Endometrial carcinoma �Pathology and Staging�

By:

Dr. Marwa Zaki

Assistant professor of pathology

Faculty of medicine-Mansoura university

Epidemiology�

• EC is most common gynecologic malignancy in developed countries.
• Incidence of endometrial carcinoma is increasing.
• Most cases arise in the postmenopausal period, with a mean age at presentation of 60 years.
• 67% of cases present at early stage.

Pathophysiology�

Endometrial carcinomas have been traditionally divided into 2 types:

Type 1:

• Includes endometrioid and mucinous carcinoma.
• Associated with long term elevated estrogen levels.
• PTEN, KRAS gene alterations are common.
• Atypical endometrial hyperplasia / endometrial intraepithelial neoplasia is regarded as the precursor lesion.

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Type 2:

• Includes serous, clear cell, undifferentiated carcinoma and carcinosarcoma.
• Lesser association with unopposed estrogen exposure.
• Serous carcinoma is characterized by early alterations in TP53.
• Serous intraepithelial carcinoma has been proposed as the preinvasive precursor.
• Precursor lesion for clear cell carcinoma has not been identified.

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��From a biologic and clinical perspective, the classification of endometrial carcinoma is evolving towards a molecular based grouping��

The need for molecular classification:

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1-Pathlogical classification by histological subtype, grade, is highly subjective and has challenges in reproducibility.

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2-The high inter-observer agreement in histological subtype observed in one-third of high-grade EC cases.

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3-Disagreement in grade assignment between diagnostic endometrial specimens and final hysterectomy specimen.

4-A more reproducible, objective, biologically informative system to classify tumours evolved.

In 2013, the Cancer Genome Atlas (TCGA) Research Network published an integrated genomic characterization of endometrial carcinoma based on:

• Used genomic information
• Somatic copy number alterations (SCNAs)
• Tumour mutation burden (TMB) �

Proposed four distinct EC classes with distinct genomic aberrations

Molecular classification correlates with clinical outcomes:

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• Survival rates are best in POLE mutated tumors, followed by copy number-low, microsatellite instability and copy number-high carcinomas

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• A recent study proposed an algorithm using POLE mutational analysis and immunohistochemistry for p53 and mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) as a valid surrogate to determine the molecular group.

Hypermutated endometrial carcinoma

• Characterized by microsatellite instability (MSI)2ry to dysfunction of one of the enzymes that repair DNA abnormalities.
• Can be identified by IHC (MLH1,PMS2,MSH2,MSH6).
• Screening can be done by immune staining of just 2 proteins (MSH6&PMS2)if both are expressed the tumor is MMR intact.
• 3-4% of endometrial carcinoma arise in patients with lynch syndrome and these tumors are MMR-D.
• In lynch syndrome patients, endometrial carcinoma tend to occur in young age.
• MMR-D endometrial carcinoma tend to be higher grade associated with peritumoral & intra tumoral lymphocytic infiltration.
• Although most are endometrioid , they may be non-endometrioid histology.

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Polymerase-epsilon gene(POLE), Ultramutated EC

• Have 10 folds more mutation than hypermutated endometrial carcinoma.
• With very favorable prognosis although they are often high grade
• Histologically, they are typically high-grade endometrioid EC (EEC) with a superficial broad front invasion pattern with the presence of tumour giant cells and prominent tumour infiltrating lymphocytes.
• It has also been noted that ECs which are morphologically difficult to classify (histo-morphologically ambiguous) are more likely to be POLE-mutant.

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Copy number- low (frequently involving mutations of PTEN and KRAS)

• Moderate number of mutations, mostly within the PI3K/Akt and Wnt signalling pathways.
• Almost exclusively composed of low grade EECs with estrogen (ER) and progesterone receptor (PR) positivity.

Copy number- high/abnormal expression pattern of P53�

• Frequent TP53 mutations (92%).
• The vast majority of serous carcinomas and 25% of high grade endometrioid tumors “serous-like”.

