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RET/PTC Translocations and Clinico-Pathological Features in Human Papillary Thyroid Carcinoma  [PDF]
Cristina Romei,Rossella Elisei
Frontiers in Endocrinology , 2012, DOI: 10.3389/fendo.2012.00054
Abstract: Thyroid carcinoma is the most frequent endocrine cancer accounting for 5–10% of thyroid nodules. Papillary histotype (PTC) is the most prevalent form accounting for 80% of all thyroid carcinoma. Although much is known about its epidemiology, pathogenesis, clinical, and biological behavior, the only documented risk factor for PTC is the ionizing radiation exposure. Rearrangements of the Rearranged during Transfection (RET) proto-oncogene are found in PTC and have been shown to play a pathogenic role. The first RET rearrangement, named RET/PTC, was discovered in 1987. This rearrangement constitutively activates the transcription of the RET tyrosine-kinase domain in follicular cell, thus triggering the signaling along the MAPK pathway and an uncontrolled proliferation. Up to now, 13 different types of RET/PTC rearrangements have been reported but the two most common are RET/PTC1 and RET/PTC3. Ionizing radiations are responsible for the generation of RET/PTC rearrangements, as supported by in vitro studies and by the evidence that RET/PTC, and particularly RET/PTC3, are highly prevalent in radiation induced PTC. However, many thyroid tumors without any history of radiation exposure harbor similar RET rearrangements. The overall prevalence of RET/PTC rearrangements varies from 20 to 70% of PTCs and they are more frequent in childhood than in adulthood thyroid cancer. Controversial data have been reported on the relationship between RET/PTC rearrangements and the PTC prognosis. RET/PTC3 is usually associated with a more aggressive phenotype and in particular with a greater tumor size, the solid variant, and a more advanced stage at diagnosis which are all poor prognostic factors. In contrast, RET/PTC1 rearrangement does not correlate with any clinical–pathological characteristics of PTC. Moreover, the RET protein and mRNA expression level did not show any correlation with the outcome of patients with PTC and no correlation between RET/PTC rearrangements and the expression level of the thyroid differentiation genes was observed. Recently, a diagnostic role of RET/PTC rearrangements has been proposed. It can be searched for in the mRNA extracted from cytological sample especially in case with indeterminate cytology. However, both the fact that it can be present in a not negligible percentage of benign cases and the technical challenge in extracting mRNA from cytological material makes this procedure not applicable at routine level, at least for the moment.
MIR141 Expression Differentiates Hashimoto Thyroiditis from PTC and Benign Thyrocytes in Irish Archival Thyroid Tissues  [PDF]
Emma R. Dorris,Paul Smyth,John J. O’Leary,Orla Sheils
Frontiers in Endocrinology , 2012, DOI: 10.3389/fendo.2012.00102
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs approximately 22 nucleotides in length that function as regulators of gene expression. Dysregulation of miRNAs has been associated with initiation and progression of oncogenesis in humans. Our group has previously described a unique miRNA expression signature, including the MIR200 family member MIR141, which can differentiate papillary thyroid cancer (PTC) cell lines from a control thyroid cell line. An investigation into the expression of MIR141 in a series of archival thyroid malignancies [n = 140; classic PTC (cPTC), follicular variant PTC, follicular thyroid carcinoma, Hashimoto thyroiditis (HT), or control thyrocytes] was performed. Each cohort had a minimum of 20 validated samples surgically excised within the period 1980–2009. A subset of the HT and cPTC cohorts (n = 3) were also analyzed for expression of TGFβR1, a key member of the TGFβ pathway and known target of MIR141. Laser capture microdissection was used to specifically dissect target cells from formalin-fixed paraffin-embedded archival tissue. Thyrocyte- and lymphocyte-specific markers (TSHR and LSP1, respectively), confirmed the integrity of cell populations in the HT cohort. RNA was extracted and quantitative RT-PCR was performed using comparative CT (ΔΔCT) analysis. Statistically significant (p < 0.05) differential expression profiles of MIR141 were found between tissue types. HT samples displayed significant downregulation of MIR141 compared to both cPTC and control thyrocytes. Furthermore, TGFβR1 expression was detected in cPTC samples but not in HT thyrocytes. It is postulated that the downregulation of this miRNA is due, at least in part, to its involvement in regulating the TGFβ pathway. This pathway is exquisitely involved in T-cell autoimmunity and has previously been linked with HT. In conclusion, HT epithelium can be distinguished from cPTC epithelium and control epithelium based on the relative expression of MIR141.
