Pathology of the Cervix Flashcards
What is the cervix defined as?
Lower part of the uterus that is cylindrical, measuring 3cm in length and 2.5cm in diameter
What is the distal opening of the cervix called?
The os (opens into the vagina)
What happens to the cervix after several pregnancies?
A nulliparous (no deliveries ever) cervix the os is small and circular
A multiparous cervix os is transverse and slit-like
What epithelium lines the ectocervix (outside of the cervix)?
Stratified non-keratinising squamous epithelium
What epithelium lines the endocervix?
Columnar, mucous secreting epithelium
What is the squamo-columnar junction?
The point at which the squamous and columnar epithelium meet
What is clinically significant about the squamo-columnar junction?
Its position changes under hormonal influences during growth to young adult and then to adult.
Zone of transition is a location of lots of pathologies related to the cervix.
It is also called the transformation zone
What infective organisms cause chronic cervicitis?
Candidia
Trichomonas
Chlamydia and Gonorrhoea
Herpes simplex virus
Human papilloma virus
Others - Gardnerella, tubercolosis, syphilis, CMV, shistoma
What causes chronic cervicitis?
Affects almost all women to varying degrees
Squamous metaplasia at transformation zone obstructs cervical gland opening leading to cyst formation and stromal inflammation (acute and chronic)
What does chronic cervicitis look like when investigated?
Clinically the cervix appears red, inflamed and irregular with a wide transformation zone.
What causes candidiasis?
Overgrowth of commensal organsis.
What symptoms does candidiasis cause?
Generally causes vulvovaginitis with pruritis, burning and white discharge.
How is candidiasis treated?
Topical/oral antifungals
How is candidiasis diagnosed?
Cervical (pap) smear
How is trichomonas vaginalis spread?
Sexual contact.
What are the symptoms of trichomonas infection?
Patients may be asymptomatic or have yellow, frothy vaginal discharge
Vulvovaginal discomfort
Dysuria
Dyspareunia
How is trichomonas infection diagnosed?
Large flagellated ovoid protozoan that can be identified by pap smear.
What are the symptoms of chlamydia and gonorrhoea in females with cervicitis caused by these organisms?
Patients can be asymptomatic or can have pain, dysuria, discharge and bleeding.
Both infections, however, can ascend through uterus to cause pelvic inflammatory disease
What are potential complicaitons of pelvic inflammatory disease?
Acute complications include:
Peritonitis and bacteremia
Endocarditis, meningitis, and suppurative arthritis
Other sequelae include:
Infertility and tubal obstruction
Increased risk of ectopic pregnancy
Intestinal obstruction due to adhesions between bowel and pelvic organs.
What kind of infection does Herpes Simplex Virus - 2 cause?
HSV-2 usually involves genital mucosa.
Initial infection can cause systemic symptoms
Clinical symptoms seen in only 1/3 of people (red papules -> Vesicles -> Painful ulcers
Infection persists indefinitely and becomes reactivated at times of immunosuppression
How can HSV changes be visualized?
Pap smear shows swollen nuclei with multinucleation, ground glass chromatin with prominent nuclear membranes, and nuclear inclusions.
Who is HPV infection must common in?
Peak prevalence seen in 20-year-olds.
Most patients are asymptomatic
What kind of virus is HPV?
Double stranded DNA virus
Over 40 genotypes can infect the genital tract
Why is control of HPV important?
Divided into low and high oncogenic risk categories
Associated with condyloma, dysplasia and cancer in anogenital tract, oral cavity, and respiratory tract in both men and women
Do HPV viruses infect indefinitely?
No, infection usually is eliminated by host in 1 - 2 years. More oncogenic strains last longer than less oncogenic strains.
Persistent infections increase the risk of development of premalignant lesions and subsequent carcinoma.
What are the most common low risk HPVs? What are the most common high risk?
Lowest risk: HPV 11 and HPV6
High risk: 16 and 18.
newly discovered high risk: 31, 35, 52, 33
How does HPV affect people?
Integration of HPV into cell DNA allows for an overexpression of E6 and E7 viral genes which encode proteins.
Both E6 and E7 enhance degradation of p53 therefore interrupting cell death pathways.
E7 binds to p21 and prevents its function as a cell cycle inhibitor
E7 inactivates the retinoblastoma gene (Rb) blocking its proliferation-inhibitory function
What is condyloma acuminatum?
An exophytic lesion arising in transformation zone or ectocervix that has low oncogenic potential
What causes condyloma acuminatum?
Usually associated with HPV6 and 11
What does histology look like in condyloma acuminatum?
Exophytic lesion characterised by papillary fronds of thickened squamous epithelium with fibrovascular cores.
HPV cytopathic effect (large, irregular cytoplasm surrounding nucleus)
What is koilocytosis?
Nuclear enlargement
Hyperchromasia
Binucleation
Cytoplasmic clearing
What do premalignant lesions usually look like on cervix?
Flat lesions
What is a cervical intraepithelial neoplasia?
Flat premalignant lesion of the cervix graded I - III depending on severity of dysplasia.
How is cervical intraepithelial neoplasia diagnosed?
Based on identification of squamous cell nuclear atypia with variation in nuclear size and shape
Hyperchromasia
Coarse chromatin granules
Increased mitotic activity
How is dysplasia graded in cervical intraepithelial neoplasia (CIN)?
CIN I has koilocytic atypia (Not as much maturation of cells to the surface)
CIN II has progressive atypia and expansion of dysplastic cells into middle third of the epithelium
CIN III Has diffuse atypia, loss of maturation, and expansion of dysplastic cells to epithelial surface.
