[Show abstract][Hide abstract] ABSTRACT: The present study describes in depth a case of Riedel thyroiditis (RT) to clarify its pathogenesis and its putative inclusion in the spectrum of IgG4-related disease. We report the clinicopathological, immunohistochemical, and ultrastructural features of a case of RT in a 39-year-old white Spanish woman, admitted with a hard goiter and cold nodule in the left thyroid lobe. This case represents 0.05 % of a series of 1,973 consecutive thyroidectomies performed in our hospital. More than 80 % of the left thyroid lobe was effaced by fibrosis and inflammation (lymphocytes, 57 IgG4+ plasma cells per 1 high-power field, an IgG4/IgG ratio of 0.67, and eosinophils) with extension into the surrounding tissues and occlusive phlebitis. Immunostaining for podoplanin (D2-40) detected signs of increased lymphangiogenesis in the fibroinflammatory areas that were confirmed by electron microscopy. A strong, diffuse stain for podoplanin and transforming growth factor ß1 was also detected in the same areas. The increased number of lymphatic vessels in RT is reported for the first time. Our findings support the inclusion of RT within the spectrum of IgG4-related thyroid disease (IgG4-RTD). Although the etiology and physiopathology of IgG4-RTD still remain elusive, the results obtained in the present case suggest the participation of lymphatic vessels in the pathogenesis of RT.
No preview · Article · Jul 2014 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
[Show abstract][Hide abstract] ABSTRACT: In the thyroid, primary neuroendocrine tumors encompass medullary thyroid carcinoma (MTC) and, rarely, other tumors such as paragangliomas. MTCs are derived from C-cells and express calcitonin and neuroendocrine markers. Besides classic MTC, some reports have documented thyroid neuroendocrine tumors, which show no calcitonin expression and raise difficult diagnostic problems. A 76-year-old man presented with a mass in the left thyroid with neither serological calcitonin elevation nor familial history. A thorough clinico-laboratorial study did not disclose any other mass elsewhere. A left hemithyroidectomy was performed, and the histological examination revealed a neuroendocrine carcinoma resembling a paraganglioma-like MTC displaying unequivocal signs of vascular invasion. Immunohistochemically, the tumor cells showed reactivity for chromogranin A, synaptophysin, thyroid transcription factor-1 (TTF-1), paired box gene 8 (PAX8), cytokeratins (AE1/AE3 and CK8/18), and calcitonin gene-related peptide (CGRP) and negativity for calcitonin, carcinoembryonic antigen, TTF-2, thyroperoxidase, and thyroglobulin. In situ hybridization showed that the tumor cells lacked expression for calcitonin and thyroglobulin mRNA. Genetic analysis did not disclose any RET mutation. A diagnosis of C-cell-derived primary neuroendocrine carcinoma of the thyroid without calcitonin expression was made, and the patient remains free of metastasis or recurrence 18 months after surgery.
No preview · Article · Mar 2014 · International Journal of Surgical Pathology
[Show abstract][Hide abstract] ABSTRACT: Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTC). Design: Retrospective observational study. Setting and patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five University Hospitals were included. Mean follow-up (±SD) was 7.8±5.8 years. Main outcome measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTC), 17.1% of follicular carcinomas (FTC), 29.0% of poorly differentiated carcinomas and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (p<0.001) and had larger tumors (p=0.002). In DTC, TERT promoter mutations were significantly associated with distant metastases (p<0.001) and higher stage (p<0.001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (p=0.009) with higher cumulative dose (p=0.004), and to more treatment modalities (p=0.001). At the end of follow-up, patients with TERT-mutated DTC were more prone to have persistent disease (p=0.001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (p<0.001)] in DTC (p<0.001), in PTC (p=0.001) and in FTC (p<0.001). After adjusting for age at diagnosis and gender, the HR was 10.35 (95%CI 2.01-53.24; p=0.005) in DTC and 23.81 (95%CI 1.36-415.76; p=0.03) in PTC. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.
Full-text · Article · Jan 2014 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: The small cell group of thyroid tumors that includes lymphoma, poorly differentiated carcinoma, medullary carcinoma, secondary neoplasms, as well as tumors with uncertain histogenesis, remains as a valid diagnostic cul-de-sac due to its heterogeneous constitution. The existence of small cell thyroid tumors with EWSR1-FLI1 rearrangement together with neuroendocrine and/or carcinomatous differentiation raises not only differential diagnostic problems but also a very interesting therapeutic dilemma. This review explores the classification of small cell tumors of the thyroid taking into account the immunophenotype and molecular profile of such tumors.
No preview · Article · Nov 2013 · International Journal of Surgical Pathology
[Show abstract][Hide abstract] ABSTRACT: Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.
No preview · Article · Jul 2013 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Clear cell renal cell carcinoma (CCRCC) is the most common origin for metastasis in the thyroid. A 51-year-old woman was referred to our hospital for a subcarinal lesion. Ten years before, the patient had undergone a nephrectomy for CCRCC. Whole-body fluorodeoxyglucose positron emission tomography revealed elevated values in the thyroid gland, while the mediastinum was normal. An endoscopic ultrasonography-guided fine-needle aspiration biopsy of the mediastinal mass was consistent with CCRCC, and this was confirmed after resection. The thyroidectomy specimen also revealed lymphocytic thyroiditis, nodular hyperplasia, one follicular adenoma, two papillary microcarcinomas, and six foci of metastatic CCRCC involving both thyroid lobes. Curiously two of the six metastatic foci were located inside two adenomatoid nodules (tumor-in-tumor). The metastatic cells were positive for cytokeratins, CD10, epidermal growth factor receptor, and vascular endothelial growth factor receptor 2. No
gene mutations were found in any of the primary and metastatic lesions. The patient was treated with sunitinib and finally died due to CCRCC distant metastases 6 years after the thyroidectomy. In CCRCC patients, a particularly prolonged survival rate may be achieved with the appropriate therapy, in contrast to the ominous prognosis typically found in patients with thyroid metastases from other origins.
