Uterus

• ICD-10: C54.1 - malignant neoplasm of endometrium

Table 1: Staging of endometrial carcinoma as per FIGO (2018 update) and AJCC 8th edition

FIGO (2018)	AJCC (2018)	Description
I	T1	Tumor confined to the uterus
1A	T1a	Tumor confined to the endometrium or invades < 50% of the myometrial wall
1B	T1b	Tumor invades > 50% of the myometrial wall
II	T2	Tumor infiltrates cervical stroma
III	T3, N1	Tumor extends outside the uterus
IIIA	T3a	Tumor involves serosa or adnexa (direct extension or metastases)
IIIB	T3b	Tumor involves vagina or parametria (direct extension or metastases)
IIIC	N1	Tumor with pelvic lymph node metastasis
IIIC1	N1 mi	Micrometastases in pelvic lymph nodes (> 0.2 mm or 200 cells but ≤ 2 mm)
	N1a	Macrometastases in pelvic lymph nodes (> 2 mm in size)
IIIC2	N2 mi	Micrometastases in para-aortic lymph nodes (> 0.2 mm or 200 cells but ≤ 2 mm)
	N2a	Macrometastases in para-aortic lymph nodes (> 2 mm in size)
IV	T4, M1	Tumor invades bladder or bowel mucosa or involves distant organs
IVA	T4	Tumor invades bladder mucosa or bowel mucosa
IVB	M1	Distant metastases (including intra-abdominal metastases and inguinal lymph nodes; excluding metastases to vagina, pelvic serosa or adnexa)
	N0i+	Isolated tumor cells in regional lymph nodes*

* Isolated tumor cells category is recognized in the AJCC (TNM) system but not in the FIGO system

Table 2: 2023 FIGO staging of cancer of the endometrium

Stage	Description
I	Confined to the uterine corpus and ovary
IA	Disease limited to the endometrium or nonaggressive histological type (i.e., low grade endometroid, with invasion of < 50% of myometrium with no or focal lymphovascular space involvement [LVSI] or good prognosis disease)
IA1	Nonaggressive histological type limited to an endometrial polyp or confined to the endometrium
IA2	Nonaggressive histological types involving < 50% of the myometrium with no or focal LVSI
IA3	Low grade endometrioid carcinomas limited to the uterus and ovary
IB	Nonaggressive histological types with invasion of ≥ 50% of the myometrium and with no or focal LVSI
IC	Aggressive histological types limited to a polyp or confined to the endometrium
II	Invasion of cervical stroma without extrauterine extension or with substantial LVSI or aggressive histological types with myometrial invasion
IIA	Invasion of the cervical stroma of nonaggressive histological types
IIB	Substantial LVSI of nonaggressive histological types
IIC	Aggressive histological types with any myometrial involvement
III	Local or regional spread of the tumor of any histological subtype
IIIA	Invasion of uterine serosa, adnexa or both by direct extension or metastasis
IIIA1	Spread to ovary or fallopian tube (except when meeting stage IA3 criteria)
IIIA2	Involvement of uterine subserosa or spread through the uterine serosa
IIIB	Metastasis or direct spread to the vagina or to the parametria or pelvic peritoneum
IIIB1	Metastasis or direct spread to the vagina or the parametria
IIIB2	Metastasis to the pelvic peritoneum
IIIC	Metastasis to the pelvic or para-aortic lymph nodes or both
IIIC1	Metastasis to the pelvic lymph nodes
IIIC1i	Micrometastasis
IIIC1ii	Macrometastasis
IIIC2	Metastasis to para-aortic lymph nodes up to the renal vessels, with or without metastasis to the pelvic lymph nodes
IIIC2i	Micrometastasis
IIIC2ii	Macrometastasis
IV	Spread to the bladder mucosa or intestinal mucosa or distance metastasis
IVA	Invasion of the bladder mucosa or the intestinal / bowel mucosa
IVB	Abdominal peritoneal metastasis beyond the pelvis
IVC	Distant metastasis, including metastasis to any extra or intra-abdominal lymph nodes above the renal vessels, lungs, liver, brain or bone

