Endometrial cancer

Author: Mikael Häggström

Presentations

• Hysterectomy
• Endometrial curettage
• Endometrial polyp
• Endometrial thickening

Comprehensiveness

On this resource, the following formatting is used for comprehensiveness:

• Minimal depth
• (Moderate depth)
• ((Comprehensive))

Gross processing

Gross pathology of extensive endometrial adenocarcinoma (endometrioid type).

A regular hysterectomy grossing is performed, but with the following sampling and additions:

• 2 longitudinal sections through ecto/endocervix (1 anterior and 1 posterior).
• 2 longitudinal sections through upper endocervix/lower uterine segment (1 anterior and 1 posterior), contiguous with sections taken from cervix.
• Tumor:

• Measure greatest dimension of tumor.

• If tumor is smaller than 3 cm, submit entirely.
• If tumor is larger than 3 cm, submit 1 per cm.

In order to determine the myometrial invasion, sample the entire distance from the uterine cavity to the serosa. If it doesn't fit into one cassette, take two contiguous slices (as seen on this uterine cross-section) inked at the contiguity so that the glass slides can be apposed to measure tumor invasion.

• Measure tumor thickness and entire thickness of the wall, at the location of greatest percentage of tumor relative to wall thickness.
• Include 2 full-thickness sections (1 anterior and 1 posterior) at locations with seemingly greatest invasion. It may need multiple contiguous sections.
• Remaining sections can be superficial to include tumor and inner myometrium, such as from lower uterine segment to fundus to maintain orientation.
• If possible, include 1 section with interface between tumor and normal.

• Sections of any additional pathology, such as leiomyomas, polyps in their entirety.
• 1 section of uninvolved endometrium if present.
• Inspect serosa for implants and submit sections if grossly detected.
• For serous carcinomas, submit the entire ovary and fallopian tube:

• Ovary, serially sectioned perpendicular to long axis.
• SEE-FIM protocol for fallopian tubes:

• Remove the distal 2 cm (fimbriae) and section it parallel to the long axis.

Section the remainder of the tube transversely at 2-3 mm intervals.

• For all other cancer types, submit adnexa as follows:

• Ovaries: 2 representative sections of each.
• Fallopian tubes: Entire fimbriae (longitudinally sectioned) and 2 representative cross-sections on each side.

• Lymph nodes

• Size smaller than 2 mm: submit intact.
• Size larger than 2 mm: serially section perpendicular to the long axis in 2 mm intervals.

• If no gross tumor, submit entirely.
• If grossly positive, submit 1-2 representative sections showing the greatest tumor dimension and extranodal fat.

Microscopic evaluation

Diagnosis

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  Relative incidences of endometrial carcinomas by histopathology, being endometrioid in a majority of cases. Endometrioid carcinoma has patterns reminiscent of normal endometrium, with many new glands formed from columnar epithelium with some abnormal nuclei:

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  Endometrioid adenocarcinoma, with low-grade being distinguished from hyperplasia with atypia by the presence of glandular crowding with endometrial stromal exclusion, and significant cribriform, confluent glandular, labyrinthine, papillary/villoglandular, or non-squamous solid architecture.

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  Endometrial intraepithelial neoplasia (EIN), for comparison, also showing gland crowding and atypia compared to normal endometrium, but without invasion.

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  Papillary serous carcinoma of uterus, with characteristic discohesiveness of cells (like falling apart) around fibrovascular cores.

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  Papillary serous carcinoma of uterus, in this case showing both papillary and micropapillary architecture.

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  Clear cell carcinoma of the endometrium with papillary architecture, characteristically small round papillae lacking overt stratification. Clear cell carcinoma is defined as a carcinoma demonstrating a combination of papillary, tubulocystic and/or solid architectural patterns, with cuboidal or polygonal cells containing nuclei with a variable pleomorphism (although usually lacking discernible pleomorphism).

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  Clear cell carcinoma of the endometrium with tubulocystic architecture.

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  Clear cell carcinoma of the endometrium with solid architecture.

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  Dedifferantiated carcinoma, a tumor that contains a component of undifferentiated endometrial carcinoma (UEC) and a component of conventional, usually lower-grade, endometrioid adenocarcinoma.

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  Carcinosarcoma of the endometrium, with carcinoma in addition to sarcoma (seen here as atypical fibrovascular cores).

Endometrioid adenocarcinoma

For endometrioid adenocarcinoma, perform architectural grading:

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  Grade 1: ≤5% solid non-glandular, non-squamous growth.

