Corpus Uteri Carcinoma

Todd M. Blodgett, MD

(T) Primary Tumor for Uterine Carcinomas			Adapted from 7th edition AJCC Staging Forms.
TNM		FIGO	Definitions
TX			Primary tumor cannot be assessed
T0			No evidence of primary tumor
Tis¹			Carcinoma in situ (preinvasive carcinoma)
T1		I	Tumor confined to corpus uteri
	T1a	IA	Tumor limited to endometrium or invades < 1/2 of the myometrium
	T1b	IB	Tumor invades ≥ 1/2 of the myometrium
T2		II	Tumor invades stromal connective tissue of the cervix but does not extend beyond uterus²
T3a		IIIA	Tumor invades serosa &/or adnexa (direct extension or metastasis)
T3b		IIIB	Vaginal involvement (direct extension or metastasis) or parametrial involvement
T4		IVA	Tumor invades bladder mucosa &/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)
¹FIGO no longer includes stage 0 (Tis). ²Endocervical glandular involvement only should be considered as stage I and not as stage II.

(N) Regional Lymph Nodes for Uterine Carcinomas		Adapted from 7th edition AJCC Staging Forms.
TNM	FIGO	Definitions
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1	IIIC1	Regional lymph node metastasis to pelvic lymph nodes
N2	IIIC2	Regional lymph node metastasis to paraaortic lymph nodes, with or without positive pelvic lymph nodes

(M) Distant Metastasis for Uterine Carcinomas		Adapted from 7th edition AJCC Staging Forms.
TNM	FIGO	Definitions
M0		No distant metastasis
M1	IVB	Distant metastasis (includes metastasis to inguinal lymph nodes intraperitoneal disease, or lung, liver, or bone; excludes metastasis to paraaortic lymph nodes, vagina, pelvic serosa, or adnexa)

AJCC Stages/Prognostic Groups for Uterine Carcinomas¹			Adapted from 7th edition AJCC Staging Forms.
Stage		T	N	M
0		Tis	N0	M0
I		T1	N0	M0
	IA	T1a	N0	M0
	IB	T1b	N0	M0
II		T2	N0	M0
III		T3	N0	M0
	IIIA	T3a	N0	M0
	IIIB	T3b	N0	M0
	IIIC1	T1-T3	N1	M0
	IIIC2	T1-T3	N2	M0
IVA		T4	Any N	M0
IVB		Any T	Any N	M1
¹Carcinosarcomas should be staged as carcinoma.

(T) Primary Tumor for Leiomyosarcoma and Endometrial Stromal Sarcoma¹			Adapted from 7th edition AJCC Staging Forms.
TNM		FIGO	Definitions
TX			Primary tumor cannot be assessed
T0			No evidence of primary tumor
T1		I	Tumor limited to the uterus
	T1a	IA	Tumor ≤ 5 cm in greatest dimensions
	T1b	IB	Tumor > 5 cm
T2		II	Tumor extends beyond the uterus, within the pelvis
	T2a	IIA	Tumor involves adnexa
	T2b	IIB	Tumor involves other pelvic tissues
T3		III²	Tumor infiltrates abdominal tissues
	T3a	IIIA	1 site
	T3b	IIB	> 1 site
T4		IVA	Tumor invades bladder or rectum
¹Simultaneous tumors of the uterine corpus and ovary/pelvis in association with ovarian/pelvic endometriosis should be classified as independent primary tumors. ²In this stage lesions must infiltrate abdominal tissues and not just protrude into the abdominal cavity.

(N) Regional Lymph Nodes for Leiomyosarcoma and Endometrial Stromal Sarcoma		Adapted from 7th edition AJCC Staging Forms.
TNM	FIGO	Definitions
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1	IIIC	Regional lymph node metastasis

(M) Distant Metastasis for Leiomyosarcoma and Endometrial Stromal Sarcoma		Adapted from 7th edition AJCC Staging Forms.
TNM	FIGO	Definitions
M0		No distant metastasis
M1	IVB	Distant metastasis (excluding adnexa, pelvic and abdominal tissues)

(T) Primary Tumor for Adenosarcoma¹			Adapted from 7th edition AJCC Staging Forms.
TNM		FIGO	Descriptions
TX			Primary tumor cannot be assessed
T0			No evidence of primary tumor
T1		I	Tumor limited to the uterus
	T1a	IA	Tumor limited to the endometrium/endocervix
	T1b	IB	Tumor invades to < 1/2 of the myometrium
	T1c	IC	Tumor invades ≥ 1/2 of the myometrium
T2		II	Tumor extends beyond the uterus, within the pelvis
	T2a	IIA	Tumor involves adnexa
	T2b	IIB	Tumor involves other pelvic tissues
T3		III²	Tumor involves abdominal tissues
	T3a	IIIA	1 site
	T3b	IIIB	> 1 site
T4		IVA	Tumor invades bladder or rectum
¹Simultaneous tumors of the uterine corpus and ovary/pelvis in association with ovarian/pelvic endometriosis should be classified as independent primary tumors. ²In this stage lesions must infiltrate abdominal tissues and not just protrude into the abdominal cavity.

