Three-dimensional telomere profiles in papillary thyroid cancer variants: a pilot study

Papillary thyroid carcinoma (PTC) has two main histologic variants: classical-PTC (CL-PTC) and follicular variant PTC (FV-PTC). Recently, due to its similar features to benign lesions, the encapsulated FV-PTC variant was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Nonetheless, specific molecular signatures are not yet available. It is well known that telomere-related genome instability is caused by inappropriate DNA repair of dysfunctional telomeres and that mechanisms involved in the damaged telomere repair processing may led to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). There was no association between BRAF expression and telomere length in all tested samples. Our data indicate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles FTA. NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and that telomere length of NIFTP overlaps with that of the FTA histotype. These preliminary findings reinforce the view that NIFTP are lesions closer to non-malignant thyroid nodules and confirmed that short telomeres are a feature of PTC.

Risk Patterns of Distant Metastases in Follicular, Papillary and Medullary Thyroid Cancer

This study of 542 patients with follicular thyroid cancer, 366 patients with the follicular variant and 1452 patients with the classical variant of papillary thyroid cancer, and 819 patients with sporadic medullary thyroid cancer operated at a tertiary referral center aimed to determine risk patterns of distant metastasis for each tumor entity, which are ill-defined. On multivariable logistic regression analyses, lymph node metastasis consistently emerged as an independent risk factor of distant metastasis, yielding odds ratios (ORs) of 2.4 and 2.8 for follicular thyroid cancer and the follicular variant of papillary thyroid cancer, and ORs of 5.9 and 6.4 for the classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer. Another independent risk factor consistently associated with distant metastasis, most strongly in follicular thyroid cancer and the follicular variant of papillary thyroid cancer (OR 3.5 and 4.0), was patient age >60 years. Altogether, 2 distinct risk patterns of distant metastasis were identified, which were modulated by other cancer type-dependent risk factors: one with lymph node metastasis as leading component (classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer), and another one with age as leading component (follicular thyroid cancer and the follicular variant of papillary thyroid cancer). Distant metastasis was exceptional in node-negative patients with sporadic medullary thyroid cancer (1.7%) and the classical variant of papillary thyroid cancer (1.4%), and infrequent in node-negative patients with the follicular variant of papillary thyroid cancer (4.4%). These findings delineate windows of opportunity for early surgical intervention before distant metastasis has occurred.

NTRK3-rearranged thyroid carcinoma, clinical and pathologic features

Introduction/Objective NTRK3 gene encodes a transmembrane protein receptor of the tropomyosin receptor kinase (Trk) family. Gene fusions involving NTRK3 result in a constitutive activation or overexpression of Trk receptor, potentially leading to oncogenesis. NTRK targeted therapies show a promising activity in varied cancer types with NTRK fusions. The aim of this case review is to describe the clinical and pathologic findings of thyroid neoplasm with NTRK3 gene fusions. Methods/Case Report The cytology fine needle aspiration (FNA), molecular testing results and pathology of surgical resections are reviewed in 220 cases of total and hemithyroidectomy from January 2018 to May 2021. Results (if a Case Study enter NA) Three cases with NTRK3 gene fusions are identified by Thyroseq or Afirma GSC from FNA of thyroid nodules with later surgical intervention. No other mutations or gene fusions were identified. Each case had total thyroidectomy. Case 1 is a 41-year-old female with FNA diagnosis of suspicious for papillary thyroid carcinoma (PTC) and ETV6/NTRK3 fusion found by Afirma GSC. Pathology diagnosis is PTC classic type, two tumor nodules 1.1cm and 1.0cm, lymphovascular invasion not identified, three lymph nodes not involved by tumor and pathologic stage pT1b(m) pN0. Case 2 is a 49-year-old female with FNA diagnosis of atypia of undetermined significance and ETV6/NTRK3 fusion detected by Thyroseq. Pathology diagnosis is infiltrative PTC follicular variant, 2.0cm, angioinvasion present, no lymph nodes submitted and pathologic stage pT1b(m) pNX. Case 3 is a 28-year-old female with FNA diagnosis of suspicious for follicular derived neoplasm and NTRK3/RBPMS fusion is detected by Afirma GSC. Pathology diagnosis is infiltrative PTC follicular variant, 1.5cm, 9 of 11 lymph nodes positive for metastatic carcinoma and pathologic stage pT1b pN1b. Conclusion Thyroid neoplasm with NTRK3-rearrangement is rare. Cases 1 and 2 with common ETV6-NTRK3 fusion show PTC classic type and infiltrative PTC follicular variant with angioinvasion. Case 3 with less common NTRK3/RBPMS fusion shows infiltrative PTC follicular variant and significant lymph node involvement. Our limited cases of NTRK3-rearranged thyroid carcinoma demonstrate infiltrative growth, diverse phenotypes, one case with angioinvasion and no lymph nodes submitted and one case with multiple lymph node metastasis. This suggests aggressive behavior of thyroid cancer with NTRK3 gene fusion and patients may benefit from targeted NTRK therapy.

