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Suresh R, Sethi S, Ali S, Giorgadze T, Sarkar FH. Differential Expression of MicroRNAs in Papillary Thyroid Carcinoma and Their Role in Racial Disparity. ACTA ACUST UNITED AC 2015; 7:145-154. [PMID: 26380656 PMCID: PMC4570618 DOI: 10.4172/1948-5956.1000340] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Objective MicroRNAs (miRNAs) are known to play important roles in the diagnosis and prognosis of papillary thyroid cancer (PTC), and they are useful in developing targeted therapies. However, there have been no studies on the existence of racial differences in miRNAs expression that could explain differential overall survival of PTC patients. Expression analysis of miRNAs in major racial groups would be important for optimizing personalized treatment strategies. In the current study, we assessed the differential expression of 8 miRNAs between normal and tumor tissues, and also assessed racial differences between African American (AA) and Caucasian American (CA). Methods First, the miRNA expression profiling was performed using formalin-fixed paraffin embedded (FFPE) tissue sections of tumor containing over 70% tumor cells. Normal and tumor sections of thyroid tissues were studied from AA and CA patients. The miRNA microarray profiling was done using miRBase version 18 (LC Sciences, Houston, TX, USA). Quantitative real-time PCR (qRT-PCR) was used to validate expression of 8 selected miRNAs. Results Ingenuity pathway analysis showed involvement of target genes, such as Ras and NF-κB. Deregulated miRNAs such as miR-221 and miR-31 were found to be statistically significant between the two races. Using qRT-PCR, we found that miR-21, miR-146b, miR-221, miR-222, miR-31, and miR-3613 were up-regulated while miR-138 and miR-98 were down-regulated in tumors compared to normal tissues. Conclusion Though sample size was small, we found several deregulated miRNAs having racial differences. The differential expression of miRNAs suggest that these miRNAs and their target genes could be useful to gain further mechanistic insight of PTC and their clinical implications, including miRNA replacement therapy or their knockdown strategies.
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Affiliation(s)
- Raagini Suresh
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Seema Sethi
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Shadan Ali
- Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Tamar Giorgadze
- Weill Cornell Medical College-Cornell University, New York, New York, USA
| | - Fazlul H Sarkar
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA ; Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
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Prognostic biomarkers in thyroid cancer. Virchows Arch 2014; 464:333-46. [PMID: 24487783 DOI: 10.1007/s00428-013-1521-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 11/25/2013] [Indexed: 12/23/2022]
Abstract
Thyroid carcinomas represent a challenging problem from the prognostic standpoint. Despite an overall good prognosis of the most frequent endocrine malignancy, 10-15 % of papillary thyroid carcinomas (PTCs) turn refractory to radioactive iodine therapy. The increased incidence of thyroid cancer has led to the search for solid prognostic biomarkers that predict the behaviour of these tumours. Clinical and histopathological prognostic factors remain the only safe elements to be used for diagnosis and prognosis of patients with thyroid tumours. Despite the huge amount of genetic information of thyroid tumours, very few new markers revealed diagnostic or prognostic value per se. BRAF mutation can have some value if associated to other clinico-pathological parameters, or in the particular setting of iodine refractory tumours. Others can prove interesting in the future as predictive biomarkers of therapeutic response, but more studies are needed to confirm these potential biomarkers.
