Human papillomaviruses, expression of p16INK4A, and early endocervical glandular neoplasia

Riethdorf, Lutz; Riethdorf, Sabine; Lee, Kenneth R.; Čviko, Aida; Löning, Thomas; Crum, Christopher P.

doi:10.1053/hupa.2002.127439

Cited by 119 publications

(83 citation statements)

References 25 publications

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“…Our findings that p16 INK4a is overexpressed in all cases of adenocarcinoma in situ are consistent with the previous observation indicating that p16 INK4a is a sensitive marker for adenocarcinoma in situ with a sensitivity of 100%. 21,22 However, in this study, p16 INK4a expression was also detected in rare scattered columnar cells in two cases of normal endocervical glands and all specimens exhibiting tubal metaplasia. A previous study by Riethdorf et al 22 also found that p16 INK4a was expressed in most cases of tubal metaplasia of the endocervical mucosa.…”

Section: Discussioncontrasting

confidence: 61%

IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16INK4a expression

et al. 2007

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Adenocarcinoma in situ of the uterine cervix remains a diagnostic challenge in a small proportion of cases. This suggests a need for biomarker that may be of help in establishing the diagnosis. The aim of this study was to evaluate the potential of insulin-like growth factor-II mRNA-binding protein 3 and cyclin-dependent kinase inhibitor p16 INK4a as biomarkers for adenocarcinoma in situ. Forty-four samples of adenocarcinoma in situ from 40 patients and 23 control cases of benign uterine cervix were included in this study. In addition to benign endocervical epithelium, 19 of these 23 control cases also showed focal tubal metaplasia. Cytoplasmic immunoreactivity for insulin-like growth factor-II mRNA-binding protein 3 was identified in 41 (93%) adenocarcinoma in situ samples, among which, 29 (71%), 10 (24%), and 2 (5%) samples showed insulin-like growth factor-II mRNA-binding protein 3 positive staining in 50% or more, 45 to o50 and o5% of adenocarcinoma in situ lesional cells, respectively. Immunohistochemical reaction intensity for insulin-like growth factor-II mRNA-binding protein 3 was found to be strong in 34 adenocarcinoma in situ samples, intermediate in five, and weak in two. All 23 control cases were negative for insulin-like growth factor-II mRNAbinding protein 3. p16 INK4a expression was identified in all of the adenocarcinoma in situ samples with intermediate staining intensity seen in seven samples and strong in the remainder. Fourteen of 19 (74%) tubal metaplasia cases showed p16 INK4a immunoreactivity in 450% of the tubal metaplastic epithelium with staining intensity ranging from weak to strong. Our findings demonstrate significant expression of insulin-like growth factor-II mRNA-binding protein 3 and p16 INK4a in adenocarcinoma in situ as compared to benign endocervical glands, suggesting that expression of these biomarkers may be helpful in the distinction of adenocarcinoma in situ from benign endocervical glands, particularly in difficult borderline cases.

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Section: Discussioncontrasting

confidence: 61%

IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16INK4a expression

et al. 2007

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“…Recent studies have demonstrated that diffuse nuclear and cytoplasmic staining for p16 INK4 was significantly associated with high-risk HPV-related lesions. 17,18 Our study demonstrated frequent expression of this protein in 93% of UEAs, whereas MDAs less frequently expressed with a rate of 30%. Even when positive, positive cells were decreased and the staining intensity was weaker.…”

Section: Discussionmentioning

confidence: 52%

“…17 This protein is overexpressed as a consequence of incorporation of E7 derived from high-risk HPV, and it has been shown to be positive in invasive and in situ adenocarcinomas of the cervix, most of which are also considered to be HPV related. 18,19 The frequent location of LEGH/PGM, a putative precursor of MDA, in the portion of internal os away from the transformation zone, 6 prompted the authors to assume that a subset of cervical adenocarcinomas with gastric phenotype may have tumorigenesis distinct from high-risk HPV-related ordinary cervical adenocarcinomas.…”

