Endometrium Flashcards
Stages of Endometrium
Secretory phase
Relatively pink appearance at low power
Convoluted, irregularly shaped glands
Single layer of columnar or cuboidal cells in glands
Early secretory phase (Day 17 - 19)
Day 17: Continuous and well developed subnuclear vacuoles in > 50% of a gland, rare mitoses
Day 18: Sub- and supranuclear vacuoles (piano keys) with nuclei in the center of cell
Day 19: Nuclei at base of cell, supranuclear vacuoles, start of luminal secretions
Mid secretory phase (Day 20 - 22)
Day 20: Maximal intraluminal secretions, stromal cells with hyperchromatic nuclei and high N:C ratio
Day 21: Increased stromal edema
Day 22: Peak stromal edema
Late secretory phase (Day 23 - 27)
Day 23: Predecidua surrounds spiral arterioles
Day 24: Predecidua bridges multiple vessels
Day 25: Thin band of predecidua beneath endometrial surface
Day 26: Thick band of predecidua beneath surface
Day 27: Abundant predecidua expanding downward from endometrial surface, increased number of stromal granulocytes
Menstrual phase
Endometrial stromal breakdown: dense round aggregates of stromal cells admixed with inflammatory cells and blood
Papillary syncytial metaplasia is common, thought to be a reparative response
Decidualisation
- Progesterone-mediated
- Transitory change of stromal cells
- Seen in pregnancy
- Seem in progesterone drugs
Cervical Deciduosis:
* Ectopic decidual tissue outside of the uterine cavity
* Multiple small, yellow/red elevations of cervical mucosa
* Clinical history of pregnancy is important –> avoid misdisgnosis of dysplasia
* Resolves spontaneously within 4-6 weeks postpartum
Micro:
* Ulcerated endocervical and ectocervical mucosa
* Sheets of cells
* Abundant pale granular cytoplasm
* Bland nuclei
* Stromal lymphoplasmaxytic infiltrate
Arias-Stella Reaction
- Benign condition
- Typically regresses post-partum
Associated with:
* Pregnancy
* Gestational Trophoblastic disease
* OCP
* HRT
* High dose progestin for endometrial hyperplasia/LG endometrial carcinoma
Micro:
* Enlarged nuclei
* Intense subnuclear and supranuclear vacuoles
* Normal N:C ratio
* Intraglandular tufts
* No mitosis/apoptosis
Endometrial Polyp
Clinical Features:
* Middle aged and post-menopausal women
* Abnormal bleeding
* Increased incidence with HRT
* Commonly associated with tamoxifen
Macro:
* Most commonly in the fundus
* Broad-based and sessile, pedunculated or slender stalk
Micro:
* Irregularly outlined glands that may be out of phase with the endometrium
* Fibrovascular stalk/Fibrous stroma with several thick-walled vesels
* May have metaplastic epithelium –> often squamous
Tamoxifen and the endometrium
- Widely used as adjuvant therapy in management of breast ca.
- Oestrogen receptor antagonist in breast
- Oestrogen receptor agonist in endomretrium
- May exert a proliferative effect on the endometrium
- Risk increases with increasing duration and dosage
Effects:
* Benign polyps
* Stromal fibrosis
* Stromal condensation around glands
* Endometrial hyperplasia
* Endometroid and non-endometroid carcinomas
Note - Tamoxifen associated polyps should be extensively sampled
Endometrial Hyperplasia
Hyperplasia without atypia
* Low level somatic mutations in scattered glands
* <1% coexistent invasive endometrial carcinoma
* Relative risk to progression to invasive ca –> 1.01
Atypical Hyperplasia / Endometroid intra-epithelial neoplasia
* Genetic changes typical for endometroid endometrial Ca.
* Micro satellite instability
* PAX2 inactivation
* PTEN
* KRAS
* CTNNB1 (beta-catenin)
* 25-60% coexistant invasive endometrial carcinoma
* Relative risk to progression to invasive ca –> 14 to 45
Endometrial Carcinoma
TYPE 1
- 55-65 years
- Clinical Setting:unopposed oestrogen, obesity, Tamoxifen, HTN, Diabetes
- Morphology: Endometrioid
- Precursor: Hyperplasia
- **Mutated genes: **PTEN, ARID IA, PIK3CA, KRAS, FGF2, CTNNB1, POLE, TP53
- Behaviour: Indolent, Spreads via lymphatics
TYPE 2
- 65-75 years
- Clinical Setting: Atrophy, Thin physique
- Morphology: Serous, Clear Cell, Mixed Mullerian Tumour
- Precursor: Serous endometrial intraepithelial carcinoma
- **Mutated genes: ** PIK3CA, FBXW7, CCNE1, PP2A, TP53
- Behaviour: Aggressive, Spreads via lymphatics and intraperitoneal
Other Risk Factors:
Ovarian pathology:
* Polycystic Ovarian Syndrome
* Stromal hyperplasia and hyperthecosis –> stromal luteinisation –> hyperandrogenism –> hyperoestrogenism
* Hormonal secreting stromal tumours –> granulosa cell tumour, thecoma
Inherited Cancer Syndromes:
* HNPCC / Lynch syndrome –> Mismatch repair proteins
* Cowden –> PTEN tumour suppressor gene
Other:
- Infertility
- Muir-Torre Syndrome
- Turner Syndrome
Lynch Syndrome and Screening
- Universal screening for all endometrial carcinomas for Lynch syndrome
- Endometroid and clear cell
- Serous carcinoma screening is controversial
Histological features of lynch syndrome associated endometrial carcinoma:
- Most are endometrioid
- Most commonly in lower uterine segment
- Associated with tumour infiltrating and peritumoral lymphocytes
- Association with dedifferentiated and undifferentiated histotypes
Molecular Classification of Endometrial Carcinomas
POLE mutation
* mutations in DNA polymerase e
* High burden of somatic mutations –> most are passenger mutations
* Morphologic ambiguity, high grade nuclear features
MMR Deficient
* Hypermutated / Microsatellite Instabilty Tumours
* Dense peritumoral lymphocytic inflammation
* High burden of somatic mutations
No specific molecular profile (NSMP).
