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1.
Nabiha Missaoui Amel Trabelsi Sihem Hmissa Bernard Fontanière Mohamed Tahar Yacoubi Moncef Mokni Sadok Korbi Lucien Frappart 《Pathology, research and practice》2010
Uterine cervix cancer is an important public health problem in developing countries. However, there is a substantial lack of inter-observer diagnostic reproducibility for its precursor lesions (CIN1). The study was performed to evaluate the usefulness of p16INK4A overexpression as a surrogate marker for uterine cervix precancerous lesions and high-risk human papillomavirus (HPV) infection. 相似文献
2.
P16<Superscript>INK4A</Superscript> positivity in benign,premalignant and malignant cervical glandular lesions: a potential diagnostic problem 总被引:2,自引:0,他引:2
Murphy N Heffron CC King B Ganuguapati UG Ring M McGuinness E Sheils O O'Leary JJ 《Virchows Archiv : an international journal of pathology》2004,445(6):610-615
A wide array of immunohistochemical markers have been evaluated with respect to their specificity in staining dysplastic cervical cells in cervical biopsies and cervical cytological smears. However, there is still a significant demand for better biomarkers to identify neoplastic cervical glandular and squamous epithelial cells precisely. The CDKN2A gene, located on chromosome 9p21, encodes the tumour suppressor protein, p16INK4A, which decelerates the cell cycle by inactivating CDK4 and CDK6. The aim of this study was to compare and contrast the expression pattern of p16INK4A in benign and neoplastic glandular lesions and tubo-endometrioid metaplasia. All cases in each category displayed some p16INK4A expression. Adenocarcinoma and in situ cases showed a combination of intense nuclear and cytoplasmic staining. It was observed that all cases of tubo-endometrioid metaplasia showed occasional nuclear positivity and definite cytoplasmic staining. These findings may have important implications for the potential utility of p16INK4A as a biomarker for glandular dysplastic lesions. While p16INK4A has been demonstrated to be an excellent marker of cervical dysplasia in squamous neoplastic lesions of the cervix, it has potential pitfalls in cervical glandular lesions that may limit the utility of this biomarker in resolving the nature of suspicious glandular lesions, particularly in cytopathology.N. Murphy and C.C.B.B. Heffron contributed equally to the work. 相似文献
3.
Boris Klingenberg Harriët C Hafkamp Annick Haesevoets Johannes J Manni Pieter J Slootweg Soenke J Weissenborn Jens P Klussmann Ernst‐Jan M Speel 《Histopathology》2010,56(7):957-967
Klingenberg B, Hafkamp H C, Haesevoets A, Manni J J, Slootweg P J, Weissenborn S J, Klussmann J P & Speel E‐J M(2010) Histopathology 56, 957–967 p16 INK4A overexpression is frequently detected in tumour‐free tonsil tissue without association with HPV Aims: Oncogenic human papillomavirus (HPV) type 16 has been strongly associated with tonsillar squamous cell carcinoma (TSCC) and appears to be of prognostic significance. Because HPV+ TSCC also accumulates p16INK4A, this cyclin‐dependent kinase inhibitor has been proposed as a potential biomarker for HPV in clinical diagnosis. The aim of this study was to determine the prevalence of HPV in tumour‐free tonsillar tissue and the value of p16INK4A overexpression in predicting its presence. Methods and results: p16INK4A overexpression was detected by immunohistochemistry in tissue sections of tumour‐free tonsils of 262 patients. They were treated for non‐oncological reasons (snoring or chronic/recurrent tonsillitis) consisting of tonsillectomy. Genomic DNA isolated from these tissues was subjected to HPV‐specific polymerase chain reaction (PCR) analysis. p16INK4A immunoreactivity was detected in 28% of samples in both crypt epithelium (49/177) and lymphoid germinal centres (52/187), which correlated with each other (P < 0.0001). No reactivity was observed in superficial squamous cell epithelium. HPV16 and 18 were detected by PCR analysis in 2/195 cases (1%), which, however, were negative on fluorescence in situ hybridization analysis and discrepant on p16INK4A immunostaining. Conclusions: No proof was found for the presence of HPV in tumour‐free tonsil tissue, despite increased p16INK4A expression in a quarter of tonsil cases. Other mechanisms than HPV infection are therefore implicated in p16INK4A up‐regulation. 相似文献
4.
