Estrogen/Progesterone Receptor Loss, CTNNB1 and KRAS Mutations Are Associated With Local Recurrence or Distant Metastasis in Low-Grade Endometrial Endometrioid Carcinoma

Abstract

A subset of endometrial endometrioid carcinomas (EECs) with low-grade histology recur with poor outcomes. Published evidence suggests that poor outcomes may be associated with loss of expression of ER-alpha (ER-α) as well as with β-Catenin-1 (CTNNB1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. This study reports on institutional experience with the incidence of recurrence in low-grade EEC and their association with CTNNB1 and KRAS mutations as well as estrogen/progesterone receptor (ER/PR) expression. Forty-eight (8.5%) out of 568 cases of low-grade EEC with biopsy-proven recurrence were identified; and were analyzed by immunohistochemistry for ER, PR, p53, MMR protein, and mutation analysis for exon 3 of the CTNNB1 and exon 2 of KRAS in relation to recurrence type, local or distant metastasis/recurrence. Twenty-three patients (4%) developed local, and 25 patients (4.4%) developed distant metastases/recurrence. Decreased expression or loss of ER/PR was found in 17/44 (38.6%) patients with recurrence. Eighty-four percent of patients with low-grade EEC and local recurrence had CTNNB1 mutations. Seventy-three percent of patients with distant metastasis/recurrence had KRAS mutations. The association of these mutations with the type of recurrence was statistically significant for both. Five cases with the morphology of low-grade EEC were reclassified as mesonephric-like carcinoma and were universally characterized by distant metastasis/recurrence, loss of ER/PR expression, large tumor size, absence of CTNNB1 mutations, and the presence of KRAS mutations. In low-grade EEC, CTNNB1 and KRAS mutations are associated with local recurrence and distant metastasis/recurrence, respectively, suggesting that these 2 different progression types may be conditioned by tumor genotype. ER/PR immunohistochemistry may be helpful in identifying poor performers in low-grade EEC. Furthermore, identification of the decreased expression or loss of ER/PR in tumors with low-grade histology should prompt consideration of mesonephric-like carcinoma, which is a more aggressive tumor than the low-grade EEC. KRAS mutations were associated with distant metastasis/recurrence in tumors with and without mesonephric-like phenotype.

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer—Genetic Instability and Clinical Implications

“…Subsequent research has confirmed this association in the majority of studies, although not universally across all investigations [85,87,88]. Lastly, a strong association of CTNNB1 and KRAS mutations linking genotype to the type of recurrence was demonstrated in low-grade endometrioid endometrial carcinoma [89].…”

Transcriptomic Analysis of Hub Genes Reveals Associated Inflammatory Pathways in Estrogen-Dependent Gynecological Diseases

“…Figure 7 shows the identified hub genes, signaling pathways, and biological processes that are potentially related to inflammation and ERα activation. KRAS gene mutations may lead to dysregulation in ERα activation that may lead to cancer proliferation, progression, tumor cell survival response, and metastasis [ 81 , 82 ]. In mice, SOS1 knock-down suppresses the Ras-ERK/P38MAPK/JNK pathway and induces epithelial-mesenchymal transition through NF-kB signaling, which may contribute to the metastasis of epithelial ovarian cancer cells [ 83 ].…”

Pulmonary metastasis of stage I, low-grade endometrioid carcinoma: two case reports and the literature review

“…The risk of endometrial cancer increases with age and BMI ( 34 ); the first case in our report involved a 70-year-old patient with a history of DM, while the second case involved a 57-year-old patient with a BMI of 33 kg/m 2 . Evidence from a previous report indicated that DM is a poor prognostic factor in patients with low-grade EEC, specifically those with KRAS mutation ( 49 ). BMI and increases with age are the main risks of endometrial cancer; it has the strongest link to obesity among the 20 most common types of tumors.…”

“…The immunohistochemistry staining of the primary tumor revealed medium positive expression of ER (50%) and PR (60%). According to a recent study, decreased expression of ER/PR detected by immunohistochemistry can serve as a valuable prognostic biomarker for identifying low-grade EEC that may have distant metastasis ( 49 ).…”