Is pole ultramutated cancer typically considered low grade or high grade?

POLE Ultramutated Cancer Grade Classification

POLE ultramutated endometrial cancers are frequently high-grade histologically, but paradoxically have excellent prognosis and are classified as low-risk for treatment purposes despite their aggressive morphologic appearance. 1

Histologic Grade vs. Molecular Classification

Histologic Appearance

• POLE-mutated tumors are commonly high-grade (60% of cases) with aggressive morphologic features including severe nuclear atypia, deep myometrial invasion, and lymphovascular space invasion 2
• These tumors frequently demonstrate high-grade endometrioid histology (FIGO grade 3) with morphological heterogeneity (52% of cases) and ambiguity (16% of cases) 2
• The severe nuclear atypia can raise concern for serous carcinoma in 28% of cases, though the majority (96%) maintain defining features of endometrioid differentiation 2

Molecular Classification Supersedes Histologic Grade

• The molecular classification into POLE ultramutated subtype takes precedence over traditional histologic grading for risk stratification and treatment decisions 1, 3
• POLE-mutated cancers are classified as low-risk regardless of their high-grade histologic appearance, with stage I/II POLE-mutated cancers considered low-risk even when grade 3 1, 3

Clinical Risk Classification

Low-Risk Designation

• All stage I/II POLE-mutated cancers are classified as low-risk for treatment purposes, regardless of grade, myometrial invasion depth, or presence of lymphovascular space invasion 1, 3
• Stage III POLE-mutated cancers may also be considered low-risk, though data on safely omitting adjuvant therapy in this setting are limited 1

Prognostic Implications

• POLE-mutated endometrial cancers have the best prognosis compared with all other molecular subgroups, regardless of treatment used 1
• This excellent prognosis is attributed to ultrahigh neoantigen burden (median 8,342 predicted neoantigens per sample), high CD8+ T cell infiltration, and robust immune response 1
• In clinical series, all POLE-mutated patients remained alive without disease at median follow-up of 33 months (range 2-102 months), with no recurrences despite high-grade features 2

Key Clinical Pitfall

The critical error to avoid is misclassifying POLE-mutated tumors as high-risk based solely on their aggressive histologic appearance. 2 These tumors:

• Are frequently high-grade histologically but biologically favorable 1, 2
• Can harbor TP53 mutations (35% of cases) but should not be misclassified as p53-aberrant/serous carcinoma 2
• Show rich tumor-infiltrating lymphocytes (84% of cases), which is a distinguishing feature 2

Treatment Implications

• De-escalation of adjuvant treatment should be explored in POLE-mutated patients, as they are unlikely to benefit from adjuvant radiation or chemotherapy despite high-grade features 1, 3
• Observation following surgery is an appropriate option for stage I-II POLE-mutated cancers after patient counseling 1
• Clinical studies documenting outcomes without adjuvant treatment are strongly encouraged for this population 1