L7 - Gynaecopathology: infection-related tumors of the cervix and the cervical screening program (Dr Francesca Maggiani) Flashcards
- Revising the anatomy of the histology of the cervix - Understanding how HPV interacts with its host - Describing the different cancers induced by HPV infection - Understanding the role of screening and vaccination program to eradicate HPV related cancers
What are the key anatomical structures of the female genital tract relevant to cervical pathology?
Vagina
Cervix
Uterus
Fallopian Tubes
Ovaries
Pouches and Surrounding Structures
Where is the location and what is the structure and function of the Vagina?
Location: Inferior to the cervix, anterior to the rectum, posterior to the bladder and urethra.
Structure: A muscular, elastic tube connecting external genitalia to the cervix
Function: Serves as the birth canal and plays a role in sexual intercourse.
Where is the location and what is the structure and function of the cervix
Location: The lower, narrow portion of the uterus extending into the vagina.
made up of subdivisions:
Ectocervix: The outer part of the cervix, visible during a speculum exam.
Endocervix: The inner canal leading into the uterus.
Function: Acts as a gateway, controlling sperm entry and preventing infections.
Where is the location and what is the structure and function of the uterus
Location: Superior to the cervix, between the bladder (anterior) and rectum (posterior).
structure/ made up of:
Fundus: Dome-shaped upper portion above the fallopian tube openings.
Corpus (Body): Main part where the endometrium thickens during the menstrual cycle or pregnancy.
Function: Essential for menstruation, embryo implantation, and fetal development.
Where is the location and what is the structure and function of the fallopian tubes
Location: Extend from the uterus to the ovaries.
structure: The fallopian tube, or oviduct, is a hollow, seromuscular organ that connects the uterus to the ovary, and has four anatomical regions: infundibulum, ampulla, isthmus, and intramural (interstitial) portion
Function: Transport ova (eggs) from the ovaries to the uterus; common site for fertilization.
Where is the location and function of the ovaries?
Location: Lateral to the uterus, connected to the fallopian tubes.
Function:
Responsible for oogenesis (egg production).
Secrete sex hormones oestrogen and progesterone.
What are some pouches that make part of the female genital tract anatomy
Vesicouterine Pouch: Located between the bladder and the uterus.
Rectouterine Pouch (Pouch of Douglas): Found between the rectum and uterus, a site where fluid can accumulate.
what are surrounding structures to the female genital tract
Pouches and Surrounding Structures
Bladder: Anterior to the uterus and vagina.
Rectum: Posterior to the vagina and uterus.
Lateral Tissues: Contain lymph nodes and vascular structures important for the spread of malignancy
What are the two main epithelial types of the cervix
- Ectocervix
- Endocervix
(Transformation zone)
What is the significance of the Ectodcervix vs the endocervix in HPV infection * and the transformation zone
Ectocervix: : The portion projecting into the vagina, lned by stratified squamous epithelium – site for HPV-related squamous cell carcinoma.
Endocervix: The canal that connects the vagina to the uterine cavity, lined by columnar glandular epithelium – site for adenocarcinoma, also linked to HPV.
Transformation zone: Area where squamous metaplasia occurs, most vulnerable to HPV infection.
What is the transformation zone of the cervix?
The transformation zone is the area where glandular epithelium transitions into squamous epithelium. It is a common site for squamous metaplasia and HPV-related changes.
Why is the transformation zone clinically significant?
It is highly susceptible to HPV infection and is the main site for cervical dysplasia and neoplasia.
Why is Henrietta Lacks significant in cervical cancer research?