• Distinct mass is usually seen on examination of the cavity.
• Lesion is typically exophytic and soft.
• Homogeneous or heterogeneous cut surface with variable hemorrhage and necrosis.
• Some cases present as diffuse endometrial thickening.
• Carcinomas with extensive squamous differentiation can have a flaky appearance, whereas those with mucinous differentiation are soft and gelatinous (colloid appearance).
• In younger women it mostly occurs at isthmus
• Small carcinomas restricted to cornu can be missed by biopsy or D&C

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Pathologic features

Microscopically

Histologic grading:

• Endometrioid and mucinous carcinomas are graded with a 3 tier system developed by FIGO:
• FIGO 1: predominant glandular growth and < 5% nons-quamous solid component.
• FIGO 2: 6 - 50% nons-quamous solid component
• FIGO 3: > 50% nons-quamous solid component

• Architectural grading is upgraded by 1 if there is severe nuclear atypia involving more than 50% of tumor cells.

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• In general, a 2 tier system can be also applied, with FIGO1 and FIGO2 being considered low grade and FIGO 3 being considered high grade.

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• Other carcinoma types (serous, clear cell, carcino-sarcoma, undifferentiated, mixed carcinomas) are by definition high grade.

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Staging of EC

• The classification applies to endometrial carcinomas and carcinosarcomas.

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• The FIGO stages are based on surgical staging. TNM stages are based on clinical and/or pathological classification.

Primary tumor [pT] and FIGO stage

Regional lymph nodes [pN] and FIGO stage

• pNX: regional lymph nodes cannot be assessed
• pN0: no regional lymph node metastasis
• pN0(i+): isolated tumor cells in regional lymph node(s) ≤ 0.2 mm
• pN1 (IIIC1): regional lymph node metastasis to pelvic lymph nodes
• pN1mi: regional lymph node metastasis (> 0.2 mm but ≤ 2 mm in diameter) to pelvic lymph nodes
• pN1a: regional lymph node metastasis (> 2 mm in diameter) to pelvic lymph nodes
• pN2 (IIIC2): regional lymph node metastasis to paraaortic lymph nodes, with or without positive pelvic lymph nodes
• pN2mi: regional lymph node metastasis (> 0.2 mm but ≤ 2 mm in diameter) to paraaortic lymph nodes
• pN2a: regional lymph node metastasis (> 2 mm in diameter) to paraaoric lymph nodes

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Distant metastasis [pM] and FIGO stage

• pM0: no distant metastasis
• pM1 (IV):
• Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver or bone.
• It excludes metastasis to para-aortic lymph nodes, vagina, pelvic serosa or adnexa.

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Notes

• Endocervical glandular involvement only should be considered as stage I and not stage II
• Presence of cervical stromal involvement defines stage II
• Depth of invasion into the cervical stroma and margin status (distal cervical / vaginal mucosa and parametrial margins) with measures should be reported, as it may affect adjuvant radiation treatment

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• If the tumor is exophytic at the point of deepest myometrial invasion, the nearest endomyometrial junction should be identified and depth should be measured from that point

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• If the carcinoma at the point of deepest invasion involves a leiomyoma, the myometrial thickness should be obtained at that point anyway (in other words, including the leiomyoma) 

• In tumors with microcystic, elongated and fragmented (MELF) pattern of invasion, the presence of desmoplasia alone is sufficient to determine the deepest area of tumor invasion.

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• (MELF) pattern of invasion is generally associated with low grade (FIGO 1 - 2); associated with higher rate of lymphovascular invasion and lymph node metastases but not overall survival.

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• Lympho-vascular space invasion (LVI) should not be included in the assessment of myometrial invasion

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Lymphovascular space invasion (LVI):

• LVI is an independent predictor of nodal metastases and local recurrence
• LVI is defined as tumor cells in a space lined by endothelial cells outside the immediate invasive border
• Extent of LVI, not just the presence, correlates significantly with regional and distal lymph node involvement, regional recurrence and survival.
• Extent should be reported as follows:
• Absent: no LVI
• Focal: up to 5 individual involved vascular spaces
• Substantial: diffuse or multifocal LVSI (>5 involved vessels)

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Serosal involvement:

• Involvement of the uterine serosa is an adverse prognostic factor and warrants a stage IIIA
• Diagnosed when the tumor perforates through the mesothelium lined outer surface of the uterus.
• According to ISGYP guidelines, tumor infiltrating the entire myometrial thickness and reaching submesothelial fibroconnective tissue should also be reported as serosal involvement.

