Pathology of Cervical Dysplasia and Malignancy Flashcards
What is the histological grading of precancerous cervical squamous lesions?
HPV infection
Cervical intraepithelial neoplasia 1 (CIN1)
CIN 2
CIN 3
Cervical intraepithelial neoplasia 3/CIN 3 is equivalent to
carcinoma in situ
Carcinoma in situ refers to
When dysplastic changes are marked and involve the full thickness of the epithelium, but the lesion does not penetrate the basement membrane, it is considered a pre-invasive neoplasm and is referred to as carcinoma in situ
Cervical intraepithelial neoplasia is a malignant/premalignant lesion?
premalignant
What is the cytological grading of precancerous cervical squamous lesions?
Low-grade squamous intraepithelial lesion
High-grade squamous intraepithelial lesion
What is the nuclear structure of HPV?
dsDNA
HPV specifically infects
squamous epithelium because it can only complete its infectious cycle in differentiated squamous epithelium
HPV types ______ are more common in skin infections
1, 2, 4
Which HPV subtypes/genotype are associated with pathology in the female genital tract?
HPV 16 and 18
DNA of HPV consists of
early and late genes
Late HPV genes encode for
capsid proteins
Early HPV genes encode for
replication, proliferation, viral release
For HPV to infect squamous epithelium, it must gain contact with
the basement membrane or the basal keratinocyte - there has to be pre-existing damage to the epithelium so they can enter and make contact
What is the pathogenesis of HPV?
capsid gains contact with BM or basal keratinocytes; enters cells and propagates through various stages of differentiation to the most superficial/terminally differentiated keratinocytes where it is packaged and released as these keratinocytes are sloughed off
In HPV infection, early genes are expressed in
E1-E7 in middle and basal keratinocyte layers
In HPV infection, late genes are expressed in
terminally differentiated keratinocytes (top layer) such that proteins encoding the capsid are expressed on the outermost cell layer for packaging and release of the HPV
In keratinocytes, what happens to HPV DNA?
can be integrated into cellular host DNA or be episomal
Episomal HPV DNA is associated with
latent disease prior to significant dysplasia in the epithelium
HPV E2 gene encodes for
a transcription factor that suppresses genes E6 and E7
Disruption in the E2 gene occurs when
a break point occurs in replication of the genome at some point as it amplifies through keratinocyte differentiation
Disruption of the E2 gene leads to
disruption of the gene and the HPV genome is able to integrate into the host chromosomal DNA
When HPV DNA is incorporated into the host cell genome, what happens relative to the E2 gene?
regulation of E6 and E7 is lost and they become significantly increased in number inside the cell
E6 binds to
p53
E7 binds to
Rb
p53
tumour suppressor gene that regulates the cell cycle by initiating apoptosis in cells with damaged DNA
Rb
retinoblastoma protein; tumour suppressor protein that prevents excessive cell growth by inhibiting cell cycle progression until a cell is ready to diide
Binding of HPV E6 to p53 results in
promotion of p53 destruction which prevents p53-triggered apoptosis in cells with damaged DNA
Binding of HPV E7 to Rb results in
disruption of its ability to halt cells at restriction point between G1 and S phase of the cell cycle; allows neoplastic cells to proliferate
The transformation zone marks
junction between cervical squamous epithelium of external cervix with glandular epithelium of the endocervical canal
If no squamous dysplasia is seen but koilocytic change is seen in nuclei on histopathology, the diagnosis is
cervical or flat condyloma; koilocytosis reflects changes in the nuclei consistent with HPV infection of the cell
When dysplasia is present in epithelium in histopathology, the diagnosis is
cervical intraepithelial neoplasia, graded 1-3 (3 = carcinoma in situ)
CIN 3 can progress to
squamous cell carcinoma
HPV-related glandular lesions include
adenocarcinoma in situ and adenocarcinoma (no 1-3 grading)
What is the histological appearance of a cervical condyloma?
squamous epithelium is significantly thickened with papillomatous appearance; parakeratosis (dead keratinocytes with nuclei) and koilocytosis
What is the histological appearance of a flat condyloma?
Koilocytes
Koilocytes appear as
Atypical keratinocytes (HPV infected); have enlarged, darker/hyperchromatic nuclei with irregular nuclear outlines in a hap-hazard non-layered arrangement with nuclei throughout all layers instead of waning off towards superficial layers as in normal keratinocytes
What is the histological appearance of CIN 1?
atypical changes (nuclear pleomorphism, overlapping nuclei, disordered nuclear architecture, nuclear enlargement, nuclear hyperchromasia) occurring at the lower 1/3 of the squamous epithelium
What is the histological appearance of CIN 2?
Atypical changes involving the middle 1/3 of the squamous epithelium
What is the histological appearance of CIN 3?
Atypical changes involving the full thickness of the squamous epithelium (anywhere above 2/3rds)
CIN 2 and CIN 3 are ______ lesions with a high chance of progressing to
high-grade; invasive squamous cell carcinoma
Normal squamous mucosa epithelium shows
squamous epithelium at the top with endocervical glands in the stroma
What is the histological appearance of invasive squamous cell carcinoma?
irregular nests of glands arranged haphazardly within the stroma with infiltrative margins
What is the histological appearance of normal glandular epithelium?
Basal nuclei with abundant cytoplasm, no mitoses
What is the histological appearance of adenocarcinoma in situ?
haphazard, atypical nuclei, loss of cell polarity, numerous mitoses, some apoptotic debris amongst epithelial cells, nuclear pleomorphism
What is the histological appearance of adenocarcinoma on low power?
Extensive glandular proliferation with stromal reactivation around invasive glands; infiltrative and destructive pattern of invasion
What is the histological appearance of adenocarcinoma on high power?
atypical cells with enlarged nuclei and decreased cytoplasm; coalescence of glands into cribiform structures or micro-papillary formations
In cytology, low-grade squamous intraepithelial lesions encompass
HPV, CN1, or both
What is seen on cytology of low-grade squamous intraepithelial lesions?
koilocytes with binucleation, cytoplasmic clearing, and irregular hyperchromatic nuclei
In cytology, high-grade intraepithelial lesions encompass
CN2 and CN3
What is seen on cytology of high-grade squamous intraepithelial lesions?
Worse cytological atypia: markedly enlarged nuclei with minimal cytoplasm, significant hyperchromacy, significant pleomorphism
What would be seen on cytology of a high-grade lesion that would suggest squamous cell carcinoma?
cytology resembles HSIL; presence of necrotic debris in background sways dx to invasive squamous cell carcinoma
What is the cytological appearance of adenocarcinoma and adenocarcinoma in situ?
trying to retain glandular structure but nuclear atypia is significant with hyperchromasia and feathering of nuclei at edges
What is the normal cytological appearance of glandular epithelium?
picket fence of glandular structures with visible columnar outlines
HPV vaccine is designed against which proteins?
late proteins for the capsid - without them the HPV cannot gain access into the cell
Unsatisfactory smears are recommended to be repeated
after 6-12 weeks
Diagnosis of a definite or possible LSIL on smear is repeated
12 mo; if negative, in another 12 mo then back to routine (2 yrs); if LSIL again or HSIL refer to gynaecology for colposcopy
Lesions that mimic cervical dysplasia include
squamous metaplasia or reactive changes in squamous epithelial cells that appear with nuclear enlargement, prominent nucleoli, irregular nuclear outlines