Henrietta Lacks’ cells, known as HeLa cells, represent the first immortalized human cell line. These cells have found extensive applications in genetic research, vaccine development, and cancer studies. While they were initially believed to originate from squamous cell carcinoma, further investigations revealed that they actually came from adenocarcinoma of the cervix which is rarer but still associated with exposure to human papillomavirus
What is an interesting aspect when it comes to gynecopathology
there is a huge amount of different etiopathogenic factors e.g. infections, horormonal dysregulation in the uterus, genetic abnormalities in the overies and fallopian tubes (wherever you look you can have a different set of changes)
What are Etiopathogenic factors and give examples in terms of gynecopathology
factors that cause the development of disease or abnormal condition e.g. infections, horormonal, genetic abnormalities in the overies and fallopian tubes
What is the WHO classification of gynaecological tumours?
The WHO classification (Blue Book) is an evolving system that categorises tumours of the female genital tract based on histology, morphology, and increasingly on genetic and molecular features to improve diagnosis, prognosis, and treatment.
Why has the WHO classification of tumours expanded over time?
Advancements in research, genetics, and molecular pathology have shown that histology and morphology alone are insufficient to predict tumour behaviour and prognosis, necessitating a more detailed subclassification.
What is a cause for concern when there is a tumour in the uterous?
That it can spread to the serosa
Why is the serosa important in uterine tumours?
If a uterine tumour spreads to the serosa, it can enter the abdominal cavity, leading to more aggressive disease progression.
How do cervical tumours spread?
Cervical tumours can spread:
Upwards to the uterus
Laterally to the soft tissue and lymph nodes
Anteriorly to the vagina and the bladder
Posteriorly to the rectum
(Due to the compact nature of the area, different types of tumors can spread to various regions, and the staging of each tumor will vary depending on its location.)
What is the embyrology of the female genital tract like
rather complex up to a certain age for the embryo development with the Mullerian duct and the mesonephric duct
What do Müllerian (paramesonephric) ducts develop into
The fallopian tubes, uterus, and cervix in females.
What happens to the Mesonephric (Wolffian) ducts in females?
They regress but leave behind small remnants (small tubule structures seen scattered close to the ovary / cervix)
How does duct development differ in males and females
Females → Müllerian ducts develop, Wolffian ducts regress and leave behind small remnants
Males → Wolffian ducts develop, Müllerian ducts regress and leave behind small remnants
How do the Müllerian ducts develop into the uterus?
The Müllerian ducts begin as two separate tubes which fuse inferiorly when their basement membranes come together and merge. This fusion causes the epithelial cells to rearrange, ultimately forming a single midline structure / tube that develops into the uterus
.
How do the cervix and vagina form from the Müllerian ducts?
After the uterus has formed, the fused Müllerian ducts extend downward and merge with the urogenital sinus. This connection ensures the proper anatomical relationship between the cervix and the vagina, allowing for reproductive tract continuity.
What is a uterine septum, and how does it affect pregnancy?
A uterine septum forms when the fusion of the Müllerian ducts is incomplete, resulting in a fibrotic band of tissue within the uterus. This abnormality can create a uterus with two separate cavities, known as a bicornuate uterus. While a bicornuate uterus may still function, it can interfere with embryo implantation and increase the risk of pregnancy complications.
Where does the name bicornuate come from
comes from the Latin “cornū,” meaning “horn,” indicating the presence of two horn-like projections.
What happens when the Müllerian ducts fail to fuse completely?
When the Müllerian ducts fail to fuse entirely, a condition called uterus didelphys occurs. This results in two separate uteri, each potentially having its own cervix and, in some cases, a duplicated vagina. Although some individuals with uterus bidelphys can conceive, the condition may lead to pregnancy complications and may require medical intervention.
Where does the name bidelphys come from
comes from the Ancient Greek words “bi-“ meaning “two” and “delphus” meaning “womb” or “uterus”
What fruit does the uterus shape resemble
an upside-down pear
What is the important function of the endometrium?
it allows for the implantation and the growth of the embryo
What is the cervix, and how is it different from the uterus in terms of lining?
The cervix is the neck of the uterus and has a different lining from the uterus. The endocervix (inner part) has a single layer of glandular epithelium (columnar) that produces mucin, while the ectocervix (outer part) has squamous epithelium, similar to the vagina.