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Vía de señalización dependiente de la proteincinasa de activación mitogénica en el carcinoma papilar de tiroides. De las bases moleculares a la práctica clínica. ACTA ACUST UNITED AC 2009; 56:176-86. [DOI: 10.1016/s1575-0922(09)70982-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2009] [Accepted: 03/18/2009] [Indexed: 11/23/2022]
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Melck A, Masoudi H, Griffith OL, Rajput A, Wilkins G, Bugis S, Jones SJM, Wiseman SM. Cell cycle regulators show diagnostic and prognostic utility for differentiated thyroid cancer. Ann Surg Oncol 2007; 14:3403-11. [PMID: 17882495 DOI: 10.1245/s10434-007-9572-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Revised: 07/19/2007] [Accepted: 07/20/2007] [Indexed: 12/22/2022]
Abstract
BACKGROUND Differentiated thyroid cancer (DTC) generally has a favorable outcome, but some patients develop local recurrence and/or distant metastases and ultimately die of their disease. Molecular markers that accurately predict tumor behavior are lacking. This study's aim was to ascertain the role of cell cycle regulators in predicting malignant histology and tumor behavior in DTC. METHODS Tissue microarrays consisting of 100 benign and 105 malignant thyroid lesions, plus 24 lymph node samples, were stained for p16, p21, p27, p53, p57, p63, cyclin D1, cyclin E, and mdm2. Statistical analysis was used to compare the expression of the markers in benign versus DTC lesions and correlate their expression with clinicopathologic characteristics. RESULTS p16, p21, cyclin D1, and cyclin E showed significantly (P < .001) increased expression in DTCs compared with benign thyroid lesions (54.7% vs. 5%, 71.7% vs. 38%, 87.1% vs. 45.7%, and 72.3% vs. 37.4%, respectively). There was no significant difference in expression between benign lesions and DTC for the remaining markers. p16 expression correlated significantly with extrathyroidal tumor extension (P = .02) and the presence of cancer in lymph nodes (P = .03). A total of 73% vs. 45% of the cancers of patients with and without lymph node involvement, respectively, stained positive for p16 (P = .01). CONCLUSIONS There is a statistically significant difference in the expression of p16, p21, cyclin D1, and cyclin E between DTCs and benign thyroid lesions, and p16 expression correlates with clinicopathologic variables predicting poor outcomes for DTC. These results suggest that evaluation of cell cycle derangement in thyroid tumors may serve as a useful tool for both DTC diagnosis and prognosis.
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Affiliation(s)
- Adrienne Melck
- Department of Surgery, St. Paul's Hospital, University of British Columbia, C303-1081 Burrard Street, V6Z 1Y6, Vancouver, BC, Canada
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Siironen P, Louhimo J, Nordling S, Ristimäki A, Mäenpää H, Haapiainen R, Haglund C. Prognostic factors in papillary thyroid cancer: an evaluation of 601 consecutive patients. Tumour Biol 2005; 26:57-64. [PMID: 15870511 DOI: 10.1159/000085586] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2004] [Accepted: 11/08/2004] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Although papillary thyroid cancer (PTC) is among the most curable cancer types, it can be a distressing disease for those patients suffering from frequent recurrences or even distant metastases leading to death. Age over 45 years is the most important indicator of poor prognosis. Our aim was to evaluate markers which might predict the outcome of an individual patient better than does TNM classification alone. MATERIALS AND METHODS Of 601 consecutive patients who underwent surgery for PTC, retrospectively we selected 36 patient pairs in which one recovered completely after primary surgery, and the other suffered from aggressive disease. Formalin-fixed, paraffin-embedded tumor samples from these 72 patients were analyzed by immunohistochemistry for COX-2, MMP-2, VEGF-C, Bcl-2, Ki-67, and p21 expression. RESULTS AND CONCLUSIONS None of the markers we studied showed a superiority over TNM classification in selecting patients likely to progress to aggressive disease. However, the expression of COX-2 and VEGF-C seemed to be increased in patients over 45, which could explain the more aggressive behavior of these tumors. Moreover, we found that age over 45, tumor size over 4 cm, extrathyroidal extension of tumor, nodal metastases, distant metastases, and stage IV had an unfavorable effect on survival.
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Affiliation(s)
- Päivi Siironen
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
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Brzeziński J, Migodziński A, Toczek A, Tazbir J, Dedecjus M. Patterns of Cyclin E, Retinoblastoma Protein, and p21Cip1/WAF1 Immunostaining in the Oncogenesis of Papillary Thyroid Carcinoma. Clin Cancer Res 2005. [DOI: 10.1158/1078-0432.1037.11.3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Abstract
Purpose: Uncontrolled cell proliferation, a hallmark of cancer, may result from an increased expression of cell cycle up-regulators, and/or from a reduced expression of cell cycle down-regulators. In the present study, we analyzed, by immunohistochemistry, the expression of a panel of three proteins: cyclin E and two cell cycle inhibitors, p21Cip1/WAF1 and retinoblastoma protein (pRb) product, in different stages of papillary thyroid carcinomas (PTC).
