Cervical pathology
The uterine cervix is made up of two portions:
- an external ectocervix: lined by stratified squamous non-keratinized epithelium.
Macroscopically it is whitish and is filled with glycogen; the opening in the
ectocervix, the external os, marks the transition from ectocervix to endocervical
canal. Normal ectocervical cells are polygonal in shape and contain keratin, with
nuclei differing in size, shape and color according to maturation state; normally
there is maturation so cells mature from the basal layer, becoming larger and
more filled with keratin when they reach superficial layers.
- an internal endocervix: lined by mucus-secreting monostratified columnar
epithelium. Macroscopically it appears reddish due to the vessels lying beneath
the epithelium; ends at a narrowing called internal os where the uterine cavity
begins. If scraped from stromal connective tissue, it appears as clusters with
nuclei at one pole and mucus in the upper portion.
The squamous and columnar epithelium meet at the squamocolumnar junction, or
transformation zone. It contains a higher % of immature (or metaplastic) basal cells of
the squamous epithelium that are more vulnerable to HPV infection, the most common
cause of cervical cancer. Mature superficial squamous cells that cover the ectocervix,
vagina or vulva cannot be infected unless there is damage to the surface epithelium,
allowing access to immature cells in the basal epithelial layer.
Epidemiology and risk factors for cervical caner
Cervical cancer is now the 8th most common cause of cancer-related deaths but was
once the 1st most frequent cause in the USA; this reduction has occurred thanks to the
introduction of Pap smear in the late 1980s. Women not screened have a 6x higher
incidence rate of invasive cancer. Screening aims to search for as-yet-unrecognized
conditions or risk markers; can be applied to individuals or to a whole population, that do
not exhibit signs and symptoms of the disease.
HPV is a naked double stranded DNA virus that spreads by direct contact or via fomites;
genital HPV infections are extremely common and usually asymptomatic and they may
not even cause tissue changes that are detectable on Pap test. Prevalence of HPV in
cervical smears in women with normal Pap test results peaks at around age 20, due to
onset of sexual activity; it declines after age 30 due to entry into monogamous
relationships with age.
HPV infection is responsible for 90% of premalignant and malignant lesions of the
cervix. Most HPV infections are transient and are eliminated by the immune response;
HPV alone is not able to cause cancer but persistence of infection, which is dependent
on immune status, exposure to carcinogens, low socioeconomic status, high risk
male partners, multiple sexual partners and early sexual exposure influences
whether HPV infection will regress or persist and eventually progress to precursor lesions
and cervical cancer. Low risk HPV strains cause cutaneous warts that may occur in the
anogenital region (condyloma acuminata) or in the mucosae e.g. cervical and
nasopharyngeal. HPV infection in men causes anal cancer.
, Pathogenesis
High-risk HPVs (16,18,31,33) can integrate
their DNA with that of the host cell and are
always associated with carcinoma. Whilst
infection occurs in immature squamous cells,
viral replication occurs in mature squamous
cells that should normally be arrested in G1
but instead continue to actively progress
through the cell cycle when infected by HPV,
which uses host cell DNA synthesis machinery
to replicate its own genome.
- E6: binds TERT, increasing telomerase
expression and blocking apoptosis; it also causes p53 degradation so increasing
proliferation
- E7: binds active form of RB and promotes its degradation because it cannot bind
to E2F; also binds p21 and p27, two important CDKIs, therefore enhancing cycle
progression and cell proliferation but also impairing the capability of cells to repair
DNA damage.
Low risk HPVs (6,11,41,44) are never observed in carcinoma, since their genome lacks
genes E6 and E7 and is maintained in a non-integrated episomal form, however they
may cause pre-neoplastic lesions (condylomas) that almost always regress
spontaneously following the host immune response.
Cervical cancer precursor lesions
Precancerous lesions related to an
abnormal growth of epithelial cells on the
surface of the cervix at the level of the
squamocolumnar junction are
characterized by a stepwise sequence from
low grade (reversible) lesions to high grade
conditions with higher risk of malignant
transformation (overt stromal invasion).
Progression of dysplasia is more common
upon infection with high risk HPVs; whilst 95%
of Pap smears are normal, in 5% of cases at
brush cytology we may find squamous
epithelial lesions or SIL (HSIL or LSIL- Bethesda
classification); then the patient undergoes biopsy and histopathologically we classify the
cervical intraepithelial neoplasia (CIN – WHO classification).
CIN diagnosis is based on identification of nuclear atypia, nuclear to cytoplasmic ratio,
irregular shape, variations in nuclear size and shape and usually by a peri-nuclear halo –
squamous cells with these structural changes are called koilocytes and are suggestive of
HPV infection. SIL and CIN grade are classified as follows:
The uterine cervix is made up of two portions:
- an external ectocervix: lined by stratified squamous non-keratinized epithelium.
