aspec
. Fig. 4.35
sampled o
Microglandular hyperplasia. (a) There is an adenomatous
of small t
pattern with cuboidal lining cells and focal squamous
the latera
metaplasia. (b) At higher magnification the cells appear
are arrang
uniform and form a reticular pattern. Note the extensive
tion remi
vacuolization of the lesion that is caused by cystic dilation
mesoneph
of intercellular spaces. There is a paucity of intracellular
low colum
mucin
contain n
mesoneph
Lobular Endocervical Glandular Hyperplasia (LEGH)
Endocervical hyperplasia can sometimes be
encountered and can take several different forms.
Lobular endocervical glandular hyperplasia (LEGH) is
a rare form, first described by Nucci et al.
distinctive gastric phenotype (pyloric gland metaplasia)
by demonstrating immunohistochemical positivity for
H1K1083, an antibody specific for gastric pyloric 180 4 Benign Diseases of the Cervix

mucin ad
m
Most cases are incidental findings in hysterectomy to
ca
specimens; some patients, however, complain of [7
abundant mucoid or watery discharge.
D
Microscopically, there is a proliferation of tightly H
packed, small-sized endocervical glands displaying a
D
well-demarcated, multilobular pattern. Several of the (D
by
lobules are centered by a larger glandular structure m
to
. Typically, LEGH is confined to the inner one-half of b)
lo
the cervical wall, and the gland- lining cells are devoid str
ep
of ‘‘malignant’’ atypia, and mitoses do not exceed 2 per wi
10 high-power fields. LEGH may be mistaken for Th
D
adenoma malignum
en
of
en
>

al
. Fig. 4.38 ar
Lobular endocervical glandular hyperplasia (LEGH). pu
(a) There is a proliferation of highly packed, small-sized sp
endocervical glands in a lobular pattern. (b) The cells lack
cellular atypia and have a gastric phenotype with a large
number of goblet type cells En

. Fig. 4.39
Diffuse laminar endocervical glandular hyperplasia
(DLEGH). (a) There is a proliferation of highly packed,
small-sized endocervical glands that is clearly
demarcated from the underlying cervical stroma. (b) The
cells lack cellular atypia and have a normal endocervical
appearance
Endometriosis
Endometriosis refers to lesions that are composed of ectopic
endometrial glands and stroma (> Chap. 9, Endometrial
Carcinoma), whereas tubo-endometrioid metaplasia refers
to endocervical glands that are lined by ciliated cells or
secretory-type cells with apical snouts that resemble those
Benign Diseases of the Cervix
. Fig. 4.40
Endocervical glandular hyperplasia – NOS. (a) There is
a proliferation of loosely packed endocervical glands.
•
(b) The cells lack cellular atypia or mitotic activity and
there is no stromal reaction to the proliferation
one or more, small, blue or red nodules, measuring a few
millimeters in diameter. Occasionally, however, the lesion
may be larger or cystic and may produce abnormal vaginal
bleeding. Histologically, the glands and stroma resemble
proliferative endometrium (> Fig. 4.42). Rarely, the glands
are secretory. Decidua may be seen in pregnancy or with
progestin therapy.
The mechanism responsible for the development of
endometriosis is unknown, but it is clear that cervical
endometriosis frequently develops following cervical
trauma. Cervical endometriosis is encountered in 5–43%
4 181
. Fig. 4.36
Mesonephric remnants. The mesonephric tubules are lined
by cuboidal epithelium with bland nuclei. Occasional
tubules contain pink, homogenoeous intraluminal
secretions
Mesonephric remnants may become hyperplastic,
resulting in a florid, tubuloglandular proliferation with
transmural involvement of the cervix (> Fig. 4.37).
Based on the architecture of the glandular structures,
mesonephric hyperplasia has been classified by some
authors into different histological types [25, 87]. The
most common type is called the lobular type and is char-
acterized by clustered mesonephric tubules, with or with-
out a centrally placed duct. The lobular form tends to
occur at a younger age, is less extensive, and tends to
arise deeper in the cervical stroma. The less common
Benign Diseases of the Cervix 4 179
. Fig. 4.37
Florid mesonephric hyperplasia. Extensive mesonephric
tubular-ductal proliferation in the deeper portion of the
cervix, resembling an invasive adenocarcinoma. Unlike the
latter, the lobular architecture is maintained in hyperplasia.
Note the mesonephric duct in the lower left surrounded
by a proliferation of small tubules
lesions have low Ki-67 staining indices [69]. In addition,
normal mesonephric remnants are usually admixed with
the hyperplastic tubules.
Lobular Endocervical Glandular
Hyperplasia (LEGH)
 Tunnel clusters
• Lobular aggregates of benign endocervical glands in the cervical
wall

• Incidental finding
• Benign proliferation of endocervical glands with lobular configuration
• Two types (A and B) have been described:
◦ Type A tunnel clusters are composed of small noncystic
glands and may show gastric metaplasia in up to 15% of
cases
◦ Type B tunnel clusters are composed of cystically dilated
glands

• Common incidental finding in cone biopsies or hysterectomy

specimens (
• More prevalent in older, multiparous and pregnant women
• Identified in 8% of adult women and 13% of postmenopausal women
Sites
• Endocervix
Pathophysiology
• May represent subinvolution of endocervical glandular hyperplasia,
for example, due to prior pregnancies
Etiology
• Unclear
Clinical features
• Typically asymptomatic
• May be associated with mucoid discharge
• Rarely visible on colposcopic examination
Diagnosis
• Histologic examination
Prognostic factors
• Excellent prognosis
• No risk of recurrence or malignant transformation
Microscopic (histologic) description
• Well demarcated, rounded, lobular proliferation of
closely packed tubules of varying size lined by Differential diagnosis
endocervical glandular epithelium
• No desmoplastic or inflammatory stromal response
• May be associated with Nabothian cysts
• Usually found close to endocervical surface epithelium
• Type A:
◦ Small elongated noncystic glands lined by
columnar to low cuboidal cells with basally
located nuclei and apical mucinous cytoplasm
◦ Mild cytologic atypia may be present with
pseudostratification, nuclear enlargement,
hyperchromasia, vesicular chromatin or
prominent nucleoli
◦ Minimal or no mitotic activity
◦ Gastric metaplasia in up to 15%
• Type B (“B” for big):
◦ Cystically dilated glands containing inspissated
mucin and lined by cuboidal or flattened
epithelium
◦ The lining cells are cytologically bland with ovoid
nuclei lacking mitotic activity
• Type A and type B tunnel clusters may be admixed
Sample pathology report
• Tunnel clusters have no clinical relevance and do not
need to be mentioned in the pathology report
• Minimal deviation adenocarcinoma
◦ Lacks lobular configuration
◦ Composed of irregular branching glands often
with deep extension in cervical wall
◦ At least focal stromal desmoplasia and
cytologic atypia
◦ Negative for PAX2
• Usual type endocervical adenocarcinoma
◦ Shows infiltrative growth with cytologic atypia,
apical mitotic figures and apoptotic bodies,
often with stromal desmoplastic reaction
◦ Diffusely positive for p16
• Adenocarcinoma in situ
◦ Demonstrates cytologic atypia with
pseudostratified hyperchromatic nuclei, apical
mitotic figures and apoptotic bodies
◦ Diffusely positive for p16
• Nabothian cysts
◦ Shows large mucin filled cysts without lobular
configuration
• Mesonephric remnants / hyperplasia
◦ May extend deeply in cervical wall
◦ Glands often contain densely eosinophilic
intraluminal secretions and are lined by
cuboidal cells lacking intracytoplasmic mucin
◦ Positive for GATA3 or TTF1
. Fig. 4.41
Endocervicosis of the cervix. Cystically dilated endocervical
glands extend into the outer third of the wall of the cervix
(Photograph courtesy of Dr. Phillip Clement of Vancouver,
Canada)
. Fig. 4.42
Endometriosis of the cervix. Both typical endometrial
glands and stroma are present beneath the squamous
portio epithelium
 trial-type epithelial components and are referred to as an otherwise benign polyp. In a polypoid carcinoma, the
the cervix

Polyp Squamous papilloma

mixed polyps. entire mass is malignant, including its base and neighbor-Mesodermal Stromal Polyp
Microglandular endocervical
hyperplasia
Condyloma acuminatum
Papillary adenofibroma

ingareas.AfocusofcarcinomainacervicalpolypwithoutMesodermal
Decidua
Granulation tissue
stromal polyps are benign, exophytic pro-
Squamous cell carcinoma
liferations of stroma and epithelium that can occur in
Adenocarcinoma
the vagina and cervix of women of reproductive ages.
involvement of its base but associated with similar carci-These lesions are seen most frequently in pregnant
Leiomyoma
Adenomyoma
Sarcoma, primary
Sarcoma, secondary
patients and arise more commonly from the vagina than
Fibroadenoma
noma in the adjacent regions should be regarded asfrom the cervix [73]. Histologically, these polyps are com-
. Table 4.3 posed of an edematous stroma that is covered by a benign

asecondary rather thanaprimary focus.Adenocarcinoma

Differential clinical diagnosis of polypoid lesions of
confined to a polyp has an excellent prognosis [2].
the cervix

Polyp Squamous papilloma

Microglandular endocervical Condyloma acuminatum Mesodermal Stromal Polyp
hyperplasia Papillary adenofibroma
Decidua Squamous cell carcinoma Mesodermal stromal polyps are benign, exophytic pro-
liferations of stroma and epithelium that can occur in
Granulation tissue Adenocarcinoma . Fig. 4.43 . Fig. 4.44
the vagina and cervix of women of reproductive ages.
Endocervical polyp. This is the most common type of Granulation tissue. Polypoid nodules of granulation tissue
Leiomyoma Sarcoma, primary endocervical polyp. Endocervical-type, tall columnar, can grossly resemble an endocervical polyp. This type of
These lesions are seen most frequently in pregnant
mucinous epithelium covers the surface and crypts lesion often leads to bleeding
Adenomyoma Sarcoma, secondary
patients and arise more commonly from the vagina than
Fibroadenoma
from the cervix [73]. Histologically, these polyps are com-
posed of an edematous stroma that is covered by a benign
•
 rhabdomyoblasts, and lack of a cambium layer.
of sarcoma botryoides [21]. However, careful inspection
will allow these lesions to be differentiated from sarcoma
botryoides by the absence of mitotic figures, lack of
Placental Site Trophoblastic
rhabdomyoblasts, Nodule
and lack of a cambium layer.

Placental site trophoblastic nodules can be found in the

endocervix,
Placentalimmediately beneath the epithelium.
Site Trophoblastic NoduleThey are
sometimes detected in endocervical curettages. These
Placental
lesions aresite trophoblastic
histologically nodules
identical can be
to early found in the
implantation
endocervix, immediately beneath the epithelium.
sites that can be detected in the endometrium of women They are
sometimes detected in endocervical curettages.
of reproductive ages [105]. Microscopically, placental site These
lesions are histologically identical to early implantation
trophoblastic nodules are well-defined lesions that have
sites that can be detected in the endometrium of women
aofhyalinized appearance
reproductive and contain
ages [105]. intermediate
Microscopically, tropho-site
placental
blasts and inflammatory cells (> Fig. 4.46). The intermedi-
trophoblastic nodules are well-defined lesions that have
ate trophoblast
a hyalinized cells are frequently
appearance degenerated
and contain and have
intermediate an
tropho-
blasts and inflammatory cells (> Fig. 4.46). The intermedi-
ate trophoblast cells are frequently degenerated and have an

. Fig.
. Fig.
4.454.45 . Fig.
. Fig. 4.46
4.46
Mesodermal
Mesodermal stromal polyp.
stromal (a)(a)
polyp. Spindle-shaped
Spindle-shapedand
and stellate
stellate Placental sitenodule.
Placental site nodule.AA hyalinized
hyalinized nodule
nodule containing
containing
fibroblasts are embedded in a loose myxoid stroma that has intermediate trophoblast is identified in an endocervical
fibroblasts are embedded in a loose myxoid stroma that has intermediate trophoblast is identified in an endocervical
a stratified squamous surface epithelium. (b) At higher curettage obtained several months postpartum
a stratified squamous surface epithelium. (b) At higher curettage obtained several months postpartum
magnification, stellate atypical fibroblasts can be seen in
the magnification,
stroma stellate atypical fibroblasts can be seen in
the stroma
 Benign Diseases of the Cervix 4 185
Benign Diseases of the Cervix 4 187

rapped within the stroma at the time of obstet-

aant
or subsequent surgical repair. Inclusion cysts
monly found on the cervix. Grossly, they pre-
low
ocular cystic structures measuring 1–2 cm in
ains
eneath the native portio epithelium [28].
pla-
cally, traumatic inclusion cysts are lined by
esquamous
of epithelium similar to that of the
cosa
k of but usually somewhat thinner. The epi-
ows
l as normal maturation with the basal cells,
way from the cyst cavity that is filled with
gen,
d epithelial cells. The cyst contents are identi-
om epidermal inclusion cysts at other sites and
of
hite, and cheesy.

