Follicular Variant Of Thyroid Carcinoma Research Articles

Analysis of Excellent Response, Persistent Disease and Recurrent Diseases of Radioiodine Treatment on Differentiated Thyroid Carcinoma Patients- 42 Years’ Experience at NINMAS

Background: Radioiodine treatment in thyroidectomized differentiated thyroid carcinoma (DTC) patients was introduced in the world in 1940s and in Bangladesh in 1980. Long experience of treatment and lifelong follow up of DTC patients with proper documentation of medical records enriched the archive of the thyroid division of National Institute of Nuclear Medicine & Allied Sciences (NINMAS). Aims: To evaluate the response of radioiodine treatment in DTC patients at NINMAS and analyze the outcome and prognostic factors in this cohort of patients in a single institute of a developing country. Patients and Methods: This is a retrospective cohort study. A total of 7525 patients with DTC received RAI ablation therapy from 1980-2021 at NINMAS, among them 5448 patients were treated with radioiodine from 1980-2017. Data were obtained from the medical records of 3482 DTC patients who were followed up until 2021 and all relevant data were available. Demographical, histopathological, surgical, radioiodine ablation doses of 131I, serum biomarkers thyroglobulin (Tg), antithyroglobulin antibody (TgAb) and biochemical investigation data were analyzed systematically. Age, gender, tumor size, presence of local and distant metastases at presentation, extrathyroidal extension (ETE), disease recurrence, and cancer-specific survival were also evaluated. Risk stratifications for recurrence and staging were calculated for dosing of radioiodine. The single dose of radioiodine ranged from 30 mCi to 200 mCi was given according to the postsurgical risk assessment. Repeated doses of radioiodine were given in the cases of persistent disease (PD) and recurrent disease (RD). Results: The median age of DTC patients was 38 years, with a range of 5-87 years (39.90± 12.67 years), with the majority of patients falling within the 30-39 age group. The ratio of female to male was 3.74:1. Compared to the previous decade, patient number increased about 72 and 16-folds in relation to the 1980s and 1990s respectively at this institute. Papillary thyroid carcinoma (PTC) and follicular variant of thyroid carcinoma (FVPTC) together were evaluated in 3311(95.09%) cases and follicular thyroid carcinoma (FTC) was diagnosed in 171(4.91%). Excellent response (ER) was observed by a single dose of radioiodine ablation in 2853(81.94%) and PD and RD were noted in 388(11.14%) and 241(6.92%) respectively. Tg and TgAb levels at pre-therapy state were significantly higher in patients who had PD (P <0.000) and RD (P <0.000). Conclusion: Significant increase in the number of DTC patients was observed in the last two decades. ER was noted in 81.94% with a single dose of radioiodine. Serum Tg and TgAb are two prognostic factors for disease outcomes showing high Tg and TgAb in PD and RD cases. Bangladesh J. Nuclear Med. 25(2): 81-87, 2022

Macrofollicular variant follicular thyroid tumors are DICER1 mutated and exhibit distinct histological features.

DICER1 germline mutations cause DICER1 syndrome, in which multinodular goitre is a common feature. Recently, somatic DICER1 mutations have been reported in sporadic thyroid carcinomas, of which the newly described macrofollicular variant of follicular thyroid carcinoma (MV-FTC) seems particularly enriched for this aberrancy. We report here histological and genetic findings in five follicular thyroid tumours with macrofollicular architecture (four carcinomas and one adenoma). We have diagnosed five cases during a year-long period at the Karolinska University Hospital, a tertiary thyroid cancer center with a catchment area of approximately 2.3 million inhabitants. Tumour DNA was interrogated using a commercially available massive parallel sequencing platform. All cases were female patients, ranging from 13 to 33years at surgery. A single patient was a DICER1 syndrome carrier; the others were sporadic cases. All tumours displayed a macrofollicular architecture with a broad capsule. The MV-FTCs displayed capsular invasion, but never vascular invasion. Areas with degenerative changes (microinfarctions) were noted in all cases, and focal papillary growth was observed in the majority. The Ki-67 proliferation index was always above 4%. All cases displayed DICER1 gene mutations, of which four of five cases displayed RNase IIIb hot-spot missense mutations adjoined by a second, deleterious variant in three of five tumouurs. Macrofollicular variants of follicular thyroid tumours are predominantly found in younger females and are strongly linked to somatic DICER1 gene mutations. Histological features such as a broad tumorous capsule, focal infarctions and areas with papillae could constitute clues prompting further genetic analyses.