• Disease limited to low grade endometrioid carcinomas involving the endometrium and ovaries (stage IA3) must be distinguished from extensive spread of the endometrial carcinoma to the ovary (stage IIIA1), by the following criteria
  1. No more than superficial myometrial invasion is present (< 50%)
  2. Absence of extensive / substantial LVSI
  3. Absence of additional metastases
  4. The ovarian tumor is unilateral, limited to the ovary, without capsule invasion / rupture (equivalent to pT1a)
• LVSI as defined in WHO 2021: extensive / substantial, ≥ 5 vessels involved
• Aggressive histological types include serous carcinomas, clear cell carcinomas, mesonephric-like carcinomas, gastrointestinal type mucinous endometrial carcinoma, undifferentiated carcinomas and carcinosarcomas
  • For endometrial endometrioid carcinomas, grade is based on the proportion of solid areas: low grade = grade 1 (≤ 5%) and grade 2 (6 - 50%); and high grade = grade 3 (> 50%)
  • Nuclear atypia excessive for the grade raises the grade of a grade 1 or 2 tumor by one
• Nonaggressive histological types are composed of low grade (grade 1 and 2) endometrial endometrioid carcinomas

Table 3: 2023 FIGO endometrial cancer stage with molecular classification (for patients with early endometrial cancer [stages I and II after surgical staging])

Stage	Description
IAmPOLEmut	POLEmut endometrial carcinoma, confined to the uterine corpus or with cervical extension, regardless of the degree of LVSI or histological type
IICmp53abn	p53abn endometrial carcinoma confined to the uterine corpus with any myometrial invasion, with or without cervical invasion and regardless of the degree of LVSI or histological type

• pTX: primary tumor cannot be assessed
• pT0: no evidence of primary tumor
• pT1 (I): tumor confined to corpus uteri
  • pT1a (IA): tumor limited to endometrium or invades < 50% of the myometrium
  • pT1b (IB): tumor invades ≥ 50% of the myometrium
• pT2 (II): tumor invades stromal connective tissue of the cervix but does not extend beyond uterus
• pT3 (III): tumor involving serosa, adnexa, vagina or parametrium
  • pT3a (IIIA): tumor involves serosa or adnexa (direct extension or metastasis)
  • pT3b (IIIB): vaginal involvement (direct extension or metastasis) or parametrial involvement
• pT4 (IVA): tumor invades bladder mucosa or bowel mucosa (bullous edema is not sufficient to classify a tumor as pT4)

Notes:

• Endocervical glandular involvement only should be considered as stage I and not stage II
• pTis is no longer a staging category
• Myometrial invasion:
  • According to the ISGYP recommendations, this variable should be reported as none or less than half (< 50%) or half or more (≥ 50%) of the myometrial wall thickness
  • This approach is relatively easy and obviates in most cases the need to locate the endomyometrial junction (which is difficult when the junction is completely obliterated or not sampled in the sections)
  • In addition, other variables than can be reported include myoinvasion in terms of absolute numbers (invasive carcinoma depth in mm / myometrial thickness in mm) and the percentage of myometrial wall involved by tumor (a derivative of the absolute measurements in mm)
  • Assessment should be performed at the deepest point of tumor invasion on a full thickness section of the wall spanning from mucosal surface to serosa (Figure 1)
  • Involvement of adenomyosis by carcinoma does not by itself portend a worse prognosis
    • These cases behave similarly to stage IA tumors (Gynecol Oncol 1990;37:401, Int J Gynecol Pathol 2010;29:445)
    • Carcinoma is confined to the endometrium / adenomyosis when:
      • Focus of carcinoma has a round or ovoid shape with a smooth and convex outer contour (regardless of its size) (Figure 2)
      • Outer contour smoothly continues with adjacent uninvolved endomyometrial interface
      • Residual endometrial type stroma or benign endometrial glands are present in the periphery or within the focus
      • There is no significant desmoplastic reaction
  • If myometrial invasion arises from areas of adenomyosis, the location of the deepest myoinvasive point with respect to the entire uterine wall should be recorded (inner versus outer wall) (Figure 3)
    • There is controversy in whether to assign stage IA or IB to a carcinoma with foci of invasion in the outer wall arising from adenomyosis; the ISGyP endometrial carcinoma consensus recommends:
      • If the foci are few and clearly arising from deep adenomyosis, it is advisable to categorize these lesions as stage IA; there is emerging evidence showing that these lesions behave more indolently, similar to stage IA tumors (Int J Gynecol Pathol 2019;38:S93, Mod Pathol 2019;32:1)
      • If, on the other hand, myoinvasive carcinoma from adenomyosis is rather extensive and seen throughout the wall, it is prudent to classify the tumor as stage IB (Int J Gynecol Pathol 2019;38:S93)
  • 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
    • Same recommendation applies to tumors arising from or involving an endometrial polyp
  • If the carcinoma at the point of deepest invasion involves a leiomyoma, the myometrial thickness should include the leiomyoma (Int J Gynecol Pathol 2019;38:S93)
  • Lymphovascular space invasion (LVI) should not be included in the assessment of myometrial invasion
• Cervical stromal involvement:
  • Presence of cervical stromal involvement defines stage II
  • Depth of invasion into the cervical stroma and margin status should be reported, as it may influence adjuvant radiation treatment (Brachytherapy 2019;18:606)
  • Assessment of cervical involvement is inconsistent between gynecologic pathologists (Am J Surg Pathol 2011;35:289)
  • Uppermost endocervical mucinous gland in the section should be considered as the upper limit of the endocervix (Adv Anat Pathol 2018;25:71)
    • If unsure whether tumor is in the cervix or lower uterine segment, identify the most proximal endocervical mucinous gland, which will define the boundary between these anatomic locations (Figures 4 and 5)
  • Stromal invasion can be seen as obviously infiltrative glands or cells with desmoplasia or as complex architecture relative to the normal endocervical glandular compartment
  • Carcinoma confined to the surface or to endocervical glands can be reported but does not modify stage or impact prognosis
  • Reporting the depth of cervical stromal invasion by endometrial carcinoma is optional
    • The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology Uterine Neoplasms lists deep cervical stromal invasion as an adverse risk factor in patients with stage II endometrial carcinoma (NCCN: Uterine Neoplasms [Accessed 9 February 2023])
    • Estimation of depth of cervical wall invasion may be used to determine the type of adjuvant radiation (Brachytherapy 2019;18:606)
    • Depth of invasion into the cervix can be measured in mm, providing the thickness of the cervical wall at that level in mm as well
    • Alternatively, it can be reported in terms of invasion confined to 33% of the wall, 66% of the wall or extending to the outer third of the wall
  • It is recommended to measure the distance between tumor and margin: distal cervical / vaginal mucosa and parametrial margins
• Serosal involvement:
  • Involvement of the uterine serosa is an adverse prognostic factor and warrants a stage IIIA
  • Involvement of the serosa is diagnosed when the tumor perforates through the mesothelium lined outer surface of the uterus; this is seen as an area of disruption of the serosa with tumor involvement, sometimes with soft tissue or other structures attached to it
  • Sometimes a desmoplastic stromal reaction is present
    • Locating the serosal plane flanking the area in question and extending the plane through the area of desmoplasia can be helpful; serosal involvement is considered present if there is disruption of that plane or carcinoma extends beyond the plane (Int J Gynecol Pathol 2022;41:S90)
  • According to ISGYP guidelines, tumor that infiltrates the entire myometrial thickness and reaches submesothelial fibroconnective tissue should also be reported as serosal involvement (Int J Gynecol Pathol 2019;38:S93)
• 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
  • However, it is often difficult to separate these scenarios on pathologic examination and one may only suggest one possibility over the others
  • Synchronous ovarian carcinoma is present in up to 30% of reproductive age women with endometrial cancer (Int J Womens Health 2014;6:691, Obstet Gynecol 2005;106:693)
    • When present, synchronous ovarian and endometrial carcinomas usually have the same histologic type (vast majority are low grade endometrioid)
    • Synchronous endometrial and ovarian endometrioid carcinoma have good prognosis, similar to those with only endometrial or only ovarian stage I cancer (Int J Gynecol Cancer 2014;24:54, Clin Cancer Res 2008;14:5840)
  • 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 lymphovascular space invasion
    • Different patterns of mismatch repair (MMR) or hormone receptor expression by IHC
  • Conversely, secondary ovarian involvement by a primary endometrial tumor should be considered when:
    • Endometrial tumor has deep myometrial invasion, lymphovascular space invasion, serosal or parametrial involvement
    • Bilateral ovarian involvement
    • Ovarian tumor involves surface and has extensive lymphovascular space invasion
    • Both tumors show similar MMR and hormone receptor expression by IHC