Min‐Zhu Huang M.B. Hong‐Bo Li M.D. Xin‐Min Nie M.D. Xin‐Yin Wu M.B. Xiao‐Man Jiang M.B. 《Diagnostic cytopathology》2010,38(8):573-578
Human papillomavirus (HPV) infection in cervix is the most important reason for cervical cancer, but only 2% cervical HPV infection will develop into cervical cancer. So how to identify patients at risk of progressive cervical lesions from those infected with HPV to avoid over treatment is a big issue in clinic. The aims of this study were to detect the expression of HPV L1 capsid protein and p16INK4a in cervical lesions and to investigate the combination expression of HPV L1 capsid protein and p16INK4a in cervical lesions and its diagnostic efficiency in clinic. Immunochemical method was used to detect the expression of HPV L1 capsid protein and p16INK4a in 169 cases of abnormal cytology. Histopathologic test was performed to identify cervical lesions of all the cases. χ2 test and spearman's rank correlation were used for statistical analysis. The diagnostic sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), accuracy, and the area under the receive operating characteristic (ROC) curve (denoted by AZ) were calculated with SPSS 13.0. All the statistical tests were two sided at the 5% level of significance. L1 expression decreased (P < 0.001), but p16INK4a expression increased (P < 0.001) with histopathologic diagnosis increasing. The expression rates of HPV L1 capsid protein, p16INK4a, and L1(?)/p16(+) in cervical intraepithelial neoplasia (CIN)2, CIN3, and squamous‐cell carcinoma were statistically different from those in CIN1 (P < 0.001). The expressions of HPV L1 capsid protein, L1(+)/p16(+), L1(+)/p16(?), and L1(?)/p16(?) were negatively correlated with the severity of cervical lesions (P < 0.001), whereas the expressions of p16INK4a and L1(?)/p16(+) were positively correlated with the severity of cervical lesions (P < 0.001). The specificity and AZ of combining L1 with p16 INK4a were statistically higher than L1 or p16 INK4a alone (P < 0.05). L1 and p16INK4a are useful biomarkers for the early diagnosis of cervical lesions. The combination of L1 and p16INK4a has a higher diagnostic accuracy than L1 or p16INK4a alone in diagnosis of cervical lesions. Diagn. Cytopathol. 2010;38:573–578. © 2009 Wiley‐Liss, Inc. 相似文献
5.
Stankiewicz E Prowse DM Ktori E Cuzick J Ambroisine L Zhang X Kudahetti S Watkin N Corbishley C Berney DM 《Histopathology》2011,58(3):433-439
Stankiewicz E, Prowse D M, Ktori E, Cuzick J, Ambroisine L, Zhang X, Kudahetti S, Watkin N, Corbishley C & Berney D M(2011) Histopathology 58 , 433–439 The retinoblastoma protein/p16 INK4A pathway but not p53 is disrupted by human papillomavirus in penile squamous cell carcinoma Aims: The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood. Human papillomavirus (HPV) may be involved in carcinogenesis, but few studies have compared cell‐cycle protein expression in HPV positive and negative cancers. The aim was to determine the extent of HPV infection in different histological subtypes of PSCC and its impact on the expression of key cell‐cycle proteins: p53, p21, p16INK4A and retinoblastoma (RB) protein. Methods and results: One hundred and forty‐eight PSCC samples were examined immunohistochemically for RB, p16INK4A, p53 and p21 protein expression. One hundred and two cases were typed for HPV by PCR. HPV DNA was detected in 56% of tumours, with HPV16 present in 81%. Basaloid tumours were related strongly to HPV infection (10 of 13), while verrucous were not (three of 13). Fifty‐nine per cent (38 of 64) of usual type SCCs had HPV infection. RB protein correlated negatively (P < 0.0001) and p16INK4A (P < 0.0001) and p21 (P = 0.0002) correlated positively with HPV infection. p53 did not correlate with HPV infection. Conclusions: HPV infection is present in more than half of penile cancers and it is responsible for RB pathway disruption. However, no link between HPV and p53 immunodetection was found. Only basaloid and half of usual‐type PSSCs correlate with HPV infection, confirming possible separate aetiologies for those tumours. 相似文献
6.
