Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular biomarkers

Baak, Jan P. A.; Kruse, A-J; Robboy, Stanley J.; Janssen, Emiel A. M.; Diermen, Bianca van; Skaland, Ivar

doi:10.1136/jcp.2005.027839

Cited by 84 publications

(88 citation statements)

References 92 publications

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“…[5][6][7] Investigators have proposed that the use of these and other biomarkers can help identify which lowergrade lesions will progress over time. 8,9 For example, in a study examining p16, Negri et al 10 reported that CIN1 cases with diffuse p16 staining had a significantly higher tendency to progress to a highgrade lesion than p16-negative cases. Hence, they recommended p16 as a useful surrogate marker for progression likelihood.…”

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confidence: 99%

Histological ‘progression’ from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review

et al. 2010

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An accurate assessment of 'progression' from a low (LSIL) to high (HSIL) grade squamous intraepithelial lesion (cervical intraepithelial neoplasia (CIN)2 or CIN3) of the cervix is critical to ascertaining HSIL outcome risk, the value of predictive biomarkers, and the need for excisional therapy. We obtained biopsy outcome data on a series of initially diagnosed LSIL to assess this risk. Consecutive biopsy diagnoses of LSIL were obtained from the archives, and the frequency of HSIL biopsy outcomes were ascertained by record and histological review. Then, a 'numerical severity score' was recorded for each diagnosis: LSIL (1-2), CIN2 (3-4) and CIN3 (5-6) with lower and higher values corresponding to the degree (low vs high) of histological severity within each category, respectively. Of 264 initial LSILs, 29 (11%) were reported with an HSIL outcome. However, histological review of 21 of these HSILs confirmed only 8 (38%) HSIL diagnoses by review with the numerical severity score: three cases scored as 5, three cases scored as 4, and two cases scored as 3; the remaining 13 cases were assigned a numerical severity score of 1 or 2. P16 immunostains of corresponding previous and subsequent biopsies were discordant in 4 of 12 cases (33%). In a blind review of a randomly selected series of HSILs from the same practice, HSIL was significantly more likely to be confirmed on re-review (10 of 13 (77%), P ¼ 0.024). These findings show that confirmed HSIL outcomes (on review) following an LSIL biopsy are infrequent (B3%). A diagnosis of HSIL following an LSIL should always be reviewed, as this diagnostic pairing may more likely be associated with a diagnostic error. Histological evaluation remains the basis for treatment and follow-up of women with cervical intraepithelial neoplasia (CIN). The fundamental premise for treating or following young women with CIN hinges on the risk of an eventual outcome of CIN2 or CIN3 (high-grade squamous intraepithelial lesion or HSIL), diagnoses for which management by cone biopsy or LEEP will be required.1 Hence, the progression rate from CIN1 to CIN2 or CIN3 is germane to conservative management of low-grade squamous intraepithelial lesions (LSILs) (CIN1 or condyloma). In a review by Ostö r 2 summarizing the findings of studies dealing with progression of CIN since 1950, the composite data indicated that the likelihood of progression from CIN1 to CIN3 was B10%. In a recent study by Pretorius et al 3 , the subsequent risk of CIN3 or cancer after a colposcopic diagnosis of CIN1 or less was found to be 1.9%, a rate that is lower than the Ostö r study. In a study from the ALTS trial, Cox et al 4 showed that a biopsy diagnosis of CIN1 was equivalent to a negative colposcopic biopsy following an HPVpositive smear showing LSIL or ASCUS, despite that fact that 11-13% of cases were followed by an HSIL outcome within 2 years. Thus, although these

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Histological ‘progression’ from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review

et al. 2010

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“…6 Moreover, in two independent studies, adjuvant chemotherapy was significantly beneficial for patients with rapidly proliferating tumors, but not for patients with slowly proliferating tumors. 7,8 A comparison between phosphohistone H3/mitotic activity index and gene signatures, however, has not yet been performed.…”

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Biologic profiling of lymph node negative breast cancers by means of microRNA expression