Clinicopathologic features of thyroid neoplasm with THADA-IGF2BP3 fusion

Introduction/Objective Thyroid adenoma-associated (THADA)-IGF2BP3 fusions is related to strong overexpression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA and protein, increased IGF2 translation and IGF1 receptor signaling via PI3K and MAPK pathways. THADA-IGF2BP3 have been identified as an oncogenic event in thyroid neoplasms, but the clinicopathologic features have not been greatly evaluated. The purpose of this cases review is to describe the clinical and pathologic findings of thyroid nodules with THADA-IGF2BP3 fusion on molecular testing. Methods/Case Report Surgical Pathology 220 cases of total and hemithyroidectomy from January 2018 to December 2019 were reviewed for cytology fine needle aspiration (FNA), molecular testing results and surgical resection pathology. Results (if a Case Study enter NA) Three cases of THADA-IGF2BP3 fusion identified by Thyroseq testing from FNA of thyroid nodules with all diagnosed as atypia of undetermined significance, Bethesda category 3. No other mutations or gene fusions are identified. Successive surgical interventions are performed. Case 1 is a 49-year-old female right hemithyroidectomy with pathologic diagnosis of papillary thyroid carcinoma (PTC) follicular variant with tumor capsular invasion and no lymphvascular invasion. The tumor is 2cm, two lymph nodes evaluated are not involved by tumor and pathological stage is pT1b pN0. Case 2 is a 71-year-old female total thyroidectomy and the pathologic diagnosis is PTC follicular variant with tumor capsular invasion and no lymphvascular invasion. The tumor is 2cm, one lymph node evaluated is not involved by tumor and pathologic stage is pT1b pN0. Case 3 is a 76-year-old male left hemithyroidectomy and pathologic diagnosis is PTC follicular variant with tumor capsular invasion and no lymphvascular invasion. The tumor is 2cm, two lymph nodes evaluated are not involved by tumor and pathologic stage is pT1b pN0. Conclusion THADA-GF2BP3 fusion is uncommon in thyroid neoplasms and only three cases are detected in 220 cases evaluated. The three cases of thyroid nodules are all diagnosed as AUS by FNA, and all are diagnosed as PTC follicular variant with capsular invasion upon resection without lymphvascular invasion or lymph node involvement. THADA-F2BP3 fusion is associated with thyroid carcinoma, with low-risk non-aggressive behavior, conservative surgery appears necessary and lobectomy is likely adequate.

DIFFERENCES IN AGE CHARACTERISTICS, TUMOR MACROSCOPIC SIZE AND HORMONE PROFILE BETWEEN CLASSIC PAPILLARY CARCINOMA PATIENTS AND FOLLICULAR VARIANTS IN Dr. KARIADI HOSPITAL, SEMARANG

Background: New cases of Papillary Thyroid Carcinoma and Carcinoma patients at Dr. Kariadi Hospital, Semarang is quite high, where the most types are Classical Papillary Thyroid Carcinoma and Follicular Variant Papillary Thyroid Carcinoma. On the other hand, in diagnosing PTC, histopathological examination which is a gold standard sometimes has a subjective value. Therefore, it is necessary to have a correlation with the clinical characteristics of the patient in order to get a correct diagnosis. Aim: Understanding the differences in age characteristics, tumor macroscopic size and hormone profile between Classical Papillary Thyroid Carcinoma and Follicular Variant patients at Dr. Kariadi Hospital, Semarang. Method: Analytic observational research with cross sectional design. The number of samples was 38 medical records in which 18 cases of Classic Papillary Thyroid Carcinoma and 20 cases of Follicular Variant Papillary Thyroid Carcinoma. Data with a nominal scale, namely age were analyzed using the Fisher exact test, while the data with a numerical scale, namely the macroscopic size of the tumor and the hormone profile, were tested for normality of Saphiro Wilk then continued with the Mann-Whitney test. Result: Based on the Fisher exact test, there was significant difference (p = 0,009) between age characteristics and Classical Papillary Thyroid Carcinoma and Follicular Variant. In the Mann-Whitney test there was no significant difference (p = 0.3) between the macroscopic size of the classical papillary carcinoma and follicular variant and there was no significant difference TSHs (p = 0.501) and fT4 (p = 0.953) hormone profiles between Classic Papillary Thyroid Carcinoma and Follicular Variants. Conclusion: There was significant difference between the characteristics of age at diagnosis, and there was no significant difference between the macroscopic size of the tumor and the hormonal profile of Classical Papillary Carcinoma and Follicular Variants in Dr. Kariadi Hospital, Semarang.

