Solid Thyroid Follicular Nodules With Longitudinal Nuclear Grooves: Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 18 Cases

Context.— Follicular thyroid nodules can be a source of diagnostic difficulties, particularly when they display atypical features commonly associated with malignancy, such as nuclear grooves. Objective.— To differentiate lesions with atypical features from similar-appearing benign and malignant lesions. Design.— Eighteen cases of atypical follicular thyroid nodules characterized by a solid growth pattern and prominent longitudinal nuclear grooves were studied and examined for clinicopathologic characteristics. Results.— The lesions occurred in 16 women and 2 men aged 36 to 88 years and measured from 0.2 to 1.5 cm. The tumors were well circumscribed and noninvasive, and histologically characterized by a predominantly solid growth pattern with rare scattered follicles or a combination of solid growth pattern with minor follicular areas. A striking feature seen in all cases was the occurrence of longitudinal nuclear grooves. Immunohistochemical stains showed negativity for cytokeratin 19 (CK19) and HBME-1 in 8 cases; in the other 10, there was focal positivity for HBME-1 in 4 cases and diffuse positivity in 6. All cases were negative for galectin-3 and for CK19, with the exception of 1 case, which was CK19+/HBME-1−. Next-generation sequencing of 16 cases with a 161-gene panel detected 14 single nucleotide variants in 12 cases, predominantly NRAS and HRAS mutations. Clinical follow-up ranging from 18 to 72 months (median, 43.7 months) did not disclose any evidence of recurrence or metastases. Conclusions.— We interpret these lesions as low-grade, indolent follicular proliferations that need to be distinguished from papillary thyroid carcinoma, follicular adenoma, and noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Solid Cell Nests Hyperplasia (Ultimobranchial Body Remnants) of the Thyroid: A Pitfall

Introduction/Objective Solid cell nests (SCN) are small epithelial cell nests interspersed within thyroid parenchyma, resembling squamous/transitional epithelium. SCNs, which are ultimobranchial remnants, are popularly considered pluripotent stem-cells responsible for developing follicular and C-cells. While SCNs are not an uncommon incidental findings in thyroid, solid cell nest hyperplasia is rare. SCNs are often mistaken for benign entities such as C-cell hyperplasia (CCH) or malignant lesions such as papillary thyroid carcinoma (PTC), metastatic squamous cell carcinoma, or medullary thyroid microcarcinoma (MTC). Methods/Case Report To reiterate this diagnostic dilemma, we present a case of a 57-year-old male with a six-year history of Hashimoto thyroiditis and multiple bilateral thyroid nodules. Ultrasonography revealed two nodules, one in each lobe, measuring 2.0x1.9x1.8cm(right) and 1.6x1.5x1.5cm(left). Both were solid, hypoechoic nodules with smooth margins and no echogenic foci. Fine-needle aspiration of right nodule was suspicious for follicular neoplasm, Hürthle- cell type, and the left nodule was atypia of unknown significance. Right-hemithyroidectomy specimen revealed follicular adenoma and oncocytic adenomatous nodules in a background of florid lymphocytic thyroiditis (Hashimoto). In two blocks, small solid nests of cells were identified, largest focus measuring 0.5 cm. The cells were polygonal to epithelioid with moderate amphophilic cytoplasm. Nuclei were centrally located, irregular to oval with occasional grooves. While nests had a squamoid appearance, they did not have intercellular bridges. Although nuclear grooves and evenly dispersed chromatin and chromocenters were noted, they lacked optical clearing or intra-nuclear inclusions characteristic for PTC. Thus, excluding these two possibilities, primary diagnostic considerations were SCN versus CCH. Immunohistochemical analysis showed cells positive for P63 and CK5/6 and negative for PAX-8, TTF-1, thyroglobulin, CEA, and calcitonin. Results (if a Case Study enter NA) NA Conclusion If wrongly diagnosed as CCH, patients may be placed in a high-risk category for possible development of MTC. It is, thus, necessary to be aware of SCN, which can occasionally become hyperplastic, to prevent misdiagnosis.

