Molecular Profile of Endometrial cancer

1. Molecular analysis of endometrial cancer
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Dr Kanhu Charan Patro
MD,DNB(Radiation Oncology),MBA,FICRO,FAROI(USA),PDCR,CEPC
HOD, Radiation Oncology
ISRo- Institute of Stereotactic Radiation oncology
Mahatma Gandhi Cancer Hospital & Research Institute, Visakhapatnam
drkcpatro@gmail.com /M- +91-9160470564/ www.drkanhupatro.com

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• Aggressive histological types are composed of
 High-grade endometroid(Grade 3),
 Serous,
 Clear Cell,
 Undifferentiated,
 Mixed-Mesonephric-like,
 Gastrointestinal Mucinous Type Carcinomas,
 Carcinosarcomas

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Nuclear atypia excessive for the grade raises the grade
of a grade 1 or 2 tumor by one.

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1. Low-grade EECs involving both the endometrium and the ovary are considered to
have a good prognosis, and no adjuvant treatment is recommended if all the below
criteria are met.
2. Disease limited to low-grade endometrioid carcinomas involving the endometrium
and ovaries (Stage IA3) must be distinguished from extensive spread of the
endometrial carcinoma to the ovary (Stage IIIA1), by the following criteria:
1. No more than superficial myometrial invasion is present (<50%);
2. Absence of extensive/substantial LVSI
3. Absence of additional metastases;
4. The ovarian Tumor is unilateral, limited to the ovary, without capsule
invasion/rupture (equivalent to pT1a).

8. Ovarian involvement
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In the case of high- grade tumors, ovarian involvement is almost always categorized as
metastatic.

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1.Pelvic peritoneal metastasis- lllB
2.Extra Pelvic peritoneal metastasis- lVA

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When molecular classification reveals p53abn or POLEmut status in Stages I and II, this
results in upstaging or downstaging of the disease (IICmp53abn or IAmPOLEmut).

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If the molecular subtype is known, this is recorded in the FIGO stage by
the addition of “m” suffix for molecular classification

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 In early endometrial cancer, the standard surgery is a total hysterectomy with
bilateral salpingo-oophorectomy via a minimally invasive laparoscopic
approach.
 Staging procedures include infracolic omentectomy in specific histological
subtypes, such as serous and undifferentiated endometrial carcinoma, as well
as carcinosarcoma, due to the high risk of microscopic omental metastases

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1. For EECs, grade is based on the proportion of solid areas: low grade = grade 1
(≤5%) and grade 2 (6%–50%); and high grade = grade 3 (>50%).
2. Nuclear atypia excessive for the grade raises the grade of a grade 1 or 2 tumor by one.
3. The presence of unusual nuclear atypia in an architecturally low-grade tumor
should prompt the evaluation of p53 and consideration of serous carcinoma.
4. Adenocarcinomas with squamous differentiation are graded according to the
microscopic features of the glandular component.

14. Nodal metastasis
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1. Macrometastases are >2 mm in size
2. Micrometastases are 0.2–2 mm and/or >200 cells
3. Isolated tumor cells are ≥0.2 mm and ≤200 cells

15. Mucinous variety
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1. Mucinous carcinoma as a variant of low-grade EECs because of its shared
molecular features and natural history.
2. It is distinguished from gastrointestinal type mucinous endometrial carcinoma, a
rare type of tumor with different features and worse prognosis, which should be
considered high-grade and included in the group of aggressive histological
types.

16. Specimen for biopsy
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Molecular subtype assignment can be done on a biopsy, in which case it
need not be repeated on the hysterectomy specimen.

17. Cervical involvement
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Cervical glandular extension is not considered for staging.

18. Floating tumor
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1. The presence of intraluminal tubal floating tumor fragments is
a controversial issue, particularly in serous carcinoma, but is
not considered for staging purposes.
2. The same applies for positive washing cytology

19. Serosal involvement
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Uterine serosal involvement is defined as a tumor reaching submesothelial fibroconnective
tissue or the mesothelial layer, regardless of whether tumor cells may or may not be present
on the serosal surface of the uterus

20. Multiple classifiers
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1. There is a small subset of tumors (approximately 5%) that combine more than one
molecular feature (e.g. POLEmut and p53abn or MMRd and p53abn), and they are
referred to as “multiple classifiers.”
2. In the case of multiple classifiers with POLEmut or MMRd and secondary p53
abnormality, the available scientific evidence indicates that they should not be
classified as p53abn, because they retain the favorable prognosis of POLEmut or
MMRd tumors; however, this is still an evolving field.
3. Patients with both POLEmut and p53abn should be considered POLEmut; patients
with both MMRd and p53abn should be considered MMRd.
4. For tumors with both a pathogenic POLEmut and MMRd, data are limited, and
therefore screening for Lynch syndrome should be considered.

