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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 16764

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Prof. Dr. Zhiyan Liu

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Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
Interests: endocrine pathology; thyroid; environmental pollutants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Thyroid cancer is indolent, and affects more women than all other endocrine malignancies combined. However, follicular-derived carcinoma was determined as high risk in the WHO classification of endocrine and neuroendocrine tumors (5th edition). It is important to differentiate low-risk neoplasms and low-risk carcinoma from high-risk thyroid carcinoma, because there are significant differences between the clinical treatment of these tumor entities. Thyroid fine needle aspiration biopsy is likely to be the best method to confirm most of the malignancy pre-surgery. Molecular detection is also available for diagnosis, risk stratification, and targeted therapy pre- and post-surgery. The forthcoming Special Issue focuses on the advances in thyroid carcinoma, including the following topics:

Risk factors for thyroid carcinoma.
Markers and new genes associated with thyroid cancer.
Morphological and genetic features of low-risk thyroid neoplasms, and low-grade and high-grade thyroid carcinoma.
Treatment related to thyroid cancer, including follicular-derived and C-cell-derived carcinoma.
Predictors of treatment responses.
Therapies and precision therapies for thyroid cancer.
Diagnostic tools: strengths and limitations.
International variations in thyroid cancer diagnosis and treatment.
Determining thyroid cancer risk by using tests for the general population.
Mitigating risk of thyroid cancer surgically or medically.

Prof. Dr. Zhiyan Liu
Guest Editor

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Keywords

thyroid
cytology
pathology
therapy
radio-iodine resistance
targeted therapy

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Recent Advances in Thyroid Carcinoma, 2nd Edition in Diagnostics

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9 pages, 1080 KiB

Open AccessArticle

Exploring the Susceptibility to Multiple Primary Tumors in Patients with Differentiated Thyroid Cancer

by Laura Valerio, Silvia Cantara, Elisa Mattii, Cristina Dalmiglio, Alfonso Sagnella, Antonia Salvemini, Alessandra Cartocci, Fabio Maino and Maria Grazia Castagna

Diagnostics 2024, 14(12), 1210; https://doi.org/10.3390/diagnostics14121210 - 7 Jun 2024

Viewed by 792

Abstract

Purpose: It was demonstrated that differentiated thyroid cancer (DTC) patients may develop multiple primary tumors (MPT) during follow-up. Many studies showed an association between reduced telomere length and cancer phenotype; in particular, the short telomeres were associated with the development of a primary tumor. However, the role of altered telomere length in MPT development has not yet been demonstrated. The aim of this study was to evaluate the possible correlation between a short telomere length in blood leukocytes and the risk of developing MPT in DTC patients. Patients and Methods: We retrospectively evaluated 167 DTC patients followed up for a median of 13.6 years. Our control group was represented by 105 healthy subjects without any thyroid disease or present or past history of tumors. Our study groups, age-matched, were evaluated for the relative telomere length measured in leukocytes of peripheral venous blood. Results: The relative telomere length (RTL) was significantly different in healthy subjects compared to the total group of differentiated thyroid cancer patients [p < 0.0001]. Shorter telomeres length was observed in DTC patients with (n = 32) and without (n = 135) MPT compared to healthy subjects (p < 0.0001 and p = 0.0002, respectively). At multivariate analysis, the parameters independently associated with the presence of MPT were RTL [OR: 0.466 (0.226–0.817), p = 0.018] and the familial DTC [OR: 2.949 (1.142–8.466), p = 0.032]. Conclusions: The results of this study suggest a role of the relative telomere length in predicting MPT development in DTC patients. Our results contribute to increasing the knowledge of the genetic mechanisms underlying MPT development in DTC patients, considering relative telomere length as a possible prognostic marker. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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21 pages, 1124 KiB

Open AccessArticle

The Impact of Total Tumor Diameter on Lymph Node Metastasis and Tumor Recurrence in Papillary Thyroid Carcinomas

by Nuray Can, Buket Yilmaz Bulbul, Filiz Ozyilmaz, Necdet Sut, Meltem Ayyıldız Mercan, Burak Andaç, Mehmet Celik, Ebru Tastekin, Sibel Guldiken, Yavuz Atakan Sezer, Semra Ayturk Salt, Ezgi Genç Erdoğan, Funda Ustun and Hakan Gurkan

