Gynae Flashcards
Define leukoplakia
Opaque, white, plaque like epithelial thickening
Can be due to a variety of non malignant and malignant causes
What is the most common histological type of vulval cancer
SqCC
What are the two groups of vulval SqCC. Which is associated with HPV
-Basaloid and warty carcinomas; high risk HPV related (HPV16)
-Keratinizing SqCC: non HPV associated. More common, accounting to 70% of cases
What precursor lesions to vulval basaloid and warty carcinomas arise from
VIN: vaginal intreaepithelial neoplasia
What are the risk factors for CIN and VIN
Early age first sexual intercourse, multiple sexual partners, male partner with multiple sexual partners (all related to early HPV exposure)
What are some histological features of vaginal keratinizing SqCC
Keratin pearls
Nests and tongues of squamous epithelium
What abnormalities are typically precursors to keratinizing SqCC of the vulva
Lichen sclerosis
Squamous cell hyperplasia
Which lead to differentiated VIN (vulval intraepithelial neoplasia)
What subtype of endometrial carcinoma is most commonly associated with dMMR?
Endometrioid
What is the recommended method to test for dMMR
IHC for MLH1, MSH2, MSH6, PMS2.
Testing for micro satellite instability is more complicated and expensive
Is endometrial or ovarian cancer more common in women with Lynch syndrome?
Endometrial
What testing should be done if there is a loss of MLH1/PMS2 expression on IHC
MLH1 promoter methylation.
This is relevant to both endometrial cancer and to colorectal cancer. MLH1 is the MMR gene most commonly affected by epigenetic changes
Why do all 4 endometrial markers need to be tested concurrently
They are not mutually exclusive, and it is relevant to know if a patient is a ‘double classifier’
What are the histological subtypes of endometrial carcinoma, and which ones are never classified as low risk
Endometrioid
Higher risk:
-serous
-clear cell
-carcinosarcoma
-undifferentiated carcinoma
-mixed
What pathological features are prognostic in endometrial carcinoma
Any myometrial invasion
Histological subtype
Grade
LVSI
What are the FIGO grades of endometrial carcinoma
Low: grade 1 and 2
High: grade 3
How are cervical pre-invasive lesions classified
LSIL (CIN1) low grade squamous intraepithelial lesion
HSIL (CIN2-3) high grade squamous intraepithelial lesion
What is the natural history of cervical LSIL
Most cases will regress spontaneously. They do not progress directly to cervical cancer, instead if the progress they will progress to HSIL.
The natural history from high risk HPV infection to cervical cancer usually takes many years/ decades.
What is the highest risk HPV. What percentage of cervical cancer is caused by it
HPV16. 60% of cervical cancer
How can HPV viral load be measured in a cervical biopsy
In situ hybridisation for HPV DNA
What are the microscopic abnormalities in cervical SIL. How is LSIL distinguished from HSIL
Hyperchromatic basal-like cells
Hyperchromatic, Pleomorphic nuclei, Nuclear enlargement
Increased N:C ratio
Cytoplasmic halo around nucleus (koilocytic atypia)
Mitosis
HSIL: loss of differentiation
LSIL has this change only in the basal third of the epithelial thickness. Mitosis confined to lower third
Other than squamous cell carcinoma, what other types of cervical cancer can occur. Which others are HPV associated
All are Caused by high risk HPV
Adenocarcinoma (15%)
Neuroendocrine (rare)
Adenosquamous (rare)
Neuroendocrine and adenosquamous have a shorter natural history, and often present with more advanced disease.
What is the defining feature of endometrial hyperplasia
Increased gland to stroma ratio
Which signalling pathway most commonly has mutations in endometrioid endometrial carcinoma
PI3K/AKT
What suppressor of the PI3K/AKT pathway is often mutated in endometrioid endometrial carcinoma
PTEN
What grade are serous endometrial carcinomas by definition
Grade 3
What are the two types of endometrial intraepithelial hyperplasia, and what is the main difference
Typical endometrial hyperplasia
Atypical endometrial hyperplasia (nuclear atypia)
What is the typical state of a uterus in which serous endometrial carcinoma arises
Atrophic , ie thin layer of endometrium
What type of growth pattern does endometrioid endometrial carcinoma have
A glandular growth pattern.
