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
Low Grade Endometrial Stromal Sarcoma
- Intermediate prognosis –> mostly depending on stage
Micro:
* Maligant
* Resembles proliferative endometrial stroma
* Infiltrative growth into the myometrium
* Lymphovascular invasion
* Tongue-like growth
Molecular:
* Jazzie Suzie
* JAZF1 and SUZ12 fusion
IHC:
* CD10
* WT1
* ER/PR
* Beta Catenin (nuclear staining without associated mutation
High Grade Endometrial Stromal Sarcoma
- Intermediate prognosis between LG endometrial stromal sarcoma and undifferentiated uterine sarcoma.
Micro:
* Maligant
* Endometrial stromal cells –> high grade round cell morphology
* Frequently myxoid
* Confluent, permeative, destructive growth
* High mitotic activity
* Necrosis
* Lymphovascular invasion
Molecular:
* YWHAE-NUTM2A/B fusions
* BCOR rearranged
* BCOR internal tandem duplication (ITD)
IHC:
* Cyclin D1+
* BCOR+
- CD10 -ve
- ER/PR -ve
- Desmin -ve
- Caldesmon -ve
- SMA -ve
Endometrial Stromal Nodule
Benign tumor composed of cells reminiscent of proliferative phase endometrial stroma with absent or minimal myometrial invasion (< 3 mm and < 3 protrusions) and lacking vascular invasion.
Features:
Benign tumor composed of cells reminiscent of proliferative phase endometrial stroma with absent or minimal myometrial invasion (< 3 mm and < 3 protrusions) and lacking vascular invasion
Can be cystic, have necrosis and hemorrhage
Excellent prognosis if completely excised.
Corpus > cervix > ovary
Gross description
Well circumscribed, nonencapsulated, soft, fleshy yellow, solitary lesion with size ranging from 1 - 12 cm
Tumors usually grow in an expansile, noninfiltrating pattern with a smooth margin
Rarely, can show some irregularities but no intravascular component
Usually located in the endometrial cavity (polypoid mass) but can also be seen in myometrium
Can be cystic
Can have necrosis and hemorrhage
Microscopic (histologic) description
Monotonous proliferations of bland endometrial stromal cells
Expansive growth pattern (not infiltrating) at the margin
Infiltration, if present, should be < 3 mm and < 3 protrusions
Usually prominent proliferative type arterioles and can sometimes show hyalinized walls
Collagen bands, plaques, infarct-like necrosis, hemorrhage and degenerative changes (cholesterol clefts, myxoid change and histiocytes) can be present
Large, thick blood vessels are uncommon; if present, usually are seen at tumor - myometrium interface
May have sex cord-like differentiation, epithelioid morphology, rhabdoid features, clear cells, granular cytoplasm, pseudopapillary, glandular element, fat cells, multinucleated giant cells, bizarre cells, myxoid change
No angiolymphatic invasion should be present
Mitotic activity is usually < 10 per 10 high power fields
Note: foci of smooth muscle metaplasia within the tumor should not be interpreted as myometrial invasion at the edge of the tumo
Positive stains
CD10, ER, PR, WT1, SMA, cytokeratin
Interferon induced transmembrane protein 1 (IFITM1) has a higher specificity than CD10 in the distinction between endometrial stromal and smooth muscle neoplasms (particularly low grade endometrial stromal sarcoma) (Mod Pathol 2014;27:569)
10 - 25% of tumor cells are negative for CD10 (Am J Surg Pathol 2002;26:403)
Tumors with sex cord-like differentiation may be positive for inhibin, calretinin, MelanA, CD99
Negative stains
Desmin, h-caldesmon (but can be positive if smooth muscle or sex cord-like differentiation is present)
CD34 (rarely positive)
Molecular / cytogenetics description
t(7;17) most common JAZF1-SUZ12
PHF1 gene rearrangements (especially if sex cord-like areas are present)