**Dysplasia and koilocytic atypia are rising from base of epithelium all the way to the epithelial surface.
What additional diagnostic tests allow diagnosis of CIN?
In situ hybridisation for high risk HPV DNA
Ki-67 showing proliferative activity throughout entire thickness of epithelium
What protein is overexpressed in people with oncogenic HPV?
p16
What terminology is used in cytology of cervical lesions (Pap smears)?
HPV infection shows Low grade squamous intraepithelial lesion (LSIL)
CIN I shows LSIL
CIN II shows High grade squamous intraepithelial lesion (HSIL)
CIN III shows high grade squamous intraepithelial lesion HSIL
*HPV infection and CIN I = low grade lesion
**CIN II and III = high grade lesion
What is the prognosis of low grade squamous intraepithelial lesions like?
60% regress spontaneously
30% persist
10% progress to HSIL
LSIL do not often progress directly to invasive carcinomas.
These are managed by screening more often (less time between screenings)
What is the prognosis of high grade squamous intraepithelial lesions like?
Significant malignant potential:
30% only regress
60% persist
10% progress to carcinoma
How are HSILs treated?
By surgical removal of the transformation zone by LLETZ or cone biopsy
How long do HSILs take to progress to invasive carcinomas?
Times vary from a few months to more than a decade. Very difficult to predict.
What is the single most important factor for cervical cancer oncogenesis?
High oncogenic risk HPVs.
HPV16 alone accounts for ~60% of cervical cancer cases and HPV18 for another 10%
What are the risk factors for cervical cancer?
Related to both host and viral characteristics:
HPV exposure (Age at first intercourse, multiple sexual partners, etc)
Viral oncogenicity (Persistent infection with high risk HPV subtypes)
Inefficiency of immune response (Immunosuppression/HIV infection)
Other risk factors (Smoking, coexisting infections, dietary deficiencies, OCP, hormonal changes)
How common is cervical cancer?
500k new cases diagnosed each year.
250k deaths per year
Where is cervical cancer most common and least common?
Most common: Underdeveloped countries (Sub-saharan Africa, Central and South America, Southeast Asia)
Least common: Western countries where screening has significantly reduced incidence of disease
How does cervical cancer present?
Most are asymptomatic
Abnormal pap smear
Abnormal bleeding (post coital, intermenstrual)
Pain
Haematuria
Weight loss
What does cervical cancer look like macroscopically?
Early lesions are only visible by colposcopy
Focal induration, ulceration, and elevated granular area that bleeds when touched
Advanced lesions can be endophytic or exophytic
What do exophytic lesions look like?
Polypoid or papillary tumour mass
What do endophytic lesions look like?
Ulcerated
What is the most common types of cells to form cervical cancer?
Squamous cell carcinoma (accounts for 80% of cases)
This is because CIN III is the precursor lesion.
What does cervical cancer consist of?
Nests and infiltrative tongues of malignant squamous cells invading the stroma.
When is microinvasive squamous cell differentiated from CIN III?
When there is invasion of the basement membrane. (into the stroma)
SCC forms nests within the basement membrane eventually
What percentage of cervical cancer are adenocarcinomas?
~15%
What is the precursor lesion for adenocarcinomas?
Adenocarcinoma in situ
What does histology of adenocarcinomas look like?
Proliferation of glandular epithelium composed of malignant endocervical cells with large, hyperchromatic nuclei and relatively mucin-depleted cytoplasm, resulting in dark appearance of the glands, as compared with normal endocervical epithelium
What other tumours besides SCC and adenocarcinomas can cause cervical cancer?
Adenosquamous and neuroendocrine carcinomas (Account for remaining ~5%)
What is the prognosis of adenosquamous and neuroendocrine carcinomas like?
Generally more aggressive and associated with less favourable prognosis
Where do cervical carcinomas progress to usually?
Extends by direct spread to involve nearby tissues like bladder, ureters, rectum, and vagina
Local and distant lymph nodes can become involved
Distant metastases may be found in the liver, lungs, and bone marrow
How is cervical cancer treated?
Depends on clinical stage:
Early carcinomas = cone biopsy only
Most = hysterectomy and lymph node dissection
Advanced = Surgery +/- adjunct radiotherapy and chemotherapy
How effective is screening in preventing cervical cancer?
In Australia 80% of women diagnosed with cervical cancer did not participate in regular screening
Screening allows detection of precancerous lesions before they develop into invasive carcinoma.
What test has replaced pap smear tests since 2017?
Cervical screening test
How is a cervical screening test conducted?
Cells from transformation zone are obtained via spatula/brush
Liquid based medium
Molecular test for HPV DNA
Reflex cytology if HPV DNA is +ve
What processes follow cervical screening tests?
If HPV is detected: reflex cytology is conducted.
If HPV infection is present ten referred to specialist for colposcopy
If low grade lesion is found repeat screening is done in 12 months and if still present referral to specialist again
What does HPV vaccine (Gardasil) cover?
Reduces incidence of cervical cancer caused by HPV16 and 18 and condylomas caused by HPV 6 and 11.
Gardasil 9 also covers the next most common HPV types that are associated with cervical cancer (31, 33, 45, 52, and 58)
When is HPV vaccine most effective?
When given to young people before they become sexually active.
Girls and boys aged 12 - 13 can receive HPV vaccine for free under national immunization program at their school.
How effective has HPV vaccine been?
Program has already shown strong signs of success in reducing HPV infections, genital warts and precancerous lesions of the cervix
Is routine screening still needed with the HPV vaccine?
Yes; vaccination does not protect against all types of cervical cancers or pre-existing HPV infections.
