These data demonstrate that the recently proposed classification system is excellent for reporting thyroid FNAs. Each diagnostic category conveys specific risks of malignancy, which offers guidance for patient management.

The Bethesda 2007 Thyroid Cytology Classification defines follicular lesion of undetermined significance as a heterogeneous category of cases that are not convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. In our institution, we refer to these cases as indeterminate, and they are further sub-classified into two: (1) low cellularity with predominant microfollicular architecture and absence of colloid (IN(a)) and (2) nuclear features not characteristic of benign lesions (nuclear atypia) (IN(b)). We reviewed these indeterminate cases to document the follow-up trend using this two-tier classification. A search of the cytology records was performed for the period between January 2008 and June 2009. All thyroid fine-needle aspiration (FNA) cases were reviewed and the ones diagnosed as indeterminate were identified. Correlating follow-up FNA and/or surgical pathology reports were reviewed. The percentage of cases showing a malignancy was calculated. One hundred and seventy-one indeterminate cases were identified, representing 2.8% of the 6,205 thyroid FNA cases examined during the time under review (107 IN(a), 64 IN(b)). Records of follow-up procedures were available in 106 (61%) cases. Malignancy was identified in 27% of all indeterminate cases. This was disproportionately more in the IN(b) (56%) compared to the IN(a) (7%) cases. A diagnosis of "IN(a)" does not carry the same implication as that of "IN(b)". The IN(b) category needs a more aggressive follow-up than the IN(a) category and may justify an immediate referral for lobectomy. Despite the vague morphologic criteria for this diagnostic category, the indeterminate rate remains relatively low and falls within the NCI recommendation (<7%).

Human papillomavirus (HPV) gene expression is dramatically altered during cervical carcinogenesis. Because dysregulated genes frequently show abnormal patterns of DNA methylation, we hypothesized that comprehensive mapping of the HPV methylomes in cervical samples at different stages of progression would reveal patterns of clinical significance. To test this hypothesis, thirteen HPV16-positive samples were obtained from women undergoing routine cervical cancer screening. Complete methylation data were obtained for 98.7% of the HPV16 CpGs in all samples by bisulfite-sequencing. Most HPV16 CpGs were unmethylated or methylated in only one sample. The other CpGs were methylated at levels ranging from 11% to 100% of the HPV16 copies per sample. The results showed three major patterns and two variants of one pattern. The patterns showed minimal or no methylation (A), low level methylation in the E1 and E6 genes (B), and high level methylation at many CpGs in the E5/L2/L1 region (C). Generally, pattern A was associated with negative cytology, pattern B with low-grade lesions, and pattern C with high-grade lesions. The severity of the cervical lesions was then ranked by the HPV16 DNA methylation patterns and, independently, by the pathologic diagnoses. Statistical analysis of the two rating methods showed highly significant agreement. In conclusion, analysis of the HPV16 DNA methylomes in clinical samples of cervical cells led to the identification of distinct methylation patterns which, after validation in larger studies, could have potential utility as biomarkers of neoplastic cervical progression.

Background/Objective: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as ‘indeterminate’ and they are further subclassified into two categories. BRAF mutation occurs in 40–60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. Study Design: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as ‘indeterminate’ were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. Results: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. Conclusions: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.

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