Diagnostics 2024, 14(3), 272; https://doi.org/10.3390/diagnostics14030272 - 26 Jan 2024

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Abstract

(1) Introduction: The impact of multifocality/bilaterality on the prognosis of papillary thyroid carcinoma (PTC) is a matter of debate. In order to clarify this debate, several studies have attempted to identify additional parameters associated with poor prognosis, including total tumor diameter (TTD), in the context of multifocal PTCs. In this context, this study was carried out to investigate the impact of TTD on tumor recurrence and lymph node metastasis (LNM) in PTCs. (2) Materials and Methods: The sample of this single-center retrospective study consisted of 706 patients diagnosed with PTC. TTD was calculated as the sum of the largest diameters of tumor foci in multifocal tumors. The resulting TTDs were grouped into TTDs ≤ 10 mm, TTDs > 10 mm, TTDs ≤ 20 mm, and TTDs > 20 mm, using 10 mm and 20 mm as cutoff values. (3) Results: There was no significant difference between multifocal papillary microcarcinomas (PTMCs) with a TTD of >10 mm and unifocal PTCs with a primary tumor diameter (PTD) of >10 mm except for advanced age and lymphovascular invasion (LVI). In addition, perineural invasion (PNI) and TTD > 10 mm were found to be significant risk factors for LNM, and PNI, TTD > 10 mm, TTD > 20 mm, and bilaterality were found to be significant risk factors for recurrence. LVI, and TTD > 10 mm were found to be independent significant predictors for recurrence, and LVI and extrathyroidal extension (ETE) were found to be independent significant predictors for LNM. (4) Conclusions: Considering TTD > 10 mm in recurrence risk categorization models and adopting a clinical approach that takes into account multifocal PTMCs with TTD > 10 mm along with unifocal PTCs with PTD > 10 mm may be more useful in terms of clinical management of the disease. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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10 pages, 423 KiB

Open AccessArticle

Early Assessment of Voice Problems in Post-Thyroidectomy Syndrome Using Cepstral Analysis

by Yeso Choi, Bo Ram Keum, Ju Eun Kim, Joong Seob Lee, Seok Min Hong, IL-Seok Park and Heejin Kim

Diagnostics 2024, 14(1), 111; https://doi.org/10.3390/diagnostics14010111 - 4 Jan 2024

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Abstract

Post-thyroidectomy syndrome (PTS), characterized by voice issues after thyroidectomy without recurrent laryngeal nerve injury, was investigated in this study. The Voice Fatigue Index (VFI) and cepstral analysis were employed for subjective and objective voice evaluation. Retrospective analysis involved 96 patients (37 males, 59 females) who underwent thyroidectomy without nerve injury from April 2018 to June 2022. Assessments pre- and post-thyroidectomy included the Voice Handicap Index (VHI) and VFI, along with auditory perceptual, acoustic (including cepstral), aerodynamic, and glottal vibration analyses. In females, although the GRBAS scale showed no significant change, both VHI and VFI increased post-thyroidectomy. Significant correlations were observed between the VHI and VFI in females. Acoustic analysis indicated a decrease in the cepstral peak prominence (CPP) of vowels (/a/) and sentences in females, with significant correlations between changes in the CPP/a/ and VHI/VFI. The maximum fundamental frequency (F₀max) exhibited a significant decrease, correlating with the VHI and VFI changes. The VFI demonstrated effectiveness in subjective PTS voice evaluation, comparable to the VHI. The present study highlights the potential of cepstral analysis as an index reflecting subjective voice discomfort, suggesting its promise for a comprehensive PTS voice evaluation. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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10 pages, 4764 KiB

Open AccessArticle

Risk of Subsequent Primary Cancer in Thyroid Cancer Survivors: A Nationwide Population-Based Study

by Min-Su Kim, Sang Jun Lee, Myeong Hoon Lee, Jay Hyug Choi, Hyun Wook Han and Young Shin Song

Diagnostics 2023, 13(18), 2903; https://doi.org/10.3390/diagnostics13182903 - 11 Sep 2023

Cited by 1 | Viewed by 1079

Abstract

Background: Despite obtaining a good prognosis and long life expectancy, survivors of thyroid cancer can nevertheless develop subsequent primary cancer (SPC). We investigated the risk and types of SPC in patients with thyroid cancer and compared them with subjects without thyroid cancer history (controls). Methods: We conducted a nationwide, population-based, retrospective cohort study based on the Korean National Health Insurance Database. A total of 432,654 patients diagnosed with thyroid cancer between 2004 and 2019 were 1:1 matched with controls for age, sex, income, and region of residence. The hazard ratios (HR) and 95% confidence intervals (CI) of SPC were estimated using Cox proportional hazard models. Results: In total, 78,584 (18.2%) patients with thyroid cancer and 49,979 (11.6%) controls were diagnosed with SPCs over a mean follow-up of 6.9 years. Patients with thyroid cancer had a higher risk of SPC at any site (adjusted HR, 1.62; 95% CI, 1.60–1.64) than the controls. The risk of SPCs was particularly high for patients diagnosed with thyroid cancer at a younger age (<40 years) and within 5 years. Conclusions: Medical caregivers should consider the long-term follow-up of patients with thyroid cancer and discuss the risk of SPC, especially if they complain of cancer-related symptoms. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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16 pages, 2317 KiB

Open AccessArticle

Thyroid Collision Tumors: The Presence of the Medullary Thyroid Carcinoma Component Negatively Influences the Prognosis

by Ion Negura, Victor Ianole, Mihai Danciu, Cristina Preda, Diana Gabriela Iosep, Radu Dănilă, Alexandru Grigorovici and Delia Gabriela Ciobanu Apostol

Diagnostics 2023, 13(2), 285; https://doi.org/10.3390/diagnostics13020285 - 12 Jan 2023

Cited by 2 | Viewed by 2273

Abstract

Thyroid collision tumors (TCTs) are rare pathological findings, representing <1% of thyroid cancers. This study aimed to compare the main pathological features of TCTs containing medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) components with MTC-only tumors and PTC-only tumors. Methods: The retrospective study included 69 cases diagnosed with TCTs (with simultaneous MTC and PTC components), MTC and PTC. All tumors were comparatively assessed for the classical histopathological prognostic features, including a new grading system for MTC. Results: The main component of TCTs had more frequent microscopic extrathyroidal extension (mETE) (p = 0.000), lymphovascular invasion (LVI) (p = 0.000), perineural invasion (PNI) (p = 0.044), and lymph node metastasis (p = 0.042). Additionally, the TCTs’ MTC component presented with more frequent LVI (p = 0.010). Comparing TCTs’ MTC and PTC components with MTC-only tumors and PTC-only tumors revealed that only the TCTs’ MTC components had statistically significant more frequent mETE (p = 0.010) than MTC-only tumors. When applied to the MTC component of TCTs, the pathological parameters of the new grading system of MTC showed no correlations with other microscopic or clinical aspects. Conclusion: Using classical pathological prognostic features, the comparative analysis revealed that the main TCTs’ component was more aggressive than the minor one. Contrary to PTCs, in TCTs, the medullary component was more aggressive than the papillary one, but also more aggressive than MTC-only tumors. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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10 pages, 1495 KiB

Open AccessArticle

Analysis of Rare Alleles of miRNA-146a (rs2910164) and miRNA-34b/c (rs4938723) as a Prognostic Marker in Thyroid Cancer in Pakistani Population

by Rashida Khan, Samina Asghar Abbasi, Qaisar Mansoor, Mehvish Naseer Ahmed, Kahkashan Bashir Mir and Ruqia Mehmood Baig

Diagnostics 2022, 12(10), 2495; https://doi.org/10.3390/diagnostics12102495 - 15 Oct 2022

Cited by 3 | Viewed by 1705

Abstract

Background: Rationale: The miRNAs are short non-coding functional RNAs that are involved in the regulation of transcriptomes. It was found that human miRNA-146a and miRNA34b/c are important microRNAs and are functioning either as onco-miRNAs, or acting as tumor suppressors, in different conditions. To date, no study has been performed to evaluate the alterations of miRNA-146ars2910164 and miRNA34b/crs4938723 polymorphism as a risk factor in the development of thyroid cancer in the Pakistani population. Mutational analysis of rs2910164 and rs4938723 of miRNA-146a and miRNA-34b/c was carried out to check their association with the development of thyroid carcinogenesis. Material and Methods: Papillary thyroid cancer (PTC) patients with age and gender-matched controls were recruited for the present study. DNA extraction, genotyping of rs2910164 and rs4938723 was carried out by ARMS-PCR. Statistical analyses were carried out using SPSS software (version 20). Results: The odds ratio for risk allele C of rs2910164 for patients and controls was 23.0168 (3.0321–174.7208) with a p-value of <0.0001, showing that the frequency of the major allele G was lower in patients while the frequency of minor allele C was higher in patients. Similarly, the odds ratio for risk allele C of rs4938723 was 1.8621 (1.0321–3.3596) with a p-value of <0.03788 showing significant association with the development of thyroid cancer. Conclusions: The study highlights the significant association of miRNAs SNPs as one of the genetic risk factor for PTC. It was concluded that miRNA-146a (rs2910164) showed higher frequency of minor allele C in patients. Similarly in miRNA-34b/c gene SNP rs4938723 was observed to have a strong association with the development of thyroid cancer as the frequency of rare allele C was higher in patients. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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10 pages, 2875 KiB

Open AccessBrief Report

Liquid Biopsies in Follicular Thyroid Carcinomas—A Brief Report

by Marie-Louise Uhre Hansen, Simone Kloch Bendtsen, Kathrine Kronberg Jakobsen, Ane Yde Schmidt, Christoffer Holst Hahn, Christian von Buchwald and Christian Grønhøj

Diagnostics 2024, 14(14), 1577; https://doi.org/10.3390/diagnostics14141577 - 22 Jul 2024

Viewed by 798

Abstract

Thyroid cancer (TC) represents a significant health burden globally, with follicular thyroid cancer (FTC) posing diagnostic challenges despite advancements. This pilot study aimed to evaluate the utility of a liquid biopsy with cell-free DNA (cfDNA) in patients with FTC. Blood samples were collected from 13 patients diagnosed with FTC, DNA extraction was performed, and cfDNA was analyzed using the Illumina’s TruSight Oncology 500 High-Throughput panel. The results revealed low tumor mutational burden and minimal pathogenic variants in cfDNA, indicating challenges such as low DNA yield and poor material quality despite adequate coverage. Our findings indicate that cfDNA as an add-on diagnostic tool in patients with FTC might not be a useful supplement. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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6 pages, 3871 KiB

Open AccessInteresting Images

An Anaplastic Thyroid Carcinoma of the Giant-Cell Type from a Mediastinal Ectopic Thyroid Gland

by Daniel Nguyen, Nyein Nyein Htun, Beverly Wang, Bonnie Lee and Cary Johnson

Diagnostics 2023, 13(18), 2941; https://doi.org/10.3390/diagnostics13182941 - 14 Sep 2023

Cited by 4 | Viewed by 1203

Abstract

Anaplastic thyroid carcinoma is a rare, aggressive form of thyroid carcinoma with a mean survival of less than 6 months. Ectopic thyroid tissue can be present in the mediastinum due to faulty embryogenesis with improper descent. Primary thyroid malignancies may arise from this ectopic tissue. A 90-year-old male with a history of prostatic adenocarcinoma, hypothyroidism, and occupational and therapeutic exposure to radiation presented with a rash on his chest. A review of the dermatopathology and excised mediastinal specimen revealed rare papillary foci that tested positive for thyroid markers from a background of poorly differentiated components. Molecular analysis confirmed a BRAF V600E mutation in the specimen. The final diagnosis was anaplastic thyroid carcinoma of the giant-cell type. Given the atrophic cervical thyroid tissue in the patient’s neck with no evidence of previous surgery, this carcinoma was believed to arise from ectopic mediastinal tissue associated with cutaneous and bony metastasis. In conclusion, anaplastic thyroid carcinoma is an aggressive and rare thyroid malignancy that can arise from ectopic thyroid tissue in the mediastinum and should be considered in the differential diagnosis of primary undifferentiated mediastinal malignancies with bony involvement. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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5 pages, 3255 KiB

Open AccessInteresting Images

A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family

by Lan Chen, Jing-Xin Zhang, Dong-Ge Liu and Hong-Gang Liu

Diagnostics 2023, 13(5), 955; https://doi.org/10.3390/diagnostics13050955 - 2 Mar 2023

Cited by 1 | Viewed by 1776

Abstract

This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected. Further molecular study of targeted sequencing also revealed a RET germline mutation (C634G) in the family tree including the three members with onset of the disease and one granddaughter who had no disease at the time of testing. Despite the syndrome being well-known, it may still be misdiagnosed because of its rarity and long disease onset. A few lessons can be learned from this unique case. Successful diagnosis requires high suspicion and surveillance and a tri-level methodology including a careful review of family history, pathology and genetic counselling. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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14 pages, 644 KiB

Open AccessProtocol

Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial

by Maaike Dotinga, Dennis Vriens, Floris H. P. van Velden, Mette K. Stam, Jan W. T. Heemskerk, Petra Dibbets-Schneider, Martin Pool, Daphne D. D. Rietbergen, Lioe-Fee de Geus-Oei and Ellen Kapiteijn

Diagnostics 2022, 12(12), 3154; https://doi.org/10.3390/diagnostics12123154 - 14 Dec 2022

Cited by 4 | Viewed by 2633

Abstract

Background: Management of patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a challenge as I-131 therapy is deemed ineffective while standard-of-care systemic therapy with tyrosine kinase inhibitor (TKI) lenvatinib is associated with frequent toxicities leading to dose reductions and withdrawal. A potential new treatment approach is to use TKIs as redifferentiation agent to restore RAI uptake to an extent that I-131 therapy is warranted. Prior studies show that short-term treatment with other TKIs restores RAI uptake in 50–60% of radioiodine-refractory DTC patients, but this concept has not been investigated for lenvatinib. Furthermore, the optimal duration of treatment with TKIs for maximal redifferentiation has not been explored. Methods and Design: A total of 12 patients with RAI-refractory DTC with an indication for lenvatinib will undergo I-124 PET/CT to quantify RAI uptake. This process is repeated after 6 and 12 weeks post-initiating lenvatinib after which the prospective dose estimate to target lesions and organs at risk will be determined. Patients will subsequently stop lenvatinib and undergo I-131 treatment if it is deemed effective and safe by predefined norms. The I-124 PET/CT measurements after 6 and 12 weeks of the first six patients are compared and the optimal timepoint will be determined for the remaining patients. In all I-131 treated patients post-therapy SPECT/CT dosimetry verification will be performed. During follow-up, clinical response will be evaluated using serum thyroglobulin levels and F-18 FDG PET/CT imaging for 6 months. It is hypothesized that at least 40% of patients will show meaningful renewed RAI uptake after short-term lenvatinib treatment. Discussion: Shorter treatment duration of lenvatinib treatment is preferred because of frequent toxicity-related dose reductions and drug withdrawals in long-term lenvatinib treatment. Short-term treatment with lenvatinib with subsequent I-131 therapy poses a potential new management approach for these patients. Since treatment duration is reduced and I-131 therapy is more tolerable for most patients, this potentially leads to less toxicity and higher quality of life. Identifying RAI-refractory DTC patients who redifferentiate after lenvatinib therapy is therefore crucial. Trial Registration: ClinicalTrials.gov, NTC04858867. Full article

(This article belongs to the Special Issue Recent Advances in Thyroid Carcinoma)

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