ike Lesions

Pseudopolyp
ine
lat-
. Fig. 4.47of the pseudodecidual change that
ppearance
ion
during pregnancy depends on the site. If the
Papillary adenofibroma of the endocervix. Fibroepithelial
ical on the exocervix, it frequently presents as
urs papillae project from the cervix. The papillae are covered
ical or pseudopolyp that can be mistaken for
que
with an endocervical-type epithelium
cinoma
the both colposcopically and microscopi-
gore gestation, cervical polyps may also contain
al pseudodecidual changes, and rarely massive
sto-
ion of endocervical stroma occurs, producing
ical Miscellaneous
protrusion from Tumors
the endocervix. Clinically,
dclei
polyps need to be differentiated from extruded
f decidua that may indicate an impeding mis-
Hemangiomas are rarely found in the cervix. They may be . Fig. 4.50
stinction is made by identifying a stalk for the
of capillary or cavernous type [37]. A single instance of
d polyp, whereas expulsed fragments of decidua Mullerian papilloma. (a) Papillary projections; (b) papillary
Areascervical lymphangioma was reported by Stout
of pseudodecidualization are and several
microscop- projections covered with cuboidal to columnar epithelium
a cases of
entiated fromlipomainvasive
of the cervixnonkeratinizing
are on record [94]. Neo-squa-
carcinoma
plasms of by the lack
neurogenic ofarising
derivation significant
in the cervixnuclear
are
mix-
ell as extremely
lack of mitotic
rare and include neurofibroma andsqua-
figures, a coexisting
of loose fibrovascular tissue (> Fig. 4.50a, b). Cytologic
nts,
pithelial lesion (SIL) and continuity with the
ganglioneuroma. Benign blue nevi of the endocervix, atypia and mitoses are absent. In the past, the lesions
Precursors of Squamous Cell
Carcinoma .
Terminology and Historical Perspective
General Features .
Human Papillomaviruses
Other Risk Factors Smoking, Diet, Oral
Contraceptives Immunosuppression
Clinical Features
Pathologic Findings LSIL ........HSIL .. Management of Cytologic Abnormalities
Behavior of SIL
Management .
Precursors of Cervical Adenocarcinoma .
Terminology and Historical Perspective
Epidemiology and Etiology
Clinical Features
Pathologic Findings
Cervical Cytology
Strengths and Limitations of Cervical
Cytology
TBS Terminology
and Cervical Cancer Precursors
the epidemiology of HPV infections {57, LSILs {160,388,412,465}. Colposcopy CIN 1) is the morphological manifestation
59,249,325,980,1916}. HPV infections does not reliably segregate LSIL from of the differentiation-dependent expres-
are verySquamous
common, affecting up to 80%cell high-grade squamous intraepithelial le-
tumours sio•n ofCervical squamous
an HPV virion producti on program intraepithelial neoplasia refers to all
squamous alterations that occur in or near the
of women in their early 20s, but being sion (HSIL) and both may co-exist in the on thetransformation
host squamous cells {465,1838, zone in association with human
and precursors
detectable in only 5% in their 50s {1627} cervix, not only in the same quadrant or 1839}.papillomavirus
There is no way to predict (HPV) HPV infection, thereby encompassing the
More than 40 HPV types infect the cervix, area of acetowhitening, but in separate type byterms 
morphology,condyloma,
although some data cervical intraepithelial neoplasia  (CIN), 
dysplasia, and squamous intraepithelial lesions.
although 13–15 high-risk (HR) and 4–6 areas or quadrants {1177}. Two distinct suggest that HPV 16 and HPV 18 produce
• low-grade squamous intraepithelial lesions encompass flat
low-risk (LR) types account for the major- areas may be due to infection by two dif- moreand rapidly growi ng and larger leimmature
exophytic, sions and mature condylomata, as well
ity of infections and most clinically valid ferent HPVs or by the same HPV {1546}. {84,249,251,836,1845,2176}.
as lesions graded The inher-as I in the CIN classification scheme.
HPV tests only test for 13–14 HR types Sophisticated molecular microdissection ent diHigh-grade
fficulty in distinguishingsquamous
pure HPV intraepithelial lesions correspond to
CIN II and III.
{981,1122,1916}. studies support the concept of “one le- infection from CIN 1 in histologically flat
sion, one virus” {1546}. epi•thelLow-grade
ium (sometimes referred to as flat intraepithelial lesion Low-grade squamous
squamous
Clinical features condylintraepithelial
oma) is understandablelesionssince, by can be divided into three morphologic
LSILs are asymptomatic lesions and are the above
subsets: definition,(1)
they arecondyloma
biologically acuminatum (exophytic condyloma), (2)
the same
immature {465,1250,1537}. Some pa- (squamous papilloma, papillary immature
condyloma
thologimetaplasia),
sts attempt to make thiands distin(3)ction flat condyloma (CIN I)
and• subdi
ThevidLower e LSILs into lAnogenita
esions showing Squamous Terminology
koilocytosi s without atypia, flat condylo- project did not support this approach,
Standardization(LAST)
matarecommending
and CIN 1. The Lower Anogeni that all of these lesions be designated LSILs,
tal
reflecting their common biology.
Squamous Terminology Standardization
(LAST)
• Aprojtwo ect ditier
d not support
system this ap-of low- and high-grade intraepithelial lesions is
proach,more biologicall relevant and histologically more reproducible
recommendi ng that all of these
than the three-tier CIN 1, CIN and CIN 3 terminology .
lesions be designated LSILs, reflecting
thei•Approximately
r“block-positive”)
common biology. one third of histological LSIL show diffuse (so called
p16 immunostaining involving the basal and
A B LSIL parabasal cell layers.on
is characteri z ed by a prol i f erati
Fig. 7.02 Patterns of p16 expression in low-grade squamous intraepithelial lesion (LSIL). Immunostaining for p16 in
of basal/parabasal-like cells that may
be minimal but at most extends no more
 Localization in the basal layer may be due to the presence characterize HPV infections in which there is no gross or
of specific receptors for HPV on the basal cells. Once HPV microscopic evidence of a HPV-induced epithelial lesion,
enters into the basal cells, it can exist within the cells in two and the virus is present at such low copy number in the
distinct biological states. One is as a nonproductive infec- epithelium that it cannot be detected with routine molec-

HPV
tion in which HPV DNA continues to reside in the basal
cells, but infectious virions are not produced. In the liter-
ature, nonproductive HPV infections have frequently been
referred to as latent infections. Usually in nonproductive
latent infections a small number of copies of the HPV
genome remain in the nucleus in a free circular form called
an episome. Replication of the episomal DNA in latent
ular detection methods.
The other form of HPV infection is a productive viral
infection. In productive viral infections, viral DNA repli-
cation occurs independently of host chromosomal DNA
synthesis. This independent viral DNA replication pro-
duces large amounts of viral DNA and results in infectious
virions. Viral DNA replication takes place predominantly

•HPVs are epitheliotropic viruses with double-stranded DNA genomes and eight
coding genes defined as “early” or “late” depending on when they are
expressed.
• Over 200 HPVs have been identified with 13 types considered oncogenic or
high risk (HR).
•HPV type 16 confers the greatest risk, being responsible for around 60% of
cervical cancers. HPV infection is common with a global point prevalence of
around 10% and most infections are transient.
The initial site of infection is thought to be either basal cells or primitive ‘‘basal-
like’’ cells of the immature squamous epithelium One is as a nonproductive
infec- tion in which HPV DNA continues to reside in the basal cells, but
infectious virions are not produced. Usually in nonproductive latent infections a
small number of copies of the HPV genome remain in the nucleus in a free . Fig. 5.12
circular form called an episome. HPV life cycle (Source: Kahn JA (2009) HPV vaccination for the prevention of cervical intraepithelial neoplasia (CIN). N Engl
J Med 361:273)

Replication of the episomal DNA in latent infections is tightly coupled to the

replication of the epithelial cells and only occurs in concert with replication of
the host cell’s chromosomal DNA.
In productive viral infections, viral DNA replication occurs independently of
host chromosomal DNA synthesis. This independent viral DNA replication pro-
duces large amounts of viral DNA and results in infectious virions. Viral DNA
replication takes place predominantly in the intermediate and superficial cell
layers of the stratified squamous epithelium. As the virally infected epithelial
cells mature and move toward the epithelial surface, cell-derived, differentiation-
specific transcrip- tional factors produced by the epithelium stimulate the
production of viral capsid proteins. This allows large amounts of intact virions to
be formed and produces the characteristic virally associated effects of HPV that
can be detected both cytologically and histologically, . These viral-associated
effects include acanthosis, cytoplasmic vacuolization, koilocytosis,
multinucleation, and nuclear atypia.
 Koilocytosis
• Marked variation in
nuclear size(three
times )
• Dark chromatin
• Irregular raisinoid
nuclear membrane
 a histologically defined precursor lesion that requires per- cervix were combined into the CIN 1 category. These
sistence of the HPV infection, and (3) invasion [167, 176, lesions have been designated in the past as koilocytotic
209]. Based on this biological model, it is highly unlikely atypia, koilocytosis, or flat condyloma.

LSIL that cervical cancer develops according to a stepwise pro-

gression that envisions CIN 1, progressing to CIN 2, to
The other entity subsumed within the morphologic
CIN spectrum is histologically ‘‘high grade.’ High-grade

• Exophytic condyloma is characterized by a verruciform

growth pattern with blunt-shaped papillae, acanthosis,
and superficial koilocytotic atypia (nuclear Transient infection Persistent HPV infection
hyperchromasia, karyomegaly, binucleation, an irregular
nuclear contour). Mild cytologic
• These exophytic lesions, which are highly associated with HPV abnormalities
HPV types 6 and 11, are relatively uncommon in the cervix.
• Immature condyloma is characterized by slender, filiform
papillae lined by squamous epithelium that shows little
keratinocyte maturation (mimicking squamous
metaplasia) but exhibits slight nuclear crowding and mild Initial
superficial koilocytotic atypia. infection
• Similar to exophytic condyloma, immature condylomas
harbor HPV types 6 and 11, which supports their inclusion Progression Invasion
in the condyloma category. Normal cervix HPV-infected cervix Precancerous Cancer
• Papillary immature metaplasia and squamous papillomas Regression lesion
Clearance
are histologically identical to immature condyloma and
also contain HPV types 6 and 11,
• Flat condyloma exhibits morphologic features similar to The three steps of cervical carcinogenesis.
condyloma acuminatum but lacks an exophytic growth The steps can be conceptualized as infection with specific high-risk types of human papillomavirus (HPV), progression
pattern. The amount of koilocytotic atypia may vary; to a precancerous lesion, and invasion, HPV infections are usually transient and are often associated with mild cytologic
however, the atypia is confined to the upper third of the abnormalities. Persistent infection with high-risk types of HPV is uncommon and is required for progression.
epithelium, with minimal basal and parabasal nuclear
atypia.
• positivity for Ki67 in the upper cell layers is characteristic . Fig. 5.1
of HPV-infected epithelium, whereas this marker is
Steps in the development of cervical cancer. Three steps in cervical carcinogenesis (Used with permission from [209])
typically confined to the lower layers in normal mucosa.
 LSIL
• LSIL (koilocytosis or flat condyloma CIN 1) is the morphological manifestation of the
differentiation-dependent expression of an HPV virion production on the host squamous cells .
• HPV 16 and HPV 18 produce more rapidly growing and larger lesion
• LSIL is characterized by a proliferation of basal/parabasal-like cells that ma be minimal but at
most extends no mor than one-third of the way up the epithe lium . Mitotic activity confined to
this zone and for most LSILs the mitoses are not abnormal. In the upper three-quarters to two-
thirds of the epithelium, the cells differentiate and gain cytoplasm; however, nuclear enlarge-
ment persists such that the nucleocytoplasmic ratio is increased. In addition there is usually
nuclear hyperchromasia, nuclear membrane irregularities and often development of a well-
defined halo- like vacuole around the nucleus
• Koilocytosis is usually most prominent in the upper third of the epithelium. The surface cells
may exhibit parakeratosis or hyperkeratosis. Other findings include bi- or multinucleation.
Importantly, all SILs have histocytological abnormalities in all layers of the epithelium. Beside
HSIL
• LSIL must be distinguished from mimics of LSIL due to a variety of infectious or inflammatory
processes that ar unrelated to HPV infection
.
 Condyloma acuminata-LSIL CIN1(condylomatous variant)
. Fig. 4.32
Exophytic condyloma acuminata. The lesions are multifocal
and form raised white projections on both the vagina and
cervix
condylomas include myriad of minute, maculopapular,
only slightly raised, condylomas involving the vagina and
the cervix.
Microscopically, the histological features of exophytic
cervical condyloma acuminata include architectural alter-
ations such as papillomatosis, acanthosis, parakeratosis,
and hyperkeratosis as well as cytologic alterations including
koilocytosis (manifested by perinuclear cytoplasmic cavita-
tion), nuclear enlargement and atypia. Multinucleation is
also frequently observed (> Fig. 4.33) (> Chap. 1, Benign
Diseases of the Vulva, > Chap. 5, Precancerous Lesions of
the Cervix).
The natural history of exophytic cervical condyloma
accuminata is one of the spontaneous regressions, good
response to conservative therapy, unpredictable recur-
rence, and sometimes persistence. Lesion regression or
apparent cure following biopsy is fairly common. The
natural history of genital condylomata in general may be
modified by host factors, notably immunosuppression
and steroid hormone levels.
Fungal Diseases
•A benign proliferation characterized by papillary fronds
containing fibrovascular cores and lined by stratified
squamous epithelium with definite evidence of HPV
infection.
•Epidemiology LSILs architecturally resembling
condylomata acuminata are much more common in
. Fig. 4.33
external genital sites than in the cervix
Exophytic condyloma acuminata. The classic histological
features are papillomatosis with acanthosis, parakeratosis, •Condylomata acuminata are associate most strongly with
hyperkeratosis, as well as cytological alterations including
multinucleation, koilocytosis and nuclear atypia
low-risk HPV types particularly HPV types 6 and 11.
involving the vagina and vulva. Antibiotic therapy, poorly
Macroscopy
controlled diabetes mellitus, and immunosuppression all
favor fungal overgrowth [93]. Cervical candidal infections The lesion looks like a genital wart on mucosal surface if
can be associated with increased numbers of polymorpho-
leukocytes present in the upper layers of the epithelium and large enough to see Colposcopy enhances visualization.
fungal hyphae that can be identified by periodic acid-Schiff
(PAS) stains, both at the surface of the epithelium and Histopathology
within the superficial layers of the epithelium.
The squamous epithelium covering the knuckle-like
Protozoal and Parasitic Diseases
fronds of the lesion exhibit acanthosis, papillomatosis and
Cervical infestation by Trichomonas vaginalis is quite
frequent and most often associated with concurrent tricho-
koilocytosis as defined in the section on LSIL. less mature
monal vaginitis. Acute trichomonal cervicitis may provoke
an intense inflammatory response with prominent repara-
variant with a metaplastic appearance (immature papillary
tive atypia in exfoliated squamous and endocervical cells, squamous metaplasia) .
with corresponding gross and colposcopic abnormalities.
Rare instances of parasitic infestations such as
echinococcosis or hydatid cysts, Chagas’ disease, and
ulceronecrotic amebiasis have been encountered in the
cervix [15]. In contrast, schistosomiasis (bilharziasis) of
the cervix, generally caused by Schistosoma mansoni, is
High grade squamous intraepithelial lesion
• A squamous intraepithelial lesion that carries a significant
risk of invasive cancer development if not treated.