(N) Regional Lymph Nodes for Adenosarcoma		Adapted from 7th edition AJCC Staging Forms.
TNM	FIGO	Descriptions
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1	IIIC	Regional lymph node metastasis

(M) Distant Metastasis for Adenosarcoma		Adapted from 7th edition AJCC Staging Forms.
TNM	FIGO	Definitions
M0		No distant metastasis
M1	IVB	Distant metastasis (excluding adnexa, pelvic and abdominal tissues)

AJCC Stages/Prognostic Groups for Uterine Sarcomas				Adapted from 7th edition AJCC Staging Forms.
Stage		T	N	M
I		T1	N0	M0
	IA¹	T1a	N0	M0
IB¹	T1b	N0	M0
IC²	T1c	N0	M0
II		T2	N0	M0
IIIA		T3a	N0	M0
IIIB		T3b	N0	M0
IIIC		T1, T2, T3	N1	M0
IVA		T4	Any N	M0
IVB		Any T	Any N	M1
¹Stage IA and IB differ from those applied for leiomyosarcoma and endometrial stromal sarcoma. ²Stage IC does not apply for leiomyosarcoma and endometrial stromal sarcoma.

Coronal graphic shows T1 tumors, those confined to corpus uteri. T1a tumors are limited to the endometrium

or involve less than 1/2 of the myometrium

; T1b tumors invade 1/2 or more of the myometrium

indicated by the tumor traversing the dotted horizontal line, marking the halfway plane of the myometrium.

Coronal graphic shows a typical T2 tumor

, which invades the cervix but does not extend beyond the uterus. Endocervical glandular involvement only should be considered stage I and not stage II.

Coronal graphic shows stage III disease, both T3a, which is tumor involving the serosa &/or adnexa

, and T3b, which is tumor that involves the vagina

by direct extension or metastases or parametrial involvement.

Sagittal graphic shows stage IVA disease with tumor that invades the bladder mucosa

/or bowel mucosa

. However, bullous edema is not sufficient to classify a tumor as T4. Stage IVB is defined as distant metastasis, including metastasis to inguinal lymph nodes, peritoneum, lung, liver, or bone.

Coronal graphic shows an example of N1 disease, defined as regional lymph node metastasis to pelvic lymph nodes

Coronal graphic shows an example of N2 disease, defined as regional lymph node metastasis to paraaortic lymph nodes

with or without positive pelvic lymph nodes

	METASTASES, ORGAN FREQUENCY
	Lung	32%
	Liver	7%
	Other sites (adrenals, breast, brain, bone, skin)	4%

OVERVIEW

General Comments

Corpus uteri carcinoma is the most common gynecologic cancer in USA
- Also most common gynecologic cancer in many other developed countries
95% of uterine malignancies are endometrial carcinomas
Malignancies of uterine corpus
- Cancers above level of the cervical os involving upper 2/3 of uterus
Endometrial cancer can be divided into 2 types
- Type I
  - Endometrioid histology
  - Includes the very common endometrioid adenocarcinoma
  - Makes up to 70-80% of new diagnoses in USA
  - Association with chronic estrogen exposure
  - Premalignant disease, such as endometrial hyperplasia, often precedes cancer
- Type II
  - Nonendometrioid histology
  - Includes papillary serous and clear cell carcinomas
  - Aggressive clinical course
  - No association with estrogen exposure has been identified
  - Not associated with readily observable premalignant disease

