Endometrial Cancer Pathologic/Molecular Features

Question 1

What proportion of EC tumors are endometrioid vs non-endometrioid?

Answer 1

80% vs 20%

Question 2

What’s the pathophysiology of endometrioid tumors?

Answer 2

• In both premenopausal and postmenopausal patients, endometrioid tumors typically arise from endometrial CAH with epithelial atypia.
• Relative estrogen excess, such as that associated with obesity, the use of unopposed estrogen for hormone-replacement therapy, and estrogen-producing tumors (e.g., ovarian granulosa-cell tumors), predispose women to the development of endometrioid-type endometrial carcinoma.

Question 3

What’s the pathophysiology with nonendometrioid tumors?

Answer 3

• Nonendometrioid tumors, in contrast, have a hormone-independent pathogenesis and no known precursor lesions.
• They typically arise in older postmenopausal patients.

Question 4

How are EC endometrioid tumors graded?

Answer 4

• FIGO system with grade 1 - 3 according to relative proportions of the glandular and solid-tumor components
  
  • Grade 1 having a solid-tumor component of <6%
  • Grade 2 having a solid tumor component 6 - 50%
  • Grade 3 having a solid tumor component >50%
  • Grade 1 and grade 2 tumors are considered low grade and generally are associated with a good prognosis, whereas
    grade 3 tumors are associated with an intermediate-
    to-poor prognosis

Question 5

Discuss the features and prognosis of non-endometrioid histologies

Answer 5

• Nonendometrioid endometrial carcinomas include endometrial serous carcinoma, clear-cell carcinoma, and carcinosarcoma.
• Endometrial serous carcinoma is the most common of the nonendometrioid tumors
  
  • typically has a poor prognosis, with extrauterine disease in up to 37% of patients with no evidence of endometrial stromal or myometrial invasion.
• Overall, the prognosis is worse with clear-cell carcinoma than
• with endometrial serous carcinoma,
  
  • although some studies have suggested that there are subgroups of women with clear-cell carcinoma who have longer survival.
• Carcinosarcomas (or malignant mixed müllerian tumors) contain distinct malignant epithelial (carcinomatous) and malignant mesenchymal (sarcomatous) components.
  
  • Pathologists regard carcinosarcoma as a high-grade metaplastic carcinoma.
  • Its pattern of recurrence and metastasis mirrors that of carcinoma rather than that of sarcoma, and clonality and mutation studies have shown that the carcinomatous and sarcomatous components derive from the same precursor.
  • Carcinosarcomas typically have worse outcomes than endometrioid, clear-cell, and serous carcinomas.

Question 6

Which mutations are seen more commonly in endometrioid histologies? What is the clinical significance of these mutations?

Answer 6

Question 7

Which mutations are more commonly seen in non-endometrioid histologies?

What is the clinical significance of these mutations?

Answer 7

Figure

copy number low = blue

copy number high = red

Question 8

Is the PI3K-AKT pathway common across all EC tumors?

Answer 8

Common across all endometrioid tumors and can be detected even in some non-endometrioid tumors

Question 9

Is CTNNB1 and MLH1 promoter methylation seen more in endometrioid or non-endometrioid?

TP53 mutations are seen in which endometrial tumors?

Answer 9

• CTNNB1 and MLH1 promoter methylation
  
  • Almost universally seen in endometrioid
• TP53 mutations
  
  • enriched in non-endometrioid tumors
  • subset of grade 3 endometrioid tumors

Question 10

TCGA characterized which EC histologies?

Answer 10

• Endometrioid carcinoma, endometrial serous carcinoma, and, to a lesser extent, carcinosarcoma have been characterized in TCGA
• Not clear cell

Question 11

What’s the significance of POLE mutations in EC?

Answer 11

Cancers with POLE mutations

• Smallest subset
• Characterized by the highest number of mutations (ultramutated) and significantly longer survival.

Question 12

Significance of hypermutated tumors in EC?

Answer 12

The hypermutated group of cancers comprises primarily endometrioid carcinomas with high levels of MSI and a high mutation rate, but not as high as that of the ultramutated group

Question 13

TCGA segreates EC into which molecular types?

Answer 13

• Copy-number low
• Copy-number high
• Hypermutated
• Ultramutated

Question 14

Significance of copy-number-low EC?

Answer 14

The “copy-number–low” group accounts for the largest number of cases and is composed primarily of microsatellite-stable endometrioid carcinomas

Question 15

How would you classify serous EC in terms of molecular features?

Answer 15

The endometrial serous carcinomas are characterized by TP53 mutations, an overall low mutation rate, and frequent copy-number alterations (“copy-number–high” group)

Question 16

What are molecular features of clear cell EC?

Answer 16

• Much less is known about the molecular changes in endometrial clear-cell carcinoma.
  
  • One study performed whole-exome sequencing of 16 cases showed that clear-cell carcinoma is genomically heterogeneous, with a subset of tumors molecularly similar to endometrioid carcinoma, another subset genetically similar to serous carcinoma, a third subset with molecular findings common to both groups, and a fourth subset that is unique

Question 17

Significance of TCGA findings?

Answer 17

• TCGA data have helped to refute the conventional wisdom that young, obese women have hormone-driven disease with a good prognosis.
  
  • Although such patients certainly have a better prognosis than those with endometrial serous carcinoma, some patients have endometrioid cancers driven not by hormones but rather by activation of the WNT–Beta-catenin signaling pathway.
  • The higher-grade and advanced-stage endometrioid cancers are similarly heterogeneous; grade 3 endometrioid tumors with a more “immune driven” genotype have better outcome