Uterine Cancer: Part 1

GuidelinesUterine Cancer
Written By Sydney Oesch

Show Notes

  1. Epidemiology

    1. Uterine cancer is the most common gynecologic cancer in the United States with over 66,000 new cases diagnosed and over 13,000 deaths in the year 2023.

    2. Incidence and mortality are rising

    3. Patients identifying as non-hispanic Black have nearly twice the mortality rate from uterine cancer when compared to non-hispanic White patients; this disparity is widening over time

    4. At time of diagnosis, 67% of cases are confined to the uterus 19% have spread to regional lymph nodes, and 10% have distant metastasis. 4% are unstaged. 

  2. Endometrial Cancer Types

    1. Historical: “type I” and “type II”

    2. New classification: “aggressive” and “non-aggressive”

      1. Non-aggressive: About 80%; these are grade I-II, with endometrioid histology, and can be any molecular subtype. 

      2. Aggressive: grade III endometrioid and non-endometrioid histologies

    3. Molecular Subtypes

      1. The Cancer Genome Atlas (TCGA) study

        1. integrated genomic, transcriptomic, and proteomic analysis of 373 endometrial carcinomas

        2.  included low-grade endometrioid, high-grade endometrioid, and serous carcinomas

      2. How to Determine

        1. 3 IHC tests (for p53, MSH6, PMS2) + 1 molecular test for POLE

        2. Order of “driving” mutation: POLE -> MMR status -> p53 expression

      3. POLE ultramutated

        1. copy number stable, will have a very high number of somatic mutations in the tumor

        2. usually high-grade tumors with deep myometrial invasion and LVS

        3. irrespective of grade, have excellent prognosis!

      4. Mismatch Repair Deficient (MMRd) or Microsatellite Instability High (MSI-H)

        1. low number of copy number alterations, but have a high mutational burden due to the abnormal mismatch repair

        2. Intermediate prognosis

      5. p53 Mutated

        1. also called “copy number high” or “serous-like” tumor

        2. most aggressive subtype, carry a poor prognosis, are responsible for up to 70% of endometrial cancer mortality

        3. ~25% have HER2 amplification

      6. No Specific Molecular Profile (NSMP)

        1. copy number low with wild type p53, have a moderate mutational load, are mostly endometrioid, and are mostly ER/PR positive

        2. Intermediate prognosis

  3. Endometrial Intraepithelial Neoplasia (EIN)

    1. GOG 167 re-evaluated pathology results from patients diagnosed with endometrial cancer precursor lesions at community hospitals.  On expert pathology review, 29% of patients with a diagnosis of atypical endometrial hyperplasia made by community hospital pathologists were upgraded to carcinoma.

    2. EIN can give rise to endometrial cancer with any of the four molecular subtypes

  4. Non-Endometrioid Histologies

    1. Serous carcinoma

      1. second most common type of endometrial cancer

      2. marked nuclear atypia, most are p53 mutated, minority of cases are HER2 amplified 

    2. Clear cell

      1. <5% of all endometrial cancer cases

      2. usually affects older patients, generally ER negative, can be any molecular subtype.   

    3. Carcinosarcoma

      1. <5% of all endometrial cancer cases

      2. Historically classified as uterine sarcomas, but have been reclassified as carcinomas

      3. Also known as malignant mixed Mullerian tumor (MMMT)

  5. Staging

    1. 5-year survival for localized disease is 95%, drops to 70% with regional spread, and is a slim 18% for distant metastasis, based on SEER data

    2. major update with 2023 staging is the incorporation of molecular subtyping, which, in some cases, may alter the stage of disease.  POLEmut and p53mut can downgrade or upgrade the stage, respectively, in stage I and II disease

    3. Once a tumor is stage III, the molecular classification does not change the stage, but it should be recorded as it has prognostic value.  MMRd or NSMP status do not modify early FIGO stages; however, these molecular classifications should also be recorded as they have prognostic value.   

    4. Stage I: The big update in stage one disease is the consideration of histologic subtype (aggressive vs non-aggressive), addition of categories for disease confined to the endometrium or a polyp, and consideration of the extent of LVSI.  This is very different than the 2009 FIGO staging which only considered depth of invasion to differentiate between stage IA and stage IB.  Stage IA3 is a new category which includes low grade endometrioid carcinomas limited to the uterus and ovary. 

    5. Stage II now also captures the misfits from stage I, instead of exclusively being about cervical stromal involvement.  These include substantial LVSI and aggressive subtypes with myometrial invasion. 

    6. Stage III: no major additions, but new system has further separated the categories

    7. Stage IV: now additional substage (IVB) for extrapelvic peritoneal metastasis


Episode Takeaways

  1. Not only is uterine cancer the most common gynecologic cancer in the US, it’s also the cancer in which we’re having a really hard time improving outcomes; both incidence and mortality are increasing, as are racial disparities in outcomes.  

  2. Risk factors for uterine cancer depend on the subtype.  Nonaggressive tumors are related to unopposed estrogen and are often preceded by a diagnosis of EIN, while risk factors for aggressive tumors include age, race, and lower BMI, but not estrogen exposure. 

  3. Whereas we used to think about type I and type II endometrial cancers, with new guidelines from FIGO, we are now classifying endometrial cancers as “aggressive” and “non-aggressive.” These mostly overlap with the previous specifications. Non-aggressive endometrial cancers are endometrioid histology, grade I-II, of any molecular subtype, and aggressive is anything not meeting that criteria. 

  4. Endometrial cancer prognosis is multifactorial, with age, stage, grade, histologic subtype, DOI, presence of LVSI, tumor size and location.  Molecular subtype also greatly impacts prognosis; POLE mutated tumors have an excellent prognosis irrespective of grade, p53 mutated tumors aka “serous like” tumors are the most aggressive subtype with poor prognosis, NSMP and MMRd both have intermediate prognostic significance. 

  5. Staging of endometrial cancer has been updated with the new FIGO 2023 staging system. The new staging system incorporates molecular subtype and uses this, in the case of stage I-II POLEmutated and P53 mutated tumors to guide therapy decisions. Histologic subtype, LVSI, presence of peritoneal metastases are some other notable new factors which are included in the staging system. The crux of this new system is that it is an attempt to offer more prognostic value. 

  6. Newly diagnosed patients with endometrial cancer should be tested for Lynch syndrome, should have at least a chest Xray done to evaluate for metastatic disease (with more extensive imaging if reason to suspect metastatic disease), and should be assessed for fitness for surgery and goals and priorities for care to help decide treatment pathways. 

References

1. Getz G, Gabriel SB, Cibulskis K, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. doi:10.1038/NATURE12113

2. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia. Cancer. 2006;106(4):812-819. doi:10.1002/CNCR.21650

3. Berek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. Int J Gynecol Obstet. 2023;162:383-394. doi:10.1002/ijgo.14923

Sydney Oesch
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Uterine Cancer: Part 2
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Introduction