Macroscopically it is whitish and is filled with glycogen; the opening in the
ectocervix, the external os, marks the transition from ectocervix to endocervical
canal. Normal ectocervical cells are polygonal in shape and contain keratin, with
nuclei differing in size, shape and color according to maturation state; normally
there is maturation so cells mature from the basal layer, becoming larger and
more filled with keratin when they reach superficial layers.
- an internal endocervix: lined by mucus-secreting monostratified columnar
epithelium. Macroscopically it appears reddish due to the vessels lying beneath
the epithelium; ends at a narrowing called internal os where the uterine cavity
begins. If scraped from stromal connective tissue, it appears as clusters with
nuclei at one pole and mucus in the upper portion.
The squamous and columnar epithelium meet at the squamocolumnar junction, or
transformation zone. It contains a higher % of immature (or metaplastic) basal cells of
the squamous epithelium that are more vulnerable to HPV infection, the most common
cause of cervical cancer. Mature superficial squamous cells that cover the ectocervix,
vagina or vulva cannot be infected unless there is damage to the surface epithelium,
allowing access to immature cells in the basal epithelial layer.
Epidemiology and risk factors for cervical caner
Cervical cancer is now the 8th most common cause of cancer-related deaths but was
once the 1st most frequent cause in the USA; this reduction has occurred thanks to the
introduction of Pap smear in the late 1980s. Women not screened have a 6x higher
incidence rate of invasive cancer. Screening aims to search for as-yet-unrecognized
conditions or risk markers; can be applied to individuals or to a whole population, that do
not exhibit signs and symptoms of the disease.
HPV is a naked double stranded DNA virus that spreads by direct contact or via fomites;
genital HPV infections are extremely common and usually asymptomatic and they may
not even cause tissue changes that are detectable on Pap test. Prevalence of HPV in
cervical smears in women with normal Pap test results peaks at around age 20, due to
onset of sexual activity; it declines after age 30 due to entry into monogamous
relationships with age.
HPV infection is responsible for 90% of premalignant and malignant lesions of the
cervix. Most HPV infections are transient and are eliminated by the immune response;
HPV alone is not able to cause cancer but persistence of infection, which is dependent
on immune status, exposure to carcinogens, low socioeconomic status, high risk
male partners, multiple sexual partners and early sexual exposure influences
whether HPV infection will regress or persist and eventually progress to precursor lesions
and cervical cancer. Low risk HPV strains cause cutaneous warts that may occur in the
anogenital region (condyloma acuminata) or in the mucosae e.g. cervical and
nasopharyngeal. HPV infection in men causes anal cancer.
, Pathogenesis
High-risk HPVs (16,18,31,33) can integrate
their DNA with that of the host cell and are
always associated with carcinoma. Whilst
infection occurs in immature squamous cells,
viral replication occurs in mature squamous
cells that should normally be arrested in G1
but instead continue to actively progress
through the cell cycle when infected by HPV,
which uses host cell DNA synthesis machinery
to replicate its own genome.
- E6: binds TERT, increasing telomerase
expression and blocking apoptosis; it also causes p53 degradation so increasing
proliferation
- E7: binds active form of RB and promotes its degradation because it cannot bind
to E2F; also binds p21 and p27, two important CDKIs, therefore enhancing cycle
progression and cell proliferation but also impairing the capability of cells to repair
DNA damage.
Low risk HPVs (6,11,41,44) are never observed in carcinoma, since their genome lacks
genes E6 and E7 and is maintained in a non-integrated episomal form, however they
may cause pre-neoplastic lesions (condylomas) that almost always regress
spontaneously following the host immune response.
Cervical cancer precursor lesions
Precancerous lesions related to an
abnormal growth of epithelial cells on the
surface of the cervix at the level of the
squamocolumnar junction are
characterized by a stepwise sequence from
low grade (reversible) lesions to high grade
conditions with higher risk of malignant
transformation (overt stromal invasion).
Progression of dysplasia is more common
upon infection with high risk HPVs; whilst 95%
of Pap smears are normal, in 5% of cases at
brush cytology we may find squamous
epithelial lesions or SIL (HSIL or LSIL- Bethesda
classification); then the patient undergoes biopsy and histopathologically we classify the
cervical intraepithelial neoplasia (CIN – WHO classification).
CIN diagnosis is based on identification of nuclear atypia, nuclear to cytoplasmic ratio,
irregular shape, variations in nuclear size and shape and usually by a peri-nuclear halo –
squamous cells with these structural changes are called koilocytes and are suggestive of
HPV infection. SIL and CIN grade are classified as follows:
