Molecular alterations in Hürthle cell nodules and preoperative cancer risk

Hürthle cell carcinoma (HCC) is a distinct type of thyroid cancer genetically characterized by DNA copy number alterations (CNA), typically of genome haploidization type (GH-type). However, whether CNA also occurs in benign Hürthle cell adenomas (HCA) or Hürthle cell hyperplastic nodules (HCHN), and have diagnostic impact in fine-needle aspiration (FNA) samples, remains unknown. To address these questions, we (1) analyzed 26 HCC, 24 HCA, and 8 HCHN tissues for CNA and other mutations using ThyroSeq v3 (TSv3) next-generation sequencing panel, and (2) determined cancer rate in 111 FNA samples with CNA and known surgical outcome. We identified CNA, more often of the GH-type, in 81% of HCC and in 38% HCA, but not in HCHN. Among four HCC with distant metastasis, all had CNA and three TERT mutations. Overall, positive TSv3 results were obtained in 24 (92%) HCC, including all with ATA high risk of recurrence or metastasis. Among 111 FNA cases with CNA, 38 (34%) were malignant and 73 (66%) benign. A significant correlation between cancer rate and nodule size was observed, particularly among cases with GH-type CNA, where every additional centimeter of nodule size increased the malignancy odds by 1.9 (95% CI 1.3–2.7; P = 0.001). In summary, the results of this study demonstrate that CNA characteristic of HCC also occur in HCA, although with lower frequency, and probability of cancer in nodules with CNA increases with nodule size. Detection of CNA, in conjunction with other mutations and nodule size, is helpful in predicting malignancy in thyroid nodules.

Download Full-text

OR21-02 Impact of Nodule Size on the Probability of Hurthle Cell Carcinoma and Other Cancers in Thyroid Nodules with Multiple Chromosomal Copy Number Alterations

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1766 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Marina N Nikiforova ◽

Alyaksandr Nikitski ◽

Jessica Tebbets ◽

Lindsey Tolino ◽

Pooja Manroa ◽

...

Keyword(s):

Copy Number ◽

Thyroid Nodules ◽

Surgical Pathology ◽

Copy Number Alterations ◽

Nodule Size ◽

Thyroid Carcinomas ◽

Hürthle Cell ◽

Chromosomal Copy Number ◽

Chromosomal Copy ◽

Probability Of Cancer

Abstract Fine-needle aspiration (FNA) of thyroid nodules yields indeterminate cytological diagnosis in ~20% of cases, confounding patient management. This includes Hurthle cell nodules, which typically yield Bethesda IV and III cytology. Chromosomal copy number alterations (CNA) are known to occur in thyroid tumors, particularly in Hurthle cell carcinomas (HCC) as well as in other typically follicular-patterned tumors including papillary thyroid carcinomas (PTC) and poorly differentiated thyroid carcinomas (PDTC). The aim of this study was to evaluate thyroid nodules tested positive for CNA but negative for all other genomic alterations using ThyroSeq v3 NGS assay in order to establish the probability of cancer in these nodules and find whether it is influenced by the pattern of CNA and nodule size. We evaluated 111 nodules with multiple CNA detected by ThyroSeq in FNA samples and available surgical pathology outcome. Of those, 69 (62%) nodules showed CNA changes consistent with genome near-haploidization (GNH) whereas 42 (38%) nodules had multiple chromosomal losses and gains (CLG). Nodule size ranged from 0.5-10.2 cm; cytology was Bethesda III in 54%, Bethesda IV in 43%, and Bethesda V-VI in 3% of cases, with Hurthle cells mentioned in the cytology report in 64% of cases. On surgical pathology, 38 (34%) of these nodules were malignant (including 24 HCC, 8 PTC, and 5 oncocytic PDTC) and 73 (66%) were benign (including 43 Hurthle cell and 18 follicular adenomas). No significant difference was observed in probability of malignancy between the two patterns of CNA (p=0.41). However, a significant correlation between the nodule size and probability of cancer was found (p=0.006). In specific CNA groups, correlation between cancer and nodule size remained significant for nodules with GNH pattern (P=0.0002), but not with CLG pattern (p=0.449). Specifically, cancer probability in nodules with GNH pattern and <2 cm in size was 14% (all cancers minimally-invasive), 2.0-2.9 cm was 33%, 3.0-3.9 cm was 50%, 4-4.9 cm was 67%, and ≥5 cm was 80%. Among high-risk cancers (widely-invasive or angioinvasive HCC, PDTC), all 10 tumors had the GNH pattern (p=0.01) and average nodule size of 4.9 cm (range, 2.1-8.5 cm). These findings suggest that CNA of both types are frequently found in Hurthle cell tumors, and probability of cancer in nodules with CNA and no other mutations increases with larger nodule size. This may help to refine the pre-operative assessment of cancer probability and risk of more aggressive disease and offer more tailored management to these patients.

Download Full-text

Thyroseq V3 Molecular Profiling for Tailoring the Surgical Management of Hürthle Cell Neoplasms

Case Reports in Endocrinology ◽

10.1155/2018/9329035 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Sarah Pearlstein ◽

Arash H. Lahouti ◽

Elana Opher ◽

Yuri E. Nikiforov ◽

Daniel B. Kuriloff

Keyword(s):

Cell Carcinoma ◽

Treatment Plan ◽

Needle Aspiration ◽

Molecular Profiling ◽

Copy Number Alterations ◽

Convincing Argument ◽

Hürthle Cell ◽

Hürthle Cell Carcinoma ◽

Risk Of Malignancy ◽

Hurthle Cell Carcinoma

Hürthle cell predominant thyroid nodules often confound the diagnostic utility of fine needle aspiration biopsy (FNAB) with cytology often interpreted as a Hürthle cell lesion with an indeterminate risk of malignancy, Bethesda category (BC) III or IV. Molecular diagnostics for Hürthle cell predominant nodules has also been disappointing in further defining the risk of malignancy. We present a case of a slowly enlarging nodule within a goiter initially reported as benign on FNAB, BC II but on subsequent FNAB suspicious for a Hürthle cell neoplasm, BC IV. The patient had initially requested a diagnostic lobectomy for a definitive diagnosis despite a higher risk of malignancy based on the size of the nodule > 4 cm alone. To better tailor this patient’s treatment plan, a newer expanded gene mutation panel, ThyroSeq® v3 that includes copy number alterations (CNAs) and was recently found to have greater positive predictive value (PPV) for identifying Hürthle cell carcinoma (HCC), was performed on the FNAB material. Molecular profiling with ThyroSeq® v3 was able to predict a greater risk of carcinoma, making a more convincing argument in favor of total thyroidectomy. Surgical pathology confirmed a Hürthle cell carcinoma with 5 foci of angioinvasion and foci of capsular invasion.

Download Full-text

Molecular alterations in Hürthle cell neoplasms of thyroid: A fine needle aspiration cytology study with cytology‐histology correlation

Cancer Cytopathology ◽

10.1002/cncy.22370 ◽

2020 ◽

Author(s):

Syed M. Gilani ◽

Julia A. Ross ◽

Manju L. Prasad ◽

Lynwood Hammers ◽

Guoping Cai ◽

...

Keyword(s):

Fine Needle Aspiration ◽

Fine Needle Aspiration Cytology ◽

Needle Aspiration ◽

Aspiration Cytology ◽

Fine Needle ◽

Molecular Alterations ◽

Hürthle Cell ◽

Needle Aspiration Cytology ◽

Cytology Study

Download Full-text

Sex-dependent differences in DNA copy number alterations in hepatocellular carcinoma

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2012.00005 ◽

2012 ◽

Vol 32 (1) ◽

pp. 5-9 ◽

Cited By ~ 1

Author(s):

Bing-ji WEN ◽

Wen-ming CONG ◽

Ai-zhong WANG ◽

Song-qin HE ◽

Hong-mei JIANG ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Copy Number ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Dna Copy Number Alterations

Download Full-text

From Benign Inflammatory Dermatosis to Cutaneous Lymphoma. DNA Copy Number Imbalances in Mycosis Fungoides versus Large Plaque Parapsoriasis

Medicina ◽

10.3390/medicina57050502 ◽

2021 ◽

Vol 57 (5) ◽

pp. 502

Author(s):

Georgiana Gug ◽

Caius Solovan

Keyword(s):

