A novel de novo intragenic duplication in FBN1 associated with early-onset Marfan syndrome in a 16-month-old: A case report and review of the literature.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder due to pathogenic variants in Fibrillin-1 (FBN1) affecting nearly one in every 10,000 individuals. We report a 16-month-old female with early-onset MFS heterozygous for an 11.2 kb de novo duplication within the FBN1 gene. Tandem location of the duplication was further confirmed by optical genome mapping in addition to genetic sequencing and chromosomal microarray. This is the third reported case of a large multi-exon duplication in FBN1, and the only one confirmed to be in tandem. As the vast majority of pathogenic variants associated with MFS are point mutations, this expands the landscape of known FBN1 pathogenic variants and supports consistent use of genetic testing strategies that can detect large, indel-type variants.

Tumor-Infiltrating Lymphocytes in Breast Cancer: Evaluating Interobserver Variability, Heterogeneity, and Fidelity of Scoring Core Biopsies.

OBJECTIVES: The aims were to evaluate breast cancer (BC) tumor-infiltrating lymphocytes (TILs) interobserver variability, heterogeneity, and the fidelity of scoring TILs in core needle biopsy (CNB). METHODS: Matching CNB and two full-face sections (FFSs) of BC cases (n = 100) were independently reviewed by two pathologists. Percentage of stromal lymphocytes (TIL-str) and intratumoral lymphocytes (iTu-Ly) were recorded. RESULTS: The weighted κ values for the degree of agreement between both raters were 0.53 to 0.71. However, there was a slight improvement in the interobserver variability for TIL-str and slight decline in iTu-Ly when ER+/HER2- cases were excluded. The intraclass correlation coefficient for FFS1 vs FFS2 was 0.91 for TIL-str and 0.96 for iTu-Ly. Spearman correlation coefficient for CNB vs FFS1/FFS2 was 0.81 for TIL-str and 0.79 for iTu-Ly. CONCLUSIONS: We conclude that the agreement in TILs scoring between the raters is acceptable. Caution should be practiced when scoring iTu-Ly in CNBs.

Prognostic Significance of Stromal Versus Intratumoral Infiltrating Lymphocytes in Different Subtypes of Breast Cancer Treated With Cytotoxic Neoadjuvant Chemotherapy.

BACKGROUND: The aim of the study was to investigate if there were differences in associations of stromal versus intratumoral tumor infiltrating lymphocytes (TILs) with pathology complete response (pCR) among breast cancer (BC) subtypes treated with neoadjuvant therapy. MATERIALS AND METHODS: The hematoxylin and eosin slides of BC-core biopsy consecutive cases (n=331) were reviewed from a single institution between 2000 and 2014. TIL-stroma (TIL-str) was scored from 0% to 100%. Intratumoral lymphocytes (iTu-Ly) were scored semiquantitatively incorporating the infiltrate grade (0 to 3) and the corresponding percentage resulting in a score ranging from 0 to 300. pCR was defined as no residual infiltrating tumor in the tumor bed and the lymph nodes. RESULTS: pCR was achieved in 29 of 95 (30.9%) triple negative cases, 25 of 77 (32.5%) HER2+, and 9 of 159 (5.6%) luminal tumors. In univariate analysis, invasive nonlobular carcinoma, higher Nottingham grade, nonluminal subtypes, trastuzumab therapy, nonadvanced clinical T stage (T1 and T2), TIL-str, and iTu-Ly-predicted pCR. In luminal subtype, iTu-Ly but not TIL-str was an independent predictor for pCR [odds ratio (OR)=1.44, 95% confidence interval (CI), 1.08-1.9, P=0.013]. In triple negative subtype, both TIL-str and iTu-Ly were independent predictors for pCR (OR=1.68, 95% CI, 1.29-2.18, P=0.001; OR=1.31, 95% CI, 1.05-1.63, P=0.017, respectively). In HER2+ subtype, neither TIL-str nor iTu-Ly predicted pCR. CONCLUSIONS: TILs are variably correlated with better neoadjuvant chemotherapy response depending on their location and clinical subtype of BC. It could indicate that TILs might be functionally heterogeneous with regard to their role in mediating antitumor immune response, depending on their location and BC subtypes.