• Synonymous with Cervical intraepithelial neoplasia, grade 2

(CIN 2); cervical intraepithelial neoplasia, grade 3 (CIN 3);
moderate squamous dysplasia; severe squamous dysplasia;
squamous carcinoma in situ (CIS)

• High-grade squamous intraepithelial lesions are

characterized by nuclear atypia in all levels of the
epithelium with a variable degree of surface
maturation.
• Lesions may exhibit surface koilocytotic change and
epithelial maturation or little or no maturation.
• These lesions are associated with high-risk HPV types,
particularly type 16.
• p16ink4, a cyclin-dependent kinase inhibitor, appears
to be a surrogate marker of HPV infection, being
strongly expressed (positivity defined as strong
cytoplasmic and nuclear staining in the lesional cells)
in lesions associated with intermediate-risk and high-
risk HPV.
 In the past, some investigators have proposed for-
mally subtyping high-grade
In the past, precursors into
some investigators have small cell for-
proposed
anaplastic, large cell keratinizing,
mally subtyping and large into
high-grade precursors cell non-
small cell the subjective nature of the morphologic criteria used to
keratinizing dysplasia distinguish it from AIS, and the infrequent coexistence of
anaplastic, large [147,
cell 157]. Because accurate
keratinizing, and large studies
cell non-
concerning the invasive potential of each of theseaccurate
subtypes endocervical glandular dysplasia with AIS, the significance
keratinizing dysplasia [147, 157]. Because studies

HSIL
are lacking, prediction of thepotential
likelihood of endocervical glandular dysplasia is not known [110].
concerning the invasive ofof progression
each to
of these subtypes A number of studies have utilized objective biomarkers
invasive carcinoma
are lacking, should of
prediction notthebelikelihood
based onofthe above to
progression including HPV DNA positivity, proliferation markers
subclassification.
invasive carcinoma should not be based on the above such as Ki-67/MIB-1, p16INK, and selective mucin staining
subclassification. to determine whether endocervical glandular dysplasia
acts as a precursor to AIS or invasive endocervical adeno-
Differential Diagnosis carcinoma [3, 10, 71, 77, 109, 111, 136, 162, 185].
Differential Diagnosis Although some of these studies have shown a similar
Immature metaplasia, reactive/reparative processes, and pattern of biomarker expression in both endocervical
atrophy are themetaplasia,
most common lesions mistaken for and glandular dysplasia and AIS, most recent studies have
LSIL spontaneously regress in the absence of treatment and the Immature
HSIL.atrophy
This isare
because
reactive/reparative
cells of these lesions
processes,
not [85, 110, 162]. Investigators who advocate the use of
the most common lesionscan show for
mistaken
risk that a woman with a LSIL will be subsequently diagnosed immaturity of theissquamous
HSIL. This epithelium,
because cells of thesenuclear
lesionsatypia,
can show
the term ‘‘glandular dysplasia’’ do so under the misguided
. Fig. 5.54
and immaturity
inflammatory notion that there is a similar relationship of glandular
with either carcinoma in situ or invasive cervi- cal cancer is of thecellular
squamous changes. In immature
epithelium, nuclear atypia, precursors to HPV infection as there is for squamous
Colposcopic appearance of SIL. An acetowhite, well-
and inflammatory cellular changes. In immature precursor lesions. As previously discussed, the histologic
relatively low. circumscribed lesion is present at the external os
manifestation of productive viral infection is LSIL (mild
dysplasia). Productive HPV infection is tightly linked to
Helper described highly atypical neoplastic cells lining
They also demonstrate that the likelihood that HSIL will regress architecturally normal endocervical glands adjacent to
squamous differentiation. Glandular epithelium does not
support productive infection. Accordingly, there is no
in the absence of treat-ment is higher than many clinicians frankly invasive endocervical adenocarcinomas [76]. comparable low-grade lesion in glandular epithelium.
Shortly thereafter, Friedell and McKay described two Since the term glandular dysplasia implies a relationship
realize and that it generally takes many years for a HSIL to patients with atypical glandular lesions of the cervix and to AIS and invasive carcinoma that does not exist, the use
progress to an invasive carcinoma. designated these lesions AIS because of their histological of this term should be discontinued. Instead, atypical
resemblance to invasive endocervical adenocarcinoma glandular proliferations that fall short of AIS should be
[61]. One of these patients had a coexistent invasive ade- evaluated using biomarkers such as p16INK and Ki-67 and
Colposcopy combined with colposcopically directed cervical nocarcinoma of the cervix and one, squamous ‘‘carcinoma classified as reparative changes if they are p16INK negative
in situ.’’ and show a low Ki-67 labeling index. In contrast, if they
biopsies are the primary modality by which women with By analogy to squamous cell cervical cancer precur- express p16INK strongly and diffusely and show a high
abnormal Pap smears are evaluated. sors, some authors have proposed parallel classification
schemata for endocervical adenocarcinoma precursors
Ki-67 proliferation index they are classified as AIS.

that include lesions with a lesser degree of abnormality

than AIS [23, 26, 69, 115]. Such low-grade putative glan- Epidemiology and Etiology
Colposcopic examination consists of viewing the cervix with a dular precursor lesions were originally termed
long-focal-length, dissecting-type microscope at a magnification endocervical dysplasia by Bousfield et al. but other terms Over the last 3 decades, endocervical glandular lesions
such as atypical hyperplasia are also used to refer to lesions have received increasing attention. This is attributable to
of about 16︎ after a solution of dilute (4%) acetic acid has been that resemble AIS, but have a somewhat lesser degree of a variety of factors. One is a perception that the prevalence
applied to the cervix. The acetic acid solution acts to remove nuclear atypia and mitotic activity [23, 81]. Gloor and of adenocarcinomas of the cervix and its precursor lesions
associates suggested that the term cervical intraepithelial is increasing. There has been a documented absolute
and dissolve the cervical mucus and causes SIL to become glandular neoplasia (CIGN) be used to refer to both increase in the prevalence of invasive adenocarcinomas
endocervical glandular dysplasia and AIS and that in specific groups of women in both the USA and Europe.
whiter than the surrounding epithelium (acetowhite), endocervical glandular dysplasia be classified as either This may be due, in part, to the increased routine use of
CIGN grade 1 or 2 and AIS be classified as CIGN grade 3 cytobrushes in screening and the widespread adoption of
[71]. The World Health Organization utilizes the term
Conservative ablative treatment modalities such as cryosurgery, excisional methods for treating SIL such as the LEEP that
glandular dysplasia to describe a ‘‘glandular lesion charac- permit pathological examination of the entire transforma-
laser ablation, and loop electrosurgical excision procedure . Fig. 5.43
terized by significant nuclear abnormalities that are more tion zone. In addition, there is an increased awareness of
. Fig. 5.44
striking than those in glandular atypia, but fall short of these lesions by pathologists, and an awareness by
(LEEP) can then be used to treat preinvasive disease, with HSIL with metaplastic
the criteria features. (a) This lesion
for adenocarcinoma is relatively
in situ’’ Stratified mucin-producing intraepithelial lesion (SMILE).
[186]. Because colposcopists that certain types of glandular lesions are
bland.appearing,
Fig. 5.43 but has considerable numbers of mitotic (a) . Fig.
These 5.44
HSIL show both colposcopically.
mucinous and squamous
success rates similar to those obtained with cone biopsies. HSIL
of the relative rarity of endocervical glandular dysplasia, difficult
with metaplastic
ink features. (a) This lesion
figures. (b) P16 staining demonstrates strong diffuse is relatively Stratified
to recogniz
mucin-producing
differentiation. (b) intraepithelial
It has a high Ki-67 lesion
labeling index and(SMIL
bland appearing, but has considerable numbers of mitotic
positivity (a) These
(c) stains HSILfor
positively show
p16both
ink mucinous and squamous
figures. (b) P16ink staining demonstrates strong diffuse differentiation. (b) It has a high Ki-67 labeling index an
positivity (c) stains positively for p16ink

Variants of HSIL
Thin HSIL is a high-grade intraepithelial lesion that is
usually < 10 cells thick. If there is doubt about the nature of
the pro- liferation (e.g. immature metaplasia versus SIL) then
p16 staining.
In keratinising HSIL, there is an abnormal keratinizing layer
on the surface and the epithelium typically contains
dyskeratotic cells with markedly atypical, often pleomorphic
nuclei.
The histology is more like the HPV-associated HSILs seen in
cuta- neous sites with keratinizing epithelium such as vulva
or perineum. Such lesions may more often be seen in
ectocervical locations
Lesions that are clinically condylomatous can histologically
harbour HSIL. Such changes may be focal, but the HSIL area
dictates prognosis and treatment.
Papillary squamous carcinoma in situ, or non-invasive
papillary squamo-transitional carcinoma is a papillary lesion
with fine and less acuminate papillations that histologically
is completely covered by epithelium that shows the features
of HSIL and may resemble urothelial neo plasia. This
diagnosis should only be made if the lesion has been
completely excised and stromal invasion excluded.
HSIL
Immunohistochemistry
• p16 immunohistochemistry can be extremely
helpful in the assessment o HSILs, particularly in
the evaluation of lesions considered
morphologically to rep resent HSIL (CIN 2) and in
the distinction between HSIL and its mimics, such a
immature squamous metaplasia and atrophy.
• Histogenesis
High-risk (HR) HPVs are found in over 90% of
cervical HSILs. Whether HSILs develop from LSILs
or evolve independentl is controversial .
Biologically, an HSIL can be thought of a a clonal
expansion of cells that are drive to proliferate by the
abnormal expression of HPV E6 and HPV E7 in cells
still capable of cell division .
 . Table 5.5
Distinguishing features of LSIL and HSIL

Feature LSIL HSIL

HPV types Any High-risk
•These lesions are anogenital typesa
distinguished from low-grade
HPV
squamous intraepithelial
lesions by (1) the presence of Koilocytosis Frequently Occasionally
nuclear atypia in the lower present present
layers, (2) increased mitotic Ploidy Mostly diploid Usually
index with mitoses in the
or polyploid aneuploid
upper half of the epithelium,
(3) loss of cell polarity and in Abnormal mitotic figures Absent Frequent
some cases (4) abnormal (AMFs)
mitotic figures and (5) the
Location of undifferentiated Lower third Upper two-
presence of markedly
atypical, bizarre cells. cells and mitotic figures thirds
a
High risk types of HPV include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,
59, 66.
 Feature
HPV types
LSIL
Any
HSIL
High-risk
Precancerous Lesions of the Cervix 5 221

anogenital typesa
HPV
Koilocytosis Frequently Occasionally
present present
Ploidy Mostly diploid Usually

