ERS30 Pathology Of Female Genital Tract Flashcards
Embryological development
- Gonads covered by Coelomic epithelium (Mesothelium)
—> Ovaries - Müllerian ducts
—> Fallopian tube
—> Uterus (Corpus + Cervix)
—> Upper vagina - Urogenital sinus
—> Lower vagina
(—> Produce similar pattern of diseases?)
Vulva, Vagina, Cervix pathologies
- Inflammation
- Non-neoplastic epithelial disorders
- Neoplasia
Clinical presentation:
- Pruritis vulva
- Leukoplakia
- Mass
Vulva + Vagina: Inflammation
~ Male genital tract
- Non-STD infection
- UTI
- Candida albicans - STD
- e.g. Herpes infection, Syphilis, Gonorrhea
- Effects and complications ***NOT confined to genital tract (spread to systemic involvement)
Vulva: Non-neoplastic epithelial disorders
- Prone to many skin disease seen in other body parts
- Specific to Vulva
- ***Lichen Sclerosis (whitish, thin epithelium, band of chronic inflammatory cells)
—> Atrophic + Friable skin, mucosa
—> fissures, adhesions, introital (vaginal opening) stenosis
—> Hyperkeratosis with thinning of epidermis + Flattening of dermo-epidermal junction
—> Hyalinisation of upper dermal collagen with subjacent band of chronic inflammatory cells - ***Squamous hyperplasia
—> Hyperplasia of stratified squamous epithelium with no specific dermatological diagnosis
Cervix: Non-neoplastic epithelial disorders
- **Endocervical Polyp
- common lesion
- single <1cm diameter
- usually asymptomatic but may result in vaginal bleeding / discharge
Vulva + Vagina + Cervix: Neoplastic
Classification:
1. **Squamous Intraepithelial Lesion (SIL)
- VIN (Vulvar) / VAIN (Vagina) / CIN (Cervical)
- Current classification (Cytology: Bethesda system / Biopsy: WHO)
- **Squamous precursor lesions
- Low grade (e.g. Condyloma / Koilocytosis —> CIN grade 1)
- High grade (e.g. CIN grade 2-3)
—> grade depend on ***thickness of epithelium involved by dysplastic squamous cells
- Dysplastic cells show malignant features: ↑ nuclear/cytoplasmic ratio, nuclear pleomorphism, ↑/abnormal mitotic figures
- Regress (some low grade may spontaneously regress) / Progress to invasive carcinoma / Remain stationary
VIN:
- Classic VIN (associated with high risk ***HPV infection)
- Differentiated VIN (associated with ***chronic irritation e.g. Lichen sclerosis / Squamous hyperplasia)
CIN:
- from ***Transformation zone of cervix (Glandular —> Stratified squamous)
- may progress to ***SCC of cervix over years (basis of cervical cancer screening)
(2. Condyloma (HPV-related changes)
—> Cervical Intraepithelial Neoplasia (CIN: grade 1 —> 3)
- Past
- Normal —> mild dysplasia —> moderate —> severe —> carcinoma-in-situ —> invasive carcinoma)
- **Types of Neoplasia:
1. SIL (Preinvasive)
2. SCC (Invasive)
3. Adenocarcinoma (Invasive)
4. Metastatic
***HPV-related Neoplasia + Warts in lower genital tract
Warts:
-
**Condyloma acuminata (anogenital wart)
- **papillomatous lesions: covered by ***Stratified squamous epithelium - Condyloma planum (flat)
Histology:
- ***Koilocytes (enlarged nucleus, perinuclear halo, thickened cytoplasmic border)
Neoplasia:
Preinvasive precursors:
- Squamous Intraepithelial Lesion (SIL) / Vulvar/Vaginal Intraepithelial Neoplasia (VIN/VAIN)
- Low / High grade SIL
Invasive cancers:
- Invasive SCC
- Basaloid / Warty SCC from Classific VIN
- Keratinising SCC from Differentiated VIN
- extend locally / lymphatic spread —> inguinal —> pelvic LN
- associated with second malignancy (usually cervical: SIL / Invasive) - Adenocarcinoma
- Vagina: secondary tumour more common
- Primary adenocarcinoma in young girls —> associated with Vaginal adenosis, Intrauterine DES (diethylstilboestrol) exposure
- Vulva: Extramammary Paget’s disease (in-situ adenocarcinoma)
- Cervix - Others (including metastasis)
Cervical Cancer incidence and Mortality rate
