Uterine Malignant Mixed Müllerian Tumors Following Treatment with Selective Estrogen Receptor Modulators in Patients with Breast Cancer: A Report of 13 Cases and Their Clinicopathologic Characteristics

BACKGROUND: Breast cancer treatment with selective estrogen receptor modulators (SERMs) increases the incidence of uterine malignant mixed Müllerian tumors (uMMMTs). We examine clinicopathologic characteristics and prognosis of SERM-associated uMMMTs (S-uMMMTs) and discuss possible pathogenetic mechanisms. METHODS: Among 28,104 patients with breast cancer, clinicopathologic features and incidence of uMMMT were compared between patients who underwent SERM treatment and those who did not. Of 92 uMMMT cases that occurred during the same period, incidence, dose, and duration of SERM treatment, as well as overall survival rate, were compared for patients with breast cancer who underwent SERM treatment and those who did not (S-uMMMT vs NS-uMMMT) and for patients without breast cancer (de novo-uMMMT). Histopathological findings and immunophenotypes for myogenin, desmin, p53, WT-1, estrogen receptor (ER) α, ERβ, progesterone receptor, and GATA-3 were compared between S-uMMMT and de novo-uMMMT. RESULTS: The incidence of S-uMMMT was significantly higher than that of NS-uMMMT (6.35-fold). All patients with SERM were postmenopausal and received daily 20–40 mg SERM. Cumulative SERM dose ranged from 21.9 to 73.0 g (mean, 46.0) over 39–192 months (mean, 107). Clinicopathologic features, such as International Federation of Gynecology and Obstetrics stage and overall survival, were not significantly different between patients with S-uMMMT and NS-uMMMT or between patients with S-uMMMT and de novo-uMMMT. All 11 S-uMMMT cases available for immunostaining exhibited strong overexpression/null expression of p53 protein and significantly increased ERβ expression in carcinomatous and sarcomatous components. CONCLUSIONS: SERM therapy seemingly increases risk of S-uMMMT development; however, clinicopathologic features were similar in all uMMMTs from different backgrounds. p53 mutation and increased ERβ expression might be involved in the etiology of S-uMMMT.

Utility of BRAF VE1 Immunohistochemistry as a Screening Tool for Colorectal Cancer Harboring BRAF V600E Mutation

BACKGROUND: BRAF mutation has been recognized as an important biomarker of colorectal cancer (CRC) for targeted therapy and prognosis prediction. However, sequencing for every CRC case is not cost-effective. An antibody specific for BRAF V600E mutant protein has been introduced, and we thus examined the utility of BRAF VE1 immunohistochemistry for evaluating BRAF mutations in CRC. METHODS: Fifty-one BRAF-mutated CRCs and 100 age and sexmatched BRAF wild-type CRCs between 2005 and 2015 were selected from the archives of Asan Medical Center. Tissue microarrays were constructed and stained with BRAF VE1 antibody. RESULTS: Forty-nine of the 51 BRAF-mutant CRCs (96.1%) showed more than moderate cytoplasmic staining, except for two weakly stained cases. Six of 100 BRAF wild-type cases also stained positive with BRAF VE1 antibody; four stained weakly and two stained moderately. Normal colonic crypts showed nonspecific weak staining, and a few CRC cases exhibited moderate nuclear reactivity (3 BRAF-mutant and 10 BRAF wild-type cases). BRAF-mutated CRC patients had higher pathologic stages and worse survival than BRAF wild-type patients. CONCLUSIONS: BRAF VE1 immunohistochemistry showed high sensitivity and specificity, but occasional nonspecific staining in tumor cell nuclei and normal colonic crypts may limit their routine clinical use. Thus, BRAF VE1 immunohistochemistry may be a useful screening tool for BRAF V600E mutation in CRCs, provided that additional sequencing studies can be done to confirm the mutation in BRAF VE1 antibody-positive cases.