Montebugnoli L Cervellati F Cocchi R Farnedi A Pennesi MG Flamminio F Foschini MP 《Histopathology》2010,57(4):528-534
Montebugnoli L, Cervellati F, Cocchi R, Farnedi A, Pennesi M G, Flamminio F & Foschini M P(2010) Histopathology 57 , 528–534 Immunohistochemical expression of p16INK4A protein as a helpful marker of a subset of potentially malignant oral epithelial lesions: study on a series with long‐term follow‐up Aim: To examine a group of lesions that progressed to oral squamous cell carcinoma (OSCC) to determine whether p16INK4A expression is an early finding during malignant transformation, and whether immunohistochemical evaluation of p16INK4A is an appropriate prognostic marker. Methods and results: Twenty cases of OSCC were investigated. All cases had had a biopsy on the same site as OSCC performed at least 1 year before OSCC (range 1–11 years; mean 3.15 ± 3.1 years). Twenty specimens from normal oral mucosa served as controls. p16INK4A expression was evaluated by immunohistochemical analysis and cases showing >5% of stained cells were defined as ‘positive’. All 20 control cases were negative for p16INK4A. Oral lesions were p16INK4A‐positive in nine cases and negative in 11. No significant relationship was found between p16INK4A positivity and the presence/absence of dysplasia. Among OSCC, nine tumours showed p16INK4A positivity and 11 showed negativity. A significant relationship (χ2 = 7.1; P < 0.01) was found between the presence/absence of p16INK4A staining in OSCC and the presence/absence of p16INK4A staining in lesions preceding OSCC. Conclusions: p16INK4A immunohistochemistry has a potential role in detecting a subset of p16INK4A‐positive lesions with malignant potential. 相似文献
7.
For evaluating the diagnostic significance of p16(INK4A) over-expression in the uterine cervical intraepithelial neoplasm and in invasive carcinoma, human papillomavirus (HPV) was detected and genotyped by oligonucleotide microarray in archival tissues of 117 cervical specimens, including 47 invasive squamous cell carcinomas (SCC), 30 cases of cervical intraepithelial neoplasia (CIN), 20 adenocarcinomas, and 20 cases of non-neoplastic cervix. The expression of p16(INK4A) protein was immunohistochemically studied in these cases and in five HPV-positive and one HPV-negative cervical cancer cell lines. HPV was detected in 50% of CIN, 61.7% of SCC, and 45.5% of adenocarcinomas. p16(INK4A) expression was seen in all 20 cases of adenocarcinoma, 78.7% (37/47) of SCC, and 96.7% (29/30) of CIN, but not in any cases of the non-neoplastic cervix. There was no difference in p16(INK4A) expression between the HPV-positive and HPV-negative cervical lesions. All HPV-positive and -negative cervical cancer cell lines expressed p16(INK4A) protein. In conclusion, the presence of p16(INK4A) expression in cervical squamous and glandular epithelium indicates the existence of dysplasia or malignancy in the uterine cervix, regardless of HPV infection. 相似文献
8.
INK4a-ARF alterations in Barrett’s epithelium,intraepithelial neoplasia and Barrett’s adenocarcinoma
Halvarsson B Lindblom A Rambech E Lagerstedt K Nilbert M 《Virchows Archiv : an international journal of pathology》2004,444(2):135-141
Introduction The INK4a-ARF [CDKN2A]- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16INK4a and p14ARF, which act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway to the carcinogenesis of Barretts adenocarcinoma, we analysed the alterations of p14ARFand p16INK4a in preneoplastic and neoplastic lesions of this disease.Materials and methods After microdissection, DNA of 15 Barretts adenocarcinomas, 40 Barretts intraepithelial neoplasms (n=20 low- and n=20 high-grade) and 15 Barretts mucosa without neoplasia was analysed for INK4-ARF inactivation using DNA sequence and loss of heterozygosity (LOH) analysis, methylation-specific polymerase chain reaction, restriction-enzyme-related polymerase chain reaction and immunohistochemistry.Results We detected 9p21 LOH, p16INK4a methylation and p16INK4a mutations in Barretts adenocarcinomas in 5 of 15 (33%), 8 of 15 (53%) and 1 of 15 (7%) patients, respectively. P14ARF was methylated in 3 of 15 (20%) adenocarcinomas. In Barretts intraepithelial neoplasia, p16INK4a was altered in 12 of 20 (60%) high-grade and in 4 of 20 (20%) low-grade intraepithelial neoplasms. In Barretts mucosa without intraepithelial neoplasia p16INK4a was methylated in one case (7%). P14ARF was intact in Barretts mucosa without intraepithelial neoplasia.Conclusions We conclude that most Barretts intraepithelial neoplasms contain genetic and/or epigenetic INK4a-ARF alterations. Methylation of p16INK4a appears to be the most frequent epigenetic defect in the neoplastic progression of Barretts tumourigenesis. 相似文献
9.