- ↓ in HK
- 7th commonest cancer in HK female
- incidence ↑ with age, peak at 40-50 yo
Cervix: Carcinoma
- ***SCC (most common)
Gross:
- Early lesions: Focal induration, Shallow ulceration, Slight granularity
- Advanced lesion: Exophytic / Endophytic (infiltrating into stroma without obvious lesion)
Histology (SCC):
- Keratinising / Non-keratinising
Spread: - Local: —> Contiguous pelvic structures —> Ureteric involvement —> cause obstruction and subsequent renal failure - Regional / Distant LN
-
**Adenocarcinoma
- from **Endocervical epithelium (Simple columnar: vs Ectocervix: Stratified squamous)
—> May have Intra-epithelial phase, Glandular dysplasia, Adenocarcinoma-in-situ
- ***HPV-associated: Abundant intracytoplasmic mucin, Apoptotic bodies, Diffusely positive with p16
HPV status of cervical cancers characterised by:
1. **HPV molecular testing —> detection + genotyping of HPV
2. Surrogate marker **p16 immunohistochemistry
—> more accurate evaluation of impact of HPV testing, HPV vaccination in cervical cancer prevention
—> new classification:
- SCC/Adenocarcinoma, HPV-associated
- SCC/Adenocarcinoma, HPV-independent
- SCC/Adenocarcinoma, Not otherwise specified
Etiology of Cervical carcinoma
Risk factors:
- ***HPV (carcinogen) —> ~99% association
- Oncogenes
- early marriage and pregnancy
- increased parity
- sexual promiscuity
- STD
- smoking
- low socioeconomic status
- immunocompromised state
- Interaction between **HPV oncogenes and host **Tumour suppressor genes (e.g. p53, retinoblastoma gene) is involved
- Relationship between men with penile warts and presence of SIL in their partners
HPV genotypes
- > 100 types
- ~30-40 Anogenital
Low risk HPV:
- ***HPV6, 11
- Non-oncogenic
—> lead to Anogenital warts (Condyloma acuminata / planum) + LSIL
High risk HPV:
- ***HPV16 (50% cervical cancer), 18 (20% cervical cancer)
- ~15-20 Oncogenic
—> lead to High grade SIL, SCC, Adenocarcinoma
HPV infection
- Common (nearly all sexually active men / women)
- Only a portion infected will progress to cancer
- HPV infection ***necessary but not sufficient factor for Cervical cancer
Prevention of Cervical cancer
One of most preventable cancers
Primary prevention (Prevent development of cancer)
- ***HPV vaccination
- Avoid risk factors
Secondary prevention
- ***Cervical Exfoliative cytology —> then Colposcopy and Biopsy
- ***HPV test screening
- Detect pre-invasive lesion (i.e. SIL)
—> ***treatment of SIL
—> prevent further progression to invasive cancer - Detect early invasive cancer
—> slow progression
—> ***reduce complications, improve clinical outcomes
N.B.:
- HPV vaccines will affect preventive strategy for cervical cancer
- ***Screening should be continued as Vaccines will not protect against HPV types not covered in vaccines
- Implementation of HPV vaccination in young women will not impact older groups initially
Detection of cervical cancer
- ***Exofoliative cytology of cervical squamous epithelial cells (塗片檢查)
- “Pap smear”
- convenient, inexpensive
- scrape squamo-columnar junction
- taken from Transformation zone —> between Endocervix (Glandular) and Ectocervix (Stratified squamous)
- Screening
—> if have HSIL in cytology —> referred for Colposcopy / Biopsy -
**Colposcopy and **Biopsy (Cone/Lip biopsy to excise Transformation zone)
- by Gynaecologist
- Observe changes in surface epithelium, vascular pattern
- Directed biopsies
- Assess ***extent of disease
- Diagnosis
Success of cervical cytology screening
Screening index ↑ —> Incidence ↓
Reasons:
1. Cervix ***easily accessible to cytological sampling (vs other inaccessible organs e.g. ovaries)
- ***Long period of progression from precursor lesion to invasive cancer