-well differentiated: almost entirely well formed glands
-moderately differentiated: <50% solid sheets of cells
-poorly differentiated: >50% solid sheets of cells
What is the typical microscopic growth pattern of serous endometrial carcinoma
Papillary growth pattern
Marked cytology all atypia, high nuclear to cytoplasm ratio, atypical mitotic figures, hyperchromasia
What are the microscopic features of uterine carcinosarcoma
A mix of adenocarcinoma cells (endometrioid, serous or clear cell) and mesenchymal/ sarcomatoid cells.
What are the benign and malignant neoplasms of the myometrium
Benign: leiomyoma (fibromas)
Malignant: leiomyosarcoma
What is the typical microscopic appearance of lyomyoma?
Smooth muscle cells that resemble normal myometrium
Uniform size and shape with small oval nuclei. Scarce mitotic figures
What genetic abnormalities do uterine leiomyosarcomas typically have
Complex karyotypes with frequent deletions
Microscopically what differentiates a leiomyoma from a leiomyoscarcoma
Nuclear atypia, high mitotic index (10+ mitosis per 10 high power field), necrosis
What are the three broad types of ovarian carcinoma based on the ovarian component that they arise from
Surface epithelial-stromal tumours
Sex cord-stromal tumours
Germ cell tumours
What are some examples of ovarian surface epithelial/stromal neoplasms.
Note that within each type they are divided into benign, borderline and malignant neoplasms
Malignant types are generally adenocarcinoma
-serous (most common)
-clear cell
-endometrioid
-mucinous
-adenosarcoma (mixed epithelial-stromal)
Which malignant ovarian subtype is most likely to have bilateral tumours.
Serous
What are some risk factors for serous ovarian adenocarcinoma
Low parity
Family history (inherited mutations)
What distinguishes high grade from low grade serous ovarian adenocarcinoma
Degree of nuclear atypia
Where are the cells that give rise to high grade serous ovarian adenocarcinoma thought to arise
From the Fallopian tubes
Are low grade and high grade serous ovarian adenocarcinoma thought to have the same origins
No. High grade thought to arise from cells of the Fallopian tubes. They tend to have very different mutation profiles. p53 mutation rare in low grade, common in high grade
What is the implication of the theorised cell of origin of high grade serous ovarian adenocarcinomas when considering prophylactic surgery for BRCA mutation carriers
A salpingoophrectomy should be performed rather than just an oophrectomy
What is a typical pattern of metastatic spread of ovarian cancers
Peritoneal and mental spread (with resulting ascites)
What proto-oncogene is mutated in the majority of mucinous ovarian cancers
KRAS
What are the three main subtypes of germ cell tumour of the ovary
Yolk sac
Teratoma
Nongestational Choriocarcinoma
What are the three subtypes of teratoma of the ovary
Mature/Benign (dermoid cyst)
Immature/ Malignant
Monodermal/highly specialised
What are the characteristic gross appearances of a dermoid cyst
Cystic structure enclosed in a wall resembling epithelium (with sebaceous glands, hair follicles)
Can have areas of tooth, calcification, nerve, muscle etc
What is the nature of malignant transformation of benign teratoma
Can transform into a malignancy of any of the cell types it contains. Eg, thyroid cancer, melanoma, SqCC
What is the difference between mature and immature teratoma
Immature teratoma contains tissues resembling immature embryonal/ fatal tissues. Can have areas of necrosis and haemorrhage. Grade of immature teratoma is based on the percentage of immature neuroepithelium.
What tumour of the ovary is the equivalent of testicular seminoma. What group of tumour markers do they express
Dysgerminoma
Express stem cell markers.