Abnormal mitotic figures

(AMFs)
or polyploid
Absent

Location of undifferentiated Lower third

cells and mitotic figures
aneuploid
Frequent

Upper two-
thirds
Precancerous Lesions of the Cervix 5 219

. Fig. 5.41
a
High risk types of HPV include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, . Table 5.5
HSIL with prominent abnormal parakeratosis. This HSIL has
59, 66. Distinguishing
a superficial layer of compacted parakeratotic cells thatfeatures of LSIL and HSIL
appear abnormally keratinized
Feature LSIL HSIL
HPV types Any High-risk
anogenital typesa
HPV
Koilocytosis Frequently Occasionally
Fig. 5.45 . Fig. 5.46 present present
mmature squamous metaplasia. Metaplastic squamous Immature squamous metaplasia.
PloidyThis lesion has a relatively Mostly diploid Usually
ells are regularly oriented with uniformly disposed nuclear uniform metaplastic appearance, but the nuclei are or polyploid aneuploid
hromatin and cellular borders. Intracellular bridges are hyperchromatic and irregular. Some mitoses are present.
Abnormal mitotic figures Absent Frequent
esent However, the lesion is found underlying columnar
(AMFs)
epithelium and the degree of nuclear atypia is insufficient
Location of undifferentiated
to warrant a diagnosis of HSIL Lower third Upper two-
etaplasia, the full thickness of the epithelium is com- cells and mitotic figures thirds
. Fig. 5.41
osed of immature parabasal cells with a high nuclear : a
High risk types of HPV include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,
. Fig. 5.40 > . Fig. 5.42 HSIL with prominent abnormal parakeratosis. This HSIL has
ytoplasmic ratio, Fig. 5.45. The cells usually are vertical 59,HSIL
66.has a metaplastic
HSIL with hyperkeratosis and parakeratosis. Prominent HSIL with metaplastic features. This a superficial layer of compacted parakeratotic cells that
nd thekeratinization
nuclei are only slightly hyperchromatic. The most
is frequently seen in HSIL. This HSIL has appearance and is covered by columnar epithelium. The
elpfula feature in distinguishing
thick plaque of keratin on the HSIL
surfacewith an often
that can immature
be degree of nuclear atypia is too great for this to be
appear abnormally keratinized
etaplastic
seen atphenotype
the time of a from immature
gynecological metaplasia
examination. is the
Clinicians metaplasia
bsencecallofplaques
nuclear of keratin on the surface
pleomorphism of the
in the cervixThe chro-
latter.
atin leukoplakia. Parakeratosis
in metaplastic squamousis alsoepithelium
present is finer and
ore evenly distributed than in HSIL. In addition, cellular lesions with both squamous and mucinous differentiation
have been referred to as stratified mucin-producing
olarity is retained, cell membranes are clearly defined,
intraepithelial lesion (SMILE) and contain cells with
nd cellular crowding
sometimes be seenis not marked.
in the Immature
superficial layers. metaplasia
p16Ink is prominent mucin droplets [145]. SMILE usually shows
pically
veryshows a diagnosing
useful in regularity these
of nuclear
lesions, >spacing and
Fig. 5.43a, b. Inthe a high Ki-67 labeling index and strong diffuse staining
sionsaddition,
lack significant
some HSIL have variation in nuclear
both squamous size and
and mucinous with p16Ink, > Fig. 5.44b, c. These lesions are often found
differentiation, > Fig. 5.44a. This reflects the multipoten- in association with both HSIL and adenocarcinoma in situ
aining pattern. Atypical cells are rarely seen in the super-
tial nature of the cells in the transformation zone. These (AIS) [145].
cial layers of the epithelium and the superficial layers of
e epithelium often appear more normal than the lower
alf. Mucinous epithelium is often present on the surface
immature metaplastic squamous epithelium but only
ccasionally overlies HSIL, > Fig. 5.46. Immature meta- . Fig. 5.47
asia may have mitotic activity, but AMFs are not present. HSIL. This lesion has a relatively uniform metaplastic
When significant numbers of mitoses are present it is appearance, but has considerable numbers of mitoses and
ore likely that the lesion represents a HSIL, > Fig. 5.47. exhibits loss of polarity. It is somewhat similar to the lesion
ometimes, there may be more pronounced nuclear shown in > Fig. 5.46. However, this lesion showed strong
ypia within immature metaplasia, > Fig. 5.48a, b. Such diffuse p16ink staining throughout its full thickness (not
sions are designated by some as atypical immature shown) and was associated with classic HSIL in other
. Fig. 5.40 . Fig. 5.42
etaplasia (AIM) [42]. Histologically, AIM lesions have sections. Immunohistochemical staining for p16ink is helpful
monomorphic population of squamous cells that retain in classifying lesions of thisHSIL
typewith hyperkeratosis and parakeratosis. Prominent HSIL with metaplastic features. This HSIL has a metaplastic
keratinization is frequently seen in HSIL. This HSIL has appearance and is covered by columnar epithelium. The
a thick plaque of keratin on the surface that can often be degree of nuclear atypia is too great for this to be
seen at the time of a gynecological examination. Clinicians metaplasia
call plaques of keratin on the surface of the cervix
leukoplakia. Parakeratosis is also present
 Superficially Invasive Squamous Cell
Carcinoma
• Early-stage invasive squamous cell
carcinoma (stage IA1) is defined by the
latest International Collaboration on
Cancer Reporting (ICCR) consensus
guidelines as less than or equal to 3 mm in
depth by 7 mm in length without capillary
lymphatic space invasion, and, unlike
patients with higher stage tumors, patients
with stage IA1 invasive squamous cell
carcinoma are amenable to conservative
(excision only) therapy without lymph node
dissection.
Carcinoma in situ (preinvasive carcinoma) T1s
Tumour confined to the cervix (extension to corpus should be
disregarded) T1
Invasive carcinoma diagnosed only by microscopy. Stromal invasion
with a maximal depth of 5.0 mm measured from the base of the
epithelium and a horizontal spread of 7.0 mm or lessc T1
Measured stromal invasion 3.0 mm or less in depth and 7.0 mm or less
in horizontal spread. T1A
Measured stromal invasion more than 3.0 mm and not more than 5.0
mm with a horizontal spread of 7.0 mm or less. T1B
 HSIL

a b c 256 6 Carcinoma and Other Tumors of the Cervix

ve squamous cell carcinoma. Small foci

us cell carcinoma present in superficial stroma
ing 5 mm in depth from the basement
of the overlying high-grade squamous
lial lesion and not exceeding 7 mm in
extent
. Fig. 6.5
Methods of measuring depth of invasion of microinvasive
squamous cell carcinoma of the cervix. The pattern of
SIL involving the endocervical crypts [8]. Two additional
histologic features predicting microinvasion include pres-
Carcinoma and Other Tumors of the Cervix 6
ence of luminal necrosis and intraepithelial squamous
stromal invasion determines the stromal depth maturation [8].
measurement that is most appropriate. (a) Origin of
invasion at surface HSIL: depth of stromal invasion is
measured from point of origin of invasion downward toClinical
the Features
last cell of the invasive focus. (b) Origin of invasion at HSIL
with gland involvement: depth of stromal invasion is Most patients with MICA are asymptomatic with a grossly
measured from site of origin downward to the last cell normal
of cervix or nonspecific findings such as chronic HSIL
the invasive focus. (c) Origin of invasion not seen: depth of
cervicitis or erosion. Cytologic studies do not accurately
stromal invasion is measured from basal lamina of surface predict the presence of microinvasion [200]. In a study of
HSIL downward to the last cell of the invasive focus 536 women undergoing laser conization, cytology

Surgical Margins predicted the presence of invasion in only 27.3% of

women with MICA [10]. In another study, cytology . Fig. 6.1
a b c
predicted invasion only in 12.5% of women with MICA Microinvasive squamous carcinoma. Irregular islands of
greatest lateral extent of the lesion, and whether
The appropriate management of early invasive [36]. A.definitive
lymphvascular invasion is present. For consistency inhistologic
Fig. 6.3 diagnosis of microinvasion is made by
the Microinvasive squamous cell carcinoma.
. Fig. 6.5
squamous
butMethods
cell carcinoma invade superficial cervical stroma
of measuring
do not exceed depth
5 mm in of invasion
depth or 7 mmof inmicroinvasive
horizontal
evaluation of cervical tissue Small foci by
removed
squamous cell carcinoma is evaluating surgical margins
measurement of the depth of stromal invasion, the follow- of squamous
conization cell carcinoma Colposcopically,
or at hysterectomy. present in superficial stroma
areas of squamous cell carcinoma of the cervix. The pattern of
extent
stromal invasion determines the stromal depth
ing guidelines are recommended. The depth of neoplastic MICAnot exceeding 5 mm in depth from the basement
usually show acetowhitening consistent with high-
of conization specimens projections should be measured from the initial sitegrade of membrane of the overlying high-grade squamous
SIL, and may contain one or more foci of bizarre
measurement that is most appropriate. (a) Origin of
invasion at surface HSIL: depth of stromal invasion is
intraepithelial lesion and not exceeding 7 mm in
invasion, either from the basal lamina of the surface surface branching vessels [159]. However, microinvasion
horizontal extent measured from point of origin of invasion downward to the
epithelium or from endocervical glands replacedfrequently by cannot be accurately detected using colposcopy. last cell of the invasive focus. (b) Origin of invasion at HSIL
intraepithelial neoplasia (> Fig. 6.5). There are cases, how-
In a study that correlated colposcopic appearances with with gland involvement: depth of stromal invasion is
ever, in which direct continuity between invasive foci histologic
and findings from a large number of LEEP speci- measured from site of origin downward to the last cell of
Treatment
ve squamous cell carcinoma. Small
SIL cannot be demonstrated, even in deeper cuts ofmens, the Murdoch et al. demonstrated that accurate the invasive focus. (c) Origin of invasion not seen: depth o
paraffin block. In such instances, it is assumed thatcolposcopic
the detection of MICA requires invasion of stromal invasion is measured from basal lamina of surface
ests and one attached elongated tongue of
invasion originated from basal cells of the overlying moreSIL. than 1 mm into the cervical stroma [187]. Because HSIL downward to the last cell of the invasive focus
The therapy for IA1 is more conservative than that for
cell carcinoma are present in superficial stroma
Therefore, the depth of invasion is arbitrarily measured it is difficult to colposcopically identify MICA, most
e overlying high-grade squamous
stage IA2, and treatment is often individualized based
lial lesion
from the basal lamina of the surface SIL. The most accu-
rate method to measure the depth of stromal penetration
colposcopists routinely treat all large biopsy-confirmed,
high-grade SIL using excisional methods such as LEEP. greatest lateral extent of the lesion, and whethe
on (1) the definition of the lesion (2) lateral extent, and
is with a calibrated slide or ocular micrometer. A more lymphvascular invasion is present. For consistency in the
convenient, but perhaps less accurate, method of measurement of the depth of stromal invasion, the follow
(3)
ping involvement
of the of cone
margins of the epithelium at the margins. The data on risk Pathologic Features
establishing the size and depth of penetrating foci consists ing guidelines are recommended. The depth of neoplastic
projections should be measured from the initial site o
factors for nodal metastases, recurrence, and death
dermal interface [57].
tablishing a diagnosis of MICA, the pathologist
of direct microscopic visualization with a transparent
metric ruler. The depth of invasion also depends onThe thediagnosis of MICA is based on the presence of one or
invasion, either from the basal lamina of the surface
. Fig. 6.2
epithelium or from endocervical glands replaced by
he suggest that
surgical margins, depthlesions with 3 mm or less stromal invasion
of stromal invasion, more tongues of malignant cells penetrating the basement
angle at which sections are prepared, and therefore efforts Microinvasive squamous
intraepithelial neoplasiacarcinoma. Some
(> Fig. 6.5). small
There nests how
are cases, of
membrane of the squamous epithelium (> Figs. 6.1–6.4).
ever, in cell
squamous which direct continuity
carcinoma between
are isolated invasive stroma,
in superficial foci and
without LVSI have virtually no potential for metastasis . Fig. 6.4 epithelium invariably demonstrates vary-
The squamous
ing grades of SIL, and
Microinvasive in most
squamous cellinstances
carcinoma.the underlying
Small
SIL cannot
whereas be demonstrated,
one larger island remainseven in deeper
attached to thecuts of the
overlying
or recurrence. Those invading 3 mm or less but with detachedglands
endocervical nests andareoneextensively
attached elongated
replacedtongue
by theof
paraffin squamous
high-grade block. In such instances, lesion
intraepithelial it is assumed that the
invasion originated from basal cells of the overlying SIL
squamousdisease.
intraepithelial cell carcinoma
Within are
thepresent in superficial
microinvasion foci,stroma
the
LVSI may potentially metastasize, beneath
cells are betterthe overlying high-grade
differentiated squamous
with abundant eosinophilic
Therefore, the depth of invasion is arbitrarily measured
from the basal lamina of the surface SIL. The most accu
intraepithelial lesion of endocervical gland involved by high-grade SIL. There is
 Squamous cell carcinoma and variants