Macrofollicular Variant of Follicular Thyroid Carcinoma (MV-FTC) with a Somatic DICER1 Gene Mutation: Case Report and Review of the Literature

Benign thyroid lesions such as multinodular goiter and adenomatoid nodules are well-circumscribed lesions displaying a macrofollicular growth pattern and lack of nuclear atypia. The highly unusual macrofollicular variant of follicular thyroid carcinoma (MV-FTC) mirrors these attributes and is thereby misclassified by cytological examination of fine-needle aspiration biopsies. The MV-FTC diagnosis is instead suggested following histological investigation, in which malignant attributes, most commonly capsular invasion, are noted. The bulk of MV-FTCs described in the literature arise in younger female patients and carry an excellent prognosis. A recent coupling to mutations in the DICER1 tumor suppressor gene has been proposed, possibly indicating aberrancies in micro-RNA (miRNA) patterns as responsible of the tumorigenic process. We describe the cytological, histological and molecular phenotype of a 35 mm large MV-FTC arising in the right thyroid lobe of a 33-year-old female with a family history of multinodular goiter. The tumor was encapsulated and strikingly inconspicuous in terms of cellularity and atypia, but nevertheless displayed multiple foci with capsular invasion. A next-generation molecular screening of tumor DNA revealed missense variants in DICER1 (p. D1709N) and MET (p. T1010I), but no established fusion gene events. After sequencing of germline DNA, the DICER1 mutation was confirmed as somatic, while the MET variant was constitutional. The patient is alive and well, currently awaiting radioiodine treatment. This MV-FTC mirrors previous publications, suggesting that these tumors carry a favorable prognosis and predominantly arise in younger females. Moreover, DICER1 mutations should be considered a common driver event in the development of MV-FTCs.

Case Report of a Clear-Cell Variant of Follicular Thyroid Carcinoma

Clear-cell variants of follicular carcinoma are rare subtypes of thyroid cancer. There is no unified view of the histopathological features of clear cell variants, but follicular carcinomas composed predominantly of clear cells are distinguished from clear cell variants. In clinical practice, it is important to determine whether clear cell variants arise primarily from the thyroid gland or are thyroid metastases of other clear cell carcinomas, such as renal cell carcinoma. We present a case in which a patient with initially suspected anaplastic thyroid carcinoma due to a rapidly progressive anterior neck mass was diagnosed with a clear cell variant of follicular carcinoma after a tissue biopsy. The patient was treated with lenvatinib, then his performance status improved, and he was discharged from the hospital. On day 188 after discharge, a contrast-enhanced computed tomography (CECT) scan of the neck showed further shrinkage of the tumor. However, a CECT scan of the chest revealed multiple lung metastases. On day 233 after discharge, the patient developed severe pneumonia resulting from tracheal rupture due to intratumoral necrosis. It was difficult to decide whether lenvatinib should have been discontinued or reduced when lung metastasis appeared. It is necessary to accumulate additional cases to make informed decisions about continuing lenvatinib therapy.