Full-text · Article · Apr 2013 · Case Reports in Oncological Medicine
[Show abstract][Hide abstract] ABSTRACT: Context:Mechanisms of thyroid physiology and cancer are principally studied in follicular cell lines. However, human thyroid-cancer lines were found to be heavily contaminated by other sources and only one supposedly normal-thyroid cell line, immortalized with SV40 antigen, is available. In primary culture, human follicular cultures lose their phenotype after passage. We hypothesized that loss of thyroid phenotype could be related to culture conditions in which human cells are grown in medium optimized for rodent culture (5H), including hormones with marked differences in affinity for the relevant rodent/human receptor.Objective:To define conditions which allows proliferation of primary human follicular thyrocytes for many passages without losing phenotype.Methods:Concentrations of hormones, transferrin, iodine, oligoelements, antioxidants, metabolites and ethanol were adjusted within normal homeostatic human serum ranges. Single cultures were identified by STRs. Human-rodent inter-species contamination was assessed.Results:We defined an 'h7H medium' enabling growth of human thyroid cultures for more than twenty passages maintaining thyrocyte phenotype. Thyrocytes proliferated and grouped as follicle-like structures (FLS); expressed Na+/I- symporter, pendrin, cytokeratins, thyroglobulin and thyroperoxidase, showed iodine-uptake and secreted thyroglobulin and FT3. Using these conditions, we generated a Bank of Thyroid Tumors in Culture (BANTTIC) from normal thyroids, Grave's hyperplasias, benign neoplasms (goiter, adenomas) and carcinomas.Conclusions:Using appropriate culture conditions is essential for phenotype maintenance in human thyrocytes. The BANTTIC generated under humanized h7H culture conditions will provide a much needed tool to compare similarly growing cells from normal versus pathological origins, and thus to elucidate molecular basis of thyroid disease.
Full-text · Article · Mar 2013 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Background:
Ectopic thyroid tissue is usually found anywhere along the embryonic descent pathway of the medial thyroid anlage from the tongue to the trachea (Wölfler area). However, ectopic thyroid tissue in the adrenal gland (ETTAG) is not easy to understand on the basis of thyroid embryology; because it is so rare, the possibility of metastasis should first be considered. Here, we describe two cases of ETTAG with pathogenetic implications and review the associated literature.
Two cases of ETTAG presented as incidental cystic adrenal masses in adult females, one having a congenital hernia of Morgagni. The ETTAG was histologically indistinguishable from normal orthotopic thyroid tissue, and its follicular nature was confirmed by immunohistochemical positivity for thyroglobulin, thyroperoxidase, thyroid transcription factor-1 (TTF-1/Titf-1/Nkx2.1), cytokeratin AE1/AE3, cytokeratin 7, pendrin, human sodium iodide symporter, paired box gene 8, and forkhead box E1 (TTF-2), as well as positivity for the messenger RNA of the thyroglobulin gene by in situ hybridization analysis. No C cells (negativity for calcitonin, chromogranin, and synaptophysin) were present. Neither BRAF nor KRAS mutations were detected with real-time polymerase chain reaction analysis. Further work-up did not show evidence of thyroid malignancy.
ETTAG is a rare finding, with only seven cases reported; women are much more frequently affected than men (8:1), and it usually presents in the fifth decade (mean age 54, range 38-67) as a cystic adrenal mass incidentally discovered on abdominal ultrasonography and/or in computed tomography images. ETTAG is composed of normal follicular cells without C cells. The expression of some transcription factors (TTF-1, paired box gene 8, and FOXE1) involved in development and/or migration of the medial thyroid anlage is preserved. Coexistence of a congenital hernia of Morgagni in one patient suggests an overdescent of medial thyroid anlage-derived cells in its pathogenesis.
Although ETTAG pathogenesis remains unknown, the lack of C cells together with the coexistence of a congenital defect of the anterior diaphragm (hernia of Morgagni) in one of our patients could suggest an overdescent of medial thyroid anlage-derived cells in the origin of this heterotopia.
No preview · Article · Mar 2013 · Thyroid: official journal of the American Thyroid Association
[Show abstract][Hide abstract] ABSTRACT: Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) usually occurs in the setting of familial adenomatous polyposis (FAP) although it can rarely arise sporadically. Poorly differentiated thyroid carcinoma (PDTC) is a follicular cell-derived neoplasm with more aggressive behavior than well-differentiated carcinomas such as CMVPTC. We report the case of a 35-year-old woman without FAP history who presented a left neck mass and complained of back pain. Imagiological examinations revealed a nodule in the left lobe of thyroid and multiple nodular lesions in the bone and lungs suggestive of metastases. The patient was submitted to total thyroidectomy and radioactive iodine. The tumor was composed of CMVPTC and PDTC components that shared the same somatic APC gene mutation (p.Cys520Tyr_fsX534). Besides this mutation, no CTNNB1, BRAF, N-RAS, and H-RAS gene mutations were detected in any of the 2 components. To the best of our knowledge, this is the first report of a sporadic CMVPTC with transformation into PDTC. Although the majority of CMVPTCs carry an indolent clinical outcome, the coexistence of poorly differentiated areas may justify the aggressiveness of the CMVPTC reported here.
No preview · Article · Jan 2013 · International Journal of Surgical Pathology