Activating KIT mutations
What is a key difference in treatment response of placental/gestational vs ovarian/nongestational choriocarcinoma
Non-gestational is very resistant to chemotherapy and usually fatal
What is the utility of WT1 in ovarian malignancy
Positive in serous ovarian carcinoma, negative or positive in serous endometrial carcinoma
Negative in other subtypes of endometrial cancer
What is a pan-positive marker in tumours of gynae tract
PAX8
Ie tumours of mullerian origin
How are HSIL and LSIL of the cervix distinguished microscopically
LSIL involves immature squamous cells in the lower 1/3 of the epithelium thickness only
What is the precursor lesions to adenocarcinoma of the cervix
Adenocarcinoma in situ
What is the typical microscopic appearance of cervical SqCC
Nests and tongues of malignant squamous epithelium
Either keratinizing or not
Invade underlying cervical stroma
What are the four main families of ovarian tumours
Surface/epithelial (70%)
Germ cell (10%)
Sex cord-stromal (15%)
Metastasis (most commonly GI tract)
What are the 5 types of ovarian germ cell tumours
Dysgerminoma (equivalent of testicular seminoma)
Yolk sac
Choriocarcinoma
Teratoma
Embryonal carcinoma
What are the 5 types of ovarian epithelial/surface tumours
Clear cell -a/w endometriosis
Mucinous- must consider GI Mets
Brenner/transitional- resembles nests of bladder cells in fibrous stroma
Endometrioid- resembles endometrial glands. a/w endometriosis
Serous - resembles fallopian tubes
-low grade (BRAF/KRAS)
-high grade (p53/ genetic instability)
What are the three sublassifications of ovarian surface/epithelial tumours
Benign: Cystadenoma & adenofibroma
Borderline/low malignant potential
Malignant: Carcinoma
All of these come in the different types of epithelial tumour. Eg mucinous cystadenoma/adenofibroma
What must be done during pathological work up to distinguish borderline from malignant ovarian epithelial tumours
Must be well samples: more than 1 slice per cm
What is the natural history of the development of low grade serous ovarian tumours
Usually arise from serous borderline tumours
Present at younger age to high grade. (50’s vs 60’s)
Share the same IHC profile: ER/PR positive. KRAS/BRAF mutations. PAX8+, P53 wild type.
Don’t respond well to platinum chemo
What is the natural history of high grade serous ovarian carcinoma
Strong association with BRCA 1/2 mutation
Most originate in fallopian tube, then spread to ovary
Normal tube -> p53 mutation -> serous tubal intraepithelial carcinoma -> invasive high grade serous carcinoma of tube -> spreads to ovary
What are the microscopic features of high grade serous ovarian carcinoma
High mitotic rate
Pleomorphic nuclei
Irregular chromatin
Solid to papillary architecture with slit like spaces
What IHC stains can be used to distinguish a mucinous ovary tumour as primary vs metastatic from GI tract
CK7: strong positive ovarian, variable GI tract (sensitive but not specific for ovarian)
SATB2 strong positive lower GI tract, negative ovarian (sensitive and specific for GI)
PAX8: variable ovarian, always negative GI tract (specific but not sensitive for ovarian)
CDX2 variable in both
CD20 variable in both
What is the IHC profile of high grade serous ovarian carcinoma
p53 over expression or null
WT1 positive
p16 block positive
ER +/-
CK7 + CD20-
PAX8 +
What IHC profile will an ovarian Brenner/transitional tumour have
Urothelial immunophenotype.
Positive: P40, p63, HMWCK, CK20/7, uroplakin III
What is the difference between testicular and ovarian germ cell tumours
Not much! Use the same microscopic and IHC features.