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Adnexal involvement (versus synchronous ovarian carcinoma):

• Distinguishing between the following is relevant for staging and treatment:
• Synchronous ovarian and endometrial tumors
• Primary endometrial with metastatic ovarian involvement
• Primary ovarian with metastatic endometrial involvement

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• However, it is often difficult to separate these scenarios on pathologic examination and one may only suggest one possibility over the others

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Features that support 2 synchronous carcinomas include:

• Different histologic types or tumor grades
• Endometrial carcinoma has absent or only superficial myometrial invasion
• Ovarian carcinoma is confined to the ovary
• Absence of LVI
• Different patterns of MMR or hormone receptor expression by IHC
• Identification of endometrial precursor lesions

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• If serous or clear cell carcinoma is present the likelihood of metastatic disease to or from the ovary is high.

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• The site of the dominant mass, either uterine or ovarian, is typically the primary site.

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Conversely, secondary ovarian involvement by a primary endometrial tumor should be considered when:

• Endometrial tumor has deep myometrial invasion, LVI, serosal or parametrial involvement
• Bilateral ovarian involvement
• Ovarian tumor involves surface and has extensive LVI
• Both tumors show similar MMR and hormone receptor expression by IHC

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• Intraoperative consultation is not appropriate for:
• Diagnosing adenocarcinoma in a patient with a preoperative diagnosis of atypical hyperplasia /EIN
• Diagnosing hyperplasia or atypia
• Section entire endometrium / mass to assess and freeze area of deepest apparent invasion
• Key information to report to surgeon (influences subsequent lymphadenectomy) (original Mayo Criteria:
• FIGO grade of tumor(*1 or 2)
• Largest tumor dimension (*< 2 cm)
• Whether tumor is 1) *endometrium confined, 2) *< 50% myoinvasive or 3) > 50% myoinvasive

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Cases meeting all * criteria do not merit pelvic lymphadenectomy

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Frozen section in EC

Endometrioid endometrial carcinoma

Microscopic features

• Architecture
• Key feature is confluent or back to back glands lacking intervening stroma
• Cribriform or microacinar configurations
• Complex papillary, micropapillary or villoglandular structures

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• Cytologic features
• Cellular / nuclear enlargement
• Nuclear rounding (rather than elongation) with large nucleoli
• Loss of polarity
• Cytoplasmic eosinophilia
• Sharp glandular luminal borders
• Foamy histiocytes in residual stroma
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Other variants of Endometrioid carcinoma

• Adenocarcinoma with squamous differentiation
• Corded and hyalinized endometrioid carcinoma(CHEC)
• Secretory carcinoma
• Ciliated / tubal carcinoma
• Spindled carcinoma
• Mixed endometrial carcinoma:
• Defined as combination of at least 2 endometrial histologic subtypes (most commonly endometrioid and serous)
• Distinction important as prognosis is similar to that of the higher grade component (i.e. serous, clear cell, neuroendocrine)
• Dedifferentiated endometrial carcinoma:
• Abrupt transition from well differentiated (FIGO 1 - 2) to undifferentiated carcinoma.

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IHC of Endometrioid carcinoma

• Positive stains

PAX8, CK7, ER / PR and vimentin

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• Negative stains

P53 (wild type)

P16 (mosaic pattern)

CK20, CEA, Napsin A

Mucinous adenocarcinoma

• Abundant intracellular mucin within more than 50% of tumor cells.
• Prominent neutrophilic infiltrate.
• The distinction from endocervical carcinoma can be made by immune stains.
• The mucinous endometrial carcinoma shows diffuse ER&PR positivity and negative P16 expression.

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Serous carcinoma

• It makes up about 10% of all endometrial carcinomas.
• The tumor is composed of high-grade anaplastic cells in complex papillary, glandular or solid growth patterns.
• Usually seen in postmenopausal women.
• It may be admixed with other variants of endometrial carcinoma.
• It is frequently associated with myometrial invasion and LVI .