Benevolo M Terrenato I Mottolese M Marandino F Muti P Carosi M Rollo F Ronchetti L Mariani L Vocaturo G Vocaturo A 《Histopathology》2010,57(4):580-586
Benevolo M, Terrenato I, Mottolese M, Marandino F, Muti P, Carosi M, Rollo F, Ronchetti L, Mariani L, Vocaturo G & Vocaturo A(2010) Histopathology 57 , 580–586 Comparative evaluation of nm23 and p16 expression as biomarkers of high‐risk human papillomavirus infection and cervical intraepithelial neoplasia 2+ lesions of the uterine cervix Aims: To investigate the clinical role of nm23 expression in identifying both high‐risk human papillomavirus (HR‐HPV) and high‐grade cervical lesions or carcinomas [cervical intraepithelial neoplasia 2+ (CIN2+)], and to compare it with p16 overexpression, as this latter biomarker has already been reported widely in HR‐HPV infected cervical lesions. Methods and results: Immunohistochemical evaluation of nm23 and p16 in 143 cervical biopsy specimens including negative, low‐ and high‐grade lesions and squamous carcinomas (SC). HR‐HPV testing by Digene hybrid capture 2 (HC2) and polymerase chain reaction (PCR) on the cervico‐vaginal samples of the same patients. In detecting CIN2+, p16 was significantly more sensitive and specific than nm23 (96.3% versus 81.8% and 66% versus 36.4%, respectively, both P < 0.0001). Concerning HR‐HPV detection by HC2, p16 showed a significantly higher specificity than nm23 (82% versus 47%, P <0.0001), although the sensitivities were comparable (71% versus 76%). We found a significantly direct correlation between nm23 and HC2 findings. However, nm23 expression did not correlate with HPV16/18 infection. In contrast, we observed a significant association between p16 overexpression and HPV16/18 genotypes. Conclusions: We confirm the diagnostic value of p16 overexpression. Moreover, despite in vitro data regarding the interaction with the HPV‐E7 protein, nm23 does not appear to be a more useful biomarker than p16 in identifying CIN2+ or HR‐HPV infection. 相似文献
10.
Chih-Ping Han Ming-Yung Lee Yeu-Sheng Tyan Lai-Fong Kok Chung-Chin Yao Po-Hui Wang Jeng-Dong Hsu Szu-Wen Tseng 《Virchows Archiv : an international journal of pathology》2009,455(4):353-361
The accurate distinction between primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) may require
the use of multiple ancillary monoclonal antibodies in panels of immunohistochemistry stains. In addition to reappraising
the expressions of four commonly used individual monoclonal antibodies [estrogen receptor (ER), Vimentin (Vim), carcinoembryonic
antigen (CEA), and p16INK4], this study was designed to investigate whether CEA and p16INK4 can be effectively exchanged between two relevant three-marker panels (ER/Vim/CEA vs. ER/Vim/p16INK4) in distinguishing ECA from EMA. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from
35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin–biotin technique, tissue array sections were
immunostained with the four aforementioned individual markers (ER, Vim, CEA, and p16INK4). In addition to the four individual monoclonal antibodies, both their respective three-marker panels, proposed here, showed
statistically significant (p < 0.05) frequency differences between these two gynecologic tumors (ECA vs. EMA). The panel performance and test effectiveness
revealed that both three-marker panels are promising and very helpful. According to our data, when histomorphological and
clinical doubt exists as to the primary site of origin, we recommend using either of these two conventional three-marker panels,
which consist of ER/Vim/CEA and ER/Vim/p16INK4. CEA and p16INK4 can be interchanged with confidence without significantly influencing the panel presentations and efficiencies in distinguishing
between adenocarcinomas of endocervical and endometrial origin. 相似文献
11.