Experimental Design: We investigated immunostaining patterns of the proteins in question in 51 resected PTC in pathologic stages, ranging from pT1a to pT4, taking into consideration their relation to clinicohistopathologic factors.
Results: We observed a significant, progressive loss of expression of p21Cip1/WAF1 with advancing tumor grade. The differences reached values of significance between pT1a [papillary thyroid microcarcinomas (PMC)] and pT2 and between PMC and pT4 stages of PTC. pRb presented a similar immunostaining pattern to that of p21Cip1/WAF1 and the differences reached values of significance between pT1a and pT2, and between PMC and pT4 stages of PTC. The results of cyclin E immunostaining corresponded to our recently published result, and a negative correlation was observed between the immunostaining index of cyclin E and pRb.
Conclusions: The results of the present study suggest that cyclin E expression and suppression of pRb and p21Cip1/WAF1 may be characteristic patterns of immunostaining for PTC with a tendency to early metastasizing. If our results are confirmed in a larger study, the diagnostic panel, constructed of the antibodies against these proteins, may become a valuable tool in predicting the metastatic potential in PTC.
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Affiliation(s)
- Jan Brzeziński
- 1Department of Endocrinological and General Surgery, Institute of Endocrinology, Medical University of Łódź; Departments of
| | - Adam Migodziński
- 2General and Vascular Surgery and Emergency Medicine, Medical University of Łódź, The M. Kopernik Memorial Hospital, Łódź, Poland and
| | - Aleksandra Toczek
- 3Cardiological and Transplantological Immunology, The M. Kopernik Memorial Hospital, Łódź, Poland
| | - Józef Tazbir
- 2General and Vascular Surgery and Emergency Medicine, Medical University of Łódź, The M. Kopernik Memorial Hospital, Łódź, Poland and
| | - Marek Dedecjus
- 1Department of Endocrinological and General Surgery, Institute of Endocrinology, Medical University of Łódź; Departments of
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Siironen P, Nordling S, Louhimo J, Haapiainen R, Haglund C. Immunohistochemical Expression of Bcl-2, Ki-67, and p21 in Patients with Papillary Thyroid Cancer. Tumour Biol 2005; 26:50-6. [PMID: 15756057 DOI: 10.1159/000084340] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2004] [Accepted: 12/04/2004] [Indexed: 12/22/2022] Open
Abstract
Papillary thyroid cancer (PTC) is a slow-growing tumor with a favorable outcome. Still, some low-risk patients develop local or distant metastases and eventually die from their disease. Many molecular markers are involved in proliferation and apoptosis, including Bcl-2, Ki-67, and p21. Because age over 45 is the most important determinant of a poor survival, we analyzed whether the expression of these tumor proliferation markers differs between young and older PTC patients. Our study comprised 108 PTC patients retrospectively selected by age, i.e. those younger than 35 or older than 55 at diagnosis. Formalin-fixed, paraffin-embedded archival tissue blocks were analyzed for Bcl-2, Ki-67, and p21 protein expression by immunohistochemistry. We showed that expression of Ki-67 increases significantly with age, indicating that tumors in older patients may grow faster. This higher proliferative activity may explain the worse prognosis in these patients. Expression of p21 was higher in large tumors and in tumors extending beyond the thyroid capsule. Expression of Bcl-2 did not correlate with clinical parameters.
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Affiliation(s)
- Paivi Siironen
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
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Su JJ, Ban KC, Li Y, Qin LL, Wang HY, Yang C, Ou C, Duan XX, Lee YL, Yang RQ. Alteration of p53 and p21 during hepatocarcinogenesis in tree shrews. World J Gastroenterol 2004; 10:3559-63. [PMID: 15534906 PMCID: PMC4611992 DOI: 10.3748/wjg.v10.i24.3559] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate p53 mutation and p21 expression in hepatocarcinogenesis induced by hepatitis B virus (HBV) and aflatoxin B1 (AFB1) in tree shrews, and to reveal the role of these genes in hepatocarcinogenesis.