Total Thyroidectomy in Multinodular Goiter: An African Experience  [PDF]
Moussa Abdoulaye Ouattara, Seydou Togo, Ibrahima Sankaré, Kadiatou Singaré, Sekou Koumaré, Issa Maiga, Allaye Ombotibé, Jacques Saye, Assa Traoré, Nouhoum Diani, Zimogo Ziè Sanogo, Sadio Yena
Surgical Science (SS) , 2015, DOI: 10.4236/ss.2015.612075
Abstract: Introduction: Total thyroidectomy is an operation that involves the surgical removal of the whole thyroid gland, with the preservation of the parathyroid glands. The aim of the present study was to assess the complication rates of total thyroidectomy on benign indication and first-time thyroid surgery and investigate the early outcome after opotherapy. Materials and Methods: In this retrospective study, patients who underwent total thyroidectomy for benign multinodular goiter in the department of thoracic surgery in our Hospital from January 2012 to December 2014 were included. In postoperative time, we evaluated surgical complication, histopathological examination and opotherapy. Results: A total 53 patients underwent total thyroidectomy for multmodular goiter; they were 49 (92.45%) bilateral and 4 (7.55%) unilateral (recurrence). The mean age was 47 years and mean diameter of goiter was 10.75 cm. Among the patients 88.68% were females and 11.32% were male. Preoperative hormonal statuses were (70%) in euthyroid and (30%) hyperthyroid following surgery complications like transient laryngeal nerve palsy (3.77%), transient hypocalcemia (7.55%), hematoma (1.9%) and wound infection (1.9%). On histopathological examination of the surgical specimen, 5.7% were reported to be malignant. Six month following surgery 92.45% of patients was a good hormonal balance. Conclusion: Total thyroidectomy for multinodular goiter has a low morbidity and mortality; this procedure olves both the problem of recurrence of disease and reintervention. The opotherapy is doable with a good hormonal balance.
COX-2 expression in papillary thyroid carcinoma (PTC) in cytological material obtained by fine needle aspiration biopsy (FNAB)
Kinga Krawczyk-Rusiecka, Katarzyna Wojciechowska-Durczyńska, Anna Cyniak-Magierska, Zbigniew Adamczewski, El?bieta Ga?ecka, Andrzej Lewiński
Thyroid Research , 2011, DOI: 10.1186/1756-6614-4-3
Abstract: Twenty three (23) patients with cytological diagnosis of PTC were evaluated. After FNAB examination, the needle was washed out with a lysis buffer and the obtained material was used for COX-2 expression estimation. Total RNA was isolated (RNeasy Micro Kit), and RT reactions were performed. β-actin was used as endogenous control. Relative COX-2 expression was assessed in real-time PCR reactions by an ABI PRISM 7500 Sequence Detection System, using the ΔΔCT method.COX-2 gene expression was higher in patients with PTC, when compared to specimens from patients with non-toxic nodular goitre (NTG).The preliminary results may indicate COX-2 role in thyroid cancer pathogenesis, however the observed variability in results among particular subjects requires additional clinical data and tumor progression analysis.The most common thyroid malignancy is papillary thyroid carcinoma (PTC), accounting for approximately 85-90% of all thyroid cancers. PTC usually grows slowly and is clinically indolent, although aggressive forms can also occur. The 10-year survival rate for all PTC patients is estimated at 80-90% [1].The introduction of fine-needle aspiration biopsy (FNAB) has made PTC identification more accurate, but still the diagnostic tools regarding the differentiation between thyroid benign and malignant lesions are not always reliable. The molecular basis of PTC has been examined and association with variety of molecular prognostic markers has been described, including RAS, RET, Trk, MET, and BRAF mutations [2].Cyclooxygenase-2 (COX-2) is an enzyme isoform involved in the conversion of arachidonic acid to prostaglandin H2, the precursor of various molecules, including prostaglandins, prostacyclines and thromboxanes. COX-2 can be expressed in response to various stimuli, such as hormones, mitogens, cytokines, inflammatory mediators and growth factors via protein kinase C and RAS-mediated signaling [3,4]. The products of COX-2 activity are believed to be involved in carcinogenes
The incidence rate of thyroid microcarcinoma during surgery benign disease  [PDF]
?ivaljevi? V.R.,Dikli? A.D.,Krgovi? K.Lj.,Zori? G.V.
