RESUMEN
OBJECTIVE: Parathyroid carcinoma (PC), atypical parathyroid tumours (APT) and parathyroid adenoma (PA), all present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. DESIGN: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. METHODS: Tissue microarray slides were immunohistochemically stained with antibodies for FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. RESULTS: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (P = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (P = 0.014, P = 0.017 and P = 0.049 respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (P < 0.001). CONCLUSION: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.
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Carcinoma/química , Filaminas/análisis , Neoplasias de las Paratiroides/química , Proteínas Supresoras de Tumor/análisis , Adenoma/química , Adenoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma/patología , Femenino , Finlandia , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/patología , Pronóstico , Receptores Sensibles al Calcio/análisis , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
The cell division cycle 73 gene is mutated in familial and sporadic forms of primary hyperparathyroidism, and the corresponding protein product parafibromin has been proposed as an adjunct immunohistochemical marker for the identification of cell division cycle 73 mutations and parathyroid carcinoma. Here, we present data from our experiences using parafibromin immunohistochemistry in parathyroid tumors since the marker was implemented in clinical routine in 2010. A total of 2019 parathyroid adenomas, atypical adenomas, and carcinomas were diagnosed in our department, and parafibromin staining was ordered for 297 cases with an initial suspicion of malignant potential to avoid excessive numbers of false positives. The most common inclusion criteria for immunohistochemistry were marked tumor weight (146 cases) and/or fibrosis (77 cases) and/or marked pleomorphism (58 cases). In total, 238 cases were informatively stained, and partial or complete loss of nuclear parafibromin immunoreactivity was noted in 40 cases; 10 out of 182 adenomas (5%), 27 out of 46 atypical adenomas (59%), and 7 out of 10 carcinomas (70%), with positive and negative predictive values of 85 and 90%, respectively for the detection of atypical adenomas/carcinomas versus adenomas, and 18 and 98%, respectively for carcinomas versus atypical adenomas/adenomas. Male patients with high-proliferative tumors were overrepresented among cases with aberrant parafibromin immunohistochemistry, and carcinomas more frequently harbored parafibromin aberrancies than atypical adenomas and adenomas (p < 0.001). We conclude that parafibromin immunohistochemistry is a useful marker in the clinical routine when applied on a pre-selected material of cases, with positive immunoreactivity as a confident rule out marker of malignancy.
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Adenoma/química , Biomarcadores de Tumor/análisis , Carcinoma/química , Inmunohistoquímica , Neoplasias de las Paratiroides/química , Proteínas Supresoras de Tumor/análisis , Adenoma/patología , Adenoma/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Carcinoma/terapia , Proliferación Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/terapia , Valor Predictivo de las Pruebas , Pronóstico , Centros de Atención Terciaria , Adulto JovenRESUMEN
Water-clear cell adenoma of the parathyroid gland is a rare neoplasm that consists of cells with abundant clear-pink cytoplasm. There have only been 19 cases reported in the English literature. Here we report a case of water-clear cell adenoma of the mediastinal parathyroid gland. A 70-year-old male patient presented to the hospital with back pain and a mediastinal mass 6 cm in size was detected. After excision and microscopic evaluation, uniform, large clear cells with fine cytoplasmic vacuolization, without nuclear atypia, and arranged in solid and acinar patterns were revealed. The cells formed nests that were separated by fine fibrovascular septae and stained positively with anti-parathyroid hormone. To the best of our knowledge, this has not been previously reported in this location. In the differential diagnosis of clear cell lesions of the mediastinum, water-clear cell parathyroid adenoma should be considered.