What is the transition zone in the cervix?
The transition zone in the cervix is where the glandular epithelium of the endocervix transitions into the squamous epithelium of the ectocervix
Why is the transition zone important?
This area is important because it is vulnerable to squamous metaplasia and infections, such as those caused by human papillomavirus (HPV) which can lead to precancerous changes.
What is assessed in a PAP test?
A PAP test assesses cytology samples for the presence of both glandular and squamous cells to determine the level of damage at the cervical mucosa. The presence of both cell types indicates that the sample includes the transition zone, which is the area most vulnerable to abnormalities.
What does the presence of only squamous cells in a PAP test suggest?
If a PAP test shows only squamous epithelium, it suggests that the sample was taken from the ectocervix or outer areas of the cervix. This could mean the sample did not reach deep enough to include the transition zone or endocervix, possibly missing the most vulnerable area.
What does the presence of only glandular cells in a PAP test indicate?
If only glandular epithelium is found in a PAP test, it suggests that the sample was taken too deep within the endocervical canal, potentially missing the transition zone and the squamous epithelium of the ectocervix. This may result in an incomplete assessment of cervical health.
What is HPV, and how is it classified?
HPV is a large family of circular ds DNA. classified into low-risk types (causing benign lesions like warts) and high-risk types responsible for 75% of cervical cancer). they can affect different epithelial sites or mucous (transformationc zones)
What sort of lesions are formed from HPV when they are on the skin surface?
dicoid, slightly elevated lesions
how many genotypes of HPV are there
at least 300 different genotypes
What are common manifestations of low-risk HPV?
Low-risk HPV can cause cutaneous warts (hands, feet) and genital warts (condyloma acuminatum). These are more of an aesthetic problem rather than a problem in change of functionality (no risk of neoplastic transformation)
what type of low risk HPV wart can cause more symtoms
genital warts which tend to be bigger (mushroom lesions in a delicate area)
Which HPV types are considered high risk for cervical cancer?
HPV 16 and 18 are the most commonly associated with cervical cancer (Other high-risk types include 31, 33, 45, 52, and 58)
Which HPV types are considered low risk
HPV 6 and 11
How common are genital warts (condyloma) caused by low-risk HPV?
Condylomas (genital warts) affect hundreds of thousands of people each year. Their treatment and management impose a significant financial burden on the NHS
How common is cervical intraepithelial neoplasia (CIN) caused by high-risk HPV and how many develop into cervical cancer / metastatic tumours per year?
Cervical intraepithelial neoplasia (CIN) affects millions of people worldwide. Among these cases, around 10,500 progress to invasive cervical cancer and approx 5,000 per year develop into metastatic tumours
Are condylomas (genital warts) considered neoplastic?
No, condyloma are not neoplastic. Although they are caused by low-risk HPV and grow exophytically (outwardly), they do not have malignant potential.
How do low risk HPV warts usually resolve on their own
Yes, they are usually self resolving as the body’s immune system cleares the HPV infection.
What are the treatment options for genital warts if needed?
If needed, genital warts can be treated using topical treatments, liquid nitrogen (cryotherapy) for freezing, or electrocautery (burning).
How do low-risk HPV strains maintain their DNA?
Low-risk HPV strains retain their DNA in a episomal form. This means the viral DNA exists as separate, circular DNA strands within the host cell, rather than integrating into the host’s genome which contributes to its generally benign nature
What are the stages of cervical cancer development
dysplasia
cervical intrapethlial neoplasia
high grade dysplasia
invasive cancer
How does high-risk HPV lead to cervical cancer?
High-risk HPV integrates oncogenic portions of their DNA into the host genome, leading to:
Inactivation of tumour suppressor genes (e.g., P53, Rb)
Increased cell proliferation
Risk of progression from dysplasia to invasive carcinoma
What cytological effects are caused by HPV integrating their DNA into the host genome
Disruption of the E2 regulatory region and loss of other genes needed to form a complete virus - the cells are not undifferentiated and do not show koilycytosis.
