Endometrial Cancer


  • A muscular organ
  • Body=Corpus
    • Two cornus at top: pierced by fallopian tubes
  • Cervix
    • Separated by the isthmus
  • Endometrium: Columnar cells forming many tubular glands
  • Myometrium: Smooth muscle fibers
  • Uterosacral and cardinal ligaments —> main supports
  • Broad and round ligaments.
  • Blood supply:
    • Uterine a.
  • Uterine lymphatic network:
    • Along the parametrium —> paracervical LN
    • Obturator LN —> External iliac & hypogastric nodes
    • —> Common iliac & periAO
    • LN from upper corpus & fundus —> periAO & upper abdominal LN
  • Femoral nodes.

Epidemiology and Risk Factors

  • Most common gynecologic malignancy
  • 75% —> confined to the uterus and cervix at the time of diagnosis
  • OS ~75%
  • Most women —> Postmenopausal
    • 25% of cases pre-menopause women
    • 5%: younger than 40yr
  • Median age —> 61 years

Risk factors:

Hormonal Factors:

  • Exposure to unopposed Estrogen
  • Nulliparity
  • Early mensturation/Late Menapause
  • Tamoxifen
  • Anovulatory cycles
  • Obesity
  • Nulliparity

Other medical conditions:

  • DM
  • HTN
  • Gallbladder disease
  • Pelvic RT

Social factors:

  • High socioeconomic
  • White race
  • Family history of endometrial ca
  • Age
  • In premenopausal women:
    • Increased incidence of infertility
    • Irregular menstrual cycles
    • History of polycystic ovarian syndrome
    • Synchronous tumors of the endometrium and ovary

Two distinct category:

  • Type I carcinomas:
    • 85% of all endometrial cancer
    • associated with hyperestrogenic state
    • low-grade
    • indoelt
  • Type II:
    • Estrogen-independent
    • Uterine atrophy
    • poor-differentiated
    • Uterine papillary serous carcinoma; clear cell carcinoma; malignant mixed mullerian tumor
    • 15%
    • Multiparous, older, and less likely to be obese
  • Familial or genetical predisposition:
    • Hereditary nonpolyposis colorectal cancer syndrome (HNPCC)=Lynch syndrome II
      • Germline mutations in mismatch repair genes (MLH1, MSH2 or MSH6) account for the majority of families with HNPCC
      • 40% to 60% lifetime risk of developing EC by age 70 and a similar risk for colon cancer.

Clinical Presentation and Natural History:

  • Postmenopausal vaginal bleeding or discharge(75%)
  • Majority at diagnosis: stage I
  • If more advanced:
    • Urinary or rectal bleeding, constipation, pain, lower extremity lymphedema; abdominal distension <— ascites; cough; hemoptysis

Malignant mesenchymal tumors of the uterus (carcinosarcomas or MMMT)

  • Menopausal patients
  • Vaginal bleeding, cramping, and a mass prolapsing through the cervix

Leiomyosarcomas are more commonly discovered incidentally in the pathologic specimen after simple hysterectomy for presumed uterine leiomyomata

  • LN(+) —> 14% of carcinosarcoma
    • But very rare in Leiomyosarcoma
      • Lung mets more common

Screening has been recommended by the American Cancer Society for women who carry, or are related to carriers of, the HNPCC mutation, starting at age 35.

Diagnostic Work-Up

  • Pathologic examination
  • Transvaginal ultrasonography —> uterine thickness
    • Thickness <5 mm ==> Risk of EC is minimal
  • Hysteroscopy to effect the dilatation and curettage
    • Insufflation of the distending medium into the canal has been associated with an increase in positive peritoneal cytology(?)
      • No clear effect on prognosis!
  • Other investigation:
    • CBC-diff —> R/O severe anemia
    • Lytes, Ca, Alb
    • KFT
    • LFT
    • CA 125 levels to predict those who are likely to deeply invasive or have extrauterine disease, and hence will benefit from extended surgical staging (ESS)
      • Pre-op: >40 U/mL ==> if not metastatic ==> Indication for full pelvic and periaortic lymphadenectomy
      • High in most advanced or metastatic patients
  • Radiology investigation:
    • CT-scan Abdo-Pelvis
    • MRI Pelvis
      • Accuracy (89%), sensitivity (90%), and specificity (88%) for deep myometrial invasion
  • FIGO staging is surgical so these investigations do not change the FIGO staging


