endometrial cancer (carcinoma)

Etiology

• risk factors:
  • age > 45 years, menopause b infertility or anovulatory cycles
    • anovulatory bleeding
  • obesity
  • nulliparity, early menarche, late menopause
  • estrogen unopposed by progesterone (see Million Women Study)
  • tamoxifen
  • family history of cancer: endometrium, breast, or GI tract
    • Lynch syndrome, Cowden syndrome
  • sugar-sweetened beverages increases risk of estrogen-dependent endometrial cancer in postmenopausal women (RR=1.4)
• protective factors:
  • high progesterone levels of pregnancy
  • use of oral contraceptive &/or hormone-replacement therapy containing both estrogen & progesterone
  • smoking
  • low body mass index
  • bisphosphonates
  • breast feeding > 3 months

Epidemiology

• most common gynecologic cancer
• peak incidence if in 6th & 7th decades of life
• black wonen with increased risk of more aggressive cancers & death from non-endometroid endometrial cancer

Pathology

• endometrial hyperplasia progresses to endometrial cancer in 10-30% of patients

Microscopic pathology

histopathologic types

• endometrioid carcinoma (80%)
• villoglandular adenocarcinoma
• adenocarcinoma with benign squamous elements, squamous metaplasia, or squamous differentiation (adenoacanthoma)
• adenosquamous carcinoma (mixed adenocarcinoma and squamous carcinoma)
• mucinous adenocarcinoma
• serous adenocarcinoma (papillary serous)
• clear cell adenocarcinoma
• squamous cell carcinoma
• undifferentiated carcinoma
• malignant mixed mesodermal tumors

Genetics

• susceptibility associated with defects in MSH2, MSH3, MSH6, MLH1
  • MLH1 & MSH2 gene mutations are assosiated with Lynch syndrome
• other implicated genes ANLN, KIAA1324, PELP1, CASC2, VTCN1, CDH1, PTEN

Clinical manifestations

• abnormal uterine bleeding
  • irregular vaginal bleeding in women > 40 years of age
  • postmenopausal bleeding
• vaginal discharge

Laboratory

• endometrial cancer genotyping

Diagnostic procedures

• Pap smear with atypical glandular cells or endometrial cells
• hysteroscopy with endometrial biopsy if endometrial thickness > 5 mm
• vaginal cytology after treatment for endometrial cancer of little or no value

Radiology

• transvaginal ultrasound
  • thickened, nodular or irregular endometrium (endometrial stripe)
    • if endometrial thickness > 5 mm, hysteroscopy with endometrial biopsy
  • fluid in the endometrial cavity
  • screening for endometrial cancer not been shown to be cost-effective
• imaging is NOT more effective than physical exam for diagnosing recurrent cancer

Staging

AJCC/TNM/FIGO

TNM	FIGO	Assessment
TX	-	primary tumor cannot be assessed
T0	-	no evidence of primary tumor
Tis	0	carcinoma in situ
T1	I	tumor confined to corpus uteri
T1a	IA	tumor limited to endometrium
T1b	IB	tumor invades less than 1/2 of myometrium
T1c	IC	tumor invades 1/2 or more of myometrium
T2	II	tumor invades cervix , does not extend beyond uterus
T2a	IIA	tumor limited to glandular epithelium of endocervix. No evidence of connective tissue stromal invasion.
T2b	IIB	invasion of stromal connective tissue of cervix
T3	III	local &/or regional spread
T3a	IIIA	tumor involves serosa &/or adnexa (direct extension or metastasis) &/or cancer cells in ascites or peritoneal washings
T3b	IIIB	vaginal involvement (direct extension or metastasis)
T4	IVA	tumor invades bladder mucosa &/or bowel mucosa
NX	-	regional lymph nodes cannot be assessed
N0	-	no regional lymph node metastasis
N1	IIIC	regional lymph node metastasis to pelvic &/or para-aortic nodes
MX	-	distal metastases cannot be assessed
M0	-	no distant metastasis
M1	IVB	distant metastasis (includes abdominal lymph nodes other than para-aortic &/or inguinal lymph nodes; excludes metastasis to vagina, pelvic serosa or adnexa)

stage	T	N	M
stage 0	Tis	N0	M0
stage I	T1	N0	M0
stage IA	T1a	N0	M0
stage IB	T1b	N0	M0
stage IC	T1c	N0	M0
stage II	T2	N0	M0
stage IIA	T2a	N0	M0
stage IIB	T2b	N0	M0
stage III	T3	N0	M0
stage IIIA	T3a	N0	M0
stage IIIB	T3b	N0	M0
stage IIIC	T1	N1	M0
-	T2	N1	M0
-	T3	N1	M0
stage IVA	T4	N_	M0
stage IVB	T_	N_	M1

