Endometrial pathology Dr Tom Dodd and Dr Georgina England
Case 1 Female age 35
Case 1 Proliferative endometrium
Case 2 Female age 38
Case 2 Secretory endometrium
Dating endometrium Assessed on the functional layer of the endometrium (superficial stratum compactum & deeper stratum spongiosum). Isthmic endometrium, with fibrous stroma & flattened & slit-like glands, is not representative. Dated to the most advanced area. Abnormal endometrium should not be dated. Inactive or atrophic endometrium. Endometritis. Polyps Hyperplasia.
Dating endometrium Functional layer of the endometrium superficial stratum compactum Decidualised stromal cells more prominent. Deeper stratum spongiosum. Stroma more oedematous in secretory phase. Basal layer Stroma relatively more prominent. No secretory activity.
Dating endometrium Proliferative endometrium can be divided into three phases: early, middle and late. Secretory phase broadly divided into two stages: Earlier predominantly glandular Cytoplasmic vacuolation, later saw-tooth pattern Later stromal Oedema and latter stromal cell decidualisation. inc. endometrial lymphocytes (CD 3 -, CD 56+). Spiral arterioles. Menstrual phase Disruption of glands Condensation of stroma Stromal leukocyte infiltration. Trap: Collapsing glands back to back pattern not to confused with hyperplasia or carcinoma. Clue : look for secretory features and decidual change in stroma.
Normal endometrium Trap: Late secretory pattern endometrium with sawtooth glands not to be confused with hyperplasia or carcinoma. Clues: Marked gland crowding or complexity Nuclear stratification and enlargement and vesicular nuclei. Stromal predecidualised cells
Further pitfalls Dissociation of glands and stroma False crowding Misdiagnose hyperplasia or carcinoma Don't diagnose complex hyperplasia without intact stroma Telescoping artefact Intussusception of glands producing a gland within gland pattern. Recognised as each gland is surrounded by a circle of epithelium.
Case 3 Female age 28
Case 3 Arias-Stella reaction
Arias-Stella reaction Nuclear atypia with nuclear enlargement, hyperchromasia and pleomorphism and vacuolated cytoplasm. Trap: confuse nuclei bulging into gland lumen with hobnail cells of clear cell carcinoma. Clues Hypersecretory features. Decidual stromal changes. Mitoses +/- p53 & MIB 1 (vs clear cell carcinoma) Marker of pregnancy intrauterine or extrauterine. Also may be induced with hormones especially progestational drugs.
Case 4 Female age 40
Case 4 Non-specific chronic endometritis
Non-specific chronic endometritis Variable features Prominent lymphoid aggregates within functionalis Especially if germinal centres present. Plasma cells (CD 138 positive) +/- neutrophils glands & stroma Neutrophils should not be present in endometrium until menstruation established. Disturbance in glands and stroma effecting dating of endometrium. Aetiology includes: Pregnancy related, post abortion etc. specific infections e.g. Chlamydia in association with polyps & tumours.
Case 6 Female age 37
Case 6 Syncytial papillary change / Papillary syncytial metaplasia
Syncytial papillary change (Papillary syncytial metaplasia) Cuboidal epithelial cells with eosinophilic cytoplasm typically heaped up to give a papillary appearance. Neutrophils are commonly present. Relatively common, and may be seen with menstrual breakdown and in infarcted polyps. Clue to the presence of non-menstrual endometrial shedding. Regarded as not a true metaplasia but a change associated with menstrual breakdown. Clue vs carcinoma Confinement to surface, bland cytology, low MIB 1 & menstrual change
Endometrial metaplasia Diverse range of changes Recognised by cytoplasmic changes. Squamous, tubal, eosinophilic, mucinous & clear cell. Frequently associated with hyperplasia, but is not diagnostic of hyperplasia or indicative of endometrial atypia. Clue: attention to the low power architectural pattern will assist in separating metaplasia alone from hyperplasia or carcinoma.