Signet ring cell variant of follicular thyroid carcinoma: Report of two cases with focus on morphological, expressional and genetic characteristics

BackgroundFollicular thyroid carcinoma (FTC) is a neoplasm that presents with a micro-follicular growth pattern and a neutrally stained cytoplasm. Seldom, FTCs display unusual morphological characteristics – but given the rarity of these histological subtypes, little is known regarding the underlying genetics and the coupling to patient outcome.Case presentationWe present two extremely rare cases of minimally invasive FTC with signet ring cell morphology (SRC-FTC) and describe the cytological, microscopic, immunohistochemical and molecular features for both tumors. Both were male patients, age 71 and 51 respectively. The preoperative cytology for both cases could not pinpoint a clear-cut signet ring cell morphology, but a tendency towards nuclear marginalization was seen. The tumors were 38 mm and 22 mm respectively and displayed evident signet ring cell features in subsets of tumor cells as well as degenerative stromal changes. The tumor cells were positive for TTF1, PAX8 and thyroglobulin, and the proliferation indexes were 4% and 1,9% respectively. Both tumors displayed capsular invasion, but not lymphovascular invasion. The tumors were sequenced for mutations in the TERT promoter and 22 additional cancer-related genes, interestingly; one patient was shown to carry a deleterious intronic variant in PTEN, a tumor suppressor gene coupled to thyroid tumorigenesis and Cowden syndrome. Both patients are alive and well awaiting postoperative radioiodine treatment.ConclusionsThe SRC-FTCs described herein were small, TERT promoter wildtype tumors exhibiting low proliferation, thereby suggesting that these exceedingly rare lesions probably carry a favorable prognosis – although the scarce availability regarding descriptions of this tumor entity nevertheless might justify careful clinical monitoring and mandate investigations in larger case series.

Meta-analysis utilizing public data suggests role of innate immunity in the pathogenesis of hurthle cell carcinoma (HCC).

e13048 Background: Hurthle Cell Carcinoma (HCC), a variant of follicular thyroid carcinoma, is a rare form of thyroid cancer. Though it accounts for 3-10% of thyroid cancer cases, very little is known about its pathogenesis. While HCC holds good survival rates, it is still vital to understand the pathogenesis of HCC in order to further optimize treatment protocols. Methods: We tagged 46 HCC samples and 90 healthy thyroid samples as a control. Gene signatures were analyzed in Ingenuity Pathway Analysis, using statistical significance p < 0.05 and absolute log ratio > 0.5 between disease and controls. Methods: Search Tag Analyze Resource was employed to conduct meta-analysis using the National Center for Biotechnologys Gene Expression Omnibus to define HCC pathogenesis. Results: Hepatic fibrosis, hepatic stellate cell activation and retinoic acid receptor (RAR) activation were the top canonical activators associated with HCC. Of the molecules involved, Defensin Beta 1 (DEFB1), Lipocalin-2 (LCN2), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) had the highest associations with HCC. The most down-regulated molecules were Hemoglobin Subunit Beta (HBB), Hemoglobin Subunit Alpha 1 and 2 (HBA1/HBA2), Cellular Retinoic Acid Binding Protein 1 (CRABP1), and BH3-Interacting Domain-Containing Protein 3 (HRK). Conclusions: These results suggest that there are a variety of factors at play regarding the development of HCC. Defensins are peptides made by neutrophils, however DEFB1 is specifically known for its ability to resist bacterial growth on epithelial surfaces, playing a major role in innate immunity. LCN2 is also known for resisting growth on surfaces and does so by sequestering iron-containing siderophores, thus effectively stopping growth of microorganisms. Additionally, ALDH1A3 and CRABP1 are associated with RAR activation. While the exact pathogenesis of HCC is not well known yet, we demonstrate that the two most up-regulated factors in HCC are strongly involved in innate immunity. This suggests that the dysfunction of innate immunity may play a vital role in the neoplastic pathogenesis of HCC.

