Two-tier subclassification of the Bethesda category III (atypia of undetermined significance/follicular lesion of undetermined significance) in thyroid cytology.

BACKGROUND: The Bethesda category III, AUS/FLUS, comprises a heterogeneous group of thyroid lesions with variable risk of malignancy (ROM). This study evaluates ROM in two subgroups of this category based on nuclear atypia and architectural atypia. METHODS: Cases in Bethesda category III were reported based on nuclear atypia (AUS) and architectural atypia (FLUS). ROM was calculated by comparing the cytologic diagnosis to the follow-up histologic diagnosis. RESULTS: Among the 610 Bethesda category III cases in this study, 306 (50.2%) and 304 (49.8%) cases were reported as AUS and FLUS, respectively. One hundred and eighty six of 306 AUS (60.8%) and 193 of 304 FLUS (63.5%) cases underwent surgical intervention. ROM of the cases in Bethesda category III was 12.8% if all cases were counted and 20.6% if only surgical cases were counted. When analyzing separately, ROM of AUS cases was 17.0% and 28.0% with all cases and surgical cases only, respectively. For FLUS cases, ROM was 8.6% and 13.5% with all cases and surgical cases only, respectively. CONCLUSION: In Bethesda category III, ROM in the cases with nuclear atypia was significantly higher than the cases with architectural atypia. Sub-classifying the Bethesda Category III cases with nuclear atypia and architectural atypia, respectively may better stratify the ROM.

The pathologic diagnosis of carcinoma in various tissues.

Carcinoma is defined as cancer arising from the epithelial cells that line an organ or tissue. The most common carcinoma in males arises in the prostate and breast in females; while the most significant cause of cancer related mortality in the United States is carcinoma of the lung. Cancers typically begin as a clonal proliferation of cells that have acquired distinct mutations, which then progress to invasive carcinoma as the cells breach the underlying basement membrane associated with the tissue of origin. This transition to invasive carcinoma carries with it the potential to invade blood vessels or lymphatic channels and metastasize to lymph nodes or distant tissues resulting in increased morbidity and mortality. The histologic diagnosis of carcinoma is rendered based on both the cytologic and architectural features of the tumor, as well as the location of the proliferating cells and the interaction with the surrounding stromal elements.

Near haploidization is a genomic hallmark which defines a molecular subgroup of giant cell glioblastoma.

BACKGROUND: Giant cell glioblastoma (gcGBM) is a rare histologic subtype of glioblastoma characterized by numerous bizarre multinucleate giant cells and increased reticulin deposition. Compared with conventional isocitrate dehydrogenase (IDH)-wildtype glioblastomas, gcGBMs typically occur in younger patients and are generally associated with an improved prognosis. Although prior studies of gcGBMs have shown enrichment of genetic events, such as TP53 alterations, no defining aberrations have been identified. The aim of this study was to evaluate the genomic profile of gcGBMs to facilitate more accurate diagnosis and prognostication for this entity. METHODS: Through a multi-institutional collaborative effort, we characterized 10 gcGBMs by chromosome studies, single nucleotide polymorphism microarray analysis, and targeted next-generation sequencing. These tumors were subsequently compared to the genomic and epigenomic profile of glioblastomas described in The Cancer Genome Atlas (TCGA) dataset. RESULTS: Our analysis identified a specific pattern of genome-wide massive loss of heterozygosity (LOH) driven by near haploidization in a subset of glioblastomas with giant cell histology. We compared the genomic signature of these tumors against that of all glioblastomas in the TCGA dataset (n = 367) and confirmed that our cohort of gcGBMs demonstrated a significantly different genomic profile. Integrated genomic and histologic review of the TCGA cohort identified 3 additional gcGBMs with a near haploid genomic profile. CONCLUSIONS: Massive LOH driven by haploidization represents a defining molecular hallmark of a subtype of gcGBM. This unusual mechanism of tumorigenesis provides a diagnostic genomic hallmark to evaluate in future cases, may explain reported differences in survival, and suggests new therapeutic vulnerabilities.