  • Endometrial Hyperplasia
    • Estrogen-dependent lesion
    • Atypical nuclei in hyperplasia
    • Abnormal contours of endometrial glands lined by pseudostratified or stratified columnar epithelium with mitotic activity
    • Atypical hyperplasia ==> increase the risk Endometrial Ca

Carcinoma of the Endometrium

  • Endometrioid Carcinoma
    • 80% of total EC
    • Estrogen-dependent
      • Unopposed estrogen stimulation of the endometrium
    • Associated with endometrial hyperplasia
    • Type I Ca
    • Usually early stage and have a better prognosis

Pathologic features:

  • Cribriform, racemose glands with varying amounts of a solid cellular component
  • Usually no stroma between glands in carcinoma
  • These tumors are graded by the amount of glandular and solid areas present:
    • Grade 1 carcinomas have no more than 5% solid areas
    • Grade 2 tumors have 6% to 50% solid areas
    • Grade 3 endometrioid carcinomas have >50% solid areas
    • High nuclear grade results in designation of one grade higher

Higher grade tumors tend to be more deeply invasive so that there is some correlation between grade and stage in many of these neoplasms.

  • Variants of endometrioid carcinoma:
    • Endometrioid carcinoma with squamous differentiation
    • Villoglandular endometrioid carcinoma
      • It is extremely important to distinguish villoglandular endometrioid carcinomas from the much more aggressive papillary serous carcinomas of the endometrium
    • Secretory carcinoma
    • Ciliated cell variant
    • All same prognosis!
  • Nonendometrioid Carcinomas
    • 10% of all EC
    • Subtypes:
      • More common:
        • Serous
        • Clear cell
        • Mucinous
        • Undifferentiated
      • Rare subtypes:
        • Squamous
        • Transitional cell

Serous and clear cell carcinomas —> type 2 tumors; in older women with atrophic endometria.

  • Serous carcinoma
    • 5-10% of all EC
    • Non estrogen-dependent
    • Not associated with endometrial hyperplasia
      • Usually atrophic endometrium
    • Endometrial intraepithelial carcinoma may be a precursor lesion
    • Widespread lymphatic invasion even when they are superficial
    • Highly aggressive neoplasm
    • Must be distinguished from villoglandular and poorly differentiated endometrioid carcinoma
      • Irregular, uneven luminal borders caused by tufting of neoplastic cells and protrusion of large, atypical nuclei. Lymphatic invasion is usually widespread, and even occurs in the absence of myometrial invasion
    • Some papillary component, although it may be predominantly solid
    • Papillae may have fibrous stroma, but they display characteristic tufting of tumor cells without stroma
    • Large nuclei with atypia
    • Numerous mitoses
    • All are high-grade
  • Clear Cell carcinoma
    • Uncommon
    • Glandular, papillary, or solid patterns
    • Abundant clear cytoplasm
    • All are high-grade
    • Better prognosis than serous carcinoma
    • Usually distant recurrence(outside pelvis)
  • Mixed Cell Type Adenocarcinomas
    • More than one type of carcinoma —> each type comprising at least 10% of the tumor

Histologic and Molecular Features of Prognostic Significance

  • Tumor type
  • Grade
  • Depth of myometrial invasion
  • Lymphovascular space invasion (LVSI)
  • Extension to the cervix (stromal invasion)
  • Tumor extension outside the uterus
  • Association with endometrial hyperplasia —> lower grade
  • Histology:
    • Serous, clear cell, and undifferentiated carcinomas —> worse prognosis
Endometrioid Serous Ca Clear Cell Ca
MSI yes and better prognosis No
ki-67 proliferation rate low high high
p53 No-unless poor-diff Mutation No
k-ras yes low
tumor suppressor gene PTEN yes low
bcl-2, E-cadherin, β-cadherin, and estrogen and progesterone receptors yes low
C-myc, C-erbB-2 and Her2-neu low yes
Ploidi Aneuploid Diploid
  • Endometrioid: Microsatellite stability in DNA mismatch repair —> better prognosis!
    • Low ki-67 proliferation index
    • Serous have high ki-67 pi
  • Serous carcinomas: Loss of heterozygosity on several chromosomes
  • Diploid —> in well and moderate diff
  • Aneuploid —> in poor-diff
    • Aneuploid DNA: independent adverse prognostic factor: associated with:
      • Advanced stage
      • High-grade
      • Serous histology
      • Higher probability of recurrence and death from EC
      • Estrogen and progesterone receptors is associated with clinically less-aggressive behaviour