Comparison of clinical characteristics of patients with follicular thyroid carcinoma and Hürthle cell carcinoma

IntroductionHürthle cell carcinoma (HCC) is an uncommon thyroid cancer historically considered to be a variant of follicular thyroid carcinoma (FTC). The aim of this study was to assess the differences between these groups in terms of clinical factors and prognoses. Patients and methodsA total of 230 patients (153 with FTC and 77 with HCC) with a median follow-up of 13.4 years were studied. The different characteristics were compared using SPSS version 20 statistical software. ResultsPatients with HCC were older (57.3±13.8 years versus 44.6±15.2 years; p<0.001). More advanced TNM stages were also seen in patients with HCC and a greater trend to distant metastases were also seen in patients with HCC (7.8% versus 2.7%, p=0.078). The persistence/recurrence rate at the end of follow-up was higher in patients with HCC (13% versus 3.9%, p=0.011). However, in a multivariate analysis, only age (hazard ratio [HR] 1.10, confidence interval [CI] 1.04–1.17; p=0.001), size (HR 1.43, CI 1.05–1.94; p=0.021), and histological subtype (HR 9.79, CI 2.35–40.81; p=0.002), but not presence of HCC, were significantly associated to prognosis. ConclusionHCC is diagnosed in older patients and in more advanced stages as compared to FTC. However, when age, size, and histological subtype are similar, disease-free survival is also similar in both groups.

Comparación de las características clínicas en pacientes con carcinoma folicular de tiroides y carcinoma de células de Hürthle

IntroductionHürthle cell carcinoma (HCC) is an uncommon thyroid cancer historically considered to be a variant of follicular thyroid carcinoma (FTC). The aim of this study was to assess the differences between these groups in terms of clinical factors and prognoses. Patients and methodsA total of 230 patients (153 with FTC and 77 with HCC) with a median follow-up of 13.4 years were studied. The different characteristics were compared using SPSS version 20 statistical software. ResultsPatients with HCC were older (57.3±13.8 years vs. 44.6±15.2 years; P<.001). More advanced TNM stages were also seen in patients with HCC and a greater trend to distant metastases were also seen in patients with HCC (7.8% vs. 2.7%, P=.078). The persistence/recurrence rate at the end of follow-up was higher in patients with HCC (13% vs. 3.9%, P=.011). However, in a multivariate analysis, only age (hazard ratio [HR] 1.10, confidence interval [CI] 1.04-1.17; P=.001), size (HR 1.43, CI 1.05-1.94; P=.021), and histological subtype (HR 9.79, CI 2.35-40.81; P=.002), but not presence of HCC, were significantly associated to prognosis. ConclusionHCC is diagnosed in older patients and in more advanced stages as compared to FTC. However, when age, size, and histological subtype are similar, disease-free survival is also similar in both groups.

Role of immunohistochemistry in metastatic clear cell variant of follicular thyroid carcinoma: A case report

Role of immunohistochemistry in metastatic clear cell variant of follicular thyroid carcinoma: A case report

An Aggressive Variant of Follicular Thyroid Carcinoma Metastasizing to the Skull Base: Case Report and Review of the Literature

Introduction: Metastasis to the skull base is rare but occurs most frequently with breast and prostate cancer. Suspicion for skull base metastasis should be elevated in patients with a history of cancer and unexpected ipsilateral cranial nerve findings. In this case report we describe the unanticipated finding of metastatic spread of poorly differentiated thyroid carcinoma to the skull base.

Does Hürthle Cell Carcinoma of the Thyroid Have a Poorer Prognosis than Ordinary Follicular Thyroid Carcinoma?

Hürthle cell carcinoma (HCC) is a rare form of thyroid carcinoma and is considered an oxyphilic variant of follicular thyroid carcinoma. However, little is known about its biological characteristics or clinical behavior. We conducted a retrospective study to determine whether the prognosis of HCC differs from that of ordinary follicular thyroid carcinoma (OFC). The subjects were the 558 patients with follicular thyroid carcinoma who underwent initial surgery at our institution between 1989 and 2010 and consisted of 73 patients with HCC and 485 patients with OFC. There were 410 females and 148 males, and their median age was 51 years. A univariate analysis was conducted in relation to cumulative cause-specific survival (CSS) according to the Kaplan-Meier method for the following variables: age at the time of initial surgery, gender, tumor size, invasiveness, distant metastasis at presentation, and histological type (HCC vs OFC). Differences between groups were analyzed for significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazard model. A total of 4 patients (5.5%) in the HCC group had distant metastasis compared with 106 patients (21.9%) in the OFC group. Significant factors in relation to CSS in the univariate analyses were age, tumor size, and invasiveness, but there were no significant differences between the HCC group and the OFC group. Multivariate analysis showed that age, tumor size, and distant metastasis at presentation were significant factors. HCC does not have a poorer prognosis than OFC.