Periostin expression and its supposed roles in benign and malignant thyroid nodules: an immunohistochemical study of 105 cases

Background Thyroid tumors are often difficult to histopathologically diagnose, particularly follicular adenoma (FA) and follicular carcinoma (FC). Papillary carcinoma (PAC) has several histological subtypes. Periostin (PON), which is a non-collagenous extracellular matrix molecule, has been implicated in tumor invasiveness. We herein aimed to elucidate the expression status and localization of PON in thyroid tumors. Method We collected 105 cases of thyroid nodules, which included cases of adenomatous goiter, FA, microcarcinoma (MIC), PAC, FC, poorly differentiated carcinoma (PDCa), and undifferentiated carcinoma (UCa), and immunohistochemically examined the PON expression patterns of these lesions. Results Stromal PON deposition was detected in PAC and MIC, particularly in the solid/sclerosing subtype, whereas FA and FC showed weak deposition on the fibrous capsule. However, the invasive and/or extracapsular regions of microinvasive FC showed quite strong PON expression. Except for it, we could not find any significant histopathological differences between FA and FC. There were no other significant histopathological differences between FA and FC. Although PDCa showed a similar PON expression pattern to PAC, UCa exhibited stromal PON deposition in its invasive portions and cytoplasmic expression in its carcinoma cells. Although there was only one case of UCa, it showed strong PON immunopositivity. PAC and MIC showed similar patterns of stromal PON deposition, particularly at the invasive front. Conclusions PON may play a role in the invasion of thyroid carcinomas, particularly PAC and UCa, whereas it may act as a barrier to the growth of tumor cells in FA and minimally invasive FC.

Does Galectin3 Immunohistochemical Marker Help in Diagnosing the Nature of Benign or Malignant Thyroid Tumor?

Introduction: Galectin-3 has been reported quite accurate to detect or exclude malignancy in nodules with prior indeterminate Fine Needle Aspiration Cytology and per operative findings. Keeping this fact in mind, Galectin-3 can have a pivotal role in separating benign from the malignant thyroid neoplasms. We aim to determine the frequency and intensity of Galectin-3 immunohistochemical expression among benign and malignant thyroid neoplasms confirmed on histopathology. Materials and Methods: We studied 78 thyroid specimens diagnosed with thyroid neoplasms on histopathology. Out of these 39 were benign cases (follicular adenoma and hurthle cell adenoma) and 39 were malignant cases (papillary thyroid carcinomas, follicular carcinoma, medullary carcinoma and poorly differentiated carcinoma). Each specimen was examined grossly and microscopically and checked for immunohistochemical staining pattern of Galectin-3 under the microscope. Results: Age range in this study was from 15 to 65 years with mean age of 44.97 ± 10.78 years. Out of these 78 patients, 17 (21.79%) were male and 61 (78.21%) were female with male to female ratio of 1:3.6. Frequency of positive Galectin-3 immuno histochemical expression among thyroid neoplasms was found in 32 (41.03%) cases with Galectin-3 showing positive staining in 21 (53.85%) of all malignant and 11 (28.21%) of all benign cases .Among the malignant neoplasms, positivity was seen most frequently in papillary thyroid carcinomas as compared to the other malignancies. Conclusion: This study concluded that positive Galectin-3 immunohistochemical expression is more in malignant thyroid neoplasms (53.85%) as compare to the benign lesions (28.21%). Therefore, we recommend that this marker cannot be used alone for the routine diagnosis of malignant lesions as it has shown less sensitivity and specificity. Moreover it also has shown no significant role in differentiating between the benign and the malignant thyroid neoplasms.

Long noncoding RNA landscapes specific to benign and malignant thyroid neoplasms of distinct histological subtypes