Acta Chirurgica Iugoslavica , 2008, DOI: 10.2298/aci0801069z
Abstract: Thyroid microcarcinoma are well-differentiated tumors less than 1 cm in diameter. A retrospective analysis was performed on patients operated of benign thyroid disease at the Center for endocrine surgery, Institute of endocrinology, Clical Center of Serbia in Belgrade, from January 1st to December 31st 2004, in order to establish the incidence of microcarcinoma. Indications for surgery were euthyroid multinodular goiter in 201 patients, thyroiditis in 31, thyroid adenoma in 178, Graves disease in 89 and Plummers disease in 79 patients. The results of this study, demonstrate that in 13,4% of the patients operated for goiter, 6,4% operated for thyroiditis, 5,6% for thyroid adenomas, 9,0% for Graves disease and 7,0% of the patients operated for Plumers disease, the presence of a microcarcinoma was noticed in the definitive histopathologic examination. The results obtained are in line with the current knowledge of high incidence of thyroid microcarcinoma.
Microscopic papillary thyroid cancer as an incidental finding in patients treated surgically for presumably benign thyroid disease  [cached]
Sakorafas G,Stafyla V,Kolettis T,Tolumis G
Journal of Postgraduate Medicine , 2007,
Abstract: Background: Papillary thyroid microcarcinoma (PTMC) is a relatively common entity in the general population. Aim: To present our experience with papillary thyroid microcarcinoma of the thyroid as an incidental finding in patients treated surgically for presumably benign thyroid disease. Settings and Design: Histology reports of patients treated surgically with a preoperative diagnosis of benign thyroid disease were reviewed to identify patients with PTMC. Patients with a preoperative diagnosis of thyroid cancer were excluded from this study. Materials and Methods: The files of 380 patients who underwent surgery for presumably benign thyroid disease in our hospital from 1990 to 2002 were reviewed. Data regarding patient′s demographics, pathology findings, management and outcomes, were retrieved. Statistical Analysis Used: The findings are expressed as absolute numbers and as percentages (with reference to the total number of patients of this study). Results: Twenty-seven patients with PTMC diagnosed incidentally following thyroid surgery for presumably benign thyroid disease (27/380 or 7.1%) (multinodular goiter = 20 patients, follicular adenoma = 6 patients, diffuse hyperplasia of the thyroid = 1 patient) are presented. Mean diameter of PTMC was 4.4 mm. In 11 patients (40.7%) the tumor was multifocal and in about half of them tumor foci were found in both thyroid lobes. In two patients the tumor infiltrated the thyroid capsule. Total/near-total thyroidectomy was performed in all these patients (in three as completion thyroidectomy). All patients received suppression therapy and 20 of them underwent adjuvant radioiodine therapy. Follow-up (mean 4.56 years, range 1-12 years) was completed in 25 patients; all these patients were alive and disease-free. Conclusions: PTMC is not an uncommon incidental finding after surgery for presumably benign thyroid disease (7.1% in our series). The possibility of an underlying PTMC should be taken into account in the management of patients with nodular thyroid disease; total/near total thyroidectomy should be considered, at least in selected patients with presumably benign nodular thyroid disease.
Multinodular keratoacanthoma
Kumar Vijay,Garg B,Baruah M,Ratnakar C
Indian Journal of Dermatology, Venereology and Leprology , 1990,
Abstract: Clinical features of Multinodular Keratoacanthoma in two patients are reported. One patient was having squamous cell carcinoma of de novo origin with secondaries in lymph nodes in addition to multinodular keratoacanthoma.
ret/PTC-1 expression alters the immunoprofile of thyroid follicular cells
Karen Denning, Paul Smyth, Susanne Cahill, Jinghuan Li, Richard Flavin, Sinead Aherne, John J O' Leary, Orla Sheils
Molecular Cancer , 2008, DOI: 10.1186/1476-4598-7-44
Abstract: A 2 × 2 matrix comprising Nthy-ori and TPC-1 cell lines and H.T. and control lymphocyte supernatant was designed and utilised as follows; activated lymphocytic supernatant from a H.T. and normal control were co-cultured with a cell line derived from normal thyroid (Nthy-ori) and also a cell line derived from a papillary thyroid carcinoma that endogenously expresses ret/PTC-1 (TPC-1). The co-cultures were harvested at 0, 6 and 18 hour time points. Gene expression analysis was performed on RNA extracted from thyrocytes using TaqMan? Immune profiling Low-Density Arrays (Applied Biosystems, CA, USA) comprising gene expression markers for 93 immune related targets plus 3 endogenous controls.Stimulation of the normal thyroid cell line model with activated T cell supernatant from the H.T. donor yielded global up-regulation of immune targets when compared with control supernatant stimulation. In particular, a cohort of targets (granzyme B, CD3, CD25, CD152, CD45) associated with cytotoxic cell death; T cell receptor (TCR) and T