Original article Pituitary metastases from the oncocytic variant of follicular thyroid carcinoma: a and diagnostic dilemmas

Metastases to the pituitary gland and sella turcica are uncommon. The distinction between primary and secondary metastatic pituitary tumours is challenging as carcinomas from distant sites might closely resemble, both clinically and histopathologically, non-functional adenomas or primary pituitary carcinomas. Among metastases to pituitary gland ones from thyroid carcinoma are extremely rare. We present a unique case of a 53-year-old male patient with a past history of thyroid carcinoma who underwent repeated surgeries over a period of 7 years for a sellar-parasellar mass with paranasal sinus involvement. Morphologically, the tumour was composed of solid sheaths of monomorphic cells exhibiting oncocytic features. In electron microscope images, the cytoplasm of tumour cells was filled with numerous mitochondria. The tumour was negative for pituitary hormones but exhibited immunoreactivity for cytokeratin AE1/AE3, thyroglobulin and thyroid transcription factor 1 (TTF-1). Based on the clinical data and immunophenotypic profile, the tumour was finally diagnosed as an oncocytic variant of follicular thyroid carcinoma. To our knowledge, this is probably the first report of such peculiar histopathological variant of follicular thyroid carcinoma metastasizing to the pituitary gland. The diagnostic dilemmas considering oncocytic features of the presented case are discussed.

Histological Patterns of Locoregional Recurrence in Hürthle Cell Carcinoma of the Thyroid Gland

Hürthle cell carcinoma (HCC) is regarded as an aggressive variant of follicular thyroid carcinoma based in part on its propensity to metastasize regionally and recur locally. The current treatment recommendation of formal regional lymph node dissection is largely based on the presumption of lymphatic dissemination to cervical lymph nodes as the main mechanism of regional spread. The purpose of this study was to better define the distribution of locoregional recurrence in HCC, and specifically to differentiate soft-tissue implants from true nodal metastases. The surgical pathology files of The Johns Hopkins Hospital were searched for cases of HCC with locoregional recurrences. The slides were reviewed to assess the histologic patterns of tumor spread, including the presence or absence of lymph node metastasis. Elastic staining was used to confirm vessel invasion. Twenty-four cases from 19 patients were identified. Thirteen were men, and the patients ranged in age from 35 to 83 years (mean 66). All had total or near-total thyroidectomies, and 16 received postoperative radioactive iodine. The time from primary diagnosis to first recurrence ranged from 0 to 12 years (mean 5 years). The locoregional disease involved the lateral neck (n=16), central neck (n=18), and larynx/trachea (n=4). In all 24 cases, the dominant tumor nodule was present as a rounded nodule of carcinoma within the soft tissues and unassociated with lymphoid tissue. Of 22 cases evaluated by elastic staining, 13 had tumor nodules within veins. True lymph node metastases were present in only six (25%) cases, and in all but one case, the lymph node metastases were <0.5 cm. When HCC spreads in the neck, it usually does so as soft-tissue implants likely resulting from spread within venous channels. True lymph node metastases are not a major source of nodular recurrences in the neck. Resolving the pattern of tumor spread could help guide and refine the management of locoregional recurrence for patients with HCC.