Nabiha Missaoui Sarra Mestiri Ahlem Bdioui Thouraya Zahmoul Hajer Hamchi Moncef Mokni Sihem Hmissa 《Pathology, research and practice》2018,214(4):498-506
Cervix cancer remains among most commonly diagnosed cancer in developing countries. Except squamous cell carcinoma and adenocarcinoma, the etiopathology and oncogenic mechanisms of rare cancers remain largely unknown. The study was performed to investigate the value of HPV infection and the expression of p16INK4A and TP53 in rare primitive cancers of the cervix.We conducted a retrospective study of rare primitive cancers of the cervix. Main clinicopathological features were reported. HPV infection was detected by in situ hybridization. Expression of p16INK4A and TP53 was analyzed by immunohistochemistry.Overall, seven cases were identified, including basaloid squamous cell carcinoma (BSCC, n?=?2), small cell neuroendocrine carcinoma (SCNEC), granulocytic sarcoma without acute myeloid leukemia, leiomyosarcoma, primitive neuroectodermal tumor and botryoid-type embryonic rhabdomyosarcoma. The mean age of patients was 53.7 years. Four cancers were diagnosed at advanced stages. The prognosis was unfavorable and associated with patient death in five cases. HPV types 16/18 were detected in BSCCs and SCNEC. Strong and diffuse p16INK4A overexpression was described in the nucleus and the cytoplasm of all tumor cells of BSCCs and SCNEC. The remaining cancers exhibited only scattered and focal p16INK4A staining. Mutated TP53 protein was detected in BSCC (case 1) and GS.Rare cancers of the cervix are aggressive and associated with poor prognosis. In contrast to mesenchymal tumors, BSCCs and SCNEC are etiologically related to high-risk HPV infection and could be identified by block positive p16INK4A overexpression as common cancers of the cervix. TP53 mutations are not a negligible genetic event in rare cervical cancers. 相似文献
12.
Cell blocks can be prepared from residual ThinPrep material, and immunohistochemical staining can be used. The objectives of the current study were (1) to investigate the role of cell block preparation in identifying significant preneoplastic cervical lesions; and (2) to assess the diagnostic value of p16INK4A and Ki-67 immunostaining on cell blocks to identify significant preneoplastic cervical lesions.Samples from residual substances of ThinPrep from 79 patients were collected for cell block preparations. Cell block sections and histological sections of the same patients were stained with hematoxylin and eosin, and were immunostained with antibodies against p16INK4A and Ki-67 antigen.The sensitivity and specificity for p16INK4A and Ki-67 immunostaining to detect high-grade squamous intraepithelial neoplasia were 95.12% and 73.68%, respectively. The positive predictive value and negative predictive value were 79.59% and 93.33%, respectively. Immunostaining of cell blocks for p16INK4A and Ki-67 exhibited a statistically significant association with the presence of significant lesions on cell blocks (P < 0.05).p16INK4A and Ki-67 immunostaining on cell blocks from residual ThinPrep material is helpful in identifying significant preneoplastic cervical lesions. 相似文献
13.
Poetsch M Hemmerich M Kakies C Kleist B Wolf E vom Dorp F Hakenberg OW Protzel C 《Virchows Archiv : an international journal of pathology》2011,458(2):221-229
Alterations in the p16/cyclinD1/Rb and ARF/Mdm2/p53 pathways are frequent events in the pathogenesis of squamous cell carcinomas.
Different mechanisms of p16 regulation have been described for penile carcinomas so far. Therefore, expression of p16 and
p53 was immunohistochemically detected with monoclonal antibodies in 52 primary invasive penile squamous cell carcinomas.
The carcinomas were analyzed for allelic loss (LOH) in p16
INK4A
and p53, as well as for mutations in the p16
INK4A
and the p53 gene. In addition, we examined the promoter status of p16
INK4A
by methylation-specific PCR. The presence of human papilloma virus (HPV) 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR.
