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BACKGROUND: In papillary thyroid carcinoma (PTC), BRAFV600E is a common mutation and is associated with aggressive clinical behaviour. Immunocytochemistry (ICC) and molecular testing are recommended in the Bethesda System for Reporting Thyroid Cytopathology 2017 (TBSRTC) category III, IV and V. AIMS: The current study aimed to evaluate the diagnostic efficacy of conventional FNAC versus FNAC with BRAFV600E immunostaining in cases of TBSRTC category IV, cases of suspicious for PTC and cases of PTC. METHODS AND MATERIAL: The study included a prospective case series of 45 patients with clinically palpable thyroid nodules with TBSRTC category IV, category V (suspicious for PTC) and PTC. The corresponding histology specimens of all the 45 cases were also analyzed. Immunostaining for BRAFV600E was performed on FNAC cell blocks and their corresponding histology sections using anti-BRAF (VE1) clone (Ventana). The diagnostic efficacy of the BRAFV600E immunostaining was compared on cytological specimens with histological specimens. RESULTS: BRAFV600E immunostaining helped to improve the sensitivity of the cytology to confirm the PTC as a diagnostic aid for thyroid FNAs. Cytology alone had a sensitivity of 62.96% and a lower specificity of 60.70%. The combination of both the tests together provided 84.62% sensitivity and much higher specificity of 100%. PPV was also increased to 100% and NPV was raised 94.12%. CONCLUSIONS: The performance of BRAFV600E immunostaining on the cytological specimen is a rapid, simple and cost-effective test and could be considered in TBSRTC category IV and suspicious and malignant cases of PTC.
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The formulations of peptide-based antitumour vaccines being tested in clinical studies are generally associated with weak potency. Here, we show that pharmacokinetically tuning the responses of peptide vaccines by fusing the peptide epitopes to carrier proteins optimizes vaccine immunogenicity in mice. In particular, we show in immunized mice that the carrier protein transthyretin simultaneously optimizes three factors: efficient antigen uptake in draining lymphatics from the site of injection, protection of antigen payloads from proteolytic degradation and reduction of antigen presentation in uninflamed distal lymphoid organs. Optimizing these factors increases vaccine immunogenicity by up to 90-fold and maximizes the responses to viral antigens, tumour-associated antigens, oncofetal antigens and shared neoantigens. Protein-peptide epitope fusions represent a facile and generalizable strategy for enhancing the T-cell responses elicited by subunit vaccines.
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Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Imunogenicidade da Vacina/imunologia , Linfócitos T/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacocinética , Albuminas/imunologia , Animais , Antígenos de Neoplasias , Fatores de Transcrição de Zíper de Leucina Básica , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Epitopos , Imunidade Celular , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Repressoras/genéticaRESUMO
INTRODUCTION: Anaplastic thyroid cancer (ATC) is rare but fatal thyroid cancer responsible for majority of thyroid cancer related mortality. ATC may originate de novo or from preexisting differentiated thyroid cancer. Complex interaction between different gene mutation has been suggested to be the main causative factor for origin of ATC in both pathways. Mostly affected pathways are MAP kinase and PI3CA kinase. Hence, we decided to study the frequent alterations in both the pathways in ATC patients. METHODOLOGY: Clinico-pathological data of 34 ATC patients were collected retrospectively and Formalin Fixed Paraffin Embedded (FFPE) blocks were taken out for genetic analysis. DNA and RANA were isolated from FFPE tissues. BRAF V600E mutations were screened by RFLP PCR method and confirmed by sequencing. RAS, PI3CA and p53 mutations were checked by sequencing. RET/PTC translocations were screened by Real Time PCR. RESULTS: A total of 34 patients were studied: Mean age 58.6+ 11.6 years with F:M- 1.8:1, 60% had history of goiter. Most common presenting symptom was rapidly growing thyroid mass followed by dyspnea, dysphasia and hoarseness of voice. Extent of disease was local, locoregional and metastatic in 32%, 35% and 33% respectively. 