The main types of thyroid neoplasms, follicular adenoma (FA), follicular thyroid carcinoma (FTC), classical and follicular variants of papillary carcinoma (clPTC and fvPTC), and anaplastic thyroid carcinoma (ATC), differ in prognosis, progression rate and metastatic behaviour. Specific patterns of lncRNAs involved in the development of clinical and morphological features can be presumed. LncRNA landscapes within distinct benign and malignant histological variants of thyroid neoplasms were not investigated. The aim of the study was to discover long noncoding RNA landscapes common and specific to major benign and malignant histological subtypes of thyroid neoplasms. LncRNA expression in FA, FTC, fvPTC, clPTC and ATC was analysed with comprehensive microarray and RNA-Seq datasets. Putative biological functions were evaluated via enrichment analysis of coexpressed coding genes. In the results, lncRNAs common and specific to FTC, clPTC, fvPTC, and ATC were identified. The discovered lncRNAs are putatively involved in L1CAM interactions, namely, pre-mRNA processing (lncRNAs specific to FTC); PCP/CE and WNT pathways (lncRNAs specific to fvPTC); extracellular matrix organization (lncRNAs specific to clPTC); and the cell cycle (lncRNAs specific to ATC). Known oncogenic and suppressor lncRNAs (RMST, CRNDE, SLC26A4-AS1, NR2F1-AS1, and LINC00511) were aberrantly expressed in thyroid carcinomas. These findings enhance the understanding of lncRNAs in the development of subtype-specific features in thyroid cancer.

The Potential Diagnostic Utility of TROP-2 & C-Kit in Thyroid Neoplasms

Background: Thyroid nodules are common finding, only 5% of nodules are malignant and the vast majority is non-neoplastic lesions or benign neoplasms. Thyroid cancer incidence is increasing faster than any other cancer types, thus representing one of the most common and clinically worrying malignant tumors of the endocrine system. Trophoblast antigen 2 (TROP2) is a transmembrane receptor glycoprotein encoded by the tumor-associated calcium signal transducer 2(Tacstd2) gene, which is located on chromosome 1p32. Although the biological function of TROP2 is unclear, accumulating evidence has demonstrated that its expression is elevated in various malignant tissues, whereas in human normal tissues relatively low or no TROP2 expression is observed. C-Kit is a type III receptor tyrosine kinase. C-Kit expression and signaling have been well characterized in several tumors, including gastrointestinal stromal tumors (GISTs). However, few studies have investigated c-Kit in the thyroid gland or in thyroid malignancies. The aim of this study was to investigate the diagnostic utility of TROP-2 on a large set of neoplastic thyroid lesions & to investigate the utility of TROP-2 & c-Kit markers to distinguish between benign and malignant thyroid neoplasms on Paraffin blocks. Methods: Immunohistochemistry for TROP2 and c-Kit was carried out on 85 different thyroid lesions (40 benign, 7 borderline and 38 malignant). Results: Malignant thyroid lesions were found to have negative expression of c-Kit in contrast to 80% of benign thyroid neoplasms. TROP2 was strong positive in 87.5% of papillary thyroid carcinomas (PTC), but there was no TROP2 expression in benign thyroid neoplasms, non-invasive follicular thyroid neoplasm with papillary like nuclear features, follicular carcinoma, anaplastic and poorly differentiated thyroid carcinoma. Conclusions: TROP2 is a good diagnostic tool for PTCs to differentiate between PTCs & other lesions with papillary like nuclear features as NIFTP, c-Kit is a good diagnostic tool for follicular adenoma & to differentiate between follicular adenoma & follicular carcinoma.

The immune landscape of the microenvironment of thyroid cancer is closely related to differentiation status

We have read with great interest the article entitled “Identification of an immune-related signature indicating the dedifferentiation of thyroid cells” by Wang et al. Their data reinforce our own previous results, here compiled. Anaplastic thyroid carcinoma had higher stromal scores, immune scores and enrichment of most immune cells than the control groups, suggesting that the immune microenvironment may correlate with differentiation status in thyroid cancer. We previously demonstrated that the differentiation status expressed by the pattern of protein expression may be related to the profile of immune cell infiltration of differentiated thyroid carcinoma. Wang et al. also explored the differences between the high-risk and low-risk score groups of samples. Among the distinct signaling pathways enriched in the high-risk score group, the epithelial to mesenchymal transition, TNFα signaling, and some common immune-related signaling pathways, including the IL-6/JAK/STAT3 pathway, interferon alpha response, interferon gamma response and inflammatory response were observed with high normalized enrichment score. We also investigated the IL-6 protein immune-histochemical expression in a retrospective study of 114 patients with papillary thyroid carcinoma and 39 patients with follicular thyroid carcinoma. We also obtained samples of 14 normal thyroid tissues from autopsies, 50 goiters and 43 follicular adenoma. We found IL-6 more frequently positive among malignant tumors than non-malignant samples. We demonstrated that IL-6 positivity was associated with infiltration of CD3 + cells, CD16 + cells and CD68 + macrophages. In addition, IL-6 expression was associated with infiltration of activated lymphocytes such as Granzyme B + cells and CD69 + cells. IL-6 positivity was not associated with infiltration of CD4+, CD8+, CD20+, FOXP3+, CD25 + cells but IL-6 was associated with tumor expression of PD-L1, FOXP3, IL-17, COX2, IL-1β, IL-10, CD134, IL-23. In summary, Wang et al. beautiful data reinforce the seminal idea that the immune landscape is closely related to the differentiation status of the tumor. This concept may help select individuals who deserve more careful attention, an essential point in the management of patients with mostly indolent tumors such as those of the thyroid. In fact, our results, here compiled, were obtained with immune-histochemistry, a routine laboratory technique that offers the possibility of simpler and practical execution.