Uterine Sarcomas

  • Less frequent than endometrial carcinomas
  • WHO classification:
    • Endometrial stromal tumors
    • Smooth muscle tumors
    • Miscellaneous mesenchymal tumors(very rare)
  • Tumor stage is the most important prognostic factor for all uterine sarcomas.
  • Pathologic components necessary for diagnosis of Leiomyosarcoma:
    • Nuclear atypia
    • High mitotic rate
    • Coagulative necrosis
    • Leiomyosarcoma are solitary lesions with fleshy appearance

Endometrial stromal sarcomas are invasive tumors that have histologic features resembling normal proliferative-type endometrial stroma. These neoplasms invade the myometrium as serpiginous cords of tan-yellow tumor. Microscopically, they display small blood vessels reminiscent of those seen in the normal endometrium. Nuclei do not show marked atypia. The mitotic rate may vary, but it is usually low. In contrast, high-grade endometrial sarcomas do not resemble endometrial stroma. They contain pleomorphic, atypical nuclei, and numerous mitoses.

Mixed Epithelial and Mesenchymal Tumors
Malignant tumors in this WHO category of uterine neoplasms include adenosarcomas and MMMTs (205). Adenosarcomas of the uterus have benign glands surrounded by malignant stroma. Neoplasms containing both malignant epithelium (carcinoma) and stroma (sarcoma) are called malignant mixed müllerian tumors. The MMMTs probably represent dedifferentiation of endometrial carcinoma that is most often the serous type. These neoplasms are often bulky, necrotic, and deeply invasive. Homologous tumors have stroma that contains cell types normally seen in the uterus, in contrast to heterologous tumors that may contain cartilage, bone, and striated muscle cells. Tumor metastases usually contain the epithelial component of the neoplasm. These are poorly differentiated, aggressive neoplasms. Disease stage is the most important prognostic factor.

Natural History of Endometrial Ca:

  • Disease of perimenopausal women
  • 25% pre-menapause
  • 5% <40yr!

How endometrial cancer extends ?

  • Local Extension
    • Through Myometrium
    • Through Cervix
  • Further local penetration
    • Bladder; Rectum; Parametrium
  • Lymphatic Extension
    • Lymphatic of the upper fundus
      • Parallel to LN of ovaries —> PARA-AORTIC lymph nodes.
    • Lymphatics of middle and lower uterus
      • Through broad ligament —> to pelvic LN
      • Few of LN in broad ligaments make network with superficial inguinal LN
  • Distant Mets
    • Lung; Liver; Bone; Brain



  • Abnormal/Postmenapausal bleeding
  • Abdnormal Glandular cells in pap smear
  • Dilation and Curettage

Prognostic Factors

  • Pathologic stage
  • Pelvic and/or para-aortic node metastases influence patterns of recurrences and adversely impact recurrence-free and overall survival.
  • When LN(-)
    • Cell type
    • Grade
    • Depth of invasion
    • LVI
    • Patient age
  • strongest predictor for hematologic metastasis: —> deep myometrial invasion
  • Cervical stromal invasion and positive nodes are associated with lymphatic recurrence
  • Predictors for peritoneal mets:
    • Stage IV or stage I-III with at least two risk factors (i.e., cervical stroma invasion, positive peritoneal cytology, positive nodes, nonendometrioid histologies)

The probability for pelvic lymph node metastases is 0%, 3%, and 18% for patients with grade 1 disease without myometrial inva- sion, myometrial invasion of < 50% or grade 2/3 disease, and deep invasion, respectively (GOG, Level III) (Creaseman et al. 1987).

Risk of Pelvic Lymph Node Metastasis

G\Myometrial Invasion Absent <50% >50%
G1 0% 3% 18%
G2 3% 3% 18%
G3 3% 3% 18%
Stage Description
IA Limited to Endometrium
IB <50% of myometrium involved
IC >50% of myometrium involved
IIA Endocervical Glandular Involved
IIB Cervical Stromal Invasion
IIIA Serosa/Adnexa/Positive Peritoneal Cyt.
IIIB Vaginal Mets
IIIC Pelvic, Para-AO mets
IVA Bladder, Bowel Mucosa
IVB DM, inguinal LN
FIGO histologic grading
G1 <5% non-squamous or non-morular growth
G2 5-50% non-squamous or non-morular growth
G3 >50% non-squamous or non-morular growth

Management of Endometrial Cancer


When to use adj boost RT to vaginal vault on top of EBRT?

  • No clear evidence.
  • When there is cervical involvement.