METHODS: Tree shrews were divided into four groups: group A, those infected with HBV and fed with AFB1 (n = 39); group B, those infected with HBV alone (n = 28); group C, those fed with AFB1 alone (n = 29); and group D, normal controls (n = 20). The tree shrews underwent liver biopsies once every 15 wk. Expression of p53 and p21 proteins and genes in the biopsies and tumor tissues of the experimental tree shrews was detected, respectively, by immunohistochemistry, and by Southern blotting and reverse transcription-polymerase chain reaction and sequencing.
RESULTS: The incidence of hepatocellular carcinomas (HCC) was higher in group A (66.7%) than that in group B (3.57%) and C (30%). The time of HCC occurrence was also earlier in group A than that in group C (120.0 ± 16.6 wk vs 153.3 ± 5.8 wk, respectively, P < 0.01). p53 protein was not detected by immunohistochemistry in all groups before the 75th wk of the experiment. At the 105th wk, the positive rates fo p53 were 78.6%, 60% and 71.4% in groups A, B and C, respectively, which were significantly higher than that in group D (10%) (all P < 0.05). An abnormal band of p53 gene was observed in groups A and C. The mutation points of p53 gene in tree shrews with HCC were at codons 275, 78 and 13. The nucleotide sequence and amino acid sequence of tree shrew’s wild-type p53 showed 91.7% and 93.4% homologies with those of human p53, respectively. The immunopositivity for p21 was found before HCC development. The incidence of HCC was significantly higher in tree shrews that were positive for p21 than those negative for p21 (80.0% vs 11.0%, P < 0.001). The incidence of HCC in p21 positive animals in group A was significantly higher than those positive for p21 in group C (P < 0.05).
CONCLUSION: A remarkable synergistic effect on HCC development exists between HBV and AFB1. p53 mutation promotes the development of HCC. HBV and AFB1 may synergistically induce p53 gene mutation, and stimulate ras gene expression. ras gene is activated at the earlier stage during hepatocarcinogenesis. p21 protein may be an early marker, and the alterations of p53 may be a late event in the development of HCC.
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Affiliation(s)
- Jian-Jia Su
- Department of Experimental Pathology, Guangxi Cancer Institute, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
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Moretti F, Nanni S, Pontecorvi A. Molecular pathogenesis of thyroid nodules and cancer. BAILLIERE'S BEST PRACTICE & RESEARCH. CLINICAL ENDOCRINOLOGY & METABOLISM 2000; 14:517-39. [PMID: 11289733 DOI: 10.1053/beem.2000.0101] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tumours derived from the thyroid follicular epithelium represent an informative model for understanding the molecular pathogenesis of multistage tumourigenesis, which is the prevailing theory on cancer development and progression nowadays. The early stages of thyroid tumour development appear to be the consequence of the activation or 'de novo' expression of several proto-oncogenes or growth factor receptors, such as ras, ret, NTRK, met, gsp and the thyrotropin (TSH) receptor. Alterations in the expression pattern of these genes are associated with the development of differentiated neoplasms, ranging from benign toxic adenomas (gsp and TSH receptor), to follicular (ras) and papillary (ret/PTC, NTRK, met) carcinomas. They may all be considered to be early events of thyroid cell transformation and, for some, experimental evidence derived from gene transfer studies supports this hypothesis. Alterations in tumour suppressor genes (p53, Rb) are associated instead with the most aggressive and poorly differentiated forms of thyroid cancer, indicating that, in the thyroid tumourigenic process, they represent late genetic events. Specific environmental factors (iodine deficiency, ionizing radiations) have been shown to play a crucial role in promoting the development of thyroid cancer, influencing both its genotypic and phenotypic features. Interestingly, a high percentage of genetic lesions causing thyroid cancer originate from gene rearrangements and chromosomal translocations (ret/PTC, NTRK, Pax-8/PPARgamma) a finding which, being a rare event in most epithelial tumours, makes the molecular pathogenesis of thyroid cancer unique. The uninterrupted flow of information on the molecular genetics of thyroid nodules and cancer will broaden the correlation between genotype and phenotype and will also provide important information for the development of more accurate preoperative diagnostic tools and more efficient treatment choices for the different forms of thyroid cancer.