57.6% were euthyroid, 20.5 % were hyperthyroid while functional status were not available in 11.7%. FNAC was suggestive of ATC only in 52.9% cases. 15 (44%) were operated. BRAF V600E mutations were observed in 10/34 (29.4%). Interestingly, all three ATC patients with DTC components had previous history of goiter with rapid increase in size and BRAF V600E mutation, while BRAF was positive only in 7/31 (22.5%) of patients with no DTC component. Mean survival of 3.5 months in BRAF positive cases in comparison to 5.5 months in BRAF negative ATC. RAS mutations were found to be positive in 5.8%, and none had RET-PTC/PI3CA mutations. P53 mutation was positive in 7 patients. 3 patients presented with history of rapid increase in size of previous goiter while rest 4 patients presented with rapidly increasing thyroid swelling of 1 to 3 months. At presentation 2 patients has disease localized to thyroid, 4 has loco-regional disease and one patient presented with metastasis. 5 out of these 7 patients were operated (Total thyroidectomy:3, thyroidectomy with neck dissection:2). Mean survival was 4 months (1-6 months). CONCLUSION: BRAF V600E was the commonest mutation followed by p53 of the 5 genes tested and BRAF was more common in patients with previous history of longstanding goiter or differentiated thyroid cancer. This provides an indirect evidence of neoplastic transformation of PTC to ATC.
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Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by various endocrine, nonendocrine, benign, and malignant tumors in various organs. VHL tumor suppressor gene, located on short arm of chromosome 3 is responsible for this. Pheochromocytoma (PCC) is one of the important endocrine manifestations that needs to be ruled out in case of VHL suspicion. In this review, we summarize the endocrine manifestations of VHL disease and their management while giving case history of five such cases.
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Primary hyperparathyroidism (PHPT) is an uncommon condition in children and adolescents. However, rapid growth spurt during puberty may result in unmasking and development of certain skeletal manifestations of PHPT. We present three cases of PHPT associated with rare skeletal manifestations of rickets. All three patients had radiological evidence of rickets with primary hyperparathyroidism. All the three patients had single gland adenoma. Literature is sparse regarding reversal of features of rickets following parathyroidectomy. In all three patients of our series, there was a complete resolution of bone/joint pain. However, in two children only the genu valgum persisted but their growth was normal and they had no proximal muscle weakness. In another child multiple corrective surgeries were done to correct the deformities.
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INTRODUCTION: Anaplastic thyroid cancers (ATCs) usually present in the sixth to seventh decades of life and little is known about the disease in young patients. The aim was to analyze the clinicopathological characteristics diagnosed with ATC in an iodine-deficient area. MATERIAL AND METHODS: The medical records of 100 patients diagnosed with ATC at a tertiary care hospital between 1991 and 2013 were reviewed. RESULTS: The mean age of patient was 58 years. About 34 patients were ≤50 years. The common presentation was that of a rapidly growing fixed and hard mass (64%). Due to rapid expansion, 27% patients experienced severe pain. About one-third presented as sudden enlargement of pre-existing goiter over few weeks. The median duration of symptoms before diagnosis was 3 months. About 41% presented with lymph node enlargement and 31% with distant metastasis. The diagnosis was established with fine-needle aspiration or core biopsy. Histopathology was available in 32 patients and showed four major patterns: spindle cell (9), giant cell (7), epithelioid (5), squamoid (1), mixed type in 10 patients. Eight patients presenting with stridor required emergency tracheostomy for airway control. Total thyroidectomy with or without lymph node dissection was possible in 21 patients. Patients received radiotherapy with or without chemotherapy. Median overall survival was 3 months. Overall survival was significantly better in patients receiving some form of treatment. CONCLUSION: ATC in endemic goiter areas presents at an earlier age. One-third of ATC is due to anaplastic transformation of pre-existing goiter and majority of the patients refuse treatment due to dismal outcome.