CIN1 and CIN3 denote cervical intraepithelial neoplasia grades 1 - 3 respectively
How does HPV cause damage to epithelial cells in the cervical mucosa?
Infection by HPV in the basal cells typically results in ~90% healing within a couple of years, as viral replication occurs. The immune system often clears the infection during this time.
How does HPV DNA progress over time in some cases?
In about 10-30% of cases, HPV DNA integrates into the tumor cell DNA after 10-30 years. This can lead to the development of cancer, with 0.8% of cases ultimately progressing to invasive cancer.
What makes the screening process important, and why do some women not take part?
The screening process is crucial because regular checks help catch any serious changes early. However, many women don’t take part because they might feel that HPV infections heal on their own. This perception, along with the fact that 90% of cases heal without progressing to cancer, can make women less likely to take the screening process seriously.
How does the cervical screening program handle HPV infection and viral integration?
The screening program is designed to detect viral integration and cellular atypia. If viral integration is seen, atypia is assessed to check for abnormalities. If no atypia is found, the individual is typically asked to follow up after a certain period of time.
What cellular changes are associated with low-risk papillomavirus infection? (and low grade CIN)
Cells show a pale halo around the nucleus, known as koilocytosis.
The nucleus appears dark, shrunken, and irregular in shape, resembling a “wrinkled raisin.”
What is koilocytosis?
Koilocytosis is a hallmark of HPV infection, where infected cells have a perinuclear halo and a dark, shrunken nucleus.
Why is cervical screening important?
Cervical screening detects HPV infection and precancerous changes early, allowing for intervention before progression to invasive cancer.
Can HPV infections regress
Yes. 90% of HPV infections clear spontaneously due to immune response. However, persistent infection with high-risk HPV increases the risk of cervical neoplasia.
What is the most invasive and common type of carcinoma in the cervix
Squamous cell carcinoma
What is the role of E6 and E7 oncoproteins in HPV-induced cancer?
E6 degrades P53 ( This prevents the cell from responding appropriately to DNA damage, promoting genomic instability and cancer progression - no BAX or PUMA genes are expressed so there is no apoptosis or senescence )
E7 inactivates Rb ( Rb can no longer bind to E2F so it is free to drive uncontrolled cell cycle progression)
How can HPV cytological damage be reduced
functional immune systems can potentially recognise damaged cells for elimination (this would cause regression)
What are the risk factors for persistent HPV infection?
Immunosuppression
Smoking
Multiple sexual partners
Early sexual activity
Lack of HPV vaccination
How does cervical cancer develop from HPV infection?
If HPV persists, it can cause progressive dysplasia (CIN 3) and eventually invasive carcinoma if left untreated.
What is the purpose of the HPV vaccine?
The HPV vaccine protects against high-risk HPV types, reducing the risk of cervical cancer.
Who should receive the HPV vaccine?
The vaccine is recommended for adolescents before sexual debut, but catch-up vaccination is available for young adults.
How does cervical screening work?
Cervical screening detects:
HPV DNA (primary screening method)
Cellular atypia (via cytology, previously used in Pap smears)
Why is regular screening important, even if the first result is normal?
HPV-related changes can develop over time, so repeated screening ensures early detection and intervention before cancer develops.
WHy are cervical squamous cell carcinoma concerning
when they metastsise to other parts of the body
What are “tongues of infiltration,” and what do they indicate?
Tongues of infiltration are extensions of tumour cells that invade surrounding tissues. They indicate the spread of cancer beyond its point of origin.
Why is blood vessel infiltration by the tumour dangerous?
Infiltration of blood vessels by the tumour can lead to haematogenous spread, allowing cancer cells to travel through the blood and potentially metastasise to organs like the liver, lungs, and brain.