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  Grade 2: >5% and ≤50% solid non-glandular, non-squamous growth.

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  Grade 2, with mucinous differentiation.

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  Grade 3: >50% solid non-glandular, non-squamous growth. Carcinomas with identifiable endometrial component, and with over 50% solid architecture should be classified as grade 3 endometrioid carcinoma.

(Also perform nuclear grading:)

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  Nuclear grade 1: Oval, mildly enlarged nucleus with evenly distributed chromatin.

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  Nuclear grade 2: Intermediate features.

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  Nuclear grade 3: Markedly enlarged and pleomorphic nuclei, with coarse chromatin and distinct nucleoli.

FIGO grading

Perform FIGO grading in case of endometrioid or mucinous carcinomas. FIGO classification is architectural grading as above, but that the presence of grade 3 nuclear atypia in an architectural pattern grade I tumor raises the grade by one point:

• FIGO grade 1: ≤5% solid non-glandular, non-squamous growth
• FIGO grade 2:

• >5% and ≤50% solid non-glandular, non-squamous growth

or

• ≤5% solid non-glandular, non-squamous growth and markedly enlarged and pleomorphic nuclei, with coarse chromatin and distinct nucleoli (in these cases, also consider a serous carcinoma of glandular variant)

• FIGO grade 3: >50% solid non-glandular, non-squamous growth

Bimodal grading

It is recommended to classify FIGO grade 1 and 2 tumors as low-grade, and grade 3 tumors as high-grade.

Staging

Preferably, stage by both the AJCC TNM system and the FIGO system: The following system is for uterine carcinoma and carcinosarcoma (but a separate staging system is used for sarcomas).

T Category	FIGO Stage	T Criteria
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
T1	I	Tumor confined to the corpus uteri, including endocervical glandular involvement
T1a	IA	Tumor limited to the endometrium or invading less than half the myometrium
T1b	IB	Tumor invading one half or more of the myometrium
T2	II	Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement.
T3	III	Tumor involving serosa, adnexa, vagina, or parametrium
T3a	IIIA	Tumor involving the serosa and/or adnexa (direct extension or metastasis)
T3b	IIIB	Vaginal involvement (direct extension or metastasis) or parametrial involvement
T4	IVA	Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)

N Category	FIGO Stage	N Criteria
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N0(i+)		Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm
N1	IIIC1	Regional lymph node metastasis to pelvic lymph nodes
N1mi	IIIC1	Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to pelvic lymph nodes
N1a	IIIC1	Regional lymph node metastasis (greater than 2.0 mm in diameter) to pelvic lymph nodes
N2	IIIC2	Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes
N2mi	IIIC2	Regional lymph node metastasis (greater than 0.2 mm but not greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes
N2a	IIIC2	Regional lymph node metastasis (greater than 2.0 mm in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes

The suffix (sn) is added to the N category when metastasis is identified only by sentinel lymph node biopsy.

M Category	FIGO Stage	M Criteria
M0		No distant metastasis
M1	IVB	Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone). (It excludes metastasis to pelvic or para-aortic lymph nodes, vagina, uterine serosa, or adnexa).

AJCC Prognostic Stage Groups

When T is…	And N is…	And M is…	Then the stage group is…
T1	N0	M0	I
T1a	N0	M0	IA
T1b	N0	M0	IB
T2	N0	M0	II
T3	N0	M0	III
T3a	N0	M0	IIIA
T3b	N0	M0	IIIB
T1-T3	N1/N1mi/N1a	M0	IIIC1
T1-T3	N2/N2mi/N2a	M0	IIIC2
T4	Any N	M0	IVA
Any T	Any N	M1	IVB

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  Calculation of myometrial invasion: The dotted lines show the position of the endometrial/myometrial junction (EMJ), and the line where the tumor would invade half of the myometrium (50 % MI). The arrows show the absolute depth of invasion (a) and tumor-free distance (b) measurements. Invasion as a percentage is calculated as:
  a / (a+b)

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  For biopsies, just look for absence or presence of myometrial invasion (pictured).

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  Generally look for lymphovascular invasion (pictured) as well.

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  For pelvic lymph nodes, minor metastasis of endometrial cancer is hard to see (left panel). Therefore, if not obviously present, perform immunohistochemistry for CK AE1/AE3 (middle panel), and correlate positive findings with adenocarcinoma on high magnification (right panel).