Galectin-3 Immunohistochemical Expression in Thyroid Neoplasms – A Study from Kalaburagi, Karnataka

BACKGROUND Thyroid carcinoma is the most common endocrine malignancy. Galectin-3 has been implicated in malignant transformation and metastasis of cancer cells and it has received notable recognition for its usefulness as a diagnostic marker for thyroid cancer. We wanted to evaluate the expression of Galectin-3 on thyroid neoplasms, establish its diagnostic accuracy and also differentiate between benign and malignant thyroid lesions. METHODS A total of 54 thyroidectomy specimens were studied over a period of 3 years (2016 - 2019) which included 20 benign and 34 malignant thyroid neoplasms. Histopathologic evaluation of H & E stained sections was done and immunohistochemistry (IHC) staining for Galectin-3 was performed for all neoplasms with the polymeric method using lyophilized mouse monoclonal antibody. (Path n Situ) and grading based on intensity of Galectin-3 expression were noted. RESULTS Galectin-3 expression was significantly higher (P < 0.001) in malignant thyroid neoplasms in comparison to the benign neoplasms. Galectin-3 expression for malignant neoplasms showed sensitivity of 88.23 %, specificity of 95.0 %, positive predictive value (PPV) of 96.8 % and negative predictive value (NPV) of 82.6 %. Galectin-3 expression in Papillary thyroid carcinoma showed a sensitivity of 95.83 % and PPV of 88.2 %. While comparing the neoplasms showing follicular pattern, Galectin-3 expression was more in the malignant neoplasms (follicular carcinoma and follicular variant of papillary carcinoma thyroid) than benign neoplasms (follicular adenoma). CONCLUSIONS Galectin-3 is a useful marker in differentiating benign and malignant thyroid neoplasms. Galectin-3 is sensitive for Papillary thyroid carcinoma (PTC) and among the follicular patterned lesions, Galectin-3 is sensitive for follicular variant of papillary carcinoma and follicular carcinoma. Thus Galectin-3 protein expression evaluated using immunohistochemistry technique acts as an adjunctive ancillary technique in thyroid cancer diagnosis. KEYWORDS Galectin-3, Immunohistochemistry, Thyroid Carcinoma, Papillary Thyroid Carcinoma

Diagnostic Value of Galectin-3 in Distinguishing Invasive Encapsulated Carcinoma from Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features (NIFTP)

Background: non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), which is considered as low-risk cancer, should be distinguished from the malignant invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Improved discrimination of NIFTPs from invasive EFVPTCs using a molecular biomarker test could provide useful insights into pre- and post-surgical management of the indeterminate thyroid nodule. Galectin-3 (Gal-3), a β-galactosyl-binding molecule in the lectin group, is involved in different biological functions in well differentiated thyroid carcinomas. The aim of this study was to determine whether Gal-3 expression as a diagnostic marker could distinguish indolent NIFTP from invasive EFVPTC on tissue specimens from surgical thyroid nodules. Methods: immunohistochemical (IHC) analysis of cytoplasmic and nuclear Gal-3 expression was performed in formalin-fixed paraffin-embedded (FFPE) surgical tissues in four specific diagnostic subgroups- benign nodules, NIFTPs, EFVPTCs and lymphocytic/Hashimoto’s thyroiditis (LTs). Results: cytoplasmic Gal-3 expression (mean ± SD) was significantly increased in invasive EFVPTCs (4.80 ± 1.60) compared to NIFTPs (2.75 ± 1.58, p < 0.001) and benign neoplasms (2.09 ± 1.19, p < 0.001) with no significant difference between NIFTPs and benign lesions (p = 0.064). The presence of LT enhanced cytoplasmic Gal-3 expression (3.80 ± 1.32) compared to NIFTPs (p = 0.016) and benign nodules (p < 0.001). Nuclear Gal-3 expression in invasive EFVPTCs (1.84 ± 1.30) was significantly higher than in NIFTPs (1.00 ± 0.72, p = 0.001), but similar to benign nodules (1.44 ± 1.77, p = 0.215), thereby obviating its potential clinical application. Conclusions: our observations have indicated that increased cytoplasmic Gal-3 expression shows diagnostic potential in distinguishing NIFTP among encapsulated follicular variant nodules thereby serving as a possible ancillary test to H&E histopathological diagnostic criteria when LT interference is absent, to assist in the detection of the invasive EFVPTC among such nodules.