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Adenoma/patología , Neoplasias del Mediastino/patología , Neoplasias de las Paratiroides/patología , Adenoma/química , Adenoma/cirugía , Anciano , Biomarcadores de Tumor/análisis , Biopsia , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Masculino , Neoplasias del Mediastino/química , Neoplasias del Mediastino/cirugía , Hormona Paratiroidea/análisis , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/cirugía , Paratiroidectomía , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: As histopathological findings of parathyroid carcinoma are not certain, the diagnosis of tumors with degenerative changes may be difficult. In these cases, immunohistochemical markers are beneficial. We aimed to research the acceptability of calcium-sensing receptor (CaSR), Galactin-3, Cyclin D1, and Ki-67 as helpful markers in parathyroid tumors in cases which are difficult to diagnose. MATERIALS AND METHODS: Those cases who had been diagnosed with atypical parathyroid adenoma and parathyroid carcinoma between 2010 and 2015 were reevaluated. Immunohistochemical markers were applied to this cases. RESULTS: About 21 cases were parathyroid adenoma, 14 were atypical adenoma, and 10 cases were parathyroid carcinoma. According to the immunohistochemical results, global loss of CaSR staining was seen in 50% (5/10) of the patients with carcinoma while there was no loss of staining in those with parathyroid adenoma (P = 0,001). Global loss of CaSR staining was found in only one out of 14 cases with atypical adenoma. The expression of Galactin-3 was found to be positive in 40% (4/10) of carcinoma cases, 71.4% (10/14) of those with atypical adenoma, and 14.3% (3/21) of those with adenoma (P = 0,002). Cyclin D1 expression was determined to be positive in 70% (7/10) of patients with carcinoma, 71.4% (10/14) of atypical adenoma cases, and 23.8% (5/21) of those with adenoma. The Ki-67 proliferation index was seen to be above 5% in 50% (5/10) of carcinoma cases and 35,7% (5/14) of those with atypical adenoma. CONCLUSION: In these studies, it has been emphasized that the global loss of CaSR staining was used as a negative marker in the diagnosis of carcinoma. In this study, we have also confirmed that the global loss of CaSR staining is a useful marker to determine potential increased malignancy.
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Biomarcadores de Tumor/análisis , Ciclina D1/genética , Galectina 3/genética , Antígeno Ki-67/metabolismo , Neoplasias de las Paratiroides/diagnóstico , Neoplasias de las Paratiroides/fisiopatología , Receptores Sensibles al Calcio/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Proteínas Sanguíneas , Ciclina D1/inmunología , Ciclina D1/metabolismo , Femenino , Galectina 3/inmunología , Galectina 3/metabolismo , Galectinas , Técnicas Histológicas/métodos , Humanos , Inmunohistoquímica/métodos , Antígeno Ki-67/inmunología , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/inmunología , Receptores Sensibles al Calcio/inmunología , Receptores Sensibles al Calcio/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (~15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. RESULTS: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. CONCLUSIONS: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.
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Adenoma/química , Citosina/análogos & derivados , Neoplasias de las Paratiroides/química , 5-Metilcitosina/análogos & derivados , Adenoma/enzimología , Adolescente , Adulto , Anciano , Western Blotting , Estudios de Casos y Controles , Citosina/análisis , Proteínas de Unión al ADN/metabolismo , Humanos , Persona de Mediana Edad , Oxigenasas de Función Mixta , Glándulas Paratiroides/química , Glándulas Paratiroides/enzimología , Neoplasias de las Paratiroides/enzimología , Proteínas Proto-Oncogénicas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
BACKGROUND: Atypical parathyroid adenoma (APA) is a rare entity, sharing clinical symptoms like solid palpable mass in the neck, laboratory changes with very high serum calcium and parathyroid hormone levels, and some histopathological features with parathyroid carcinomas (PC). However, clinical behavior of APA seems to comply with benign parathyroid tumors (PA). There is some evidence that loss of the membranous staining pattern of E-Cadherin (E-Cad) suggests a key role of epithelial mesenchymal transition in the tumorigenesis of PC. Thus, the aim of this study was to compare clinical and surgical characteristics and immunohistochemical expression of E-Cad in APA, PC, and PA. METHODS: Data of patients who underwent surgery for primary hyperparathyroidism (pHPT) between 1985 and 2010 were retrospectively evaluated. All data were analyzed with special regard to distinctive criteria of APA, including trabecular growth, broad fibrous bands, nuclear atypia, mitosis, pseudocapsular invasion or strong adherence to the surrounding tissue, and potential invasive growth of a grossly altered and enlarged parathyroid gland. In addition, laboratory and clinical data were evaluated and additional immunohistochemical staining with E-Cad was performed in suspicious APA patients with available tissue. RESULTS: In 68 patients (39 female, 29 male), the parathyroid tumor was suspicious for APA. In 46 patients, a bilateral cervical exploration was performed. 15 patients underwent an en bloc resection including a hemithyroidectomy and lymphonodular dissection of the ipsilateral central compartment due to the malignant macroscopic aspect of the parathyroid. In seven patients, a focused parathyroid resection was done. The available parathyroid tissue of 38 APA patients was immunopositive for membranous E-Cad staining. During follow-up, only one patient with a successful initial surgery suffered from recurrent pHPT due to another solitary PA 10 years after initial surgery but without evidence of malignancy. CONCLUSIONS: In contrast to PC, parathyroid tumors suspicious for APA are characterized by a strong membranous E-Cad staining and, like PA, by a benign clinical course.