Data were compared to clinical data. Concerning p16, 26 (50%) tumors showed positive immunohistochemistry, 32 (62%) tumors
showed allelic loss and 22 tumors (42%) showed promoter hypermethylation. All tumors with negative p16 immunohistochemistry
showed LOH near the p16
INK4A
locus and/or hypermethylation of the p16
INK4A
promoter. HPV 16 DNA was detected in 17 tumors, ten of them with positive p16 immunostaining. The remaining seven tumors
with negative p16 staining showed allelic loss and/or promoter hypermethylation. Evidence of lymph node metastasis was significantly
associated with negative p16 immunohistochemistry as well as with combined LOH and promoter hypermethylation (p = 0.003 and p = 0.018, respectively). Allelic loss around p53 was found in 22 tumors (42%), and seven mutations of the p53 gene could be
demonstrated in our tumors. No correlations could be found between any p53 alteration and clinical parameters. 相似文献
14.
Chiung-Ling Liao Jeng-Dong Hsu Ming-Yung Lee Lai-Fong Kok Yi-Ju Li Po-Hui Wang Chung-Chin Yao Chih-Ping Han 《Virchows Archiv : an international journal of pathology》2010,456(4):377-386
Gynecological pathologists are used to operating many panels of various markers in combination for the diagnostic distinction
between primary endocervical and endometrial adenocarcinomas. The conventional 3-marker (ER/Vim/CEA) panel is the most promising
tool. In this study, our aim is to investigate whether a 2-marker panel is enough to distinguish between these two gynecologic
malignancies. Additionally, we wish to determine which one is the most favorable among eight panels tested, including six
2-marker (ER/CEA, PR/CEA, Vim/CEA, ER/p16INK4a, PR/p16INK4a, Vim/p16INK4a) and two 3-marker (ER/Vim/CEA, ER/Vim/p16INK) panels. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens,
including 14 primary endocervical adenocarcinomas and 21 primary endometrial adenocarcinomas. Utilizing the avidin-biotin
complex (ABC) method, tissue array sections were immunostained with five commercially available antibodies (ER, Vim, CEA,
PR, and p16INK4a) to evaluate their individual frequencies of expression. We found that all eight aforementioned panels showed an encouraging
range of overall accuracy (69.2% to 78.3%). However, one panel of 2-markers (Vim, CEA) exhibited the most efficiency (78.3%)
in the diagnostic distinction between primary endocervical and endometrial adenocarcinomas. Based on the analyzed data, we
conclude that the 2-marker (Vim/CEA) panel seems adequate to be an appropriate, convenient, and efficient means to distinguish
between primary endocervical and endometrial adenocarcinomas. Even though there were a limited number of cases, this study
still provides valuable references to help avoid wasting resources and unnecessary marker testing. 相似文献
15.
Queiroz C Silva TC Alves VA Villa LL Costa MC Travassos AG Filho JB Studart E Cheto T de Freitas LA 《Pathology, research and practice》2006,202(10):731-737
Interaction of human papilloma virus oncoproteins E6 and E7 with cell cycle proteins leads to disturbances of the cell cycle mechanism and subsequent alteration in the expression of some proteins, such as p16INK4a, cyclin D1, p53 and KI67. In this study, we compared alterations in the expression of these proteins during several stages of intra-epitelial cervical carcinogenesis. Accordingly, an immunohistochemical study was performed on 50 cervical biopsies, including negative cases and intraepithelial neoplasias. The expression patterns of these markers were correlated with the histopathological diagnosis and infection with HPV. The p16INK4a, followed by Ki67, showed better correlation with cancer progression than p53 and cyclin D1, which recommends their use in the evaluation of cervical carcinogenesis. These monoclonal antibodies can be applied to cervical biopsy specimens to identify lesions transformed by oncogenic HPV, separating CIN 1 (p16INK4a positive) and identifying high-grade lesions by an increase in the cellular proliferation index (Ki67). In this way, we propose immunomarkers that can be applied in clinical practice to separate patients who need a conservative therapeutic approach from those who require a more aggressive treatment. 相似文献
16.