What is the significance of lymphatic vessel invasion by the tumour?
If the tumour invades lymphatic vessels, it can spread to nearby lymph nodes, increasing the likelihood of cancer dissemination throughout the body.
Describe the macroscopic appearance of cervical squamous cell carcinoma.
Macroscopically, cervical squamous cell carcinoma often appears as a “cauliflower-like” mass with a highly irregular surface. It may visibly extend toward the uterus or externally.
What does it mean (for surgery) if the squamous cell carcinoma spreads towards the uterus / externally
This may require a more extensive/aggressive surgical procedure, such as a radical hysterectomy, where both the uterus, fallopian tubes, ovaries or surrounding tissues need to be removed to ensure all cancerous cells are excised.
What are the different stagings of cervical carcinoma and their 5 year survival rate
Stage 0: carcinoma in situ with a 100% 5 year survival rate
Stage 1: Confined to the cervix with an 85% 5 year survival rate
Stage 2: Disease beyond cervix but not to pelvic wall or lower 1/3rd of vagina with a 65% 5 year survival rate
Stage 3: Disease to pelvic wall or lower 1/3 of vagina with a 35% 5 year survival rate
Stage 4: invades bladder, rectum or metastasis with a 7% 5 year survival rate
How does the extent of tumour spread influence surgical decisions?
If the tumour spreads toward the uterus or externally, more aggressive surgical procedures may be required, potentially including the removal of fallopian tubes and ovaries.
Why might a uterine cavity be cut open during examination?
The uterine cavity may be cut open to better observe how the tumour has grown and to assess the extent of infiltration.
What is the typical structure of normal endocervical mucosa?
It normally consists of a single layer of cells.
What cytological changes are seen in cervical glandular intraepithelial neoplasia (CGIN)?
Darker nuclei, cellular pleomorphism, and abnormal stratification (“pluristratification”) that should not normally occur.
What can cause CGIN and adenocarcinomas of the cervix
high risk HPV types (e.g. HPV-16 and HPV-18) which can be screened for
Unlike squamous cell abnormalities, which arise in the ectocervix, what type of cells do CGIN and adenocarcinomas originate from
Glandular epithelium of the endocervical canal
What is the difference between CGIN and adenocarcinoma of the cervix?
CGIN (Cervical Glandular Intraepithelial Neoplasia) is a precancerous lesion affecting the glandular cells of the cervix. It represents abnormal cell growth but has not yet invaded deeper tissues. On the other hand, adenocarcinoma is an invasive cancer, meaning the abnormal glandular cells have spread beyond the epithelial layer and can invade surrounding tissues.
How does CGIN progress to adenocarcinoma?
CGIN is considered a high-grade precancerous condition that, if left untreated, can progress to adenocarcinoma over time. This progression occurs when high-risk HPV (especially HPV-18) causes increasing genetic mutations, leading to uncontrolled glandular cell growth and eventual invasion of deeper cervical structures.
How does CGIN appear histologically under a microscope?
It would have hyperchromatic nuclei (darkly stained, enlarged and irregularly shaped), increased nuclear-to-cytoplasmic ratio, loss of normal glandular architecture but no invasion. This is less obvious than CIN
How does adenocarcinoma of the cervix appear histologically
irregular shaped, fused glands with back to back growth that lack normal architecture, marked nuclear pleomorphism (variation In nuclear size and shape), increased and normal mitotic activity, signs of stromal invasion ( indicating malignancy)
Why are fistulas common in the gynaecological tract?
The close proximity of organs makes it easy for lesions or trauma to create connections between the bladder and vagina or between the vagina and rectum, particularly after traumatic labour.
What is the prognosis for cervical cancer if the tumour is confined to the cervix?
The prognosis is quite good, and in early-stage high-grade CIN, the cervix can often be partially removed (via LLETZ) without needing to remove the uterus.
Why is preserving the uterus important in some cases of cervical cancer treatment?