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Adenoma/química , Cadherinas/análisis , Carcinoma/química , Proteínas de Neoplasias/análisis , Neoplasias de las Paratiroides/química , Adenoma/patología , Adenoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Carcinoma/cirugía , Femenino , Humanos , Hiperparatiroidismo Primario/etiología , Hiperparatiroidismo Primario/cirugía , Masculino , Persona de Mediana Edad , Disección del Cuello , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/cirugía , Paratiroidectomía , Estudios Retrospectivos , Tiroidectomía , Adulto JovenRESUMEN
BACKGROUND: Parathyroid cancer is rare. Differentiating parathyroid carcinoma from degenerative changes at histopathology can be difficult and studies investigating the value of single immunohistochemical markers have had variable results. In this study we aimed to investigate whether a panel of immunohistochemistry markers could aid the diagnosis of parathyroid cancer. METHODS: All cases of parathyroid cancer at our institution from 1998 to 2012 were identified retrospectively. Cases were classified as definite cancers (those with evidence of metastatic spread) or histological cancers (those with features of carcinoma without evidence of metastasis). Controls with benign parathyroid disease were included for comparison. Immunohistochemistry for parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1 was analysed by an experienced endocrine pathologist. RESULTS: There were 24 cases and 14 benign adenomas. Four cases had evidence of metastatic spread and 20 were diagnosed on histological criteria alone. Sixteen of the 24 cases had further surgery with ipsilateral thyroid lobectomy and 15 also had a prophylactic level VI lymph node dissection. Apart from one patient with distant metastases at presentation, none developed recurrence at follow-up (median = 38 months). Immunohistochemistry results associated with parathyroid cancer were seen in 11/24 parafibromin, 13/24 galectin-3, 8/24 PGP9.5, 5/24 Ki67, and 2/24 cyclin D1. None of the controls had immunohistochemical staining suggestive of cancer. Nineteen of the 24 patients had at least one immunohistochemical result associated with parathyroid cancer (sensitivity 79 %, specificity 100 %). Cyclin D1 did not suggest malignancy in any case that did not already have another abnormal marker, and so did not add value to the panel in this study. CONCLUSION: A panel of immunohistochemistry (PGP9.5, galectin-3, parafibromin, and Ki67) is better than any single marker and can be used to supplement classical histopathology in diagnosing parathyroid cancer.
Asunto(s)
Adenoma/química , Biomarcadores de Tumor/análisis , Carcinoma/química , Carcinoma/diagnóstico , Proteínas de Neoplasias/análisis , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/diagnóstico , Adenoma/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/secundario , Estudios de Casos y Controles , Ciclina D1/análisis , Femenino , Galectina 3/análisis , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/patología , Estudios Retrospectivos , Sensibilidad y Especificidad , Proteínas Supresoras de Tumor/análisis , Ubiquitina Tiolesterasa/análisisRESUMEN
BACKGROUND: The molecular bases for parathyroid carcinomas present in conjunction with sporadic primary hyperparathyroidism are not fully elucidated. Gene copy number variations (CNVs) play an important role in tumorigenesis. The aim of the current study was to explore whether the CNVs of specific tumor-associated genes are involved in parathyroid carcinogenesis. METHODS: A multiplex ligation-dependent probe amplification method was used to compare differences in copy number in 39 common tumor-associated genes among 7 patients with parathyroid carcinoma and 14 age- and sex-matched subjects with parathyroid adenoma. RESULTS: It was shown that amplification of CCND1, a gene encoding cyclin D1, was more prevalent in parathyroid carcinomas than in adenomas (71 vs. 21 %, p = 0.056). This result was confirmed quantitatively by real-time polymerase chain reaction. Expression of CCND1 mRNA level was significantly higher in carcinomas than in adenomas (p = 0.003). Western blot and immunohistochemical analysis also demonstrated higher expression of CCND1 in carcinoma specimens than in adenoma samples. CONCLUSIONS: It is thus inferred that gain in copy number of CCND1 is implicated in the molecular pathogenesis of parathyroid carcinoma.