* p53 wild type
* Low grade features
p53 Mutated
* Mutations in the TP53 gene and abnormal expression of p53 protein
Endometrioid Carcinoma
- High vs Low grade
Metastasis
* LG –> uncommon
* HG –> LNs and Distant Organs
Prognosis
* LG –> Favourable
* HG –> Poor
Micro:
* Glandular or villoglandular architecture
* Lined by stratified columnar epithelium
* Nuclear atypia is usually mild to moderate
* Variable mitotic index
* Areas of squamous differentiation seen
IHC:
Positive:
- PAX8
- CK7
- ER / PR
- Vimentin
Negative:
- p53 wild type (patchy and weak expression in scattered nuclei)
Caveat: high grade (FIGO 3) tumors can show aberrant expression - p16 mosaic (patchy and weak nuclear / cytoplasmic expression)
- CK20
- CEA
- HNF-1B
- Napsin A
Serous Carcinoma
- High grade
- Post menopausal women
- Often arises in endometrial polyps
- BG endometrium often atrophic
- Possible associated with BRCA1/2 mutations
Prognosis:
* Worse prognosis than endometrioid carcinoma
* Can present at high stage
Micro:
* Complex papillary architecture
* Large atypical nuclei, prominent nucleoli, scant cytoplasm
* Numerous mitotic figures
* Myometrial invasion –> gaping glands
Molecular:
* Often TP53
* PI3K / AKT / mTOR and MAPK pathways
* ERBB2 (HER2) overexpression >30% –> often benefit from trastuzumab with carboplatin and paclitaxel regimen
IHC:
* p53: mutation type staining either strong and diffuse, complete absence of staining (“null type” pattern) or abnormal cytoplasmic localization
* p16: often strong and diffuse (not related to HPV infection)
* AE1 / AE3
* CK7
* PAX8: strong nuclear staining
* MLH1, MSH1, MSH2 and MSH6: typically retained but can show loss of at least one marker in 10% of cases
Clear Cell Carcinoma
- <5% all endometrial carcinomas
- Older, postmenopausal women
- Rarely associated with Lynch Syndrome
Micro:
* Polygonal/hobnail shaped cells
* Clear cytoplasm
* Tubulocystic, papillary or solid architecture
* Prominent nuclear atypia
* Numerous mitotic figures
* Extracellular globules or hyaline bodies
IHC:
* CK7
* EMA
* PAX8
* HNF1β: sensitive but not specific
* Napsin A
* AMACR: specific but not sensitive
Adenosarcoma
- Mixed epithelial and mesenchymal tumour
- Epithelial –> benign
- Stroma –> LG malignant
- Uterine corpus > Cervix > Ovary/Pelvis
- Cervical primaries –> Younger
- Corpus and Ovarian –> Postmenopausal
- Generally behave benign, but have local recurrence risk
Micro:
* Papillary/Polypoid projections of cellular stroma
* Dilated gland lumens
* Collaring around benign surface glands –> ‘Cambium’ layer
* Stroma resembles endometrial stroma but is often more fibroblastic
Molecular:
DICER1 mutations in 50% cases
IHC:
Stroma:
* CD10
* ER
* PR
Prognostic Factors:
* Presence of sarcomatous overgrowth –> recurring potential, more aggressive
* Histologic grade
* Depth of myometrial invasion
Carcinosarcoma
- Biphasic tumour
- HG carcinoma (epithelial)
- Sarcoma (mesenchymal)
- Sarcomatous component is derived from the carcinomatous component – > due to metaplasia / Transdifferentiation
- Poor Prognosis –> Frequent pelvic recurrences and LN mets of carcinomatous component
Clinical:
* Post-menopausal women
* Vaginal bleeding
* Large pelvic mass that prolapses out of the cervix in 1/2 cases
Aetiology:
* Almost all are sporadic
* Tamoxifen use
* Pelvic radiation therapy
* Oestrogen exposure
* Nulliparity
* Diabetes
* Obesity
Molecular:
Frequent TP53 mutations
Micro:
* Admixure of carcinoma and sarcoma elements
* Carcinoma –> serous or endometroid carcinoma
* Sarcoma –> often HG, non-specific… can show rhabdomyosarcoma, chondrosarcoma, osteosarcoma
IHC:
Carcinomatous component:
* PAX8
* EMA
* Cytokeratin positive
* Aberrant p53 expression
Endometrioid components:
* ER, PR positivity
Sarcomatous component:
* Aberrant p53 expression
Rhabdomyosarcoma:
* desmin
* myogenin
Liposarcoma and chondrosarcoma:
* S100
Endometrial Stromal Neoplasms
Risk Factors:
Prolonged Oestrogen or Tamoxifen use
Pelvic radiation
Types:
Endometrial Stromal Nodule
- Benign
- Resembles proliferative endometrial stroma
- Well-circumscribed margin
Low grade Endometrial Stromal Sarcoma
High grade Endometrial Stromal Sarcoma
Undifferentiated Stromal Sarcoma
- Diagnosis of exclusion
- Malignant mesenchymal tumour of uterus
- TP53 mutations
- Complex copy number alterations