- from LSIL (CIN1) to HSIL (CIN2, 3) (progressive dysplasia) (CIN3: carcinoma-in-situ in old days) (absence of stromal invasion / dissemination)
—> take many years - ***Cost effective cytology test
- ***Early treatment is effective
Natural history of SIL
Stationary / Regress / Progress to invasive SCC (within 2-10 years)
LSIL: **60% regress, 30% persist, 10% progress
HSIL: 30% regress, **60% persist, 10% progress
HPV vaccination
- ***Prophylactic vaccines (prevent HPV (re)infection, but cannot cure/remove HPV-infected individuals)
- **Bivalent / Tetravalent vaccines:
- protect against HPV 16, 18 (i.e. 70% of CA cervix)
- **9-valent (Nonavalent) HPV vaccines:
- Oncogenic: 16, 18, 31, 33, 45, 52, 58 (90% CA cervix)
- Non-oncogenic but cause most Condyloma: 6, 11 (***包埋Condyloma HPV)
- Therapeutic vaccines (in clinical trials)
Uterine Corpus pathologies
Endometrium:
- Inflammation
- Acute / Chronic (plasma cell infiltrate)
- related to abortion, parturition, retained products of gestation, pelvic inflammatory disease, IUD users, TB - Endometrial polyp
- local overgrowth of endometrium —> may cause abnormal bleeding
- rare malignant change - ***Endometrial hyperplasia
- see next - ***Endometrial carcinoma
- see next - Tumour of endometrial stroma
- tumours with pure endometrial stromal features (e.g. Stromal Sarcoma)
- tumours with a combination of stromal (sarcoma) + epithelial (carcinoma) elements (e.g. Mixed Mullerian tumours) - Gestational Trophoblastic Disease (GTD)
- heterogeneous group of diseases arising from Trophoblasts
- complete / partial hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumour (PSTT), epitheloid trophoblastic tumour (ETT)
- Choriocarcinoma, PSTT, ETT are frank malignant tumours
- Hydatidiform mole may just be abnormal placentas prone to malignant transformation
Myometrium:
- Adenomyosis
- Leiomyoma (common)
- Sarcoma (rare) (e.g. Leiomyosarcoma)
Endometrial hyperplasia
Diffusely / Focally involved
Associated with ***↑ Estrogen
- ***endogenous Estrogen: Ovarian cyst / tumour (functioning Theca cell, Granulosa cell tumour), Repeated anovulatory cycles
- ***exogenous Estrogen: Tamoxifen (for breast cancer, estrogenic at endometrium)
Risk factors: obesity, diabetes, hypertension, infertility
2 types:
- Hyperplasia without atypia (low risk of progression to carcinoma)
- ***Atypical hyperplasia (considered as carcinoma precursor)
- cytological atypia present
- risk of progressing to carcinoma
Endometrial Cancer incidence and Mortality rate
↑ significantly in HK (esp. in Type 1 cancer category)
Endometrial cancer
2 types:
1. **Endometrioid (Type I) (90%)
- look like normal endometrium
- indolent
- Localised polypoid masses / Diffusely involve endometrial surface
- arise from **Atypical hyperplasia
—> often **Estrogen dependent (Associated with ↑ Estrogen: endogenous/exogenous)
- Risk factors: Tamoxifen, **Obesity, diabetes, hypertension, infertility
- Genetic: ***HNPCC syndrome (involve DNA repair genes) (prone to Endometrial cancer as well on top of Colorectal cancer)
- Spread:
—> Local: myometrium, parametrium, Fallopian tubes, ovaries, vagina, pelvis
—> LN: Para-aortic LN involvement (early)
- Special variants (Type II)
- Clear cell
- Serous
—> Estrogen-independent
—> Aggressive tumour with poor prognosis
Polycystic Ovaries and Endometrial cancer
Polycystic ovaries (Follicular cysts)
—> **Many Granulosa cells produce Estrogen
—> **High Estrogen
—> stimulate ***proliferation of endometrium
—> cancer development
Myometrium pathologies
-
**Adenomyosis
- Nests of **Endometrium (gland + stroma) embedded in Myometrium
—> these nests no communication with uterine cavity
—> **blood accumulation
—> painful symptoms, palpable mass
- Uterus enlarged with faintly whorled look on cut surface
- Small **blood-containing cysts spaces may be present