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Adenoma/genética , Carcinoma/genética , Ciclina D1/genética , Variaciones en el Número de Copia de ADN , Neoplasias de las Paratiroides/genética , Adenoma/química , Adulto , Anciano , Carcinoma/química , Ciclina D1/análisis , Femenino , Humanos , Hiperparatiroidismo Primario/complicaciones , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Neoplasias de las Paratiroides/química , ARN Mensajero/análisis , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
GATA3 is a member of a group of zinc-finger transcription factors that is involved in cell development and differentiation. Recent studies have shown that, among tumors, GATA3 is commonly expressed in both urothelial tumors and breast epithelial neoplasms. With the exception of salivary gland and parathyroid tumors, GATA3 has been reported to be either absent or only rarely expressed in other epithelial tumors. Owing to its restricted expression in urothelial and breast carcinomas, GATA3 has proved to be a useful immunohistochemical marker for assisting in distinguishing these 2 groups of neoplasms from other malignancies with which they may be confused.
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Biomarcadores de Tumor/análisis , Factor de Transcripción GATA3/análisis , Inmunohistoquímica , Neoplasias/química , Anticuerpos , Biopsia , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Carcinoma/química , Carcinoma/patología , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Neoplasias/patología , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/patología , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/patología , Urotelio/química , Urotelio/patologíaRESUMEN
BACKGROUND: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT). MATERIALS AND METHODS: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (n=3) or from euthyroid patients without PHPT during thyroid surgery (n=7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR. RESULTS: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36- and 0.45-fold change (P<0.001) and CD1 and PTH mRNAs were increased by 9.4- and 17.4-fold change respectively (P<0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (r=0.864; P<0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (r=0.715; P<0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions. CONCLUSIONS: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.
Asunto(s)
Adenoma/química , Ciclina D1/análisis , Hiperparatiroidismo Primario/metabolismo , Glándulas Paratiroides/química , Hormona Paratiroidea/análisis , Neoplasias de las Paratiroides/química , Receptores de Calcitriol/análisis , Receptores Sensibles al Calcio/análisis , Población Blanca , Adolescente , Adulto , Anciano , Niño , Ciclina D1/genética , ADN Complementario/síntesis química , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , India , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/genética , ARN Mensajero/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Calcitriol/genética , Receptores Sensibles al Calcio/genética , Regulación hacia ArribaRESUMEN
OBJECTIVE: Parathyroid adenomas are the most common cause of primary hyperparathyroidism. Biological studies have shown that parathyroid adenomas are monoclonal proliferations. Up to date, five cell types have been identified in normal parathyroid tissues; chief cells, vacuolated chief cells, dark chief cells, oxyphil cells and transitional oxyphil cells. Most parathyroid adenomas are predominantly composed of chief cells. In this study, we aimed to indicate the relationship between the predominant cell type in parathyroid adenomas and proliferating cell nuclear antigen, Ki-67 antigen, and serum parathormone levels and the gland weight. MATERIAL AND METHOD: 15 cases who had a diagnosis of parathyroid adenomas were included in the study. Histopathologically, the predominant cell type was determined in all the cases. Paraffin blocks were immunohistochemically stained with proliferating cell nuclear antigen and Ki-67. RESULTS: The average parathormone level of the cases was 239.52 ± 36.61 pg/ml before surgery. Mean gland weight was 1.69 ± 0.49 g. Two of the cases showed atypical adenoma characteristics. The predominant cell type was vacuolated chief cell. Immunohistochemical investigation showed that the mean average Ki-67 index value was 4.26 ± 0.86%. The mean proliferating cell nuclear antigen index was 93.20± 45.72/10³. There was a meaningful relationship between gland weights and serum parathormone levels. There was no meaningful relationship between predominant cell types and serum parathormone levels, proliferating cell nuclear antigen index, and Ki-67 index. The chief cell was identified as the predominant cell type. CONCLUSION: It can be concluded that parathyroid adenomas come into existence as a result of neoplastic proliferation of chief cells, especially vacuolated chief cells.