Sabah M Cummins R Leader M Kay E 《Virchows Archiv : an international journal of pathology》2005,447(5):842-848
Deletions of the short arm of chromosome 9 have been observed in many tumours and cell lines. This chromosomal region is frequently
targeted during malignant transformation because it contains at least two known tumour suppressor genes: p16
INK4
and p15
INK4B
. p16
INK4A
acts as a negative cell cycle regulator by inhibiting G1 cyclin-dependent kinases that phosphorylate the retinoblastoma protein and therefore block the progression of the cell cycle
from G1 to S phase. The role of p16
INK4A
in the development of synovial sarcoma has not been comprehensively investigated. Ten samples of synovial sarcomas were examined
for allelic imbalance/loss of heterozygosity (AI/LOH) of the 9p region and p16 protein expression. DNA was isolated from microdissected
sections of normal and tumour cells, amplified by polymerase chain reaction and analysed for AI/LOH by using six microsatellite
markers that map to the 9p region. Immunohistochemistry for p16 expression was done. AI/LOH with at least one microsatellite
marker on 9p21 was detected in six of ten samples. The most frequent allelic deletions were observed within the coding sequence
of p16
INK4A
. Loss of p16 immunoreactivity was detected in eight samples, six of which showed evidence of alterations at 9p21 region.
These findings suggest a possible role of loss of p16
INK4A
in the development of synovial sarcoma. 相似文献
17.
Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia 总被引:11,自引:0,他引:11
Tringler B Gup CJ Singh M Groshong S Shroyer AL Heinz DE Shroyer KR 《Human pathology》2004,35(6):689-696
p16(INK4a) is known to play a critical role as a negative regulator of cell cycle progression and differentiation by controlling the activity of the tumor-suppressor protein pRb. The present study evaluated the expression of p16(INK4a) and pRb in cervical squamous and glandular neoplasia. Immunohistochemical staining was performed for p16(INK4a) and pRb in formalin-fixed, paraffin-embedded tissue sections of the uterine cervix using an indirect immunoperoxidase method. p16(INK4a) staining was detected in 7 of 108 sections (6.5%) of normal squamous mucosa, in scattered ciliated columnar cells in 33 of 88 sections (37.5%) of normal endocervical glands, in 9 of 30 sections (30%) with Nabothian cysts, and in 4 of 4 areas (100%) of tubal metaplasia. In contrast, strong p16(INK4a) staining was found in 13 of 18 cases (72.2%) of cervical intraepithelial neoplasia (CIN) I and in all cases of CIN II/III (n = 46), squamous cell carcinoma (n = 18), endocervical glandular dysplasia (n = 10), adenocarcinoma in situ (n = 23), and invasive adenocarcinoma (n = 12). pRb expression was detected in each diagnostic category; however, the proportion of pRb-positive cells was relatively decreased in high-grade premalignant and malignant lesions of the squamous and endocervical mucosa and showed a generally inverse correlation with the expression of p16(INK4a) at the tissue level. These findings confirm a correlation between the expression of p16(INK4a) and pRb in cervical neoplasias and indicate that p16(INK4a) is a specific marker for premalignant and malignant lesions of the squamous and endocervical mucosa. 相似文献
18.
Mitomi H Fukui N Kishimoto I Tanabe S Kikuchi S Saito T Hayashi T Yao T 《Human pathology》2011,42(10):1505-1513
Gastrointestinal stromal tumors feature a wide spectrum of biologic behavior, ranging from benign to extremely malignant. To determine the role of p16INK4a alteration in progression of gastrointestinal stromal tumors of the stomach, we have investigated protein expression and gene methylation in correlation with clinicopathologic factors and survival. In addition to immunohistochemical analysis of p16INK4a in a series of 95 cases, real-time quantitative methylation specific polymerase chain reaction for p16INK4a and immunostaining for cyclin D1, cyclin E, pRb, DP-1, E2F-1, and Ki-67 were also evaluated in randomly selected samples. The p16INK4a labeling indices ranged from 0% to 74% (median, 21%), demonstrating a significant inverse correlation with size (P = .046). On univariate (P = .003) and multivariate (P = .067) analyses, loss of p16INK4a expression increased the likelihood of a poor tumor-related survival. In addition, size (P = .036) and the mitotic index (P = .005) had independent prognostic influence. The p16INK4a methylation index, which ranged from 0% to 100% (median, 17%), was significantly higher in larger tumors (P < .001) and in high-risk category lesions (P = .001) and inversely correlated with protein expression. Hierarchical cluster analysis based on expression of p16INK4a network members identified 2 clusters in 27 randomly selected tumor samples, containing 11 and 16 tumors each. Former cluster samples demonstrated higher risk category (P = .022), higher p16INK4a methylation (P < .001), and more reduced pRb expression (P < .018). In addition, p16INK4a network members clustered into 2 groups: (1) showing down-regulated p16INK4a protein and up-regulating of both cyclin D1 and DP-1 and (2) down-regulated pRb and up-regulated E2F-1. We conclude that p16INK4a alteration has an important role in progression of gastrointestinal stromal tumors of the stomach. Furthermore, the study provides a possible link between regulation of p16INK4a network members and gastrointestinal stromal tumors. 相似文献
19.