Mycosis Fungoides ◽

Copy Number ◽

Snp Array ◽

Chromosome 1 ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Large Plaque ◽

Inflammatory Dermatosis ◽

Fresh Frozen ◽

Dna Copy Number Alterations

Background and Objectives: Mycosis fungoides (MF) and large plaque parapsoriasis (LPP) evolution provide intriguing data and are the cause of numerous debates. The diagnosis of MF and LPP is associated with confusion and imprecise definition. Copy number alterations (CNAs) may play an essential role in the genesis of cancer out of genes expression dysregulation. Objectives: Due to the heterogeneity of MF and LPP and the scarcity of the cases, there are an exceedingly small number of studies that have identified molecular changes in these pathologies. We aim to identify and compare DNA copy number alterations and gene expression changes between MF and LPP to highlight the similarities and the differences between these pathologies. Materials and Methods: The patients were prospectively selected from University Clinic of Dermatology and Venereology Timișoara, Romania. From fresh frozen skin biopsies, we extracted DNA using single nucleotide polymorphism (SNP) data. The use of SNP array for copy number profiling is a promising approach for genome-wide analysis. Results: After reviewing each group, we observed that the histograms generated for chromosome 1–22 were remarkably similar and had a lot of CNAs in common, but also significant differences were seen. Conclusions: This study took a step forward in finding out the differences and similarities between MF and LPP, for a more specific and implicitly correct approach of the case. The similarity between these two pathologies in terms of CNAs is striking, emphasizing once again the difficulty of approaching and differentiating them.

Download Full-text

Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas

Cancer Research ◽

10.1158/0008-5472.can-08-3913 ◽

2009 ◽

Vol 69 (9) ◽

pp. 4036-4042 ◽

Cited By ~ 118

Author(s):

Kuan-Ting Kuo ◽

Bin Guan ◽

Yuanjian Feng ◽

Tsui-Lien Mao ◽

Xu Chen ◽

...

Keyword(s):

Copy Number ◽

Molecular Genetic ◽

Low Grade ◽

High Grade ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Genetic Changes ◽

Dna Copy Number Alterations ◽

Serous Tumors

Download Full-text

Follow-up of Benign Thyroid Nodules—Can We Do Less?

Canadian Association of Radiologists Journal ◽

10.1016/j.carj.2018.10.001 ◽

2019 ◽

Vol 70 (1) ◽

pp. 62-67 ◽

Cited By ~ 1

Author(s):

Manijeh Mohammadi ◽

Carrie Betel ◽

Kirsteen Rennie Burton ◽

Kevin McLughlin Higgins ◽

Zeina Ghorab ◽

...

Keyword(s):

Fine Needle Aspiration ◽

Thyroid Nodules ◽

Descriptive Study ◽

Needle Aspiration ◽

Thyroid Malignancy ◽

Fine Needle ◽

Nodule Size ◽

Benign Thyroid Nodules ◽

Benign Thyroid

Objective To determine the incidence of malignancy, follow-up ultrasound (US), and repeat fine needle aspiration (FNA) in thyroid nodules that have been previously biopsied as benign. Methods This is a retrospective, descriptive study of benign thyroid nodules evaluated by US between 2010-2011. We determined the frequency of follow-up ultrasounds and FNAs, mean years of follow-up, interval between follow-up US, change in nodule size, reasons for repeat FNA (rFNA), frequency of thyroidectomy, and thyroid malignancy during 5 years of follow-up. Results A total of 733 benign thyroid nodules were reviewed in 615 patients. Mean years of US follow-up was 3.47 ± 1.65 years; 275 (37.5%) had no follow-up US; 109 (14.9%) had 1 follow-up US; 93 (12.7%) had 2 follow-up US; and 256 (34.9%) had 3 or more follow-up US. Assessment of thyroid nodule size showed that 215 (28.8%) nodules decreased in size, 145 (19.4%) increased in size by less than 50%, and 91 (12.1%) increased in size by more than 50%. Of the 733 nodules, 17 nodules (2.3%) underwent thyroidectomy for which the pathology result of 9 (1.2%) showed malignancy, and 65 (8.9%) thyroid nodules underwent rFNA. When applying the 2015 recommendations for repeat FNA, 35% were done unnecessarily. Conclusion In our sample of initially benign thyroid nodules, only 9 patients (1.2%) had pathology-proven malignancy after a mean follow-up of 3.5 years. Over 30% of patients had more than 3 rUSs. Decreased interval and frequency of rUS should be considered in future guidelines for thyroid management.

Download Full-text