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Adenoma/química , Proliferación Celular , Inmunohistoquímica , Antígeno Ki-67/análisis , Glándulas Paratiroides/química , Neoplasias de las Paratiroides/química , Antígeno Nuclear de Célula en Proliferación/análisis , Adenoma/sangre , Adenoma/patología , Adenoma/cirugía , Anciano , Biopsia , Femenino , Humanos , Persona de Mediana Edad , Tamaño de los Órganos , Glándulas Paratiroides/patología , Glándulas Paratiroides/cirugía , Hormona Paratiroidea/sangre , Neoplasias de las Paratiroides/sangre , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/cirugía , TurquíaRESUMEN
Parathyroid tumours are heterogeneous and in some cases the diagnosis may be difficult using histological features. In this study we used a two-dimensional electrophoresis (2D)/mass spectrometry (MS)-based approach to examine the global changes of parathyroid adenoma tissues protein profile compared to the parathyroid normal tissues. Validation of protein expression was performed by immunoblotting using specific antibodies. Ingenuity software was used to identify the biological processes to which these proteins belong and to construct a potential network. A total of 30 proteins were found to be differentially expressed, of which 22 resulted in being over-expressed. Proteins identified by 2D/MS/MS proteomics were classified into functional categories and a major change (≥ 2-fold) in terms of expression was found in proteins involved in response to biotic stimuli, cell organization and signal transduction. After Ingenuity analysis, 14-3-3 ζ/δ appears to be a key protein in the network of parathyroid adenoma, where it is linked to other proteins such as annexin A2, B box and SPRY domain-containing protein (BSPRY), p53 and epidermal growth factor receptor (EGFR). Our results suggest that the proteomic approach was able to differentiate the protein profiles of normal parathyroid and parathyroid adenoma and identify a panel of proteins which are differentially expressed. The functional role of these proteins in the network of intracellular pathways is discussed.
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Glándulas Paratiroides/metabolismo , Neoplasias de las Paratiroides/metabolismo , Proteínas/metabolismo , Proteómica/métodos , Electroforesis en Gel Bidimensional , Humanos , Espectrometría de Masas , Glándulas Paratiroides/química , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/diagnóstico , Proteínas/análisis , Programas InformáticosRESUMEN
Glial cells missing 2 (Gcm2) is a master regulatory gene of parathyroid gland development, and it is exclusively expressed in the parathyroid gland. Diagnostic application of anti-Gcm2 antibody has not been reported yet. In this study, a total of 58 cases of parathyroid lesions including 40 adenomas, 2 atypical adenomas, 2 carcinomas, 9 hyperplastic lesions, 4 parathyroid cysts, and 1 case of recurrent hyperplasia of an autograft gland were stained with anti-Gcm2 antibody. Anti-Gcm2 was also applied to a variety of endocrine tumors, including thyroid tumors and nonendocrine tumors, and normal tissues from a variety of organs, including the parathyroid and thyroid glands. Gcm2 nuclear expression was seen in all the normal parathyroid glands, and cystic, hyperplastic, and neoplastic parathyroid lesions in a diffuse manner, whereas no Gcm2 expression was seen in any other normal tissues and tumors, including those of the thymus and thyroid gland. Anti-Gcm2 antibody is a highly sensitive and specific marker for parathyroid lesions. Although the immunohistochemistry stain for parathyroid hormone is a useful marker, its reaction tends to be variable in extent and intensity in parathyroid neoplasia, and it is often negative in parathyroid cysts, and Gcm2 would serve as a useful adjunct marker.
