Core needle biopsy: an efficacious adjunct to cytological diagnosis in thyroid tumours suspected of anaplastic carcinoma - single-centre experience.

Introduction: Ultrasound-guided fine- needle aspiration biopsy (FNAB) remains the primary method for diagnosing thyroid nodules, providing adequate information for definitive diagnosis and treatment decisions in most cases. However, cytological examinations sometimes yield inconclusive or non-diagnostic results. For rapidly growing tumours with suspected malignancy, a swift and accurate diagnosis is crucial to initiate timely treatment. Cases suggestive of anaplastic thyroid cancer (ATC) or poorly differentiated cancer present unique challenges in obtaining satisfactory diagnostic material through FNAB, due to advanced necrosis or extensive inflammatory components. In these instances, core needle biopsy (CNB) emerges as a complementary diagnostic tool when FNAB results are ambiguous. This study aimed to evaluate the effectiveness of CNB in diagnosing rapidly growing thyroid tumours with clinical indication of ATC. Material and methods: Between 2019-2023, 31 CNBs were performed on large, rapidly expanding thyroid tumours. Results: All cases exhibited clinical signs of malignancy, with previous FNAB outcomes being either equivocal or inconclusive. The subsequent CNBs demonstrated accurate results with minimal complications among the patients. While reservations about CNB for thyroid nodules persist, it offers a valuable diagnostic alternative, potentially preventing unwarranted surgical biopsy or removal of the thyroid. Conclusions: Core needle biopsy deployment should be judicious, reserved for select cases, and carried out in a hospital environment to ensure diagnostic precision with the least risk of complications.

Fine needle aspiration biopsy of parathyroid; is it meaningful? A cytologic study of 81 cases with histological and clinical correlations.

BACKGROUND: Recognizing the parathyroid gland and distinguishing the parathyroid from thyroid lesions in fine needle aspiration (FNA) is challenging. This study aimed to identify cytomorphologic features suggestive of parathyroid origin and to assess the utility of cytopathology in conjunction with ancillary tests in the identification of parathyroid glands. MATERIALS AND METHODS: Ultrasound (US) guided FNA of parathyroid gland and lesions in 81 patients were reviewed concerning clinical history and correlated to histopathologic findings in available cases. FNA smears were evaluated for cellularity, architectural patterns, cellular and nuclear features, and background of the smears. In 78 cases, FNA was supplemented by a measurement of parathormone (PTH) levels in the needle washout fluid (FNA-PTH assay) and/or GATA3/PTH/chromogranin-A immunostainings. RESULTS: Sixty-four cases were diagnosed cytologically as parathyroid lesions in conjunction with FNA-PTH assay and/or immunocytochemical examinations. In an additional nine cases, a diagnosis of parathyroid lesions was rendered after repeated FNA with FNA-PTH assay. The histolopathologic diagnosis of surgically excised cases (n = 75) included parathyroid adenoma (60 cases), atypical parathyroid adenoma (4 cases), parathyroid hyperplasia (10 cases), and parathyroid carcinoma (1 case). Major cytological findings of parathyroid tissue included high cellularity, scattered naked nuclei, cribriform and three-dimensional clusters, stippled chromatin, and oxyphilic cytoplasm while papillary pattern or colloid-like material was identified in three cases respectively. No nuclear grooves or inclusions were seen in any case. CONCLUSIONS: High cellularity scattered naked nuclei, cribriform and three-dimensional patterns, stippled chromatin and oxyphilic cytoplasm are cytomorphologic features that favour parathyroid origin. A combination of these features with FNA-PTH assay and/or GATA3, PTH, and chromogranin-A immunostainings on cytologic specimens aid in the identification of parathyroid glands and the distinguishing of parathyroid from thyroid lesions.

Thyroglobulin measurements in washouts of fine-needle aspiration biopsy in the monitoring of patients with differentiated thyroid carcinoma.

INTRODUCTION: Approximately 35% patients with papillary thyroid carcinoma (PTC) and 13% with follicular thyroid carcinoma (FTC) present with metastases of cervical lymph nodes (LNs) at the time of diagnosis. In addition, 15-20% of patients treated with total thyroidectomy develop, after an interval of five years, metastases to the neck LNs on ultrasound examination. Fine-needle aspiration biopsy (FNAB) represents the gold standard technique for the detection of cervical LNs metastases. The aim of the study was to evaluate the diagnostic performance of the technique of thyroglobulin (Tg) measurement of washout FNAB (FNAB-Tg) in diagnostics of LNs metastases in different groups of patients with differentiated thyroid carcinoma (DTC). MATERIAL AND METHODS: Two hundred FNAB-Tg samples from 200 patients [158 women; 42 men; mean age 51.37 ± 16.77 (53)] diagnosed with DTC were examined for the assessment of the diagnostic utility of FNAB-Tg from suspicious LNs. FNAB-Tg ranged from 1.96 to 5000 ng/mL in metastatic LNs [mean; 1510 ± 1486 ng/mL (958.5)] and from 0.04 to 635.9 ng/mL in nonmetastatic LNs [mean; 57.86 ± 319.19 ng/mL (1.96)], p < 0.001. RESULTS: The most accurate diagnostic performance was displayed for the concentration of 33.28 ng/mL in FNAB-Tg with AUC of 0.91 and high sensitivity and specificity (0.92 and 0.93). FNAB-Tg in conjunction with the cytopathological examination of suspicious LNs in differentiated thyroid carcinoma (DTC) patients increases the diagnostic accuracy of FNAB (sensitivity 0.99; specificity 0.99; AUC 1.00). CONCLUSIONS: FNAB-Tg may be particularly useful in detecting LN metastases in DTC patients, and in differential diagnosis of various LN metastasizing malignancies. The combination of FNAB and FNAB-Tg measurement has high specificity and sensitivity in the detection of LN metastases of DTC.

Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer.

PURPOSE: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC. EXPERIMENTAL DESIGN: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013. RESULTS: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P = 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P = 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P = 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P = 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P = 0.013). CONCLUSIONS: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy.

Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations.

Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance.

SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility.

BACKGROUND: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative. OBJECTIVES: The objective of this study was to identify susceptibility genes for PTC. METHODS: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies. RESULTS: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants. CONCLUSIONS: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.