Histopathological features of endometrial carcinomas associated with POLE mutations: implications for decisions about adjuvant therapy

Abstract

Aims To characterize the histomorphological features of endometrial carcinomas (ECs) harbouring polymerase ε (POLE) mutations. Methods and results Forty-three ECs with POLE mutations were compared with a cohort of 202 ECs. Most POLE-mutated ECs were endometrioid [34/43 (79%]; the remaining tumours were mixed [6/43 (14%)], serous [2/43 (5%)], and clear cell [1/43 (2%)]. The endometrioid carcinomas were predominantly International Federation of Gynecology and Obstetrics grade 3 (27/43, 63%). The histotype distribution did not differ from that of control ECs (P = 0.69), but the grade of the EC was higher (P < 0.0005). Both nuclear grade and mitotic index were significantly higher in POLE-mutated ECs than in the comparison cohort. POLE-mutated ECs were associated with peritumoral lymphocytes and numerous tumour-infiltrating lymphocytes. Lymphovascular invasion was present in 20 of 43 tumours. Adjuvant radiotherapy and adjuvant chemotherapy would be offered in up to 80% and 40% of patients, respectively, on the basis of stage, grade, lymphovascular invasion, and histotype. Conclusions POLE-mutated ECs are typically of high grade, with prominent lymphocytic infiltration, but they are not sufficiently distinctive to allow accurate diagnosis based on routine haematoxylin and eosin staining. Even though POLE-mutated tumours are associated with an excellent prognosis, current guidelines for giving adjuvant treatment for EC result in most patients receiving adjuvant therapy.

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

“…However, we can hypothesize that there may be a threshold of mutational burden that tumor cells can tolerate (38). There is also evidence that POLE ultramutated tumors are associated with peritumoral lymphocytes and tumor-infiltrating lymphocytes (28), which exhibit an enhanced T-cell antitumor response to antigenic neoepitope expression (39,40). This immune response may play a mechanistic role in the observed favorable prognosis, as an increased immune response in these tumors may decrease metastatic potential leading to a less-aggressive tumor (28).…”

“…There is also evidence that POLE ultramutated tumors are associated with peritumoral lymphocytes and tumor-infiltrating lymphocytes (28), which exhibit an enhanced T-cell antitumor response to antigenic neoepitope expression (39,40). This immune response may play a mechanistic role in the observed favorable prognosis, as an increased immune response in these tumors may decrease metastatic potential leading to a less-aggressive tumor (28). An increase in tumor-infiltrating T cells has also been observed in microsatellite unstable endometrial and colorectal tumors, where the immune response may also contribute to antitumor effects and in the case of colorectal cancers, improved prognosis (39,41).…”

Programmed Death Ligand 1 Expression Among 700 Consecutive Endometrial Cancers: Strong Association With Mismatch Repair Protein Deficiency

“…1 The resulting increased immunogenicity has a clear histologic correlate by means of conspicuous lymphocytic infiltrates seen in both MMR deficient 2 and POLE mutated 3 ECs. Moreover, in a case-control study by Bakhsh et al, 3 International Federation of Gynecology and Obstetrics grade 3 endometrioid histology was documented in 27 (63%) of 43 POLE mutated tumors, and overall histologic grade was significantly higher when compared with a 202 EC control group. Similarly, International Federation of Gynecology and Obstetrics grade 3 endometrioid histology is overrepresented among POLE mutated ECs in The Cancer Genome Atlas data.…”

The changing landscape of gynaecological cancer diagnosis: implications for histopathological practice in the 21st century

“…Recent studies incorporating molecular classification in high‐grade endometrial carcinomas have demonstrated that the greatest lack of agreement in histotype diagnosis lies within the ultramutated/POLE, hypermutated/MSI and copy‐number high/serous‐like categories . The first group, ultramutated/POLE, accounting for 8–10% of cases, has been characterized recently as showing endometrioid morphology with high‐grade or ambiguous features (Figure ) but very favourable clinical outcome . The second category, hypermutated/MSI, has been better characterized over many years; features described as Lynch syndrome‐related are ambiguous morphology and combinations of histotypes (including the presence of an undifferentiated component), isthmic location and lymphocytic infiltrates .…”