Metastatic Thyroid Carcinoma Presenting as Hypervascular Lesion of the Mandible: A Case Report and Review of Literature

Mandibular metastasis with the thyroid gland as the primary site is a rare event, and the reported incidence is estimated at approximately 1%. 1 Meyer I. Shklar G. Malignant tumors metastatic to mouth and jaws. J Oral Surg. 1965; 20: 350 Abstract Full Text PDF Scopus (265) Google Scholar In 29% to 33% of cases, the metastatic lesion might be the first indication of an undiscovered primary malignancy at a distant site. 2 Lim S.Y. Kim S.A. Ahn S.G. et al. Metastatic tumors to the jaws and oral soft tissues; A retrospective analysis of 41 Korean patients. Int J Oral Maxillofac Surg. 2006; 35: 412 Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar , 3 Hirshberg A. Leibovich P. Buchner A. Metastatic tumors to the jaw bones: Analysis of 390 cases. J Oral Pathol Med. 1994; 23: 337 Crossref PubMed Scopus (228) Google Scholar , 4 Peacock T.R. Fleet J.D. Condylar metastasis from bronchogenic carcinoma. Br J Oral Maxillofac Surg. 1982; 20: 39 Abstract Full Text PDF Scopus (22) Google Scholar Because of the bloodstream dissemination of these lesions, most are a consequence of the follicular variant of thyroid carcinomas, which are highly prone to cause vascular invasion and may present as hypervascular lesions mimicking arteriovenous malformations. We present one such rare case of a hypervascular osteolytic lesion of the mandible that proved to be a metastatic follicular thyroid carcinoma (FTC).

Macrofollicular variant of follicular thyroid carcinoma: a clinical, cytologic, morphologic, and image analysis study of a unique case

Thyroid lesions composed of large follicles that contain abundant colloid are usually regarded as benign hyperplastic or adenomatous nodules both by fine-needle aspiration cytology and histology. In such cases, the pathologist is less likely to request a complete inclusion of the capsule into paraffin block and to look for vascular and/or capsular invasion, the only criteria that permit the differential diagnosis between a benign nodule and a follicular carcinoma. We report the first case of a follicular thyroid carcinoma composed predominantly (>90%) of macrofollicles with a surface area that was up to 5 times larger than the surface area of normal follicles, as calculated with an image analysis system. Capsular invasion was detected in 2 separate foci. The tumor was classified as a minimally invasive follicular carcinoma, macrofollicular variant. This case is detailed to highlight the potential pitfall that may arise from an incomplete histological analysis of a macrofollicular lesion, with particular attention paid to the differential diagnoses.

Hürthle cell carcinoma of the thyroid: Retrospective review of 62 patients treated at the Royal Marsden Hospital between 1946 and 2003

Introduction Previous studies have included Hürthle cell carcinoma (HCC) as a variant of follicular thyroid carcinoma in analysis of clinical outcome and others have failed to adequately distinguish between benign and malignant Hürthle cell neoplasms. The aim of this study was to report our experience of histologically confirmed malignant HCC, identifying patient, tumour and treatment factors that predict outcome. Methods A retrospective review was undertaken of all patients treated with HCC between 1946 and 2003. Study end-points were disease-free survival (DFS) and cause-specific survival (CSS). Demographic, pathological and treatment-related factors were all correlated with the study end-points. Results Sixty-two patients were followed up for a median (range) of 58 months (2–629). On multivariate analysis, only extent of surgery ( p < 0.001) was an independent factor affecting CSS. Lymph node status ( p = 0.008), presence of metastases at diagnosis ( p = 0.005) and tumour stage ( p = 0.009) were independent predictors of DFS. Conclusions HCC appears to be a separate entity from follicular thyroid carcinoma (FTC), with a more aggressive disease profile. Lymph node status, tumour stage, and the presence of metastases are independent predictors of DFS. Radical surgery may improve outcome in HCC.

Accumulation of p27(kip1) is associated with cyclin D3 overexpression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma

Background: The down regulation of protein p27kip1 (p27) in most cases of thyroid cancer has relevant diagnostic and prognostic implications. However, the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma...

Point mutation in GRIM-19: a new genetic lesion in Hurthle cell thyroid carcinomas

Point mutation in GRIM-19: a new genetic lesion in Hurthle cell thyroid carcinomas