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confidence: 99%

Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and ‘adenoma malignum‘

et al. 2004

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Gastrointestinal phenotype in cervical adenocarcinomas was examined by immunohistochemistry and correlated with morphologic features. Antibody panels included anti-MUC2, MUC6, CD10, chromogranin A (CGA) and HIK1083. In addition, expression of p16 INK4 , a cyclin-dependent kinase inhibitor which is expressed in a variety of high-risk HPV-related conditions, was studied. A total of 94 invasive adenocarcinomas including 20 minimal deviation adenocarcinomas (MDAs) and 72 adenocarcinomas in situ (AIS) were examined. MDAs were most frequently positive for HIK1083 and/or MUC6, two representative gastric markers, with a rate of 95%, followed by intestinal-type adenocarcinomas (IAs) with a rate of 85% whereas only 27% of 56 usual endocervical-type adenocarcinomas (UEAs) were positive. MUC2, a goblet cell marker, was positive in 85% and 25% of IAs and MDAs, respectively, while in only 14% of UEAs. CD10 was positive in 15% of IAs, indicating incomplete intestinal differentiation without a brush border in most of the cases. CGA-positive cells were frequently seen in MDAs and IAs with rates of 60% and 62%, respectively. Nuclear and cytoplasmic p16 INK4 positivity was identified in 93% of UEAs, whereas 30% of MDAs were positive for p16 INK4 . Results in AISs were comparable to their invasive counterparts, but morphologically usual-type AISs identified in eight cases of MDA were frequently positive for HIK1083 (75%) and MUC6 (63%), and p16 INK4 . Of note was the existence of lobular endocervical glandular hyperplasia (LEGH) with atypical features including cytologic abnormalities, and/or papillary projection, which were identified in this study in pure form (n ¼ 3) or in association with MDAs (n ¼ 6), but not in cases of other types of adenocarcinomas. These observations indicate that gastrointestinal phenotype is frequently expressed in MDAs and IAs, and there seems to be a possible link between MDA, and LEGH and morphologically usual-type AIS with gastric immunophenotype in histogenesis. Frequent absence of p16 INK4 expression in MDAs suggests a possibility that high-risk HPV does not play a crucial role in development of MDAs, in contrast to the majority of endocervical adenocarcinomas. p16 INK4 immunohisto-

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“…[12][13][14] It may be inactivated by mutation or by promoter hypermethylation. In gynecologic specimens, p16 immunohistochemistry has been used as an indirect assay for HPV infection 1,15,16 and an even more indirect method of determining the primary site of origin [1][2][3] (in human papillomavirus (HPV)-associated cervical cancers, viral oncoproteins E6 and E7 bind activated RB with consequent upregulation of p16 and promotion of DNA synthesis 15,17 ). Well-recognized problems with this approach have been published; p16 expression has been described in non-neoplastic ciliated cells, the cells of tuboendometrioid metaplasia 16,18,19 and even in endometrial cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In gynecologic specimens, p16 immunohistochemistry has been used as an indirect assay for HPV infection 1,15,16 and an even more indirect method of determining the primary site of origin [1][2][3] (in human papillomavirus (HPV)-associated cervical cancers, viral oncoproteins E6 and E7 bind activated RB with consequent upregulation of p16 and promotion of DNA synthesis 15,17 ). Well-recognized problems with this approach have been published; p16 expression has been described in non-neoplastic ciliated cells, the cells of tuboendometrioid metaplasia 16,18,19 and even in endometrial cancer. 1,2,20 In endometrial cancer, the expression pattern is generally described as weak and patchy, in contrast to the strong immunoreaction typically encountered in endocervical adenocarcinomas of the usual type.…”

Section: Discussionmentioning

confidence: 99%

Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis

et al. 2006

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Many endometrial adenocarcinomas, particularly those of endometrioid type, express estrogen receptors (ERs), progesterone receptors (PRs), and vimentin. This typical immunophenotype is frequently considered a standard against which others are compared when immunohistochemistry is used for differential diagnosis. We tested large numbers of endometrial cancers, enriched for high-grade tumors, to determine whether this reported immunophenotype was valid and whether expression differences between types of endometrial carcinoma could be exploited for diagnostic purposes. Immunohistochemical stains were performed on the following types of endometrial cancers using established methodology: International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 endometrioid-42; FIGO grade 3 endometrioid-40; serous-24; clear cell-11; carcinosarcoma-9. In total, 92% of serous carcinomas expressed p16 strongly compared to weak-tomoderate expression of p16 in 7-67% of other tumors (FIGO grades 1 and 2 carcinoma and carcinosarcoma, respectively). A total of 84% of FIGO grades 1 and 2 carcinomas expressed ER compared to 9-54% of other tumors (clear cell and serous carcinomas respectively); 83% of FIGO grades 1 and 2 expressed PR compared to 11-54% of other carcinomas (carcinosarcoma and serous carcinoma, respectively). Most carcinomas were negative for monoclonal carcinoembryonic antigen (mCEA), and those that were positive showed mostly only focal membrane expression. Vimentin was expressed in nearly every tumor. Most tumors were diffusely vimentin positive, but a large range of expression patterns, from focal to diffuse and from weak to strong, was noted. Only 70% of FIGO grades 1 and 2 endometrioid carcinomas and 26% of grade 3 endometrioid carcinomas possessed the reportedly characteristic endometrial cancer immunophenotype p16 (À), ER ( þ ), PR ( þ ), mCEA (À), and vimentin ( þ ). Endometrial cancers demonstrate substantial immunophenotypic diversity that remained apparent even within groups of similar histologic subtype and grade. ER, PR, and p16 expression was more illustrative of tumor type and degree of differentiation than they were of endometrial origin. In contrast, the vimentin-positive/CEA-negative phenotype remained the most constant among all endometrial cancers.

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Human papillomaviruses, expression of p16INK4A, and early endocervical glandular neoplasia

Cited by 119 publications

References 25 publications

IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16INK4a expression

IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16INK4a expression

Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and ‘adenoma malignum‘

Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis

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