et al. 2010

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Breast cancer is a heterogeneous disease. Different subgroups can be recognized on the basis of the steroid receptors, HER-2, cytokeratin expression and proliferation patterns. As a result of mRNA-profiling studies, five major groups can be recognized, of which the triple-negative and basal-like tumors have the worst prognosis. Many of these tumors have a high proliferation that has the strongest prognostic value in node negative breast cancer. In the current study we analyzed the microRNA pattern in 103 lymph node negative breast cancers and compared these profiles with different biological characteristics and clinicopathological features. Unsupervised hierarchical cluster analysis divides the patients into four main groups, of which the basal-like/triple-negative group is the most prominent (11% of all cases), the luminal A cancers containing the Her2 negative and estrogen receptor/progesterone receptor-positive tumors is the largest group (57%), and the group of luminal B (32%) is more heterogeneous and contains the Her2 positive/estrogen receptor-negative patients as well. The highest overall classification values by analysis of variance followed by cross validation (leave one sample out and reselect genes) were found for cytokeratin 5 and 6, triple-negative and estrogen receptor, with 97, 90 and 90% accuracy, respectively. MiR-106b gene is prominent in all of these signatures and correlates strongest with high proliferation. Other interesting observations are the presence of several microRNAs (miR532-5p, miR-500, miR362-5p, and miR502-3p) located at Xp11.23 in cancers with a triple-negative signature, and the upregulation of several miR-17 cluster members in estrogen receptor-negative tumors. The current study shows that estrogen receptor negativity and cytokeratin 5 and 6 expression are important, and specific biological processes in lymph node negative breast cancer, as microRNA signatures are strongest in these subgroups. Modern Pathology (2010Pathology ( ) 23, 1567Pathology ( -1576 doi:10.1038/modpathol.2010 published online 3 September 2010 Keywords: breast; cancer; microRNA; profiling Since the publication of the human genome and the development of high-throughput array-based gene expression profiling platforms, knowledge about breast cancer and its genetic background has increased enormously. On the basis of the gene expression, invasive breast cancers can be classified into three major subtypes: luminal, basal-like and Her2/neu-overexpressing.1 Many investigators have used surrogate immunohistochemical markers to classify these tumors: estrogen receptor, progesterone receptor, and HER2 negative breast cancers ( ¼ triple-negative breast cancer profile) are classified as normal breast-like if basal cytokeratins and epidermal growth factor receptor are lacking, and basal-cell-like cancers when basal cytokeratins (cytokeratin 5 and 6 and/or cytokeratin 14) are expressed.2 Most breast cancer series contain 8-15% triple-negative tumors and 10-15% basal-like tumors. Triple-negative and basal-like breast...

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“…It is believed that biomarkers such as p16 can help in evaluating the likelihood for progression and regression in a particular CIN. 7 Such markers may be particularly useful in assisting triage of patients with borderline smears reported as ASC-US. Our study on an Asian screening population in Hong Kong showed that, similar to other screening populations, ASC-US is the most common abnormal cytologic finding 2 and is associated with a significantly higher chance to develop cervical cancer and its high-grade precursors.…”

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confidence: 99%

“…5,6 Although HPV test shows high sensitivity, additional markers are necessary to improve the specificity of identifying cervical cancers or high-grade precursors. [7][8][9][10][11] It is also necessary to discover adjunct markers for management of LSIL as HPV testing is not so effective in triage management of LSIL. …”

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P634A4 and TAp73 immunocytochemistry in liquid-based cervical cytology—potential biomarkers for diagnosis and progress prediction of cervical neoplasia

Cheung

Tsun

et al. 2010

Modern Pathology

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P63 and p73 are two homologues of the important tumor suppressor gene p53. In this study, we investigated p63 and p73 expression by immunocytochemistry using antibodies for TAp73 and p634A4 isoforms in 91 highgrade and 107 low-grade squamous intraepithelial lesions, 212 atypical squamous cells of undetermined significance, 9 squamous cell carcinomas and 63 normal samples from an Asian screening population together with 47 hospital samples of carcinomas. There was significant correlation between the TAp73 and p634A4 indices (Po0.0001). Significantly, higher TAp73 and p634A4 indices were found in high-grade lesions or carcinoma when compared with atypical squamous cells and low-grade lesions (Po0.0001). Among atypical squamous cells, p634A4 indices of cases that subsequently progressed to low-grade (P ¼ 0.031) or high-grade lesions (P ¼ 0.006) were significantly higher than those that did not. For atypical squamous cells positive for high-risk human papillomavirus (HPV) as detected by Digene (61%), cases with high p634A4 index were still more likely to have subsequent high-grade lesions detected (P ¼ 0.016). Among low-grade lesions, significantly higher TAp73 (P ¼ 0.038) was found in cases that subsequently progressed to high-grade lesions. There was significant correlation between presence of high-risk HPV and p634A4 index (P ¼ 0.01). In summary, p63 and p73 immunocytochemistry are potential good markers for detection of carcinoma and high-grade lesions in cervical cytology samples and for triage management of women with atypical squamous cells and low-grade Cervical cytology screening is effective in the prevention of cervical cancer by detecting asymptomatic cervical cancer and its precursors although there is limitation in its sensitivity and specificity. 1 Among cytological abnormalities detectable in a screening population, atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL), especially the former, are the most common diagnostic categories. [2][3][4] Both were associated with a higher possibility of subsequent development of cervical cancer when compared with women with negative cytology. 3 Colposcopic examination of all such cases poses significant demand on the community resources. To improve the efficiency of cervical cancer screening, human papillomaviruses (HPV) DNA testing has been introduced for the triage of women with ASC-US and for primary screening. 5,6 Although HPV test shows high sensitivity, additional markers are necessary to improve the specificity of identifying cervical cancers or high-grade precursors. [7][8][9][10][11] It is also necessary to discover adjunct markers for management of LSIL as HPV testing is not so effective in triage management of LSIL.

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Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular biomarkers

Cited by 84 publications

References 92 publications

Histological ‘progression’ from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review

Histological ‘progression’ from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review

Biologic profiling of lymph node negative breast cancers by means of microRNA expression

P634A4 and TAp73 immunocytochemistry in liquid-based cervical cytology—potential biomarkers for diagnosis and progress prediction of cervical neoplasia

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