Elisabetta Carico Franco Fulciniti Maria Rosaria Giovagnoli Nunzia Simona Losito Gerardo Botti Giulio Benincasa Maria Giuseppina Farnetano Aldo Vecchione 《Virchows Archiv : an international journal of pathology》2009,455(3):245-251
An immunohistochemical (IHC) study has been conducted on 34 cases of untreated endocervical adenocarcinomas collected among
three institutions (Ospedale S. Andrea, Rome; Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples; and Clinica Malzoni,
Avellino). The E-cadherin and α- and β-catenin complex status has been investigated along with p16INK4a in all studied cases
with the aim to study whether the pattern of expression of the cadherin–catenin complex could be causally related to the expression
of P16INK4a protein. Results were evaluated for statistical significance by a non-parametric test (Kruskal–Wallis). Endocervical
adenocarcinomas as a group were uniformly expressing p16INK4a except for two cases, and all lesions displayed downregulation
of the cadherin–catenin complex, without demonstrating statistically significant differences among the different histotypes.
The lack of nuclear accumulation of β-catenin found in this group of lesions probably implies that no alteration of the β-catenin/Wnt
metabolic pathway is present in endocervical adenocarcinoma, as opposed to what is found in the literature for squamous carcinoma
of the cervix. The diffuse expression of p16INK4a protein in this group of neoplasms stresses the important role of high-risk
human papillomavirus infection in neoplastic causation possibly via the viral E7-mediated inactivation of pRB tumor-suppressor
protein and also underlines the useful role of p16INK4a immunostaining in the diagnostic algorithm of endocervical adenocarcinomas.
In consideration of these findings, investigation of downstream β-catenin genes c-myc and cyclin D1 is sought as possibly
contributive in the molecular pathogenesis of endocervical adenocarcinoma. 相似文献
20.
Mee Soo Chang Sohee Oh Eun‐Jung Jung Jeong Hwan Park Hye‐Won Jeon Taek Sang Lee Jung Ho Kim Euno Choi Sun‐Ju Byeon In‐Ae Park 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2014,122(5):427-436
The purpose of this study was to examine the implication of high‐risk human papillomavirus (HPV) load in cervical intraepithelial neoplasia (CIN) and cancer, and to detect biomarkers in cervical disease. We conducted high‐risk HPV DNA load and cervical cytology tests in 343 women, cervical tissue biopsy in 143 women, and immunohistochemistry for p16INK4A, cyclin D1, p53, cyclooxygenase‐2, Ki‐67, GLUT1, hPygopus2, and beta‐catenin. As a result, HPV load [relative light units (RLU) value] was correlated with the histological severity of cervical disease (p < 0.05). In the ‘atypical squamous cells of undetermined significance’ cytology group, 2.385 of HPV load seemed to be the cut‐off value at which ‘benign’ or CIN I can be differentiated from ‘CIN II or more severe’ (AUC = 0.712), but not statistically significant. The relative risk (odds ratio) of p16INK4A and GLUT1 overexpression increased gradually according to the histological severity of cervical disease. The p16INK4A showed statistically significant odds ratios in CIN II, CIN III, and cancer; GLUT1, in CIN II and CIN III; hPygopus2, in CIN III; and beta‐catenin, in CIN III and cancer. Conclusively, HPV load, p16INK4A, and GLUT1 can be instrumental in predicting the severity of HPV‐related cervical disease. The beta‐catenin/hPygopus2 signaling may be involved in proceeding to CIN III. 相似文献