Case 7 Female age 45
Case 7 Endometrial hyperplasia (hyperplasia without atypia)
Case 8 Female age 48
Case 8 Endometrial hyperplasia and squamous metaplasia
Endometrial hyperplasia Assessment of endometrium may be difficult and to a degree is subjective and a variety of nomenclatures have been proposed. WHO 2014 system Hyperplasia without atypia Atypical hyperplasia / endometrioid intraepithelial neoplasia Serous endometrial intraepithelial carcinoma (SEIC) WHO 1994 system Simple hyperplasia Complex hyperplasia Atypical hyperplasia
Hyperplasia without atypia Typically thickened endometrium Endometrial glands show variation in size with cystically dilated glands being typical. Problem: Separation from disordered proliferative endometrium. Clues: Hyperplasia typically diffuse vs focal & variable. Gland to stromal ratio increases greater 1 : 1 in hyperplasia. Glands lack infolding, budding and branching. Lining epithelium resembles proliferative endometrium Columnar pseudostratified cells. Nuclei are oval with even chromatin and inconspicuous nucleoli. Problem: separation from postmenopausal cystic atrophy Clues: atrophic epithelium lacking mitoses in glands & stroma.
Complex hyperplasia No longer used Either classified as hyperplasia without atypia or atypical hyperplasia
Atypical hyperplasia Cellular features of malignancy Loss of polarity Increase in N:C ratio Nuclear pleomorphism & hyperchromasia Coarse chromatin Prominent nucleoli Irregular nuclear membranes Degree of atypia is not usually graded (some recommend grading mild, moderate severe), and may be focal. Architectural features must be considered to separate from carcinoma.
Differential diagnosis Atypical polypoid adenomyoma Frequently younger premenopausal women with a polyp often in lower uterus. Polypoid biphasic lesion cellular smooth muscle stroma. Variable glandular complexity, atypia and squamous morules. Absence of severe cytological atypia & low architectural complexity. Usually some benign proliferative or secretory endometrium in sample.
Case 9 Female age 55
Case 9 Endometrioid adenocarcinoma
Endometrioid adenocarcinoma Problem: Distinction between atypical endometrial hyperplasia and endometrioid adenocarcinoma may be difficult on curettage specimens. Clues: include: Confluent glands with a cribriform architecture or labyrinth pattern Total absence of stroma between neoplastic glands. Prominent surface villous or papillary growth pattern particularly with second and third degree branching or cribriform budding. Irregular glands infiltrating fibrotic stroma.
Endometrioid adenocarcinoma Grading should be undertaken FIGO architectural and cytological features. Grade 1 < 6% non-gland forming growth. Grade 2 < 6 50 % non-gland forming growth Grade 3 > 50% non-gland forming growth Grade 1 & 2 increase one grade I if grade 3 nuclei present. Nuclear grade Oval -> round Marked variation in size & shape Hypochromasia - > hyperchromasia Variation in staining intensity Even chromatin - > Coarse clumped chromatin Nucleoli not prominent - > prominent nucleoli. Sparse mitoses - > frequent and abnormal mitoses. Concordance with curette & hysterectomy specimen 45 75% prove to have a higher grade. (Mitchard,J Hirschowitz, l Histopathology. 42(4):372-378, April 2003). Reflecting sampling and reproducibility of grading.
Lynch syndrome 2-5% of endometrial carcinomas Approx 10% of endometrial ca at < 40 years Surveillance for colorectal carcinoma in Lynch syndrome reduces mortality by 65% Occurs in 3 settings: Germline mutations in: MSH2, MSH6, MLH1, PMS2 MSH6 mutations most common in EC Germline EPCAM mutation downregulation of MSH2 Constitutive epimuation widespread methylation of genes including MLH1 MMR IHC followed by sequencing is the most cost effective approach BRAF of limited utility in EC
Case 10 Female age 64
Case 10 Serous carcinoma
Serous carcinoma May occur in association with endometrioid and clear cell components. Background endometrium may show surface epithelium exhibiting high grade malignant cells referred to as endometrial intraepithelial carcinoma.
Serous carcinoma - histology Analogous to ovarian equivalent. Complex papillary architecture, Cellular budding High grade cytology Psammoma bodies (25%)
Pitfalls in serous carcinoma Problem: Separating tumours with a glandular pattern from endometrioid carcinoma. Clues: the epithelium is pleomorphic with rounded nuclei and prominent nucleoli. polarity of endometrioid carcinoma is absent. ICC All or nothing staining with p53 Usually negative ER/PR/beta catenin High MIB 1 > 75% of cells
Case 11 Female age 65
Case 11 Clear cell carcinoma
Clear cell carcinoma Uncommon, occurs in older women. Background atrophic pattern, but some cases show endometrial hyperplasia. Identical to ovarian counterpart. Histological appearances: Clear cells with a solid, tubulocystic or papillary growth pattern. Hobnail cells are characteristic. +/-Oncocytic cytology with eosinophilic cytoplasm High grade by definition May occur in association with serous or endometrioid pattern carcinomas.