Can TP53-mutant follicular adenoma be a precursor of anaplastic thyroid carcinoma?

Mutations of the TP53 tumor suppressor gene are highly prevalent in thyroid anaplastic carcinomas (AC) but are also reported in some well-differentiated cancers and even benign adenomas. The natural history of TP53-mutant adenomas, and whether they may represent a precursor for well-differentiated cancer or AC is largely unknown. Similarly, the frequency of TP53 mutations in thyroid nodules found on routine molecular analysis of fine-needle aspiration (FNA) samples is not established. A database on 44,510 FNA samples from thyroid nodules with predominantly indeterminate cytology tested using ThyroSeq v3 was reviewed to identify TP53-mutant cases and analyze their genetic profile and available clinicopathological findings. Among 260 (0.6%) selected thyroid nodules, 36 had an isolated TP53 mutation, and 224 carried a combination of TP53with other genetic alterations. No significant difference was observed between these groups with respect to patient age, gender, nodule size, and spectrum of TP53mutations. Histopathologically, 86% of the resected nodules with isolated TP53mutations were benign (mostly adenomas), whereas 82% of nodules carrying TP53mutations co-occurring with other alterations were cancers (P=0.001), including de-differentiated AC. TP53-mutant benign tumors and well-differentiated cancers often had scattered single neoplastic cells with bizarre nuclei resembling those comprising AC. Our study demonstrates that a small but distinct proportion of thyroid nodules carry a TP53mutation, either as a single genetic event or in combination with other alterations. While the latter are mostly cancers prone to dedifferentiation, there is at least a theoretical possibility that TP53-mutated adenomas may represent a precursor for such cancers, including AC.

“Thyroid nodular disease and PTEN mutation in a multicentre series of children with PTEN hamartoma tumor syndrome (PHTS)”

Purpose To report the incidence of 4–12% of differentiated thyroid cancer (DTC) and up to 50% of benign thyroid nodular disease and to describe nodular thyroid disease in a multicentre pediatric population with PTEN mutations. Methods: Retrospective data of pediatric patients with PTEN mutations collected from tertiary Departments of Pediatric Endocrinology of Turin, Milan and Genua, Italy, in the period 2010–2020. Results Seventeen children with PTEN mutations were recruited in the study. Thyroid involvement was present in 12/17 (70.6%) subjects, showing a multinodular struma in 6/17 (35.3%), nodules with benign ultrasound features in 5/17 (29.4%) and a follicular adenoma in 1/17 (6%). No correlation was found between thyroid disease and gender, puberty, vascular manifestations, delayed development, or brain MRI abnormalities, while multiple lipomas were associated with thyroid disease (p = 0.03), as was macrocephaly. Standard Deviation (SD) score head circumference was 4.35 ± 1.35 cm in subjects with thyroid disease, 3 ± 0.43 cm (p = 0.02) in the group without thyroid disease. Thyroid involvement was present in all subjects with mutations in exon 6 (4/4) and exon 8 (3/3) of the PTEN gene (p = 0.02). Conclusion In the presented cohort, benign thyroid disorders were prevalent, with no evidence of DTC. A correlation was found between thyroid lesions and head circumference and the occurrence of multiple lipomas. Future studies in larger cohorts should assess whether risk stratification is needed when recommending surveillance strategies in children or young adolescents with PTEN hamartoma syndrome.