Unsolved Issues in the Integrated Histo-Molecular Classification of Endometrial Carcinoma and Therapeutic Implications

Abstract

Endometrial carcinoma (EC) is the most frequent gynecological cancer, with an increasing incidence and mortality in recent times. The last decade has represented a true revolution with the development of the integrated histo-molecular classification of EC, which allows for the stratification of patients with morphologically indistinguishable disease into groups with different prognoses. Particularly, the POLE-mutated subgroup exhibits outstanding survival. Nevertheless, the indiscriminate application of molecular classification appears premature. Its prognostic significance has been proven mainly in endometrioid EC, the most common histotype, but it has yet to be convincingly confirmed in the other minor histotypes, which indeed account for a relevant proportion of EC mortality. Moreover, its daily use both requires a mindful pathologist who is able to correctly evaluate and unambiguously report immunohistochemical staining used as a surrogated diagnostic tool and is hampered by the unavailability of POLE mutation analysis. Further molecular characterization of ECs is needed to allow for the identification of better-tailored therapies in different settings, as well as the safe avoidance of surgery for fertility preservation. Hopefully, the numerous ongoing clinical trials in the adjuvant and metastatic settings of EC will likely produce evidence to refine the histo-molecular classification and therapeutic guidelines. Our review aims to retrace the origin and evolution of the molecular classification for EC, reveal its strengths and limitations, show clinical relevance, and uncover the desired future developments.

Keywords: checkpoint inhibitors; classification; endometrial; endometrial cancer; history; targeted therapy.

Figure 1

WHO diagnostic algorithm for molecular classification of ECs and, on the right, the relative approximative prevalence of different molecular subtypes. Acronyms: POLEmut, POLE-mutated; +, POLE pathogenically mutated or abnormal immunohistochemistry (IHC) pattern; -, POLE without pathogenic mutated or normal IHC pattern; IHC, immunohistochemistry; EC, endometrial carcinoma; MMR, mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2); MMRd, mismatch repair-deficient; NSMP, no specific molecular profile.

Figure 2

The risk groups for endometrial carcinoma without residual disease and therapeutic indications are shown as a concentrical graph [89]. Carcinosarcomas should be treated as high-risk carcinomas, not as sarcomas. p53abn EC without myometrial invasion belongs to the high-intermediate risk; for this risk group, further subclassification includes the pN0 stage versus lymph node staging not performed. For p53abn carcinomas restricted to a polyp or without myometrial invasion, adjuvant therapy is generally not recommended. Adjuvant chemotherapy can be considered, especially for HG and/or SLVI ECs. For patients with POLEmut EC, stage III–IVA, there are no outcome data with the omission of the adjuvant treatment. Prospective registration is recommended. Acronyms: VBT, vaginal brachytherapy; ERBT, external beam radiation therapy; CT, chemotherapy; MMRd, mismatch repair deficient; NSMP, no specific molecular profile; POLEmut, POLE-mutant; p53abn, p53 abnormal; EMC, endometrioid carcinoma. LG, low-grade; HG, high-grade; LVI, lymphovascular space invasion; SLVI, substantial LVI; MMI, myometrial invasion; SMMI, substantial MMI.