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Parathyroid carcinoma (PC) is a rare neoplasm accounting for 0.5-6 % of primary hyperparathyroidism. Histological criteria are currently considered as established means to diagnose malignancy in parathyroid neoplasms; however, it does not accurately predict the risk of aggressive behaviour of PC. Immunohistochemical (IHC) markers have been used in the literature with variable results. This work was planned to study whether IHC markers would have any added advantage over histology in predicting outcome in parathyroid neoplasms. Two hundred twenty-seven parathyroid neoplasms were reviewed according to older and revised histological criteria. IHC was performed for parafibromin, APC, galectin-3, PGP9.5 and Ki67. Diagnostic categories were correlated with clinical, biochemical, histological features and IHC markers. Chi-square test was used to analyse categorical variables. Review of histology by earlier and revised criteria showed a change in diagnosis of five cases of atypical adenoma (15.1 %), all of which were diagnosed as carcinoma according to earlier criteria. Change in diagnosis did not affect behaviour of disease as none of the cases showed recurrence or metastasis on follow-up. Combination of PF, Gal-3 and PGP9.5 showed 50 % sensitivity, 97.9 % specificity and 95.4 % predictive accuracy for PC. Histological criteria still remains the most established method for predicting risk of malignancy in parathyroid neoplasms irrespective of whether old or revised criteria are used. Combination of positive (Gal-3, PGP9.5) and negative (PF) IHC markers may be used as an adjunct to histology in histological, atypical and malignant parathyroid neoplasms to obviate the need for repeated follow-up.
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Biomarcadores Tumorais/análise , Neoplasias das Paratireoides/patologia , Adulto , Idoso , Proteínas Sanguíneas , Feminino , Galectina 3/análise , Galectina 3/biossíntese , Galectinas , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sensibilidade e Especificidade , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/biossíntese , Ubiquitina Tiolesterase/análise , Ubiquitina Tiolesterase/biossínteseRESUMO
INTRODUCTION: The clinical entity of large parathyroid adenomas (LPTAs) has not been well defined. It is speculated that LPTAs would have biochemical, histological, and molecular characteristics different from small adenomas. Our study aimed to find out occurrence of atypia and carcinomas in large parathyroid lesions and the presence of distinct molecular abnormalities in LPTAs. MATERIALS AND METHODS: We divided the parathyroid lesions into large (>7 g, i.e., LPTAs) and small (<7 g) adenomas. We performed parafibromin, APC (adenomatous polyposis coli), galectin 3, and PGP9.5 (protein gene product 9.5) analysis by immunohistochemistry in adenomas without atypia, atypical adenomas, and carcinomas. RESULTS: Mean serum calcium, alkaline phosphatase, and intact PTH were significantly higher in large parathyroid tumor group. The presence of both atypical adenoma and carcinoma was higher in large parathyroid tumor group. There was higher percentage of atypia in patients with LPTAs >10 g (33%), and 68% of tumors showed at least one marker suggestive of malignancy in this group. Detailed analysis of immunohistochemical features of LPTA >10 g revealed that six patients showed complete loss of parafibromin immunoreactivity (out of these four showed atypia), while seven showed partial loss. In histopathologically proven malignancy (n = 9), six patients showed complete loss of parafibromin staining, 5 (55%) APC negativity, and 45% showed both galectin 3 and PGP9.5 positivity. Three out of these showed all IHC markers s/o malignancy, and all of them had evidence of metastases or recurrence. 32% of atypical adenoma and 13% of atypical adenoma showed complete loss of parafibromin staining, however none developed metastases or recurrence in follow-up (median follow-up 40 months). Loss of parafibromin staining (complete or partial) was higher in LPTA group (56%) than that in small adenoma (39%); however, it was not statistically significant. APC, galectin 3, and PGP9.5 markers suggestive were higher in LPTA group but were not significant. CONCLUSION: LPTAs may show some morphological and immunohistochemical features suggestive of malignancy and can be considered a separate entity. However, the immunohistochemical markers are unable to clearly segregate those LPTAs that may show premalignant potential. Further, we would like to recommend that LPTAs showing complete parafibromin loss together with atypia should be kept under close follow-up.