Many young women with cervical cancer may still want to complete their families, so retaining the uterus is beneficial.
What surgical procedure can remove part of the cervix while preserving the uterus?
Large Loop Excision of the Transformation Zone (LLETZ).
What complication may require placing a band (Cerclage) around the uterus post-cervical removal?
This is done to keep the uterus closed during pregnancy following cervical removal.
What is a cervical cerclage, and why is it used?
A cervical cerclage is a surgical procedure in which a band or stitch is placed around the cervix to help keep it closed during pregnancy. It is used to prevent preterm birth or pregnancy loss in women with cervical insufficiency (when the cervix shortens or dilates too early).
How has the HPV vaccination programme impacted cervical cancer cases?
It has led to a reduction in cases; however, many women who did not participate or comply with screening programmes are still developing these cancers.
What 3 key steps were outlined by the WHOs global strategy to accelerate the elimination of cervical cancer
Vaccination, screening and treatment (implementation of all 3 could reduce 40%+ new cases of the disease and 5 million related deaths by 2050)
What other cancers are associated with HPV besides cervical cancer?
Cancers of the penis, perineal area, and head and neck.
Who is the HPV vaccine typically given to
teenage girls before they become sexually active
Why has the HPV vaccination programme been extended to boys in some countries?
Boys spread the infection and are also affected by HPV-related cancers, especially men who have sex with men, who lack effective screening programmes.
how often is HPV screening offered to women 25-49 and women aged 50-64
Women aged 25-49 are invited every 3 years whilst women aged 50-64 are invited every 5 years.
What happens if an HPV screening test is positive but cytology is normal?
The patient is rescreened in 12 months because the infection can clear naturally.
What follow-up is required if cytology results show abnormalities after a positive HPV test?
A colposcopy is performed to examine the cervix more closely.
What happens if the patient tests HPV negative vs HPV positive after 12 months rescreen after finding normal cytology
HPV negative - return to normal screening program
HPV positive - cytology examination (normal cytology - rescreen in 12 months or abnormal - colonoscopy referral)
What is a colposcopy?
A procedure where a specialist visually examines the cervix for abnormal changes using a magnifying instrument (colposcope)
Why is a PAP test important in HPV screening?
It allows detection of cellular abnormalities in the cervix, which can indicate pre-cancerous or cancerous changes.
What do normal cervical cells look like in a PAP test?
They have mature, small, dark nuclei and large amounts of cytoplasm.
What are atypical cells in a PAP test?
cells that look abnormal, often with irregular shapes and darker nuclei, indicating potential dysplasia.
How has the PAP test procedure improved over time?
It is now cleaner and easier to interpret because debris, bacteria, and blood are filtered out, leaving only epithelial cells.
Why can’t a PAP test alone confirm invasive cancer?
A histological sample is needed to assess for tissue invasion.
Besides the cervix (59%), where else can HPV-associated cancers develop in women?
The oropharynx ( 10%) , vagina (3%), vulva (13%) , and anus (15%).
What is the most common HPV-associated cancer in men?
Oropharyngeal cancer (77%) (others include the penis and anus)
What are common symptoms of cervical cancer?
Bleeding between periods and discomfort.
Why are adenocarcinomas difficult to detect with HPV screening?
They are not HPV-dependent and may not be identified through routine screening.
What are examples of rare adenocarcinoma types in the cervix?
Gastric-type, clear cell type, and mesonephric type adenocarcinomas.
How has the approach to cervical cancer screening changed?
Previously, cytology was examined first, followed by viral testing; now, HPV testing is performed first, followed by cytology if needed.
What is a potential reason for increased cervical cancer cases in postmenopausal women?
Reduced use of protection during sexual activity and absence of pregnancy concerns.
what needs to be consiered in terms of cervical screening
it has become increasingly recognised that a significant proportion of cervical carcinomas, in particular adenocarcinomas are HPV independent