• An invasive epithelial tumor composed of

neoplastic cells with varying degrees of
squamous differentiation
• Most common type of cervical carcinoma
• Nearly all cases are associated with high risk
human papillomavirus (HPV) and arise from a
precursor lesion, high grade squamous
intraepithelial lesion (HSIL)
• Predominantly associated with HPV 16 and
HPV 18 (HPV 16 > HPV 18)
• More common in low resource countries and
women without adequate cytologic screening
• Variable morphology with several histologic
variants described
• Fourth most common type of cancer (15.1 per
100,000) and cause of cancer mortality (8.2 per
100,000) among women worldwide in 2018 .
• Most common type of cervical carcinoma (>
90% of cases)
• Most patients are 40 - 54 years old.
•
Sites
• Most cases arise at the squamous-columnar junction of the cervix
Pathophysiology
• High prevalence of HPV infection among adolescents and young women
• Most infections spontaneously regress
• Persistent infection with high risk HPV subtypes is necessary but not sufficient for developing
high grade squamous intraepithelial lesion and squamous cell carcinoma
• Most
• tumors are due to progression of a precursor lesion, HSIL
• Progression of HSIL is variable among women and may take decades
• Risk factors significantly increase risk of HPV persistence
• High risk HPV acts via E6 and E7 oncogenes,
◦ E6 binds to tumor suppressor p53, causing its proteolytic degradation and inactivating
p53 mediated DNA damage and apoptosis pathway
◦ E7 binds to retinoblastoma gene (Rb), displacing transcription factors normally bound by
Rb and inactivating Rb mediated cell cycle regulation pathway
◦ Rb inactivation leads to overexpression of p16, a tumor suppressor gene involved in cell
cycle regulation by inhibiting cyclin dependent kinases
◦ p16 immunohistochemistry is used as a surrogate marker for high risk HPV infection
• Usually spreads through cervical lymphatics to regional lymph nodes or via direct extension to
vagina, uterus, parametrium, lower urinary tract, uterosacral ligaments; distant metastases may
involve aortic and mediastinal lymph nodes, lungs, bones and adnexa
• HPV vaccination of women 16 - 23 years of age offers durable protection for at least 12 years;
the US Center for Disease Control (CDC) recommends HPV vaccination in 2 or 3 doses
depending on age (Two doses for children and adolescents of any gender ages 9 - 14 years
◦ Three doses for adolescents and adults of any gender ages 15 - 26 years
Etiology
• Nearly all cases are associated with persistent
infection by high risk HPV subtypes such as 16,
18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 and
others
• HPV 16 is the major causal agent for squamous
cell carcinoma, in contrast to HPV 18 typically
associated with endocervical adenocarcinoma
• Previous or concurrent history of HSIL
• Additional risk factors:
◦ Younger age at first intercourse and higher
lifetime number of sexual partners Single
contact with infected partner may result in • Tumor stage, patient age, depth of invasion,
infection and risk plateaus with many
contacts)
◦ Immunodeficiency, including human
immunodeficiency virus (HIV) infection,
transplantation and medications Cigarette
smoking > 20 years,)
◦ Multiparity and early age at first birth (Long
term oral contraceptive use.
◦ Chronic inflammation or concurrent
sexually transmitted diseases, such as
chlamydia
◦ Positive family history
◦ No circumcision in male partner
Clinical features
• Abnormal cervical cytology in asymptomatic
patients
• Cervical mass
• Vaginal bleeding or discharge
• Pain, urinary symptoms (ureteral obstruction
leading to anuria or uremia, hematuria, frequency,
vesicovaginal fistula), gastrointestinal symptoms
(tenesmus, rectovaginal fistula), lymphedema in
the lower extremities in advanced tumors
• Prognostic factors
disease volume, lymphovascular invasion
• Overall 5 year disease free survival by tumor
stage:
◦ Stage IA: 95%
◦ Stages IB1 and IIA: 70 - 85%
◦ Stages IB2 and IIB: 50 - 70%
◦ Stage III: 30 - 50%
◦ Stage IV: 5 - 15%
• Better prognosis for lymphoepithelial and
verrucous variants
• Worse prognosis with lower CD4+ cell counts in
HIV seropositive patients
 FIGO staging of carcinoma of the cervix uteri (2018).

Stage I:The carcinoma is strictly confined to the cervix uteri (extension to the corpus should be disregarded)
• IA Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion <5 mma
• ○

IA1 Measured stromal invasion <3 mm in depth
• ○

IA2 Measured stromal invasion ≥3 mm and <5 mm in depth
• IB Invasive carcinoma with measured deepest invasion ≥5 mm (greater than stage IA), lesion limited to the cervix uterib
• ○

IB1 Invasive carcinoma ≥5 mm depth of stromal invasion and <2 cm in greatest dimension
• ○

IB2 Invasive carcinoma ≥2 cm and <4 cm in greatest dimension
• ○

IB3 Invasive carcinoma ≥4 cm in greatest dimension
Stage II:The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall

• IIA Involvement limited to the upper two‐thirds of the vagina without parametrial involvement
• ○

IIA1 Invasive carcinoma <4 cm in greatest dimension
• ○

IIA2 Invasive carcinoma ≥4 cm in greatest dimension
• IIB With parametrial involvement but not up to the pelvic wall
Stage III:The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or non‐functioning kidney and/or involves pelvic and/or paraaortic
lymph nodesc

• IIIA Carcinoma involves the lower third of the vagina, with no extension to the pelvic wall
• IIIB Extension to the pelvic wall and/or hydronephrosis or non‐functioning kidney (unless known to be due to another cause)
• IIIC Involvement of pelvic and/or paraaortic lymph nodes, irrespective of tumor size and extent (with r and p notations)c
• ○

IIIC1 Pelvic lymph node metastasis only
• ○

IIIC2 Paraaortic lymph node metastasis
Stage IV:The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be
allotted to stage IV

• IVA Spread of the growth to adjacent organs

• IVB Spread to distant organs
• a Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages.
• b The involvement of vascular/lymphatic spaces does not change the staging. The lateral extent of the lesion is no longer considered.
• c Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node
metastasis, the stage allocation would be stage IIIC1r and, if confirmed by pathological findings, it would be Stage IIIc1p. The type of imaging modality or pathology technique used should
Gross description
Stage I

• Red, friable, indurated or

ulcerated lesion or elevated
granular area in early stage
tumors
• Exophytic, papillary, polypoid,
nodular or ulcerated mass
• Deeply invasive mass with Stage III
infiltration into surrounding Stage IV
structures
• Variable size
Microscopic (histologic) description
• Tumor cells infiltrating as irregular anastomosing
nests or single cells within desmoplastic or
inflammatory stroma
• Stromal loosening, desmoplasia or increased
epithelial cell cytoplasmic eosinophilia in tumors
with superficial stromal invasion
• Lymphovascular invasion may be present

Molecular / cytogenetics description

• Mutations in PIK3CA most frequent (37%); low
frequency of KRAS mutations
• TP53 mutations in 16% of cases
• Loss of heterozygosity (LOH) in multiple loci (1q,
3p, 3q, 6p, 6q, 11q, 17p, 18q)
◦
 Histological Typing
• WHO- Invasive squamous cell carcinomas into
two groups,
• keratinizing and nonkeratinizing
small cell undifferentiated carcinoma with neuroendocrine features in
a separate category.
Keratinizing carcinomas are characterized by the presence of well-
differentiated squamous cells that are arranged in nests or cords that
vary greatly in size and configuration.
The defining feature of keratinizing carcinomas is the presence of
keratin pearls within the epithelium, and the presence of a single
keratin pearl is sufficient to classify a tumor as a keratinizing
carcinoma.
Keratin pearls are composed of clusters of squamous cells that have
undergone keratinization and are arranged in a concentric nest. The
neoplastic squamous cells not forming keratin pearls frequently have
abundant eosinophilic cytoplasm and prominent intracellular bridges.
The nuclei are often enlarged, but mitotic figures are not numerous.
Nonkeratinizing squamous cell carcinoma is characterized by nests
of neoplastic squamous cells that frequently undergo individual cell
keratinization but, by definition, do not form keratin pearls. The cells
have relatively indistinct cell borders. The nuclei tend to be round to
oval with coarsely clumped chromatin. Mitotic figures are numerous.
 Variants
• Morphologic variants:
◦ Keratinizing
▪ Keratin pearls, abundant
keratohyaline granules and
intercellular bridges
▪ Large, hyperchromatic nuclei with
coarse chromatin and
inconspicuous nucleoli
◦ Nonkeratinizing
▪ Polygonal cells forming sheets or
nests
▪ Intercellular bridges but not
keratin pearls
▪ Large nuclei with unevenly
distributed, coarsely granular
chromatin and one or multiple
nucleoli
▪ Numerous mitoses
◦ Warty
▪ Warty surface and low power
architecture resembling a
condyloma or bowenoid lesion of
the vulva
◦ Squamotransitional
▪ Resembles squamotransitional carcinoma of the
urinary bladder
▪ Papillae with fibrovascular cores lined by
multilayered epithelium with transitional
differentiation resembling HSIL
▪ May occur in a pure form or in association with
squamous elements
▪ Not related to transitional cell metaplasia
◦ Lymphoepithelial-like carcinoma
▪ Resembles nasopharyngeal lymphoepithelial-like
carcinoma
▪ Poorly defined nests of undifferentiated,
discohesive squamous cells with uniform,
vesicular nuclei, conspicuous nucleoli and
moderate amounts of cytoplasm in a background
of abundant lymphocytes
▪ Indistinct cell borders impart a syncytial-like
appearance
▪ No evidence of keratinization and lack of
intercellular bridges
▪ Associated with HPV, not Epstein-Barr virus (EBV)
◦ Spindled / sarcomatoid (J Cancer Res Ther 2008;4:39)
▪ Spindled cells with hyperchromatic nuclei,
conspicuous nucleoli and brisk mitoses
▪ May be admixed with more conventional
epithelioid areas
▪ Occasional osteoclast-like giant cells
▪ Necrosis may be present
• Rare findings are focal mucinous differentiation, pseudoglandular
pattern due to acantholysis, amyloid, signet ring cells, melanin
granules, HSIL-like growth pattern
 Microscopic Grading Carcinoma and Other Tumors of the Cervix 6 2

Some investigators have reported that this classifica-

•The most commonly used grading
tion system for
has prognostic squamousincell
significance carcinoma
patients is with
treated a
modification of the original system proposed by Broders
radiotherapy [279]. Others authors have reported no sig-
nificant difference in prognosis between patients with
•Histologic grading divides squamous
large cell carcinomas
cell nonkeratinizing intocell
and large three groups, well
keratinizing squa-
differentiated (grade 1), mous carcinomas
moderately when treated
differentiated with2),
(grade radical
and surgery
poorly [297].
differentiated (grade 3).
Microscopic
•In well-differentiated (grade 1) tumors,Grading
the most striking feature is abundant
keratin, which is deposited
Theas keratin
most pearls in
commonly thegrading
used center of neoplastic
system for squamous
epithelial nests. The cells appear
cell mature,
carcinoma with
is a abundant eosinophilic
modification of the original system
cytoplasm. Individual cellproposed by Broders
keratinization in 1920 [32].
(dyskeratosis) This method
characterized by was
based on the proportion of the tumor undergoing kerati-
intense cytoplasmic eosinophilia may also
nization with be present.ofThe
the formation cells are pearls
squamous tightly and
. Fig. 6.9
packed and have well- developed
a number ofintercellular bridges.histologic
mitoses. Currently The nuclei are large,
grading divides
Squamous cell carcinoma. Poorly differentiated carcinoma
irregular, and hyperchromatic.
squamous Mitotic figures are into
cell carcinomas present most
three notably
groups, well at the
differ-
is composed of sheets of atypical cells
entiated (grade 1), moderately differentiated (grade 2),
periphery of the advancing epithelial nests. The stroma is often infiltrated by
and poorly differentiated (grade 3). Most squamous cell
chronic inflammatory cells.
carcinomas are moderately differentiated (grade 2),
followed by poorly differentiated (grade 3) and well dif-
•In moderately differentiated (grade(grade
ferentiated 2) squamous
1). cell carcinomas, the
neoplastic cells are more pleomorphic than in grade
In well-differentiated (grade1 1)
tumors, have
tumors, large strik-
the most
irregular nuclei, and haveingless abundant
feature cytoplasm.
is abundant The cellular
keratin, which isborders andas
deposited
keratin pearls in the center of neoplastic epithelial nests.
intercellular bridge appear indistinct. Keratin pearl rare, but individual cell
The cells appear mature, with abundant eosinophilic cyto-
keratinization is seen in plasm.
the center of nestscell
Individual of keratinization
tumor cells. Mitotic figureschar-
(dyskeratosis) are
more numerous than in grade 1 carcinomas
acterized by intense cytoplasmic eosinophilia may also be
present. The cells are tightly packed and have well-
• Poorly differentiated (grade 3) squamous
developed cellbridges.
intercellular carcinomas are generally
The nuclei are large, irreg-
composed of cells with hyperchromatic oval nuclei and scant are
ular, and hyperchromatic. Mitotic figures indistinct
present most
notably at the periphery of the advancing epithelial nests.
cytoplasm, resembling The
the malignant cells of high-grade SIL .Clear-cut
stroma is often infiltrated by chronic inflammatory
squamous differentiation manifested
cells, by keratinization
and occasionally maygiant
a foreign body be difficult to is
cell reaction
find. Mitoses and areasobserved.
of necrosis are abundant. Poorly differentiated
In moderately differentiated (grade 2) squamous cell . Fig. 6.10
lesions are occasionally composed of large, pleomorphic cells with giant, Squamous cell carcinoma. Poorly differentiated carcinoma
carcinomas, the neoplastic cells are more pleomorphic
bizarre nuclei and abnormal
than in grade figures.
mitotic 1 tumors, have large irregular nuclei, and has some cells with spindled morphology
• have less abundant cytoplasm. The cellular borders and
intercellular bridge appear indistinct. Keratin pearl forma-
tion is rare, but individual cell keratinization is seen in the nuclei and abnormal mitotic figures. In rare instances, the
center of nests of tumor cells. Mitotic figures are more neoplastic cells assume a spindle-shaped configuration
Histopathologic Prognostic Features
Stage is the most important prognostic factor in cervical carcinoma.
Histologic typing and grading have little direct influence on survival
within any stage .

The most significant pathologic prognostic fac- tors in women with

surgically treated stage IB and IIA squamous cell carcinoma are
tumor size, depth of inva- sion, parametrial involvement, and nodal
status

Behavior and Treatment

The three basic therapeutic modalities for squamous cell carcinoma
are surgery, radiation, and combinations of radiation and surgery or
radiation with concurrent chemotherapy. Recently targeted therapies
have shown some promise.