Classification

Primary malignant tumors (WHO classification)
- Endometrial carcinoma
  - Endometrioid adenocarcinoma
    - Several forms
  - Mucinous adenocarcinoma
  - Serous adenocarcinoma
  - Clear cell adenocarcinoma
  - Mixed cell adenocarcinoma
  - Squamous cell carcinoma
  - Transitional cell carcinoma
  - Small cell carcinoma
  - Others
- Mesenchymal tumors
  - Endometrial stromal and related tumors
    - Endometrial stromal sarcoma, low grade
    - Endometrial stromal nodule
    - Undifferentiated endometrial sarcoma
  - Smooth muscle tumors
    - Leiomyosarcoma (epithelioid and myxoid variants)
    - Smooth muscle tumor of uncertain malignant potential
    - Leiomyoma, not otherwise specified
  - Miscellaneous mesenchymal tumors
- Mixed epithelial and mesenchymal tumors
  - Carcinosarcoma
  - Adenosarcoma
  - Carcinofibroma
  - Adenofibroma
  - Adenomyoma
- Gestational trophoblastic disease
  - Trophoblastic neoplasms
    - Choriocarcinoma
    - Placental site trophoblastic tumor
    - Epithelioid trophoblastic tumor
  - Molar pregnancies
    - Hydatiform mole
  - Nonneoplastic
    - Nonmolar trophoblastic lesions
- Miscellaneous tumors
  - Sex cord-like tumors
  - Neuroectodermal tumors
  - Melanotic paraganglioma
  - Tumors of germ cell type
  - Others
- Lymphoid and hematopoietic tumors
  - Malignant lymphoma
  - Leukemia

PATHOLOGY

Routes of Spread

Direct extension
- Most common
Lymphatic spread
- Common nodes include
  - Pelvic (N1)
  - Paraaortic (N2)
  - Inguinal nodes (less common)
Hematogenous spread
- Lungs
- Liver
- Bone
- Skin
- Brain (uncommon)
Peritoneal spread
- Intraperitoneal implants
- Common in papillary serous carcinoma

General Features

Comments
- Endometrioid adenocarcinoma
  - Represents 75-80% of endometrial cancers
Genetics
- Rare hereditary form
  - Lynch II family cancer syndrome
    - Nonpolyposis colorectal cancer
    - Ovarian cancer
    - Endometrial cancer
- Type I endometrial cancers
  - Microsatellite instability
  - KRAS mutations
  - PTEN mutations
  - DNA mismatch repair defects
  - Mutations in p53
    - Less frequent
    - Late occurrence in development (differing from type II cancers)
- Type II endometrial cancers
  - Mutations in p53
    - Common mutation
  - Nondiploid karyotype
  - Her-2/neu (c-erB-2) overexpression
Etiology
- Carcinoma that spontaneously arises from endometrium that is atrophic or inert
Epidemiology & cancer incidence
- Estimated 2009 statistics in USA for endometrial cancer overall
  - 42,160 new cases
  - 7,780 deaths
- Represents 6% of all cancers in women
- Risk factors
  - Estrogen hormone replacement therapy
    - Increases risk 2-10x
  - Obesity
    - Increases risk 2-20x
  - Polycystic ovarian syndrome (PCOS)
    - Increases risk 3x
  - Chronic anovulation
    - Increases risk 3x
  - Tamoxifen
    - Increases risk 2-3x
  - Nulliparity
    - Increases risk 2-3x
  - Early menarche
    - Increases risk 2-3x
  - Late menopause
    - Increases risk 2-3x
  - Hypertension
    - Increases risk 2-3x
  - Diabetes
    - Increases risk 2-3x
- Demographics
  - Age
    - Most common in 6th and 7th decades of life
  - Ethnicity
    - Common in Eastern Europe and USA
    - Uncommon in Asia
Associated diseases, abnormalities
- Endometrial hyperplasia
  - Associated with 20-40%

Microscopic Pathology

H&E
- Histological patterns can be broadly divided into type I and type II endometrial cancers
  - Endometrioid histology
  - Nonendometrioid histology
- Histopathologic types
  - Endometrioid carcinomas
    - Most common endometrial cancer (75-80% of cases)
    - Most are well differentiated
    - Back-to-back glandular proliferation of endometrium lacking intervening stroma
  - Villoglandular adenocarcinoma
    - Many villous fronds
    - Delicate central fibrovascular cores of villi and simpler branching pattern differentiates it from papillary serous carcinoma
  - Adenocarcinoma with benign squamous elements, squamous metaplasia, or squamous differentiation (adenoacanthoma)
  - Adenosquamous carcinoma (mixed adenocarcinoma and squamous cell carcinoma)
  - Mucinous adenocarcinoma
  - Serous adenocarcinoma (papillary serous)
    - Bizarre nuclei
    - Scant cytoplasm
    - Nuclear stratification
    - Marked nuclear atypia
    - Complex papillary architecture
    - Psammoma bodies (seen in 30% of cases)
    - Aggressive nature
    - Often presents late
  - Clear cell carcinoma
    - Possible patterns include tubulocystic, papillary, or solid
    - Psammoma bodies may be present but not as commonly as in papillary serous tumors
    - Clear cell appearance due to glycogen
    - Myometrial invasion is common (80% of carcinomas)
    - Aggressive nature
    - Often presents late
  - Squamous cell carcinoma
  - Undifferentiated carcinoma
  - Malignant mixed mesodermal tumors