Uterine clear cell tumours Clear cell carcinoma HNF1b positive, ki 67 50% Endometrioid carcinoma Secretory variant Clear cell change Squamous metaplasia with clear cells Serous carcinoma with clear cells P16 and P53 positive, Ki67 >75% PEComas HMB45, Melan A and SMA positive
Bokhman classification of endometrial carcinomas Type 1 70% Endometrioid carcinoma Post menopausal High oestrogen states: Obese, PCOS, Granulosa cell tumours Background of endometrial hyperplasia / endometrial intraepithelial neoplasia PTEN, KRAS, CTNNB1, PIK3CA, MSI Type 2 30% Serous and clear cell carcinomas Atrophic endometrium +/- endometrial intraepithelial carcinoma HER2 TP53
Case 12 Female age 55
ER P16 CEA Vimentin
Case 12 Endometrial carcinoma with a microglandular-like pattern (aka Low grade mucinous microglandular adenocarcinoma)
Endometrial carcinoma with a microglandular-like pattern Low aggressive endometrial carcinoma resembling endocervical microglandular hyperplasia. Postmenopausal women Numerous neutrophils in gland lumens, scattered mitoses, mild nuclear atypia. IHC: Positive: CD10, vimentin, CEA, ER, p16. Negative: PAX2, p63, CD34 Ki67 >10% DDx - microglandular hyperplasia negative for these antibodies.
Endometrioid vs endocervical Endocervical carcinoma typically: Greater nuclear atypia & mitoses. Mucinous differentiation may occur in both sites Immunohistochemistry: Endometrial: vimentin +, ER +,CEA Cervical: vimentin -, ER weak + or -, CEA + p16 strong in endocervical, (negative in unusual subtypes). endometrial endometrioid ca weak/focal, strong in rare cases
Case 16 Female age 73
Case 16 Endometrial adenosarcoma
Endometrial adenosarcoma Biphasic tumour with benign epithelial component and sarcomatous stroma. Polypoid mass Histology: Glands: compressed with a branched leaf-like pattern and lined typically with endometrioid-type epithelium. Stroma IHC: Sarcomatous Periglandular condensation. Variable degree of nuclear pleomorphism, and mitotic activity 20% may have heterologous elements +/- sarcomatous overgrowth prognostic signifciant. Positive: oestrogen receptor (ER), progesterone receptor (PR), CD10, WT1 and smooth muscle actin 80% no or limited myometrial invasion Sarcomatous overgrowth worse prognosis.
Case 13 Female age 71
Case 13 Malignant Mixed Mullerian Tumour / carcinosarcoma
Malignant Mixed Mullerian Tumour carcinosarcoma Malignant epithelial and stromal elements. Ratio of components varies, and curettage specimens may be composed entirely of sarcoma Presence of heterologous elements may be particularly helpful. Immunohistochemistry: Epithelial and mesenchymal elements may stain with cytokeratins. Pattern of carcinoma should be noted. Metastases may be purely carcinoma, biphasic or rarely purely sarcoma.