Dysgerminoma = seminoma, both most common germ cell tumour for male/ female
= germinoma when in arises in the CNS, still same morphological features
What is the rate of progression from acute hpv infection to persistent infection to precursor lesions (LSIL) to invasive cervical carcinoma
10% rule. 10% risk of progression of each
(But once 10% of LSIL progress to HSIL the majority (70%) will then progress to invasive disease
What makes HPV 16/18 high risk for causing cancer compared to low risk variants such as 6/8
E7/E6 from low risk variants have lower affinity for Rb and p53
What is the rate of progression from cervical HSIL to invasive carcinoma
70% progression at 5 years old
What is the IHC pattern of cervical SqCC
p16+
Keratin+
P53 loss of expression (due to E6)
P63+
CK5/6+
CEA+
What is the typical IHC pattern of cervical adenocarcinoma, how does this differ from endometrial carcinoma
Cervical: p16+, CEA+ (100%), ER/PR- or weak, CK7+/CK20-, vimentin-
Endometrial carcinoma: CEA-, p16-, ER/PR+, vimentin +, CK7+/CK20-
Both PAX8 positive
What is the differential diagnosis for a cervical mass
Malignant:
-SqCC
-Adenocarcinoma
-adenosquamous
-small cell carcinoma (NETs extremely rare)
-lymphoma, melanoma, sarcoma, adenoid cystic
Benign:
-endocervical polyp
-cyst
-glandular hyperplasia
-endometriosis
What is the microscopic appearance of cervical metaplasia
Can closely resemble HSIL, but difference is:
p16-ve
Uniform chromatin
Minimal nuclear contour irregularities
More likely to have residual mucinous epithelium
What is the p16 status of cervical LSIL, and why
p16 negative
Because HPV DNA has not integrated into the host DNA in LSIL, and therefore E7 is not being over produced.
Note: p16 negative SIL extending 1/3-2/3 of epithelial thickness is classified as LSIL
What is the microscopic appearance of cervical squamous cell carcinoma
Keratinisation (but majority are non keratinizing)
Sheet like growth, bands and single cells
Desmoplastic/inflammatory stroma
What are the microscopic and IHC features of cervical adenocarcinoma in situ
Cell crowding, pseudostratification, mucin depletion
Enlarged, variable nuclei
“Floating” atypical mitosis
p16 diffuse positivity
Loss of ER/PR staining
What is the microscopic appearance of endocervical adenocarcinoma
Most well to moderately differentiated
Cribriform to papillary architecture
Mucin-poor glands
Psudostratified, enlarged, hyperchromatic nuclei
Frequent mitosis and apoptosis
What non HPV related adenocarcinoma can occur at the cervix
Gastric type
Much worse prognosis than hpv associated
Compare the microscopic appearance of usual type VIN versus differentiated VIN
Usual type: HPV associated; therefore most of the same appearances as cervical HSIL. Koilocytes etc. can get warty or basaloid subtypes
Differentiated: lichen sclerosis associated. Very subtle atypia. No viral associated atypia
What are malignant differentials for vulva lesions
SqCC (keratinizing or verrucous)
Bartholins gland adenocarcinoma
Melanoma
Merkel cell carcinoma
Sebaceous carcinoma
Rhabdomyosarcoma
Which type of VIN is more likely to progress to invasive malignancy
Differentiated VIN.
Usual type VIN left untreated has a 10-16% risk
What are the two aetiological pathways of development of vulval SqCC
HPV dependent: usual type VIN. Younger patients. Associated with basaloid subtype
HPV independent: differentiated VIN. p53 associated. Worse prognosis. Associated with verrucous subtype. Verrucous cause firm masses, well demarcated tumours lined by well differentiated squamous epithelium. Minimal atypia
What are two patterns of growth of vulval SqCC associated with higher risk disease
Spray pattern: fingers of tumour extending deeper than main tumour
Diffuse pattern: connected tumour of >1mm in dimension
What is the most common site of metastasis of vulval SqCC
Lung
What are the microscopic features of lichen schlerosus
An autoimmune condition most commonly affecting post menopausal women
-hyalinization of papillary dermis (homogenised collagen)
-band like lymphocytic infiltrate deep to homogenised collagen
-epidermal atrophy
What is the single most important risk factor for vulval SqCC
Lymph node involvement
What are the two main histological types of vulval SqCC
Keratinizing: associated with differentiated VIN (HPV neg) p16- p53 abnormal. Univocal
Basaloid: usual type VIN/ HPV associated. p53 neg, p16+. Histologically basal cells.
Both: desmoplasia or inflamed stroma (ie same as cervical SqCC)
What are the patterns of myometrial invasion for endometrial cancer
Single gland pattern (diffusely Infiltrative): most common, poor prognosis, a/w LVSI, high grade
Pushing/expansile pattern: good prognosis, difficult to distinguish from in situ
Adenomyosis-like pattern: good prognosis
MELF: microcystic, elongated and fragmented pattern, commonly associated with low grade endometrial