21. Lymph vascular space involvement
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1. “LVSI negative” (0 vessels);
2. “LVSI focal” (< 5 vessels);
3. “LVSI substantial/extensive” (=5 vessels).

22. Molecular and prognosis
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1. POLEmut denotes a favorable prognosis.
2. MMRd and NSMP indicate an intermediate prognosis and
therefore do not alter the stage
3. p53abn indicates a poor prognosis.

23. Change of staging with markers
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1. POLEmut and p53abn molecular groups can increase or
decrease the stage of endometrial cancer in Stages I and II.
2. No changes occur through the molecular staging in Stages III
and IV. Stage III and IV cases, for

24. Endometrial cancer molecular profiling.
Needs in risk stratifying.
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Molecular profiling has predictive significance.
Adjuvant treatment cannot ignore its influence.

27. Molecular and clinicopathological features of
endometrial cancer molecular subgroup

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If endometrium is not molecular classified
Designate NOS as histologically classified.

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Attach m suffix to define the stage.
If molecular profiling is in your cage

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If endometrium is not molecular classified
Designate NOS as histologically classified.

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P53, MMRd. NSMP and POLE mutation
All these will decide adjuvant decision

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POLE mutation downgrades the staging.
P53 mutation upgrades the staging.

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POLE is excellent and P53 mutation is worse.
NSMP and MMRd are intermediate course.

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Molecular and histological together define the risk.
Low. Low intermediate, high intermediate and high risk

36. Management of endometrial cancer
Ye Yang/Int J Gynecol
Obstet/2023
12th JAN 2024/ENDOMETRIUM

37. Management of endometrial cancer
Ye Yang/Int J Gynecol
Obstet/2023

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POLE proofreading hypermutation
Causes more neoantigen formation.
That leads to tumor suppressor function.
So, it is under low-risk stratification.

39. POLYMERASE EPSILON (POLE) MUTATIONS –GOOD PROGNOSIS - HOW?
XUAN XUAN XING/CANCERS/2022

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PTEN, mTOR, AKTP,13K signaling pathway.
Together called (NSMP) nonspecific molecular pathway
NSMP has staged intermediate prognosis.
Consider post op vaginal brachy in diagnosis.

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MMRd does DNA repair problematization.
That helps in cancer formation.
Same time bad for tumor formation.
And enhances the effect of radiation.
Again, by DNA repair inhibition.
So, it is under intermediate stratification.

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p53 is a tumor suppressor gene.
Mutation leads to abnormal scene.
p53 mutation needs aggressive treatment.
Chemoradiation in the management.

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Histological analysis by 1,2,3 PORTEC
Molecular analysis by 4 and RAINBO PORTEC
Wait for
Retrospective molecular analysis from old PORTEC
Prospective analysis from 4a and RAINBO PORTEC

45. PORTEC 4a design in endometrial cancer

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Adding PRAP inhibitor in p53 mutation
Whether MMRd needs immunization.
In NSMP hormonal addition
Or POLE needs only observation.
All are under investigation.
Under PORTEC randomization

47. TransPORTEC RAINBO program of clinical trials.
YANG et al./Int J Gynecol Obstet/2023

48. Management of low and intermediate endometroid cancer
ESMO GUIDELINE

49. Management of high intermediate and high risk endometroid cancer
ESMO GUIDELINE

50. Management of locally recurrent endometroid cancer
ESMO GUIDELINE

51. Management of recurrent metastatic endometroid cancer
ESMO GUIDELINE

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60. Summary
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Treatment policy changed according to
molecular level
New staging and molecular level both
changed the policy
PORETC 4a may give a new dimension
Role of treatment intensification or dose
de-escalation will be answered by
PORTEC rainbow sturdy

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