In stage IB and early stage II patients, virtually identical results are

seen with radical hysterectomy with bilateral pelvic
lymphadenectomy and radiation therapy. In young women with Stage
IA1/2 and IB1 lesions, particularly those measuring <2 cm in
diameter and desire to preserve their fertility, radical trachelectomy
combined with laparoscopic pelvic lymphadenectomy has been
widely accepted

•
 as (20%) [279].
ion between the
cell carcinomas
l cell carcinomas
. Fig. 6.7
hose described in
Squamous cell carcinoma. Solid sheets of carcinoma contain
n of invasive cer-
cells with clear cytoplasm; this variant lacks the
tiated carcinoma
characteristic cytologic and architectural features of clear
ate category and
cell carcinoma and should not be misclassified as such
nomas into two
[278].
rized by the pres-
cells that are
eatly in size and
eratinizing carci-
within the epithe-
pearl is sufficient
rcinoma. Keratin
amous cells that
are arranged in ◦ Basaloid squamous cell carcinoma
amous cells not
bundant eosino- ◦ Well defined nests of immature basaloid cells
ular bridges. The
figures are not (resembling the cells of HSIL) with peripheral
noma is charac- palisading of pleomorphic, hyperchromatic nuclei,
us cells that fre-
nization but, by brisk mitoses and scant cytoplasmGeographical
. The cells have
uclei tend to be
. Fig. 6.8
Squamous cell carcinoma. Basaloid variant resembles high- or comedo-like necrosisFocal keratinization but
no keratin pearlsResembles basaloid squamous
romatin. Mitotic grade squamous intraepithelial lesion within endocervical
C is composed of glands but nests within desmoplastic cervical stroma are

cell carcinomas at other sites usually exhibiting

sm (> Fig. 6.7). indicative of invasive tumor

an aggressive behavior
◦ Verrucous- Very rare and poorly understood form
of squamous cell carcinoma in the cervix.Highly
differentiated.Exophytic growth with undulating,
2 6 Carcinoma and Other Tumors of the Cervix
warty surface and hyper or parakeratotic and
frond-like acanthotic squamous epithelium.Broad
based pushing invasion with bulbous epithelial
pegsAbundant cytoplasm, minimal cytologic
atypia and rare mitoses.Absence of koilocytes
◦ Papillary- Thin or broad papillae with
fibrovascular cores lined by multilayered
epithelium with squamous differentiation
resembling HSIL,Stromal invasion may not be
seen in superficial biopsies

. Fig. 6.15 . Fig. 6.16

Papillary squamous cell carcinoma. Atypical squamous Lymphoepithelioma-like carcinoma. Large, atypical,
epithelium displaying loss of maturation and nuclear discohesive cells simulating lymphoma are intimately
hyperchromasia with pleomorphism associated with a mixed chronic inflammatory cell infiltrate
•

cells are more basaloid and resemble those of a high-grade undifferentiated cells surrounded by a dense stromal
 Immunohistochemistry
Positive stains
6 268 Carcinoma and Other Tumors of the Cervix

• Pancytokeratin Histopatholo
• CK5/6 Stage is the mo
• EMA carcinoma. His
• p63 influence on su
• p40 grading’’). The
• p16: diffuse, block-like staining (except tors in women
squamous cell
verrucous variant)
sion, parametr
• PDL1: positive in up to 71% of cases; 297]. A study o
reported as combined positive score (CPS)  tomy with bila
= (number of positive tumor cells, squamous cell
lymphocytes and macrophages / total measuring <2
number of tumor cells) x 100CEA invaded <10 m
disease-free sur
• CK7 (in 66 - 87% of cases) ( . Fig. 6.11
had a 5-year di
• PAX8 (in ~25% of cases) Squamous cell carcinoma. Tumor exhibits characteristic
series of patien
• GATA3 (in ~33% of cases, usually weak and diffuse/strong p16 expression of a high-risk HPV-related
treated surgical
focal) Negative stains carcinoma
third of the cer
• Inhibin, MEL-CAM, HPL (Napsin A free survival, w
• HNF-1B outer third pro
• p53: rarely aberrant p53 expression In the same GO
val was 70%
• CK20
(LVSI) compar
most series of s
proven to be s
and depth of
mous cell carci
ters or the prop
 Differential diagnosis
• Clear cell carcinoma (versus squamous cell carcinoma with cytoplasmic clearing):
◦ Papillary, tubulocystic and solid growth patterns, hobnail cells, no squamous differentiation
◦ Positive for HNF-1B and Napsin A, negative for p63
• Adenoid basal carcinoma:
◦ Deeply infiltrative nests of basaloid squamous cells with nuclear palisading and focal lumina, no desmoplastic stromal reactio
• Adenoid cystic carcinoma:
◦ Cribriform, solid and tubular growth patterns, luminal epithelial cells and basal cells, basement membrane-like material
◦ p63 positive in myoepithelial cells, positive for MYB-NFIB fusion
• Small cell neuroendocrine carcinoma (versus basaloid squamous cell carcinoma):
◦ Nests, cords, trabeculae and rosettes of small cells with scant cytoplasm, hyperchromatic nuclei with molding and crush artifa
brisk mitoses, apoptotic debris, geographic necrosis
◦ Positive for neuroendocrine markers
• Carcinosarcoma (versus sarcomatoid squamous cell carcinoma):
◦ Malignant mesenchymal component with or without heterologous elements
◦ Negative for p63 and p40
• Epithelioid trophoblastic tumor:
◦ Well circumscribed tumor with neoplastic cells arranged around vessels and areas of necrosis, no keratinization
◦ Positive for inhibin, HPL and CK18
• Immature squamous metaplasia:
◦ Uniform cells lacking significant nuclear atypia
◦ Negative for p16
• Placental site nodule:
◦ Well circumscribed nodules of bland intermediate trophoblast cells, no keratinization, no or rare mitotic activity
◦ Positive for inhibin and HPL
• HSIL involving endocervical glands:
◦ Well defined nests with smooth borders, preserved polarity of basal epithelial cells, no abrupt maturation at interface, no
desmoplastic stromal reaction
 How do I section the tumour?
A.For hysterectomy-
The position of the tumour in the cervix should be
recorded.
Macroscopic tumour involvement of the parametrial and
paracervical tissues should be noted and recorded and
may determine the method of dissection and block
taking. The Para cervical tissue may need to be inked. It
can be examined microscopically along with the main
tumour sections.
The tumour sections are taken so as to include maximum
tumour invasion into the cervical stroma.
The parametrial tissue can be sectioned separately. All
the parametrial tissue need to be examined.
Parametrial involvement is a poor prognostic indicator
for early stage cervical carcinoma regardless of lymph
node status, and is an adverse prognostic indicator for
advanced stage cervical carcinoma.
For small tumours, or in cases where no
macroscopic tumour is identified, the whole of the
cervix should be blocked as in the case of cone/loop
biopsies.
Large Loop Excisionof the Transformation Zone
(LLETZ;Also Known as Loop
ElectrosurgicalExcision Procedure, LEEP)
These specimens should be blocked in their entirety.
Two methods for sectioning LEEP or cone biopsy
can be followed. The first is serial slicing at 2– 3mm
intervals, from one edge to the other in a sagital and
parasagital plane ,
perpendicular to the transverse axis of the external
so.
The second method (mainly for full cone excision
biopsies) involves serial wedge shaped slices
according to the hours on a clock face.
In either case, the slices should be submitted in
sequential, individually designated cassettes (from
RCPath cancer dataset explanation)
 Specimens
• Simple Hysterectomy/Trachelectomy
• This may be performed in cases where
persistent abnormal cytology has been
reported, after therapeutic conization
or loop excision of an earlier cervical
lesion, or for persistent cytological
changes where the transformation zone
cannot be visualized colposcopically
(because of cervicalstenosis or scarring
from previous cervical loop biopsies or
conization). This may also be carried out
in women as an option instead of
conization when the family is complete.
• In some instances,SIL may be an
incidental finding when simple
hysterectomy has been performed for
other clinical reasons.
• Radical Trachelectomy
• This procedure is performed
for low-stage cervical cancers,
where surgical treatment with
preservation of fertility is
desired. The following
structuresare included in
radical trachelectomy
specimens:
• • Cervix
• • Parametrium
• • Vaginal cuff
• • Pelvic lymphadenectomy
(this may be carried out as a
separate surgical procedure)
 Specimens
• Radical Hysterectomy
• Traditionally this has been the standard treatment for cases of cervical
carcinoma at stage IA2, IB, and IIA.
• With the greater use and equivalent survival
• results using radical chemoradiotherapy, this procedure is becoming
more infrequent, particularly in countries with a successful cervical
screening program.
• This is carried out in cases where there is a
• very low chance of adjuvant therapy being indi-
• cated.
• The surgical specimen includes the parametria, vaginal cuff, and
pelvic+/- para-aortic lymphnode dissection. The adnexa are usually
included but, in younger women, the ovaries may be conserved to
prevent premature menopause.
 Specimens: Wertheims hysterectomy
The uterus with cervix measures ____ X ____ X _____ cm.

An ulceroproliferative tumour is seen in the anterior lip / posterior lip /
circumferentially / ______
________________________________________ measuring ____ X
____ cm with thickness of _____ cm. The tumour invades less than /
more than half the thickness of the cervical stroma. The vagina is
macroscopically not involved / involved.
The tumour free cervical adventitial margin is _____ cm.
 is _____ cm. Lymphovascular emboli are seen / not seen.
The various vaginal cut margins are: anterior - _____ cm, posterior -
_____ cm, right lateral - _____ cm and left lateral - _____ cm.

Length of the anterior vaginal fornix is _____ cm and the posterior
vaginal fornix is _____ cm.
The endometrium measures _____ cm in thickness and is
______________________________ The myometrium measures
_____ cm in thickness and is ______________________________
The right ovary measures ____ X ____ X ____ cm and is
______________________________ The right fallopian tube is _____
cm long and is ______________________________________ The left
ovary measures ____ X ____ X ____ cm and is
_______________________________ The left fallopian tube is _____
cm long and is _______________________________________ Right
parametrium measures ____ X ____ X ____ cm and is
___________________________. Left parametrium measures ____ X
____ X ____ cm and is ____________________________
Lymph nodes:
HISTOLOGY
Specimen:
______________________________________________________
_________ ___________ differentiated
____________________________ carcinoma of the cervix.
The tumour invades in the inner half / outer half of the cervical
stroma. Distance of tumour free margin from the cervical adventitia


Perineurial invasion is seen / not seen.
The vagina is __________
The vaginal cut margins are __________The adjacent cervical
mucosa shows __________________________________________
The right and the left parametria are___________
The endometrium is____________The myometrium is ________The
right ovary is _________ The right fallopian tube is
_____________________________________________________
The left ovary is ______ The left fallopian tube is _
Lymph nodes:
IMPRESSION
th
TNM Stage (8 Edition): T N
Question
1)Which of the following statements is true regarding squamous cell carcinoma of the cervix?

• AMost cervical squamous cell carcinomas are associated with HPV 18

• BNearly all cases of cervical squamous cell carcinoma are associated with high risk HPV and arise from a
precursor lesion, HSIL
• CPoorly differentiated squamous cell carcinomas are associated with high risk HPV subtypes, while low
risk HPV subtypes are more likely to cause well differentiated tumors
• D Squamous cell carcinoma is the second most common type of cervical cancer following endocervical
adenocarcinoma

B. Nearly all cases of cervical squamous cell carcinoma are associated with high risk HPV and arise from a
precursor lesion, HSIL.
2)What are the most significant risk factors of cervical squamous cell carcinoma?