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• Psammoma bodies are seen in approximately  30%  of serous carcinomas of the endometrium. They may occasionally be seen in endometrioid carcinomas as well.

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• Background endometrium, if present, is often atrophic.

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• Not graded into low and high grade as done in the ovary but by default is a high grade carcinoma

IHC of endometrial serous carcinoma

Positive stains

• p53: mutation type staining either strong and diffuse or complete absence of staining (“null type” pattern)
• p16: often strong and diffuse (not related to HPV infection)
• CK7: strong staining
• PAX8: strong nuclear staining

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Negative stains

• CK20
• ER / PR: decreased expression; often negative or focally positive in approximately 50% of cases
• WT-1: may be focally positive in 30% of cases; if strong and diffuse, extra-uterine serous carcinoma enters the differential

Clear Cell Carcinoma�

• About 5% of endometrial carcinomas.
• They consist of clear cells or hobnail cells in papillary, tubular, or solid growth patterns .
• The cytoplasm ranges from clear to eosinophilic.
• Cytologic atypia ranges from minimal to marked.
•  Dense stromal hyalinization in some cases.
• Thought to be related to papillary serous carcinoma with which it shares some morphologic features.

IHC of clear cell carcinoma

Positive stains:

• HNF-1B (hepatocyte nuclear factor 1 beta) (67 - 100%)
• Napsin A (56 - 93%)
• AMACR (Alpha methyacyl CoA racemase (AMACR) (75 - 88%)
• Mismatch repair (MMR) expression (PMS2, MSH2, MSH6, MLH1) is intact in 80 - 90%
• CK7
• p53 (wild type pattern in 67% of cases) ,
• Negative stains
• ER, PR (only rarely focally expressed)
• Cd 10

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Mesonephric-like carcinoma

•“New” entity recognized in WHO 5th Ed (2020): “

•Defined as “tumors exhibiting the classic morphologic features of mesonephric carcinoma, but occurring outside of the cervix and without convincing mesonephric remnants” .

•Represents 1% of endometrial carcinomas

•Compared to low grade endometrial carcinomas, mesonephric-like carcinomas are larger, present at advanced stage, more frequently show LVI; patients are possibly younger.

Which of the following prognostic variables modifies the FIGO / AJCC stage of endometrial carcinoma?

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1. Depth of myometrial invasion
2. Involvement of adenomyosis
3. Lymphovascular space invasion
4. Molecular group
5. Superficial (glandular) cervical involvement

Which of the following is true regarding the endometrial serous carcinoma?

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1. Likely arose in a patient less than 30 years of age
2. Considered an estrogen dependent endometrial carcinoma
3. Even without definitive invasion, can present at high stage with tumor dissemination in the peritoneal cavity
4. Often shows monotonous nuclei with little pleomorphism and low proliferation index

Which of the following variables modifies the FIGO / AJCC stage of endometrial carcinoma?

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1. Extranodal extension by carcinoma involving a lymph node
2. Lower uterine segment involvement
3. MELF pattern of invasion
4. Number of intravascular tumor foci
5. Size of lymph node tumor metastases

The immunoprofile of most endometrial clear cell carcinomas includes

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1. Immunonegativity for AMACR
2. Immunopositivity for progesterone receptor
3. Immunoreactivity for Napsin A
4. Mutant pattern staining for p53

The defining feature of stage T3a / IIIA carcinoma of the uterine corpus is:

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1. Involvement of bladder or rectal mucosa
2. Involvement of cervical stromal tissue
3. Involvement of uterine serosa or adnexa
4. Involvement of vagina or parametrial tissue
5. Pelvic lymph node metastases

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Which of the following is true regarding serous carcinomas of the endometrium?

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1. Mutations in p53 are the most common driving molecular event
2. WT-1 is often strong and diffusely positive
3. Show well formed glands with sharp luminal borders
4. p16 overexpression indicates a role for HPV infection in the etiology

References�

• WHO classification of tumors, female genital system, 5^Th edition, 2020.
• Blaustein's Pathology of the Female Genital Tract 7th ed. 2019.
• www.pathologyoutlines.com

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