Further workup

Generally perform the following molecular testing on endometrial carcinomas:

• Mismatch repair (MMR) genes (MLH-1, PMS-2, MSH-2 and MSH-6) on all cancer types and grades. If MLH1 is lost, test for MLH1 promotor methylation.
• ER/PR and p53 for all high grade carcinomas regardless of stage.
• HER2 on all high grade carcinomas, or only on serous carcinomas, or those that are stage III or IV or recurrent.

For MMR genes, scoring is as follows:

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  0% nuclear expression in tumor cell nuclei: Loss of expression (expression seen in stromal cells in image)

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  More than 0% but less than 10%: Indeterminate expression

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  10% or more: Retained expression

This image shows different patterns of p53 expression in endometrial cancers on immunohistochemistry, whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying p53 mutation, and correlates with higher grade carcinoma. Wild-type expression, upper left: Variable proportion of tumor cell nuclei staining with variable intensity. This pattern should not be reported as “positive,” because this is ambiguous reporting language. Overexpression, upper right: Showing strong staining in virtually all tumor cell nuclei (as can be compared with the internal control of fibroblasts in the center). There is some cytoplasmic background indicating that this staining is quite strong but this should not be interpreted as abnormal cytoplasmic pattern. Complete absence of expression, lower left. In comparison, there wild-type pattern in normal atrophic glands at 12 and 6 o’clock. Both cytoplasmic and nuclear expression, lower right. This case has similar intensity of the two, whereas stroma and normal endometrial glands show nuclear wild-type pattern.

Microscopy report

Example for a polypectomy:

(Endometrium, polypectomy:) Endometrial adenocarcinoma, endometrioid type, FIGO grade 2, (nuclear grade 2) with mucinous differentiation. Carcinoma focally invades myometrial smooth muscle.

Example for a hysterectomy:

A. Uterus, cervix, bilateral (fallopian) tubes and ovaries, hysterectomy and bilateral salpingo-oophorectomy: (Endometrial) endometrioid adenocarcinoma FIGO grade 1, (nuclear grade 2). Carcinoma invades 40% of the myometrial thickness. Involvement of the lower uterine segment is present. Benign cervix Benign (fallopian) tubes and ovaries. See synoptic report {{and comment}}. B. Left pelvic sentinel lymph nodes, excision: Three ((0/3)) benign lymph nodes(, negative for metastatic carcinoma on H&E and cytokeratin AE1/AE3 stains.) C. Right pelvic lymph nodes, excision: Two ((0/2)) benign lymph nodes(, negative for metastatic carcinoma.)

For cancers, generally include a synoptic report, such as per College of American Pathologists (CAP) protocols at cap.org/protocols-and-guidelines. Example, following the hysterectomy above:

SYNOPTIC REPORT:

• Procedure: Total hysterectomy and bilateral salpingo-oophorectomy
• Tumor Site: Endometrium
• Tumor Size: 5.3 centimeters (cm)
• Histologic Type: Endometrioid carcinoma, NOS
• Histologic Grade: FIGO grade 1
• Two-Tier Grading System: Low grade (encompassing FIGO 1 and 2)
• Myometrial Invasion: Present
• Depth of Myometrial Invasion: 10 mm
• Myometrial Thickness: 25 mm
• Percentage of Myometrial Invasion 40%
• Adenomyosis: Present, uninvolved by carcinoma
• Uterine serosa involvement: Not identified
• Lower uterine segment involvement: Present, superficial (non-myoinvasive)
• Cervical stromal involvement: Not identified
• Other tissue/organ involvement: Not identified
• Peritoneal/ascitic fluid: Not submitted / unknown
• Lymphovascular invasion (LVI): Not identified
• Margin Status: All margins negative for invasive carcinoma
• Regional lymph nodes

• Regional lymph node status: All regional lymph nodes negative for tumor cells
• Total number of pelvic nodes examined: 5
• Number of pelvic sentinel nodes examined: 3
• Total number of para-aortic nodes examined: 0
• Number of Para-aortic Sentinel Nodes Examined: 0

• Pathologic Stage Classification (pTNM, AJCC 8th Edition)

• pT Category: pT1a
• pN Category: pN0

• Additional Findings: leiomyomas

Results of immunohistochemical testing for mismatch repair (mmr) proteins, performed on block "A5":

• MLH-1: Intact nuclear expression
• PMS-2: Intact nuclear expression
• MSH-2: Intact nuclear expression
• SSH-6: Intact nuclear expression

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