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Adenoma/química , Carcinoma/química , Quistes/química , Proteínas Nucleares/análisis , Enfermedades de las Paratiroides/metabolismo , Glándulas Paratiroides/química , Neoplasias de las Paratiroides/química , Factores de Transcripción/análisis , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Biomarcadores de Tumor/análisis , Carcinoma/patología , Quistes/patología , Femenino , Humanos , Hiperplasia , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Enfermedades de las Paratiroides/patología , Glándulas Paratiroides/patología , Neoplasias de las Paratiroides/patologíaRESUMEN
A 65-year-old female patient was admitted to our hospital presenting with a superior mediastinal big mass that was elastic, hard, and painless. Laboratory data including serum calcium level and thyroid and parathyroid hormonal functions revealed no abnormalities. Further examination consisting of computed tomography, magnetic resonance imaging, and ultrasonography demonstrated that it was a solid tumor extending into the superior mediastinum. Technetium (Tc-99) sestamibi scan revealed a hypofunctioning focus in that area. The preoperative diagnosis was a thyroid tumor or a metastatic lymph node. Parathyroid carcinoma was suspected on intraoperative frozen pathological examination. The tumor was successfully removed with left thyroid lobectomy, and neck node dissection was performed. Macroscopically, it appeared as a dark reddish solid tumor, and the cut surface presented opalescence. Immunohistology confirmed that there was proliferation of tumor cells with positive chromogranin A staining. Thus, the tumor was diagnosed as parathyroid carcinoma histopathologically despite a lack of clinical evidence for hyperparathyroidism. This patient has been followed with no evidence of recurrence, a normal serum calcium 4 years after surgery, and postoperative radiotherapy. This report describes a case of nonfunctional parathyroid carcinoma with a massive mass that technetium (Tc-99) sestamibi scan failed to detect, and we showed negative immunostaining for parathyroid hormone (PTH) (N).
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Carcinoma/diagnóstico , Neoplasias de las Paratiroides/diagnóstico , Anciano , Carcinoma/química , Carcinoma/cirugía , Femenino , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Disección del Cuello , Hormona Paratiroidea/análisis , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/cirugía , Tomografía de Emisión de Positrones , Radiofármacos , Tecnecio Tc 99m Sestamibi , Tiroidectomía , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Aberrant accumulation of beta-catenin has been found in various types of human tumors. The aim of this study was to evaluate whether Wnt/beta-catenin signaling is activated in parathyroid carcinomas and adenomas. We studied 154 parathyroid tumors (18 carcinomas (13 with distant metastases), six atypical adenomas, and 130 adenomas). Three normal parathyroid tissues were used as control. Direct sequencing of exon 3 of the CTNNB1 gene showed absence of stabilizing mutations in all the tumors. Immunostaining of beta-catenin was performed in all carcinomas and in 66 adenomas (including three atypical). Normal parathyroid showed a homogeneous distinct outer cell membrane staining in the majority of cells and no nuclear staining. A weak cytoplasmic staining was observed in one case. All tumors showed negative nuclear staining. With the exception of one carcinoma, which had a negative membrane staining, all other samples showed a membrane staining which was similar to that of the normal parathyroid. beta-Catenin expression was heterogeneous with a range of positive cells between 5 and 80%, independently of tumor type. Our results suggest that the Wnt/beta-catenin signaling pathway is not involved in the development of parathyroid carcinomas and adenomas.
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Adenoma/fisiopatología , Carcinoma/fisiopatología , Proteínas de Neoplasias/fisiología , Neoplasias de las Paratiroides/fisiopatología , Transducción de Señal/fisiología , Proteínas Wnt/fisiología , beta Catenina/fisiología , Adenoma/química , Adenoma/genética , Carcinoma/química , Carcinoma/genética , Transformación Celular Neoplásica/genética , Citoplasma/química , Análisis Mutacional de ADN , Exones/genética , Humanos , Proteínas de la Membrana/análisis , Proteínas de Neoplasias/análisis , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/genética , beta Catenina/análisisRESUMEN
BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal disease caused by inactivating germ-line mutations of HRPT2 gene, with subsequent loss of Parafibromin expression. It is characterized by familial HPT, ossifying jaw tumors, and other associated neoplasms. METHODS: Clinical, histopathological, and genetic features of three large Italian unrelated HPT-JT kindred were assessed. RESULTS: Three different germ-line HRPT2 inactivating mutations were identified. Seventeen affected members and six healthy mutation carriers were found. HPT was diagnosed in virtually all affected patients, at a median age of 36.3 years (range 11-71). In all cases, a single parathyroid involvement was found at surgery, although a metachronous multiglandular involvement causing recurrence after selective parathyroidectomy occurred in 17.6% of cases, after a mean disease-free interval of 13.7 years (range 5-27). Parathyroid carcinoma, atypical parathyroid adenoma, and jaw tumor occurred in one case; uterine involvement in 61.5% of women; other associated neoplasms were thyroid carcinoma (two cases) and renal and colon carcinoma (one case). Immunohistochemistry confirmed the loss of Parafibromin as the distinctive feature of the disease both in parathyroid and uterine tumors. CONCLUSIONS: HPT-JT has a frequent single-gland parathyroid involvement and a relatively increased risk of parathyroid carcinoma. The penetrance of the disease is high but incomplete. Regardless of the denomination of the syndrome, jaw tumors occur rarely, while uterine involvement is frequently present. Selective parathyroidectomy may be an effective strategy, but a prolonged follow-up is required because of the risk of recurrences and malignancies. A systematic investigation is also required because of associated malignancies.