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Affiliation(s)
- F Moretti
- Institute of Experimental Medicine, National Research Council
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10
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Basolo F, Caligo MA, Pinchera A, Fedeli F, Baldanzi A, Miccoli P, Iacconi P, Fontanini G, Pacini F. Cyclin D1 overexpression in thyroid carcinomas: relation with clinico-pathological parameters, retinoblastoma gene product, and Ki67 labeling index. Thyroid 2000; 10:741-746. [PMID: 11041450 DOI: 10.1089/thy.2000.10.741] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Cyclin D1 is a G1 cyclin participating in the control of cell cycle progression through interaction with the retinoblastoma gene product (pRB). The overexpression of positive regulators (such as cyclin D1) has been reported in a variety of neoplasms, but their role in thyroid tumorigenesis is yet to be established. In our series of 54 thyroid carcinomas, cyclin D1 overexpression (detected by both immunohistochemistry and by Northern blotting) was correlated with prognostic variables, proliferative activity and pRB. Cyclin D1 overexpression was observed in 35% of thyroid carcinomas with a significantly higher expression of this cyclin in neoplastic tissues than in matched normal parenchyma. In well-differentiated carcinomas, the cyclin D1 mRNA overexpression was inversely correlated with nodal status (p = 0.03), while the protein product was higher in tumors from patients less than 40 than patients over 40 years of age. Inversely, there was no significant correlation with gender and tumor status, pRB and with proliferative activity.
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Affiliation(s)
- F Basolo
- Department of Oncology, University of Pisa, Italy.
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Maiorano E, Ciampolillo A, Viale G, Maisonneuve P, Ambrosi A, Triggiani V, Marra E, Perlino E. Insulin-like growth factor 1 expression in thyroid tumors. Appl Immunohistochem Mol Morphol 2000; 8:110-9. [PMID: 10937058 DOI: 10.1097/00129039-200006000-00005] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Insulin-like growth factor 1 (IGF-1) likely is involved in thyrocyte proliferation via autocrine mechanisms, but limited data are available on its in vivo expression in thyroid neoplasms. This prompted us to explore IGF-1 expression at the protein and mRNA levels and IGF-1 receptor (IGF-1rec) immunoreactivity in normal and neoplastic thyroids (50 adenomas and 53 carcinomas). We documented increased IGF-1 and IGF-1rec immunoreactivity in adenomas (31 of 50 and 40 of 50 cases, respectively) and carcinomas (38 of 53 and 42 of 53 cases) compared with normal thyroid, which only showed minimal immunoreactivity for the ligand and its receptor. A corresponding up-regulation of IGF-1 mRNA was documented in carcinomas, whereas adenomas exhibited down-regulated expression of IGF-1 mRNA. Immunoreactivity for IGF-1 and cognate receptor positively correlated with tumor diameter and wide intrathyroidal extension but not with patients' gender and age or with the stage of the tumors and the occurrence of lymph node metastases. These data emphasize a possible role of the IGF-1 system in thyroid tumorigenesis, as indicated by in vitro studies. In addition, the evaluation of IGF-1 and IGF-1rec immunoreactivity might have clinical implications, because it positively correlates with the aggressiveness of these tumors.
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Affiliation(s)
- E Maiorano
- Istituto di Anatomia Patologica, Università degli Studi di Bari, Italy.