- Menorrhagia / Dysmenorrhea present
Smooth muscle tumours
- Leiomyoma (benign, common)
- one of most common tumours
- multiple
- subserosal / submucosal / intramural sites
- **effect on fertility / pregnancy
- ↑ in size during pregnancy, ↓ after menopause
- well-circumscribed spherical nodules + white whorled appearance
- **bundles of smooth muscle + some fibrous tissue - Leiomyosarcoma (malignant, rare)
- less well-demarcated
- necrosis + haemorrhage
- ↑ cellularity, cytological atypia, mitotic figures
Fallopian tube patholgies
- Salpingitis (Inflammation)
- impair fertility
- predispose to ectopic pregnancy
- Acute (ascending infection via uterine cavity) / Chronic / Granulomatous (TB Salpingitis due to haematogenous spread) - Ectopic pregnancy
- surgical emergency (rupture of tubal pregnancy —> bleeding)
- at Ampulla (most common)
- Chorionic villi of placenta, Trophoblast (Cytotrophoblast + Syncytiotrophoblast) proliferation seen in Fallopian tube —> permeate tubal wall - Endometriosis
- abnormal foci of endometrial glands, stroma in tubes (not supposed to be there) - Carcinoma (cause of cancer spreading to ovary / peritoneum)
- Primary carcinoma rare
—> Must exclude Metastasis from genital / extragenital sites
- often diagnosis made only at Laporatomy
- usually Papillary Adenocarcinoma
Ovary pathologies
- Inflammation
- ***Non-neoplastic cysts
- commonest cause of ovarian enlargement
- often asymptomatic
- torsion may occur —> haemorrhagic infarction + pain
- rupture —> hemoperitoneum
- abnormal production of Estrogen / Gonadotropic hormones —> hormonal effects
- Germinal inclusion cysts, Follicular cysts, Corpus luteum cysts, Theca lutein cysts
—> lined by Simple epithelium / Granulosa cells / Theca cells
—> without / without Luteinisation
Example:
- **Ovarian endometriotic cyst (lined by endometrial gland, stroma —> able to respond to hormone and proliferate —> shedding —> bleeding —> collection of altered blood in cyst: **“Chocolate cyst”)
- **Follicular cyst (lined by Granulosa cells —> can **produce Estrogen —> Endometrial cancer)
- Endometriosis
- Ovarian neoplasia
- **Epithelial tumours (Coelomic epithelium) (60% overall, 80% primary malignancy)
- **Germ cell tumours
- Sex cord-Stromal tumours
- Miscellaneous e.g. Lymphoma, Tumours of mesenchymal origin (affect other parts of body)
- Metastatic tumours
Epithelial tumours of Ovaries
60% overall, 80% primary ovarian malignancy
Young patients:
- mostly Benign / Borderline tumours
- invasive tumours less common <40 yo
Clinical presentation:
- Pelvic mass S/S
- Early detection by screening is difficult
Staging:
- depends on presence of capsular / contralateral ovary involvement, malignant ascites, nodal, pelvic, intraperitoneal / distant metastasis
2 Broad groups:
- ***Type I carcinoma (Mucinous, Endometrioid, Clear cell, Low grade Serous)
- Develop from benign / borderline tumour -
**Type II carcinoma (High grade Serous)
- Arise De novo, may develop from tubal fimbrial epithelium
- harbours **p53 mutations
- more associated with ***BRCA mutations
Classification: Type of malignancy: 1. Benign 2. Borderline 3. Malignant
- **Histological:
1. Mucinous (~Endocervix: glandular epithelium) - ~ Endocervical glandular epithelium
- associated with Pseudomyxoma peritoneii +/- Co-existing Appendiceal lesion
- see next
- Serous (~Tube)
- ~ Fallopian tube +/- Psammoma bodies (calcified spherules)
- Bilateral +/- Peritoneal lesions
- Low / High grade
- see next - Endometrioid (~Corpus)
- ~ Endometrium
- +/- Co-existing Endometriosis / Concurrent Endometrioid carcinoma of endometrium - Brenner (~Urinary tract)
- Benign form (commonest): round masses of ***Transitional epithelium surrounded by Ovarian stroma - Clear cell
- in form of Clear cell carcinoma