Histologic grading:

GX: grade cannot be assessed

G1: well differentiated

G2: moderately differentiated

G3-4: poorly differentiated or undifferentiated

G1: 5% or less of a non-squamous or non-morular solid growth pattern

G2: 6% - 50% of a non-squamous or non-morular solid growth pattern

G3: more than 50% of non-squamous or non-morular solid growth pattern

• notable nuclear atypia inappropriate for architectural grade raises grade to 3
• serous, clear cell and mixed mesodermal tumors are high risk & considered grade 3
• adenocarcinomas with benign squamous elements are graded according to the nuclear grade of the glandular component.

• stage 1: confined to corpus
• stage 2: involves corpus & cervix
• stage 3: extends outside the uterus, but not outside the pelvis
• stage 4: extends outside the pelvis or involves the bladder or rectum

stage	T	N	M
stage 0	Tis	N0	M0
stage I	T1	N0	M0
stage IA	T1a	N0	M0
stage IB	T1b	N0	M0
stage IC	T1c	N0	M0
stage II	T2	N0	M0
stage IIA	T2a	N0	M0
stage IIB	T2b	N0	M0
stage III	T3	N0	M0
stage IIIA	T3a	N0	M0
stage IIIB	T3b	N0	M0
stage IIIC	T1	N1	M0
-	T2	N1	M0
-	T3	N1	M0
stage IVA	T4	N_	M0
stage IVB	T_	N_	M1

Histologic grading:

GX: grade cannot be assessed

G1: well differentiated

G2: moderately differentiated

G3-4: poorly differentiated or undifferentiated

G1: 5% or less of a non-squamous or non-morular solid growth pattern

G2: 6% - 50% of a non-squamous or non-morular solid growth pattern

G3: more than 50% of non-squamous or non-morular solid growth pattern

• notable nuclear atypia inappropriate for architectural grade raises grade to 3
• serous, clear cell and mixed mesodermal tumors are high risk & considered grade 3
• adenocarcinomas with benign squamous elements are graded according to the nuclear grade of the glandular component.

• stage 1: confined to corpus
• stage 2: involves corpus & cervix
• stage 3: extends outside the uterus, but not outside the pelvis
• stage 4: extends outside the pelvis or involves the bladder or rectum

Complications

• recurrence of gynecologic cancer most often detected by symptoms or physical examination

Management

• surgical resection
  • total abdominal hysterectomy with bilateral salpingo-oophorectomy
  • radiation therapy &/or chemotherapy may be added in higher risk patients
• radiation therapy alone in high-risk surgical patients
• chemotherapy is not very effective
  • cisplatin
  • carboplatin
  • doxorubicin
  • epirubicin
  • paclitaxel
• recurrent endometrial cancer
  • symptom monitoiring & physical examination as effective as imaging for diagnosis of recurrent endometrial cancer
  • treatment of recurrent endometrial cancer is poor
    • combination of medroxyprogesterone acetate & tamoxifen
      • median progression-free survival 3.8 months
    • combination of everolimus & letrozole
      • 25% response
      • median progression-free survival 6.3 months
• prognosis
  • 5 year survival by stage at presentation
    • stage 1: 89%
    • stage 2: 80%
    • stage 3: 30%
    • stage 4: 9%
• storing of embryos prior to therapy is an option in women of reproductive age
• genetic classification of endometrial cancer may better estimate prognosis & facilitate treatment
• screening:
  • not recommended, does not reduce mortality
  • atypical endometrial cells reported on Pap Smear should be further evaluated
  • carriers of MLH1 gene & MSH2 gene mutations should be screened by endometrial biopsy (Lynch syndrome)

More general terms

• uterine cancer
• carcinoma

Additional terms

• Breast Cancer Detection Demonstration Project
• endometrial cancer genotyping
• Million Women Study

Patient information

endometrial cancer patient information

Database

• OMIM: https://mirror.omim.org/entry/608089