BACKGROUND:Quality management practices empower cytology laboratories to deliver consistent, high-quality patient care. Monitoring of key performance indicators is one way by which laboratories can identify patterns of error and focus their improvement activities. Cytologic-histologic correlation (CHC) identifies error by retrospectively reviewing cytology cases when discordant surgical pathology diagnoses are reported. Analysis of CHC data can elucidate patterns of error and direct quality improvement initiatives.METHODS:CHC data of nongynecologic cytology specimens were reviewed over a 3-year period (2018-2021). Errors were separated by anatomic site and classified as either sampling or interpretive errors.RESULTS:A total of 364 discordant cases were identified out of 4422 cytologic-histologic pairs (a discordant rate of 8%). The majority (272; 75%) were sampling errors, with fewer interpretive errors (92; 25%). Sampling errors were found to occur most commonly in lower urinary tract and lung. Interpretive errors were most commonly found in lower urinary tract and thyroid.CONCLUSIONS:Nongynecologic CHC data can be a valuable resource for cytology laboratories. By studying the types of errors, quality improvement activities can be targeted toward problem areas.

Abstract Thyroid nodules are common in the United States and are currently diagnosed using fine needle aspiration (FNA) biopsy. FNA evaluation provides a definitive diagnosis in the majority of cases, but about 20-30% of nodules are deemed indeterminate. Targeted next generation sequencing (NGS) and gene expression analysis have been used as ancillary tests to provide additional information about the malignancy risk for indeterminate thyroid lesions. Here we develop a 31 gene NGS panel, as well as a 14 gene expression panel, and test their performance on thyroid lesions with known diagnosis. Formalin-fixed paraffin embedded tissue from 23 resected thyroid lesions (1 non-neoplastic, 3 follicular adenomas (FA), 1 medullary carcinoma (MC), 7 follicular carcinomas (FC), 7 papillary carcinomas (PC), 4 follicular variant of papillary carcinomas (FVPC)) was evaluated. Total nucleic acid extraction, NGS (31 genes including: NRAS, HRAS, KRAS, CTNNB1, PIK3CA, BRAF, RET, PTEN, AKT1, TP53, GNAS, ALK, DDR2, EGFR, ERBB2, FGFR1/2/3, GNA11, GNAQ, IDH1/2, KIT, MAP2K1, MET, MTOR, NOTCH1, PDGFRA, EPHA2, ESR1, RAC1, and ROS1) through Bio Reference Laboratories, and gene expression analysis (14 genes: KRT7, TTF-1, TG, PGK-1, CK-20, PTH, CALCA, RAP2A, PLAB, HMGA2, FN-1, GAL-3, CK19, and NIS) were performed. This assay detected mutations in 14/19 malignant lesions including 4/7 FCs (NRAS, TP53), 4/4 FVPC (BRAF, NRAS, HRAS, PTEN), 5/7 PCs (BRAF, NRAS), and 1/1 MC (RET). No mutations were detected in the non-neoplastic thyroid and 1/3 FAs contained a KRAS mutation. All three mutation-negative FCs were oncocytic variants and showed upregulation of ≥2 cancer-associated genes including FN-1, GAL-3, HMGA2, PLAB, and RAP2a. The two mutation-negative PCs showed upregulation of 4 cancer-associated genes including FN-1, CK-19, GAL-3, HMGA2, and PLAB. This upregulation was not seen in non-neoplastic thyroid and was seen in only 1 of the FAs (FN-1, GAL-3, and PLAB). This small study demonstrates that a combination of NGS and gene expression increases the assay sensitivity (100% versus 74% sensitivity) and negative predictive value (100% versus <45% for NGS or gene expression alone). The positive predictive value of the combined assay was 90% versus 93% for either assay alone. The addition of gene fusions will likely further improve the assay’s diagnostic capacity. In conclusion, the addition of a gene expression assay to this thyroid NGS assay allowed for identification of mutation-negative thyroid malignancies. The improved detection of malignant thyroid lesions will allow for better risk assessment for indeterminate nodules as well as improved treatment algorithms. Citation Format: Vivian L. Weiss, Robert Daber, Michael Moreau, Alisa Gaskell, Kim Ely, Alice Coogan, Thomas Stricker. Diagnosing indeterminate thyroid nodules: combining next generation sequencing and gene expression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5639. doi:10.1158/1538-7445.AM2017-5639

Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. OSCC invasion into the lymph nodes and mandible correlates with increased rates of recurrence and lower overall survival. Tumors that infiltrate mandibular bone proliferate rapidly and induce bone destruction. While survival rates have increased 12% over the last 20 years, this improvement is attributed to general advances in prevention, earlier detection, and updated treatments. Additionally, despite decades of research, the molecular mechanisms of OSCC invasion into the mandible are not well understood. Parathyroid Hormone-related Protein (PTHrP), has been shown to be essential for mandibular invasion in OSCC animal models, and our previous studies demonstrate that the transcription factor Gli2 increases PTHrP expression in tumor metastasis to bone. In OSCC, we investigated regulators of Gli2, including Hedgehog, TGFβ, and Wnt signaling to elucidate how PTHrP expression is controlled. Here we show that canonical Hedgehog and TGFβ signaling cooperate to increase PTHrP expression and mandibular invasion in a Gli2-dependent manner. Additionally, in an orthotopic model of mandibular invasion, inhibition of Gli2 using shRNA resulted in a significant decrease of both PTHrP expression and bony invasion. Collectively, our findings demonstrate that multiple signaling pathways converge on Gli2 to mediate PTHrP expression and bony invasion, highlighting Gli2 as a therapeutic target to prevent bony invasion in OSCC.

Nasopharyngeal carcinoma is an uncommon cancer in North America. Its clinical course is typified by locally advanced disease at diagnosis and has a high propensity for both regional and distant spread. It is, therefore, typically treated with a combination of radiation and chemotherapy. This report describes our 10-year clinical and radiological findings in a 48-year-old Vietnamese male patient with locally-advanced T4N1M0 lympho-epithelial carcinoma of the nasopharynx. Despite a long remission period after his initial course of aggressive chemoradiation, his tumor recurred locally after 4 years. Thereafter, throughout a period of over 10 years, he has been treated with multiple courses of re-irradiation and three different trials of chemotherapy. He was ultimately provided with over 30 months of progression-free tumor control with the epidermal growth factor receptor (EGFR)-inhibitor cetuximab. This case illustrates the commonly protracted course of this disease and its responsiveness to multiple treatment modalities.