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Utrilla JC, Martín-Lacave I, San Martín MV, Fernández-Santos JM, Galera-Davidson H. Expression of c-erbB-2 oncoprotein in human thyroid tumours. Histopathology 1999; 34:60-5. [PMID: 9934586 DOI: 10.1046/j.1365-2559.1999.00563.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS c-erbB-2 expression has been found to be a potential marker of aggressive biological behaviour in some tumours, but the role played by this oncoprotein in the development and maintenance of thyroid tumours is still controversial. Therefore our objective was to determine whether c-erbB-2 was overexpressed in a large retrospective series of human thyroid tumours, including both from follicular and C-cell differentiation. METHODS AND RESULTS We have studied 67 thyroid tumours (10 follicular adenomas, 11 follicular carcinomas, three anaplastic carcinomas, 25 papillary carcinomas and 18 medullary carcinomas and 16 metastases) by immunohistochemistry using an antigen retrieval method for paraffin-embedded material and a specific polyclonal antibody against the intracytoplasmic part of c-erbB-2 oncoprotein. There are marked differences in the pattern of c-erbB-2 immunoreactivity depending on the type of thyroid tumour. Thus, no expression of the oncoprotein has been found in follicular adenomas, follicular carcinomas and anaplastic carcinomas, but 52% of papillary carcinomas (membranous and diffuse cytoplasmic patterns) and all medullary carcinomas (granular cytoplasmic pattern) are immunopositive. CONCLUSIONS Our results indicate that overexpression of c-erbB-2 oncoprotein is easily identifiable by immunohistochemistry in paraffin sections of certain thyroid tumours after applying an antigen retrieval method. This study suggests that c-erbB-2 oncoprotein may play some role in disease progression in papillary and medullary thyroid carcinomas, but the significance of the different immunohistochemical patterns merits further investigations.
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Affiliation(s)
- J C Utrilla
- Department of Cytology and Histopathology, University of Seville, Spain
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Clark OH. Thyroid cancer: predisposing conditions, growth factors, signal transduction and oncogenes. THE AUSTRALIAN AND NEW ZEALAND JOURNAL OF SURGERY 1998; 68:469-77. [PMID: 9669359 DOI: 10.1111/j.1445-2197.1998.tb04806.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- O H Clark
- UCSF/Mount Zion Medical Centre, San Francisco 94143-1674, USA.
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14
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Newman KD, Black T, Heller G, Azizkhan RG, Holcomb GW, Sklar C, Vlamis V, Haase GM, La Quaglia MP. Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children's Cancer Group. Ann Surg 1998; 227:533-41. [PMID: 9563542 PMCID: PMC1191309 DOI: 10.1097/00000658-199804000-00014] [Citation(s) in RCA: 169] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This study was done to define the extent of disease and evaluate the effect of staging and treatment variables on progression-free survival in patients with differentiated thyroid carcinoma who were less than 21 years of age at diagnosis. SUMMARY BACKGROUND DATA Differentiated thyroid cancer in young patients is associated with early regional lymph node involvement and distant parenchymal metastases. Despite this, the overall long-term survival rate is greater than 90%, which suggests that biologic rather than treatment factors have a greater effect on outcome. METHODS Variables analyzed for their impact on progression-free survival in a multi-institutional cohort of 329 patients included age, antecedent thyroid irradiation, extrathyroidal tumor extension, size, nodal involvement, distant metastases, technique of thyroid surgery and lymphatic dissection, initial treatment with 131Iodine, residual cervical disease, and histopathologic subtype. Surgical complications were correlated with the specific procedures completed on the thyroid gland or cervical lymphatics. RESULTS The overall progression-free survival rate was 67% (95%, CI: 61%-73%) at 10 years with 2 disease-related deaths. Regional lymph node and distant metastases were present in 74% and 25% of patients, respectively. Progression-free survival was less in younger patients (p = 0.009) and those with residual cervical disease after thyroid surgery (p = 0.001). Permanent hypocalcemia was more frequent after total or subtotal thyroidectomy (p = 0.001) while wound complications increased after radical neck dissections (p < 0.00001). CONCLUSIONS The progression-free survival rate was better after a complete resection and in older patients. Progression-free survival rate was the same after lobectomy or more extensive thyroid procedures, but comparison was confounded by the increased use of total or subtotal thyroidectomy in patients with advanced disease. The risk of permanent hypocalcemia increased when total or subtotal thyroidectomy was done. Thyroid lobectomy alone may be appropriate for patients with small localized lesions while total or subtotal thyroidectomy should be considered for more extensive tumors.