• A HPV 16, history of HSIL, multiple sexual partners, multiparity, smoking, immunodeficiency
• B HPV 16, history of HSIL, multiple sexual partners, nulliparity, smoking, immunodeficiency
• C HPV 16, history of LSIL, multiple sexual partners, nulliparity, smoking, immunodeficiency
• D HPV 18, history of LSIL, single sexual partner, multiparity, smoking, immunodeficiency
A. Risk factors of cervical squamous cell carcinoma include persistent high risk HPV infection, particularly
HPV 16, history of HSIL, multiple sexual partners, multiparity, smoking and immunodeficiency.
Glandular tumors and precursors- Adenocarcinoma in situ
• An intraepithelial lesion containing malignant-
appearing glandular epithelium that carries a
significant risk of invasive adenocarcinoma if not
treated.
• Adenocarcinoma in situ typically occurs in
young women in their reproductive years with
an average age at presentation of 38 years.
• Pap smear examination has a lower sensitivity
for detecting both adenocarcinoma in situ and
invasive adenocarcinoma, which is probably
related to incomplete sampling of the
endocervix as well as inherent difficulty in
distinguishing benign from neoplastic glandular
epithelium in cytologic preparations.
• Adenocarcinoma in situ almost always arises at
the squamocolumnar junction (transformation
zone) cephalad to the ectocervix or mature
transformation zone as a spatially continuous
lesion, although rarely it may develop in the
upper endocervix or be multifocal.45,46 
• . In 30% to 50% of cases, adenocarcinoma in
situ is associated with a squamous
intraepithelial lesion, which can be low or high
grade.
 Glandular tumors and precursors- Adenocarcinoma in situ
•Histologically, normal cervical glandular architecture
is preserved, with the glands being lined by crowded
cells with enlarged, hyperchromatic, stratified, or
pseudostratified nucleiabrupt transition from
normal to neoplastic epithelium within a gland is
characteristic.
•Nucleoli are usually small and inconspicuous, but
occasionally may be prominent.
•mitotic figures are typically located on the luminal
side, having a suspended appearance. Basally located
apoptotic bodies are common
•Adenocarcinoma in situ may sometimes have a more
complex growth pattern, with intraluminal papillary
infolding or cribriform growth.however, the overall
benign glandular architecture is maintained.
•An early form of conventional adenocarcinoma in
situ is recognized  It is considered an early form of
the disease because it occurs in a younger age group
(mean 26.7 years vs 37 years for conventional
adenocarcinoma in situ), it involves the superficial
aspect of the cervical mucosa (surface mucosa and
crypt openings), and it has less pronounced atypia as
well as a lower frequency of apoptosis, apical
mitoses, and anisokaryosis.
•Similar to conventional adenocarcinoma in situ, this
variant is associated with high-risk HPV and thus is
also strongly positive (“block-staining” pattern) for
the biomarker p16.
 Comparison of adenocarcinoma in situ and mimics
Adenocarcino Tubal/tubulo- Endometriosis Arias Stella Radiation Cervicitis
ma in situ endometrioid reaction effect
metaplasia
Location Transformation Upper Transformation sup or deep sup > deep Transformation zone, sup
zone, sup or endocervical, zone, sup or glands glands glands
deep glands deep >sup deep glands
glands
Partial gland Characteristic Occasional Unusual Characteristic Unusual Unusual
involvement
Nuclear Present Less Present Present Absent Less pronounced
stratification pronounced
Hyperchromas Present Less Present Present Present Less pronounced
ia pronounced
Nuclear Present Less Uncommon Present Present Present
enlargement pronounced
Nucleoli Uncommon May be May be Present Present Present
present present
Mitosis Present Uncommon Present Rare Rare Present

Apoptosis Present rare/absent Uncommon Absent Absent May be present

Cilia May be present Present Occasional Absent Absent Absent
Complex May be present Absent Uncommon Uncommon Absent Absent
architecture
MiB1 High Low Variable Low Low Variable
Adenocarcinoma, NOS

• An invasive epithelial tumour showing glandular

differentiation.
• Adenocarcinoma currently comprises 10–25% of
all cervical carcinomas in developed countries,
compared to 5–10% three decades ago.
• This increase has resulted from a decline in
squamous carcinomas secondary to screening pro-
grams and better identification of glandular lesions
in cervical cytology samples.
• A potential association with long-term oral
contraceptive use, particularly with pro-
gestational agents and with unopposed estrogen
use, has been postulated but not proven. The mean
age at presentation is about 50 years
• The majority (94%) of cervical adenocarcinomas
are associated with high-risk HPV (with
exceptions noted below), most commonly types
18, 16 and 45.
 Adenocarcinoma, NOS
Clinical features
Abnormal uterine bleeding and a mass lesion are present in about 80% of cases.
Macroscopy
Approximately 50% of tumours show exophytic growth patterns. A smaller per- centage
show surface ulceration or diffuse infiltration of the cervical wall, leading to a barrel
shaped cervix.
Histopathology
Each of the variants has in common glands with cytoarchitectural atypia that infiltrate the
cervical stroma. A surface component with a papillary architecture may also be
prominent. In some adenocarcinomas, particularly those that are high-grade, non-specific
patterns such as nests, clusters and individual cells are seen.
Lesions with only minimal stromal invasion may be referred to as early invasive
adenocarcinoma. Criteria for early invasion include frankly infiltrating glands or tumour
cells nests, extension of atypical glands beyond the depth of the normal endocervical
glands, neoplastic endocervical glands that are too complex to be adenocarcinoma in situ
or with stromal reaction in the form of oedema, chronic inflammation or desmoplasia.
 Endocervical adenocarcinoma, usual type

• The most common form of endocervical adenocarcinoma, with

relative mucin depletion. extreme
• The usual type of endocervical adeno carcinoma constitutes malignu
about 90% of a adenocarcinomas of the cervix.

• Clinical features Epidem

In Japa
Abnormal uterine bleeding and a mas lesion are present in about
80% of cases
represe
adenoc
• Macroscopy
tremely
Approximately 50% of tumours show a exophytic growth pattern. A deviatio
smaller per centage show surface ulceration or dif fuse infiltration of lignum)
the cervical wall lead ing to a barrel-shaped cervix.
enocarc
• Histopathology age at
Most often, the tumours are well- to moderately differentiated, {637,75
having complex ar chitectural patterns composed of round to oval Jeghers
mucin-poor glands that exhibi cribriform or papillary structures.
Pattern resembling microglandular hyperplasia of the cervix or
microcysts may be seen, a may single-cell patterns. Clinica
Fig. 7.15 Endocervical adenocarcinoma, usual type. The presence of large, confluent cribriform glands favours the The typ
Large pools of mucin may occasionally be present withi the stroma.
diagnosis of an invasive carcinoma. The usual type of adenocarcinoma shows apical mucin depletion, pseudostratification
The neoplastic epitheliu shows a characteristic pseudostratifie d bleedin
architecture with enlarged, elongated and hyperchromatic nuclei and necrotic debris within gland spaces.
tion with
seen.
and is attributable to the apical zone of ICD-O code 8480/3

Mucinous carcinoma, NOS
• A mucinous adenocarcinoma that
cannot be classified as any of the
specific types of cervical
adenocarcinoma.
•This tumour is an invasive
adenocarcinoma that shows evidence
of mucinous differentiation but does
not show the specific features of
usual type, gastric type, intestinal
type or signet-ring-cell type
with high-risk HPV {47}. areas and infolded papillae. The atypical
Definition glands extend below the normal level ex-
A mucinous adenocarcinoma that shows pected for benign endocervical glands.
Mucinous carcinoma, NOS
gastric type differentiation {1268}. The glands are characteristically irregu-
lar and dilated, but may also be fused or
Definition ICD-O code 8482/3 show a cribriform pattern {961,1013}. The
A mucinous adenocarcinoma that cannot surrounding stroma may show desmo-
be classified as any of the specific types Synonyms plasia but in some regions this is absent
of cervical adenocarcinoma. Minimal deviation adenocarcinoma (if or minimal. These tumours are composed
A B
Fig. 7.16 A Mucinous carcinoma, gastric type. This neoplasm shows gastric type differentiation with abundant clear to eosinophilic cytoplasm and obvious nuclear atypia. There are
cribriform glands present. The cells have been shown to stain with markers of pyloric gland mucin. B Adenoma malignum (minimal deviation adenocarcinoma). The cytoplasm shows
gastric differentiation, but nuclei are bland and little, if any, stromal reaction is present.
Glandular tumours and precursors 185

adenocarcinoma.
Mucinous carcinoma, signet-ring cell
type -A rare adenocarcinoma that
shows focal or diffuse signet-ring cell
differentiation.
 diagnosis can
Minimal deviation adenocarcinomas are uncommon hyperplastic endometrium. Although the glands may but instead re
tumors and account for only 1–3% of all cervical adeno- exhibit a branching arrangement similar to that of the specimen. Im
carcinomas [102, 127]. In a study of 389 primary adeno- normal endocervical glands, characteristically glands found highly

Gastric type including Minimal deviation

carcinomas of the cervix on file at the Armed Forces
Institute of Pathology, only 1.3 % of cases represented
MDA [127]. Patients with MDA range in age from 25 to
72 years (average 42 years). When sensitive PCR tech-
with bizarre angular outpouchings, which vary greatly in
size, are present [86]. Desmoplasia is frequently present
surrounding the angular outpouchings of MDA or in the
deep portion of the tumor. Large areas of invasive tumor . Fig. 6.29
areas of posi
reduced com
[86, 259]. Im
and progeste
Minimal deviation adenocarcinoma. Very well-

adenocarcinoma(Adenoma Malignum)
niques are utilized, MDA are usually found to be negative may be devoid of any stromal reaction. In such areas, the MDA, and th
for HPV [210]. MDA is more likely to either precede or presence of glands adjacent to thick-walled blood vesselsdifferentiated
is mucinous gland has vesicular nuclei with these tumors
develop coincidentally with an ovarian carcinoma than a helpful finding in determining that stromal invasionconspicuous
is nucleoli, the characteristic cytologic features [259]. Stains
other types of cervical adenocarcinomas. The ovarian neo- of this adenocarcinoma
present. The most reliable criterion to assess the malignant since MDA is
plasms with which MDA is most likely to be associated and Ki-67 pro
include mucinous adenocarcinomas and sex cord tumors tivity for a m
with annular tubules. Both MDA of the cervix and ovarian cell mucin (H

• New category of endocervical

sex cord tumors with annular tubules have been strongly positive in g
associated with Peutz–Jeghers syndrome [294]. In one endocervical
series, 4 of 27 women with Peutz–Jeghers syndrome devel- believe that
adenocarcinomas-gastric subtype
oped MDA [294]. Therefore, close surveillance of women
with Peutz–Jeghers syndrome is recommended, including
endocervical
usual-type AI
careful endocervical cytologic examination and periodic
The diffe
endocervical curettage.
• Extremely well diffs-adenoma
The characteristic microscopic features of MDA are
the presence of cytologically low-grade but architecturally
conditions in
7 mm from
endocervical
atypical glands that vary in size, shape, and location
malignum rare 1-2%—Not assod with
(> Figs. 6.26–6.28). In the mucin-producing forms, the
glands are lined by a single layer of tall columnar epithe-
cysts, endocer
hyperplasia [2
ters, mesonep
HPV.Reproductive age gp.
lium that usually has minimal, if any, nuclear atypia but
careful scrutiny will almost always disclose cells with clear- are usually m
of MDA and
cut atypia. The nuclei are bland, may have conspicuous . Fig. 6.27
. Fig. 6.30 outpouchings

6
nucleoli, and are located at the base of the epithelium Minimal deviation adenocarcinoma. Smaller invasive well-

• PZ syndrome 10-15%STK11
(> Figs. 6.29–6.30). In the endometrioid type, the cells
lining the glands resemble either normal proliferative or are present adjacent to a larger hyperplastic gland
Minimal deviation adenocarcinoma. Invasive glands have
differentiated mucinous glands within desmoplastic stroma
atypical vesicular Carcinoma
282 nuclei withand
nucleoli whereas
Other Tumors of hyperplastic
the Cervix
MDA. The b
response.
gland has small uniformly hyperchromatic basally situated

•
nuclei
Histo-Deeply infiltrative, irregular adenoc
Villogland
the th
regard
glands, bulbous protrusions. nature of MDA is the haphazard arrangement of glands
that extend beyond the level of normal endocervical
Villoglandula
crypts
form of cerv
Becaus
glands and the presence of occasional mitoses in glandular nantly in you
essenti

•
cells. Mitoses are quite uncommon in the normal, [121, 292]. T
IHC - CK7,PAX8,CDX2,HIK1083,MUC6. nonneoplastic, endocervical epithelium, and the presence
of mitoses should alert the pathologist to the possible
diagno
a surface com
but ins
by epithelium
specim
presence of MDA. However, occasional mitotic figures in (> Fig. 6.31).

•
found
CEA,CK20 and NE markers may be otherwise normal-appearing glands should not be taken as
sufficient for a diagnosis of MDA. Minimal deviation
display endoc
>
areas o
( Figs. 6.32–
reduce

positive. . Fig. 6.26 . Fig. 6.28

. Fig. 6.29
Minimal deviation adenocarcinoma. Very well-
[86, 2
and p
Minimal deviation adenocarcinoma. Highly differentiated Minimal deviation adenocarcinoma. Smaller invasive well- MDA,
differentiated mucinous gland has vesicular nuclei with

•
these t
Loss of PAX2 mucinous glands in fibrous stroma are present along with
irregular infiltrative glands in deeper edematous stroma
differentiated mucinous glands within desmoplastic stroma
are present adjacent to a larger hyperplastic gland
conspicuous nucleoli, the characteristic cytologic features
of this adenocarcinoma
[259].
since M
and Ki
tivity f
cell mu
positiv
endoce
believe
endoce
usual-
Th
condit
 Villoglandular carcinoma

•A variant of endocervical adenocarcinoma which

shows a distinct exophytic villous-papillary growth.
•Well-differentiated villoglandular adenocarcinoma
This carcinoma typically occurs in a young er age
population as compared to the usu al type (average
about 35 years.
This variant typically presents as an exophytic mass.
The lesions are by definition architecturally well
differentiated.
Cytological atypia is mild or moderate at most. The
exophytic portion of the tumour show villous fronds of
variable thickness, that are covered by tall,
endocervical-typ columnar cells with limited or no
mucin
Mitotic figures and pseudostratification are present.
 Villoglandular Carcinoma
These tumours have distinctive cellular, fibrous
stroma with a prominent spindled component.
Polymorphonuclear leukocytes may permeate
the stroma of the exophytic papillae
Invasion is typically superficial but some cases
may exhibit deep stromal invasion
HPV types 16, 18 or 45 are the main causative
genotypes identified
Prognosis and predictive factors
When superficially invasive, this variant is only
rarely associated with lymph node metastasis
and has an excellent prognosis.
conservative management ha been suggested as
appropriate only in superficial lesions of pure
villoglandular morphology, without high-grade
atypic and with no lymphovascular invasion
 Endometrioid carcinoma