- Poorer prognosis - Seromucinous
- Undifferentiated
Ovarian cancer risk factors
Genetic predisposition:
- Breast and Ovarian cancer syndrome (***BRCA1/2 mutation: tumour suppressor genes)
- ***HNPCC syndrome (DNA repair genes) (lower risk)
Environmental:
Obesity (less strong association than Endometrial cancer)
Borderline tumour
Distinct entity, Good prognosis
Different from benign tumour:
- Presence of epithelial budding
- Increased mitotic activity
- Nuclear stratification and Atypia
Different from malignant tumour:
- Absence of destructive stromal invasion
Serous Epithelial tumours of Ovaries
Classification:
1. Benign
- Serous cystadenoma / adenofibroma / surface papilloma
—> Fallopian Tube-like
- Borderline
- Serous borderline tumour - Malignant
- Low-grade serous carcinoma
—> **Low proliferation (MIB1)
—> **Wild type p53
—> Do not respond well to platinum-based chemo
- High-grade serous carcinoma —> ***High proliferation (MIB1) —> ***p53 mutation often exists —> ***Associated with BRCA loss —> Usually respond well to platinum-based chemo (recurrence may occur)
Mucinous Epithelial tumours of Ovaries
Benign / Borderline / Malignant
Associate with Pseudomyxoma Peritonei:
- Difficult to treat
- Peritoneal cavity filled with abundant mucin (histology show mucinous epithelium)
Germ cell tumour of Ovaries
2nd largest group of Ovarian neoplasms behind Epithelial neoplasms
- **Heterogenous group of tumours (combinations may occur in a patient):
1. ***Teratoma (Mature, Immature, Malignant transformation) - see next
- Dysgerminoma
- ~ Seminoma
- young women - Embryonal carcinoma
- usually combined with other germ cell tumours - Choriocarcinoma
- usually combined with other germ cell tumours - Yolk sac tumour / Endodermal sinus tumour
- young female - Mixed
Children, Adolescents: >60% of Ovarian neoplasms, 1/3 Malignant
Adults: mostly Benign: ***Mature cystic Teratoma (most common germ cell tumour)
Germ cell (Oogonia —> Dysgeminoma)
—> Totipotent cell
—> (Embryonal carcinoma: transition state between primitive / differentiated tumour)
—> Extra-embryonic tissue
1. Trophoblast (placenta) (Choriocarcinoma)
2. Yolk sac / Endodermal sinus (Yolk sac tumour / Endodermal sinus tumour)
OR
—> Embryonic tissue (i.e. Ectoderm, Mesoderm, Endoderm) (***Teratoma —> major difference in Male / Female)
Teratoma of Ovary
Vs Teratoma of Testes
- Similar morphologically
- Different clinically from Teratoma of Testes
Male Teratoma: Malignant
Female Teratoma: ***Mature Cystic Teratoma —> Benign
- Mature Cystic Teratoma (most common germ cell tumour)
- still need to be treated ∵ complications e.g. torsion, rupture, malignant change (2%, usually SCC) - Immature Teratoma
- Teratoma with malignant transformation e.g. SCC
Sex cord-Stromal tumour
Sex cord:
- Sertoli cells (Seminiferous tubules)
- Granulosa cells (Graafian follicles)
Stroma:
- Leydig cells
- Theca cells
-
**Granulosa cell tumour
- Low grade
- Indolent
- all ages, most commonly after menopause
- Solid / Cystic tumour with Granulosa cells forming follicles / trabeculae
—> Grooved nuclei “coffee-bean appearance”
—> can produce **excessive Estrogen
—> Children: Precocious puberty, Adult: Endometrial hyperplasia / adenocarcinoma - Thecoma-Fibroma
- Benign
- from Ovarian stromal cells
- Spindle cells ~ Fibroblasts / Polygonal cells ~ Theca cells - Ovarian Sertoli Leydig cell tumour
- Malignant
- ***Androgen secreting
—> Virilisation, Breast atrophy, Hirsutism, Amenorrhea, Receding hairline
These tumours can be found in BOTH testes / ovaries
Metastatic tumour of Ovaries
Most commonly from Breast, Lower genital tract, GI tract
Extra-genital sites - colon - stomach —> Krukenberg tumour: metastatic adenocarcinoma from stomach, Mucin-filled Signet ring cells - breast - lung - etc.