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Affiliation(s)
- K D Newman
- Department of Pediatric Surgery, Children's National Medical Center, Washington, DC, USA
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Abstract
The molecular genetics of endocrine tumours is an area of great interest, due to the heterogeneity of endocrine tumour types, the association of hormone over-production in some cases, and the wide variation in tumour behaviour. Genes implicated fall into functional categories such as oncogenes, in which mutations tend to cause activation, and tumour suppressor genes, in which mutations lead to loss of function. Oncogenes include the receptor tyrosine kinases such as RET, signal transduction proteins and other molecules such as cell cycle regulators and nuclear proteins. Tumour suppressor genes include cell cycle regulators such as p53 and other molecules such as the MEN 1 gene. Loss of heterozygosity studies help in the initial localisation of the latter. Endocrine tumours, as with other tumours, develop as a result of a combination of genetic events, and in the paediatric age group they often occur in the setting of familial cancer syndromes. In this review we analyse the main genetic lesions which have been described in endocrine tumours. There has been an explosion of knowledge in the last 5 years including the identification of the causative genes for MEN 2 and most recently for MEN 1. Characterisation of such genes also aids in the study of somatic mutations in sporadic versions of the same tumour types as occur in the familial syndromes. Identification of a genetic predisposition to a certain tumour has management implications that are still to be clarified in most cases, although in the case of MEN 2 the guidelines for prophylactic thyroidectomy are generally well accepted.
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Affiliation(s)
- D L Learoyd
- Molecular Genetics Unit, Kolling Institute of Medical Research, St. Leonards, NSW, Australia
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Köhrle J. Thyroid carcinoma: interrelationships between local thyroid hormone metabolism by the type I 5'-deiodinase and the expression of thyroid hormone receptors and other thyroid-specific (de-)differentiation markers. CURRENT TOPICS IN PATHOLOGY. ERGEBNISSE DER PATHOLOGIE 1997; 91:83-116. [PMID: 9018918 DOI: 10.1007/978-3-642-60531-4_8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- J Köhrle
- Medical Policlinic, University of Würzburg, Germany
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Abstract
A growing body of literature supports the view that the proliferative activity (PA) of tumor cells is an important prognostic indicator for a variety of different tumors. We examined the role of PA in diagnosis and prediction or malignancy of endocrine tumors (ETs) of pituitary gland, pancreas, thyroid, parathyroid glands, adrenal glands, paraganglia, gastroenteric tract, and lung. The data in the literature indicate that the assessment of PA is not a diagnostic indicator of malignancy especially at the individual case level, whereas it can be useful for identifying subsets of malignant tumors with different aggressiveness potential, as well as for choosing therapeutic options in metatstatic lesions. We hope that, in the near future, multiparametric approaches including PA markers, cell growth and differentiation factors, and oncogenes will yield valuable information for diagnosis and prognosis of ETs also in individual cases.
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Pollina L, Pacini F, Fontanini G, Vignati S, Bevilacqua G, Basolo F. bcl-2, p53 and proliferating cell nuclear antigen expression is related to the degree of differentiation in thyroid carcinomas. Br J Cancer 1996; 73:139-143. [PMID: 8546897 PMCID: PMC2074326 DOI: 10.1038/bjc.1996.26] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Thyroid carcinomas are heterogeneous in terms of histology, clinical presentation, treatment response and prognosis. Since bcl-2 and p53 gene alterations are frequently involved in both lymphoid and epithelial malignancies, we analysed the expression of bcl-2, p53 and proliferating cell nuclear antigen (PCNA) in a group of 134 patients with thyroid neoplasms. The same markers were evaluated in fetal and adult normal thyroids as well as in 40 benign lesions. The study was carried out by immunocytochemistry on archival material using antibodies against bcl-2 and p53 protein on tissue sections of 40 adenomas (As), 20 medullary carcinomas (MCs), 70 well-differentiated carcinomas (WDCs), 20 poorly differentiated carcinomas (PDCs) and 24 undifferentiated carcinomas (UCs). bcl-2 immunoreactivity was detected in 36 out of 40 (90%) As, 20 out of 20 (100%) MCs, 60 out of 70 (85.7%) WDCs, 20 out of 20 (100%) PDCs, and 8 out of 24 (33.3%) of UCs. p53 expression was present in 11.4% of WDCs, 5% of PDCs, 5% of MCs and 62.5% of UCs. By contrast, no p53 immunoreactivity was detected in 40 adenomas and in all the normal thyroid tissues studied. We observed a positive correlation between the expression of p53 and PCNA (r = 0.42; P = 0.035) in a group of UCs, but not in WDCs, PDCs and MCs. Neither p53 nor bcl-2 expression were correlated with clinicopathological parameters, such as age, sex, pTNM and survival. Our results suggest that in tumours of the follicular epithelium p53 and bcl-2 protein abnormalities are associated with more advanced carcinomas and especially with undifferentiated carcinomas, while they are only rarely altered in tumours of the parafollicular C cells.