• 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 para-aortic lymph nodes, with or without positive pelvic lymph nodes
  • pN2mi: regional lymph node metastasis (> 0.2 mm but ≤ 2 mm in diameter) to pelvic lymph nodes
  • pN2a: regional lymph node metastasis (> 2 mm in diameter) to pelvic lymph nodes

Notes:

• Emerging data shows that patients with low volume disease (isolated tumor cells and micrometastases) have better recurrence free survival compared to those with macrometastatic nodal disease (Ann Surg Oncol 2016;23:1653, Gynecol Oncol 2017;146:240)
• When measuring size of tumor within lymph nodes, tumor foci should be measured separately; then the largest individual size is reported
• It is recommended to report extranodal extension if present (although it is not a mandatory staging criterion)

• FIGO grading applies to endometrial carcinomas of the endometrioid type:
  • Grade 1: ≤ 5% of a nonsquamous or nonmorular solid growth pattern
  • Grade 2: 6 - 50% of a nonsquamous or nonmorular solid growth pattern
  • Grade 3: > 50% of a nonsquamous or nonmorular solid growth pattern

Notes:

• Areas of squamous and morular differentiation are excluded from the solid component
• Notable nuclear atypia, inappropriate for the architectural grade, raises the grade by 1 (1 to 2 and 2 to 3)
• NCCN guidelines group FIGO grade 1 and 2 as low grade carcinoma and FIGO grade 3 as high grade (NCCN: Uterine Neoplasms [Accessed 9 February 2023])
• Nonendometrioid endometrial carcinomas are by definition high grade: serous, clear cell, undifferentiated / dedifferentiated, mixed carcinoma and carcinosarcoma

Contributed by Carlos Parra-Herran, M.D.

What is the defining feature of stage T3a / IIIA carcinoma of the uterine corpus?

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

C. Involvement of uterine serosa or adnexa. Serosal or adnexal involvement by endometrial carcinoma is the defining feature of stage T3a (AJCC) / IIIA (FIGO). Bladder / rectal mucosal involvement, cervical stromal involvement, vaginal / parametrial involvement and lymph node metastases are the defining features of stages T4 / IVA, T2 / II, T3b / IIIB and N1 / IIIC1, respectively.

Comment here

Reference: Uterus - Staging-carcinoma and carcinosarcoma

What is the defining feature of stage T2 / II carcinoma of the uterine corpus?

1. Involvement of bladder or rectal mucosa
2. Involvement of cervical epithelium
3. Involvement of cervical stromal tissue
4. Involvement of vagina or parametrial tissue
5. Myometrial invasion involving 50% of the uterine wall or more

C. Involvement of cervical stromal tissue. Cervical stromal involvement by endometrial carcinoma is the defining feature of stage T2 (AJCC) / II (FIGO). Bladder / rectal mucosal involvement, vaginal / parametrial involvement and outer half myometrial invasion are the defining features of stages T4 / IVA, T3b / IIIB and T1b / IB, respectively. Cervical involvement confined to the epithelium does not affect staging.

Comment here

Reference: Uterus - Staging-carcinoma and carcinosarcoma