cell signaling were up-regulated in the normal cell line model. When the ret/PTC-1 expressing thyroid cell line was co-cultured with H.T. lymphocyte supernatant, in comparison to control supernatant stimulation, down-regulation of the same subset of immune targets was seen.Co-culturing H.T. lymphocyte supernatant with a normal thyroid cell line model leads to over-expression of a subset of targets which could contribute to the pathogenesis of H.T. via cytotoxic cell death and TCR signalling. Stimulation of the ret/PTC-1 positive cell line with the same stimulus led to a down-regulated shift in the gene expression pattern of the cohort of immune targets. We hypothesize that ret/PTC-1 activation may dampen immunogenic responses in the thyroid, which could possibly facilitate papillary thyroid carcinoma development.Lymphocytic infiltration is a feature of many thyroid diseases, both benign and malignant. Hashimoto Thyroiditis (H.T.), an autoimmune thyro
Immunocytochemistry as an Adjunct to Fine-needle Aspiration of Thyroid in Distinction Between Benign and Malignant Thyroid Neoplasms
Arturs Ozolins, , Zenons Narbuts, , Ilze Strumfa, Guna Volanska, Peteris Prieditis, Kaspars Stepanovs, Janis Gardovskis
Acta Chirurgica Latviensis , 2011, DOI: 10.2478/v10163-012-0007-7
Abstract: Introduction. Thyroid nodules are very common therefore distinction between benign and malignant tumors is essential for proper clinical management. Aim of the study. The study was performed to evaluate the diagnostic value of molecular markers in different thyroid tumors. Materials and methods. Forty-eight thyroid FNA cases confirmed by subsequent surgical resection specimens were selected. Immunocytochemistry for HBME-1, CD56 and E-cadherin (E-CAD) was performed. The study group consisted of 15 papillary thyroid cancers (PTC) and 1 follicular carcinoma (FC) as well as 12 follicular adenomas (FA) and 20 cases of colloid goiter (CG). Results. The expression of HBME-1 in PTC was significantly higher than in another thyroid lesions. E-CAD and CD56 expression was found in 8/12 (66.6%) and 6/12 (50%) cases of FA respectively. In contrast, PTC showed very low expression (1/15) of both E-CAD and CD56. Expression of the three analyzed markers was not more than 10% in case of CG. Conclusions. We concluded that immunocytochemical (ICC) staining is of value as an ancillary test to enhance the diagnostic accuracy of thyroid FNA biopsies. Larger studies dedicated to evaluate the role of these or other markers for distinction between FC and FA can be particularly useful. We recommend the small panel consisting of three ICC markers, HBME-1, E-CAD and CD56 as an adjunct to standard cytomorphology criteria to enhance the diagnostic accuracy of thyroid nodules with follicular-patterned cytologic features.
Utility of immunohistochemical markers in differentiating benign from malignant follicular-derived thyroid nodules
Husain A Saleh, Bo Jin, John Barnwell, Opada Alzohaili
Diagnostic Pathology , 2010, DOI: 10.1186/1746-1596-5-9
Abstract: We investigated immunoexpression in 98 surgically removed benign thyroid nodules including 52 hyperplastic nodules (HN) and 46 follicular/Hurthle cell adenomas (FA), and 54 malignant tumors including 22 follicular carcinoma (FC), 20 classic papillary carcinoma (PTC), and 12 follicular variant papillary carcinoma (FVPC).The staining results showed that malignant tumors express galectin-3, HBME-1, CK19 and Ret oncoprotein significantly more than benign nodules. The sensitivity of these markers for the distinction between benign and malignant lesions ranged from 83.3% to 87%. The sensitivity of two-marker panels was not significantly different. Immunoexpression was usually diffuse and strong in malignant tumors, and focal and weak in the benign lesions.Our findings indicate that these immunomarkers are significantly more expressed in malignant tumors compared to benign lesions and may be of additional diagnostic value when combined with routine histology.Thyroid tumors are the most common endocrine tumors in the United States, and about 40% of the population between 30 and 60 years-old have thyroid nodules, most of which are benign [1]. Difficulties in the diagnosis of follicular patterned thyroid lesions on fine needle aspiration (FNA) cytology examination are well know problems, and histologic evaluation of surgically resected follicular patterned lesions can be challenging as well. One common diagnostic dilemma is encountered when an encapsulated lesion with follicular growth pattern has some but not all the nuclear features diagnostic of papillary thyroid carcinoma [2-6]. Also, follicular neoplasms are classified as benign or malignant depending on the presence or absence of capsular and/or vascular invasion. However, evaluation of these features can be challenging on histologic examination due to the presence of incomplete capsular penetration or equivocal vascular invasion, and for this reason, many end up with a general inconclusive diagnosis of "follicular lesi
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