WHO classification of mixed epithelial and mesenchymal tumours 2014 Adenomyoma Atypical polypoid adenomyoma Adenofibroma Adenosarcoma Carcinosarcoma
Case 14 Female age 55
CK ER GCDFP Mammoglobin
Case 14 Metastatic lobular carcinoma
Metastatic malignancies Metastatic carcinoma may represent a major diagnostic challenge. Common sites: Breast, G.I. tract, lung and melanoma Mimics for endometrial stromal sarcoma. Mimics for endometrial stromal sarcoma Lobular breast carcinoma mucin vacuoles, cytokeratin +, & breast associated antigens + Lymphoma CD 45 +
Case 15 Female age 60
Case 15 Leiomyosarcoma
Leimyosarcoma Typically, non-specific symptoms of pain and abnormal bleeding. Smooth muscle differentiation usually straight forward and aided with ICC for desmin. Care with assessing necrosis, mitotic index and cytological atypia prior to diagnosing malignancy on limited curettings. atypical smooth muscle tumour Differential diagnosis Combined stromal and smooth muscle tumours Epithelioid tumours Spindle cell carcinoma (Cytokeratin positive)
Case 17 Female age 52
Immunohistochemical stains CD10 Cytokeratin
Case 17 Endometrial Stromal Sarcoma
Endometrial Stromal Sarcoma (ESS) WHO classification of stromal tumours 2014 Endometrial stromal nodule Endometrial stromal sarcoma, low grade Endometrial stromal sarcoma, high grade Undifferentiated endometrial sarcoma high grade pleomorphic, mitotically active and show necrosis and lack specific differentiation. Sarcoma composed of cells resembling proliferative endometrial stroma and myometrial or vascular invasion. Small regular cells with oval nuclei fine stippled chromatin and inconspicuous nucleoli. Highly vascular with arterioles and a network of slit like capillaries. Hyaline fibrosis and foamy macrophages.
Problems with diagnosis of ESS Curettings containing cellular proliferating endometrial stromal tissue. Endometrial biopsy specimen may not allow distinction between endometrial stromal nodule and low-grade endometrial stromal sarcoma. Depends on assessment of margin. May show occasional benign glands. Smooth muscle differentiation. CD10 immunohistochemistry may be of assistance. Raise possibility of stromal tumour & further assessment including imaging.
Case 5 Female age 28
Immunohistochemical stains Cytokeratin Inhibin
Case 5 Placental site nodule
Placental site nodules Indicative of past pregnancy & incidental finding. Paucicellular circumscribed eosinophilic nodule within endometrium Composed of chorionic type intermediate (extravillous trophoblast) and may be hyalinised. Positive for cytokeratin, hpl and inhibin. Ki 67 < 5% Trap: Differential diagnosis with epithelioid trophoblastic tumour. Clues: Superficial, small, circumscribed and lack atypia. Proliferative index < 8%
Case 18 Female age 22
Case 18 Hydatidiform mole
Hydatidiform mole Gross vesicles significantly larger in complete mole Mole shape Hydrops increase with increasing gestational age, but scalloping of villi is more common in partial mole Polypoid villi complete mole Implantation site trophoblastic atypia focal & mild in partial mole vs diffuse & marked in complete mole. Villous stromal karyorrhexis Feature of complete mole Vascularity can be detected with CD 34 of most moles. Partial mole generally present. Complete mole inconspicuous.
Further investigation P57 Immunohistochemistry Paternally imprinted (ie not expressed) maternally transcribed gene, therefore complete loss of labelling of cytotrophoblast in complete moles Partial moles Labelling of cytotrophoblast villous stomal cells in & hydropic abortions. Ploidy Partial moles generally triploid Complete moles generally diploid (some tetraploid) with only paternal chromosomes.
What is the significance? 2-3% of complete moles will develop choriocarcinoma 0.5% of partial moles will develop choriocarcinoma
Case 19 Female age 28
Case 19 Choriocarcinoma
Choriocarcinoma Trimorphic population of intermediate trophoblastic cells, syncytiotrophoblast and cytotrophoblast with ABSENT chorionic villi Historically: ~ 50% hydatidiform mole ~ 25% normal pregnancy ~ 25% abortion Currently: 50% follow normal pregnancy Pathology Haemorrhagic mass Dismorphic cytotrophoblast & syncytiotrophoblast Haemorrhage, necrosis & mitoses +++ Cytokeratin, hcg, inhibin +
Differential diagnosis Complete mole Placental site trophoblastic tumour Biphasic pattern of choriocarcinoma hpl positive hcg levels (typically lower in PSTT) and ICC staining. Exaggerated placental site reaction Similar cellular population Occasional villi may be present. MIB 1 near 0% in placental site reaction vs high in choriocarcinoma. Placental site nodule Bland cytology of intermediate trophoblast No haemorrhagic necrosis. Carcinoma Leiomyosarcoma
WHO classification of gestational trophoblastic disease 2014 Neoplasms Choriocarcinoma Placental site trophoblastic tumour Epithelioid trophoblastic tumour Non-neoplastic lesions Placental site nodule and plaque Exaggerated placental site Molar pregnancies Hydatidiform mole Complete Partial Invasive Abnormal villous lesions (nonmolar)