• An adenocarcinoma arising in the cervix that has

endometrioid morphological features. They are similar to
usual type endocervical adenocarcinoma.
• Macroscopy They are similar to usual type endocervical
adenocarcinoma.
• Histopathology
These tumours are morphologically similar to endometrioid
adenocarcinomas arising in the uterine corpus.
The most important differential diagnosis is with endometrial
adenocarcinomas of endometrioid type extending from the
uterine corpus.
Endometrioid endocervical adenocarcinomas are typically
diffusely and strongly p16 positive in contrast to tumours of
endometrial origin, which most often have a patchy pattern of
p16 expression.
In endometrial carcinomas, this staining can be somewhat
extensive, with up to 80% of tumour cells positive in some
cases, but with only rare/occasional tumours having diffuse
expression .
Clear cell carcinoma
An adenocarcinoma composed predominantly of clear or hobnail cells
whos architectural patterns are solid, tubulo cystic and/or papillary.
Clear cell adenocarcinomas of the cervix are rare and have arisen in two
distinct populations; in association with in uter diethylstilbestrol (DES)
exposure .
Serous carcinoma
A rare adenocarcinoma of the cervix with an identical histological
appearance to endometrial or adnexal serous carcinoma.
Serous carcinoma of the cervix is exceedingly rare. Tumours with this
morphology that occur in young patients are most often associated with
HPV and represent “serous-like” usual type adenocarcinomas, while
older patients have tumours with mutant p53 expression akin to their
endometrial and adnexal counter- parts.
These tumours present with abnormal vaginal bleeding, watery
discharge, and abnormal cervical cytology.
The tumours display a complex papillary architecture with cellular
budding and frequent psammoma body formation. Glandular areas may
also be seen. Nu- clear atypia is generally high-grade. Cer- vical
involvement by the far more com- mon endometrial and adnexal serous
carcinomas must be excluded.
Prognosis and predictive factors
poor prognosis was associated with older age, higher stage, tumours
greater than 2 cm, invasion greater than 1 cm, lymph node metasta- sis,
and elevated serum CA125
 Mesonephric carcinoma
• Adenocarcinoma arising from mesonephric remnants.
• These tumours are not associated with high-risk HPV
• Mesonephric adenocarcinoma is a rare adenocarcinoma variant. It has a wide age
of presentation with a mean of about 50 years
These tumours commonly arise in the lateral to posterior cervical wall and may
be deeply invasive and bulky or exophytic.
• They more commonly involve the lower uterine segment than do other cervical
adenocarcinomas.
Characteristically, there are a variety of architectural patterns, including tubula
glands lined by mucin-free cuboidal epi thelium containing eosinophilic, hyalin
secretion within their lumina. Other pat terns include branching, slit-like space with
intraluminal fibrous papillae (reti form), solid, papillary, ductal, and spindle cell
patterns.
Distinction from benign mesonephric hyperplasia (which is ofte found in
association) is based on archi tectural gland crowding, haphazard in filtrative
growth, elevated mitotic activity intraluminal cellular debris and nuclea atypia
(which can be variable).
Meso nephric adenocarcinomas are uniformly reactive for cytokeratin and epithelial
membrane antigen, and often express calretinin, vimentin and CD10 (apical and
luminal). They are typically negative for estrogen and progesterone receptor and
CEA. They may express PAX8, TTF and p16 focally.
Prognosis and predictive factors
these neoplasms may be indolent, the have a propensity for late recurrence an
metastasis
• Adenosquamous carcinoma. This invasive
carcinoma exhibits both glandular and squamous
differentiation.
• Glassy cell carcinoma Sharp cytoplasmic margins
with ground glass” eosinophilic cytoplasm and
large round-to-oval nuclei with prominent nucleoli
characterize this tumour.
• Adenoid basal carcinoma- well-differentiated cords
and nests of basaloid cells with scanty cytoplasm
and focal gland formation.
• Adenoid cystic carcinoma- The tumour is
composed of island of basaloid cells with punched-
out spaces containing basophilic material.
 Low-grade neuroendocrine tumour
•Cervical low-grade NETs are extremely rare and are
primarily defined by the same architectural and cytological
features used at other site.
•The recommended terminology for neuroendocrine tumours
arising in the cervix is similar to that used for gastro-entero-
pancreatic neuroendocrine tumours
•Low-grade, neuroendocrine tumours exhibit neuroendocrine
and organoid differentiation . This category includes both
grade 1 and grade 2 tumours.
•For carcinoid tumour: Low-grade neuroendocrine tumour,
grade I
•For atypical carcinoid tumour: Low-grade neuroendocrine
tumour, grade 2
• High-risk HPV 18 can be identified in most cervical NETs.
• The presentation and macroscopy of neuroendocrine tumours
(NETs) are similar to other cervical carcinomas with vaginal
bleeding/discharge and or detection of a cervical mass NETs
are only infrequently detected
• The macroscopic appearance of NETs is not distinctive.
NETs (especially of low-grade) may produce a variety of
peptides such as calcitonin, gastrin, serotonin, substance P,
vasoactive intestinal peptide, pancreatic polypeptide,
somatostatin, and adrenocorticotrophic hormone
•Grade 1 tumours are characterized by abundant cytoplasm,
characteristic granular chromatin and visible to prominent
nucleoli. Growth patterns can be organoid, spindled, nested,
islands or trabecular.
•Grade 2 tumours are distinguished from grade 1 tumours by
their greater degree of nuclear atypia and mitotic activity, as
well as rare areas of necrosis.
Immunohistochemistry for synaptophysin, chromogranin, CD56
and neuron- specific enolase can facilitate the histological
diagnosis
The most frequent allelic loss in NETs is localized 3p deletion
Occasional 9p21 deletions have also been identified
Grade 1 neuroendocrine tumours generally follow an indolent
course; however, they retain the potential for metastatic spread.
Grade 2 neuroendocrine tumours are more aggressive
neoplasms, although few cases have been reported with
available follow-up . Their behaviour may be similar to large
cell neuroendocrine carcinomas .
 High-grade neuroendocrine carcinoma
• High-grade neuroendocrine carcinomas are composed of high-
grade malignant cells and may be of either small cell or large cell
type. Both types are considered grade 3.

• For small cell neuroendocrine carcinoma small cell carcinoma;

neuroendocrine carcinoma, small cell type, grade 3
For large cell neuroendocrine carcinoma neuroendocrine
carcinoma, large cell type, grade 3

• high grade neuroendocrine carcinoma of small cell type

(SCNEC) is by far the most common of these tumours.Like
their pulmonary counterparts, they are extremely aggressive,
even at low stage.

• High-grade neuroendocrine carcinom (NEC) of small cell type

(SCNEC) is characterized by the presence of a monotonous
population of small cells with ovoid hyperchromatic nuclei,
often exhibiting moulding, and scanty cytoplasm. There is
usually abundant mitotic and apoptotic activity with extensive
necrosis, lymphovascular and perineural invasion.

• SCNEC may be accompanied by in situ or invasive squamous

or adenocarcinoma.
 Tumors that have been categorized as well-differentiated
carcinoid tumors of the cervix were originally described by Large Cell Neuroendocrine Carcinoma
Albores-Saavedra et al., and were classified as carcinoid
High-grade neuroendocrine carcinoma
Large cell neuroendocrine
tumors because they contained neuroendocrine granules carcinomas are poorly differen-
and were histologically similar to intestinal carcinoid tiated tumors that typically grow in organoid, trabecular,
tumors [4]. Microscopically these well-differentiated or cord-like patterns, although some cases only grow in
tumors grow in trabecular, nodular, or cord-like patterns. sheets (> Fig. 6.46). Peripheral palisading of the cells and
Rosette-like structures are common, but follicles with
• High-grade neuroendocrine carcinoma (NEC) of large
eosinophilic material are uncommon. The neoplastic
cell type (LCNEC) has a diffuse, organoid, trabecular,
cells
or cord-like have round
pattern and is to oval spindle-shaped
composed of neoplasticnuclei and finely
cells
granular
with abundant cytoplasm.
cytoplasm, largeMitoses areprominent
nuclei, rare. Atypical carcinoids
share
nucleoli, and the same
a high architectural
mitotic patterns
rate. Focal of growth as typical
glandular
carcinoids,
differentiation may be butpresent.
are much more cellular than typical carci-
noids and have increased mitotic activity (5–10 mitoses/10
• The differential diagnosis
high-power includes
fields), cervical
moderate carcinomas
cytologic atypia, and focal
of both squamous and glandular type.
areas of necrosis (> Table 6.9) [3]. These tumors stain
positivelyisfor
• Cervical SCNEC synaptophysin,
reliably associatechromogranin
with high-riskA, and neu-
HPV. HPV-18ron-specific enolase.
is identifie more Neurosecretory
frequently thangranules
in can be iden-
cervical squa
tifiedmous celltumors
in these carcinoma .
by electron microscopy.
Typical and atypical carcinoid tumors are uncommon
Genetic factors
[282]. Some of the tumors that have been previously
Amplification described as well-differentiated
of chromosome cervical carcinoid
3q ha been identified in tumors
neuroendocrine tumours . Fig. 6.46
appear to be adenocarcinomas of the cervix that focally
Neuroendocrine carcinoma. Solid islands of carcinoma
resemble carcinoid tumors of the intestinal tract and have
exhibit some cords and palisading typical of
neuroendocrine differentiation. It should be noted that
neuroendocrine differentiation; nuclei are atypical and
neurosecretory granules can be identified in many carci-
numerous mitotic figures are evident
nomas of the cervix if a diligent search is made. Although

. Table 6.9
Histologic features used for distinguishing neuroendocrine tumors of the cervix
nomas of the cervix if a diligent search is made. Although

. Table 6.9
Histologic features used for distinguishing neuroendocrine tumors of the cervix

Neurosecretory
Tumor Patterns Mitoses Nuclear atypia granulesa Necrosis
Typical carcinoid tumor Trabecular, insular, Rare No Yes No
sheetlike
Atypical carcinoid tumor Trabecular, insular, 5–10/10 HPF Moderate Yes Focal
sheetlike
Large cell Sheets, organoid 10/10 HPF Marked Yes Moderate
neuroendocrine trabecular, cordlike
carcinoma
Small cell carcinoma Sheets,nests,trabecular, 10/10 HPF Moderate Sometimes Extensive
cordlike
a
By electron microscopy or immunohistochemistry.
HPF, high-power fields.
 NE Carcinoma
• chromogranin, synaptophysin, CD56) may provide
support for a diagnosis of SCNEC, but a
proportion of these neoplasms may not express any
neuroendocrine markers .
• TTF1 is not uncommonly positive
• SCNEC must be distinguished from lymphoma
and a squamous cell carcinoma with small cells.
• Diffuse p63 nuclear immunoreactivity is typical
of squamous cell carcinoma.
• SCNEC may occasionally fail to express
cytokeratins.
• CD56 and synaptophysin are the most sensitive
markers for SCNEC; chromogranin and PGP9.5
are less so.
• However, CD56 staining can be present in
nonneuroendocrine carcinomas
• LCNECs may be p63 positive . Isolated
neuroendocrine cells may be found in cervical
squamous cell carcinomas and adenocarcinomas
and, without the typical morphological features,
Mesenchymal tumours and tumour-like lesions
Adenosarcoma. Malignant melanoma
 Questions
Which of the following is true?
• Typical carcinoids are commonly positive for high risk
HPV
• Typical carcinoids commonly present with carcinoid
syndrome
• Typical carcinoids frequently metastasize
• Typical carcinoids lack nuclear atypia, mitotic figures
and necrosis
Answer 1
D. Typical carcinoids lack nuclear atypia, mitotic figures and
necrosis
Question 2
Which of the following is false?
• Necrosis is an important feature of typical carcinoid
• Presence of neuroendocrine component (even in
combination with SCC or adenocarcinoma) needs to
be documented in pathology report
• There are no specific Ki67 labeling index criteria to
define typical carcinoids
• Typical carcinoids generally follow an indolent course
Answer 2
A. Necrosis is an important feature of typical carcinoid
Question 3
Which of the following immunoprofiles would be
expected in type A tunnel clusters?
   
Type A tunnel clusters
• Positive for PAX2, p16 and CEA, Ki67 > 10%
• Positive for PAX2, p16 and CEA, Ki67 > 10%,
variable HIK1083
• Positive for PAX2, negative p16 and CEA, Ki67
< 1%, variable HIK1083
• Negative for PAX2, p16 and CEA, Ki67 < 1%
Answer 3
C. Positive for PAX2, negative p16 and CEA, Ki67 <
1%, variable HIK1083. Type A tunnel clusters are
positive for PAX2 and negative or focally positive for
p16 and CEA. The Ki67 labeling index is low. HIK1083
may also be positive if gastric metaplasia is present.
•
 • Which of the following immunoprofile would be expected
• Which of the following immunoprofile would be
in an HPV related (usual type) adenocarcinoma in situ?
expected in gastric type adenocarcinoma in situ?
• Block-like p16, high Ki67 index, diffuse ER
• Block-like p16, high Ki67 index, diffuse ER
• Block-like p16, high Ki67 index, focal ER
• Block-like p16, high Ki67 index, focal ER
• Focal p16, low Ki67, focal ER
• Focal p16, variable Ki67, focal ER
• Focal p16, low Ki67, diffuse ER
• Focal p16, variable Ki67, diffuse ER
Answer 24
Answer 25 B. HPV related usual type adenocarcinoma in situ is
C. Most cases of gastric type adenocarcinoma in situ are characterized by diffuse, block-like staining for p16, high Ki67
characterized by negative or focal staining for p16, variable index and negative or focal ER expression
Ki67 index and focal ER staining
References

R
THANK YOU