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Affiliation(s)
- L Pollina
- Institute of Pathology, University of Pisa, Italy
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20
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Akslen LA, Varhaug JE. Oncoproteins and tumor progression in papillary thyroid carcinoma: presence of epidermal growth factor receptor, c-erbB-2 protein, estrogen receptor related protein, p21-ras protein, and proliferation indicators in relation to tumor recurrences and patient survival. Cancer 1995; 76:1643-54. [PMID: 8635070 DOI: 10.1002/1097-0142(19951101)76:9<1643::aid-cncr2820760922>3.0.co;2-#] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND The prognostic relevance of activated oncogenes and oncoproteins has not been well studied in papillary thyroid cancer, which is slow-growing, with only regional spread in most cases. Therefore, the influence of some protein markers and tumor cell proliferation on disease progress in a series of patients with surgically treated papillary thyroid carcinoma was studied. METHODS One hundred twenty-seven patients with papillary thyroid carcinoma larger than 10 mm in greatest dimension were studied retrospectively, and the majority were treated with total or near-total thyroidectomy. Immunohistochemical and flow cytometric analyses of paraffin embedded tumor material were performed and the results were related to time to recurrence and thyroid cancer deaths using the univariate product-limit survival analysis and the multivariate Cox' regression method. RESULTS Immunohistochemical expression of c-erbB-2 protein, estrogen receptor-related protein (p29), which may be regarded as an indicator of hormone-dependent growth, S-phase, G2M-phase, sex, age, histologic grade, and primary tumor extent were all of significant prognostic importance in univariate analyses of patient survival. In the final Cox' model, however, only male sex (P = 0.017), older age, (P < 0.00005) and high grade histologic features (P = 0.006) were associated independently with decreased survival. Among females, decreased expression of c-erbB-2 protein was independently related to decreased patient survival (P = 0.019). In multivariate analysis of time to recurrence, lymph node status (P = 0.0001), epidermal growth factor (EGF) receptor expression (P = 0.013) and estrogen receptor-related protein (P = 0.007) were independent risk indicators, and S-phase fraction (P = 0.074) showed a borderline significance. CONCLUSION In this study, sex, age, and histologic grade were independent indicators of deaths from thyroid cancer. Lymph node metastases, EGF-receptor expression, and decreased estrogen receptor-related protein staining persisted as prognostic variables in the final multivariate analysis of recurrence free survival. Alterations in these oncogenes thus seem to play some role in disease progression in papillary thyroid carcinoma, although conventional variables are still important as prognostic indicators.
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MESH Headings
- Adolescent
- Adult
- Aged
- Biomarkers, Tumor/metabolism
- Carcinoma, Papillary/metabolism
- Carcinoma, Papillary/mortality
- Carcinoma, Papillary/pathology
- Child
- Child, Preschool
- DNA, Neoplasm/analysis
- ErbB Receptors/metabolism
- Female
- Flow Cytometry
- Follow-Up Studies
- Heat-Shock Proteins/metabolism
- Humans
- Immunohistochemistry
- Infant
- Lymphatic Metastasis
- Male
- Middle Aged
- Multivariate Analysis
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/pathology
- Oncogene Proteins/metabolism
- Ploidies
- Prognosis
- Proto-Oncogene Proteins p21(ras)/metabolism
- Receptor, ErbB-2/metabolism
- Receptors, Estrogen/metabolism
- Regression Analysis
- Retrospective Studies
- Survival Rate
- Thyroid Neoplasms/metabolism
- Thyroid Neoplasms/mortality
- Thyroid Neoplasms/pathology
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Affiliation(s)
- L A Akslen
- Department of Pathology, Gade Institute, Haukeland Hospital, Bergen, Norway
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