Asunto(s)
Hiperparatiroidismo Primario/genética , Neoplasias Maxilomandibulares/genética , Síndromes Neoplásicos Hereditarios , Neoplasias de las Paratiroides/genética , Adenoma/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Mutación de Línea Germinal , Heterocigoto , Humanos , Hiperparatiroidismo Primario/etiología , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/química , Linaje , Proteínas Supresoras de Tumor/análisis , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Parathyroid neoplasms encompass a spectrum of proliferative lesions that include adenomas, atypical adenomas, and carcinomas. While the diagnosis of adenomas is usually straightforward, parathyroid carcinomas (PTCAs) often present considerable diagnostic challenges. Fibrosis and mitotic activity are common in PTCAs, but these features are not specific for malignancy. An unequivocal diagnosis of PTCA should be restricted to those tumors that invade adjacent soft tissues, thyroid gland, blood vessels, or perineural spaces or to those cases with documented metastases. Atypical adenomas include those tumors that share some of the features of PTCA but lack evidence of invasive growth. A variety of genetic abnormalities, including HRPT2 mutations, occur in PTCAs. Mutations of the HRPT2 gene, which encodes parafibromin, are responsible for the development of the hyperparathyroidism-jaw tumor syndrome and have also been implicated in the development of a high proportion of sporadic PTCAs. Correlative immunohistochemical studies have revealed nuclear parafibromin immunoreactivity in adenomas but absence or partial loss of staining in PTCAs. While parafibromin immunohistochemistry represents an important step in the ability to diagnose PTCA, additional studies will be required to test the validity of this approach and to determine the roles of other genes in the development of these tumors.
Asunto(s)
Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Neoplasias de las Paratiroides/diagnóstico , Adenocarcinoma/química , Adenocarcinoma/genética , Adenoma/química , Adenoma/genética , Biomarcadores de Tumor/análisis , Núcleo Celular/química , Núcleo Celular/patología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Mutación , Invasividad Neoplásica , Neoplasias de las Paratiroides/química , Neoplasias de las Paratiroides/genética , Proteínas Supresoras de Tumor/análisis , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Aberrant accumulation of beta-catenin plays an important role in a variety of human neoplasms. We recently reported accumulation of beta-catenin in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT). In CTNNB1 exon 3, we detected a stabilizing mutation (S37A) in 3 out of 20 analyzed adenomas. The aim of the present study was to determine the frequency and zygosity of mutations in CTNNB1 exon 3, and beta-catenin accumulation in a large series of parathyroid adenomas of Swedish patients. RESULTS: The mutation S37A (TCT > GCT) was detected by direct DNA sequencing of PCR fragments in 6 out of 104 sporadic parathyroid adenomas (5.8%). Taking our previous study into account, a total of 9 out of 124 (7.3%) adenomas displayed the same mutation. The mutations were homozygous by DNA sequencing, restriction enzyme cleavage, and gene copy number determination using the GeneChip 500 K Mapping Array Set. All tumors analyzed by immunohistochemistry, including those with mutation, displayed aberrant beta-catenin accumulation. Western blotting revealed a slightly higher expression level of beta-catenin and nonphosphorylated active beta-catenin in tumors with mutation compared to those without. Presence of the mutation was not related to distinct clinical characteristics. CONCLUSION: Aberrant accumulation of beta-catenin is very common in parathyroid tumors, and is caused by stabilizing homozygous mutation in 7.3% of Swedish pHPT patients.