Is p16INK4A expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies

Nieh, Shin; Chen, Su Feng; Chu, Tang-Yuan; Lai, Hung Cheng; Lin, Yaoh Shiang; Fu, Earl; Gau, Ching H.

doi:10.1016/j.ygyno.2004.11.034

Cited by 68 publications

(47 citation statements)

References 28 publications

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“…Cervical cancer associated with HPV, therefore, has increased p16 expression 29,30 and its expression is used by some as a surrogate marker for HPV infection in cervical lesions. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] It has been hypothesized that HPV infection might similarly play a role in the development of urinary bladder squamous cell carcinoma. In contrast to our findings and the previously mentioned reports, others have shown a positive correlation between high-risk HPV infection and high-grade urothelial cancers of the bladder.…”

Section: Resultsmentioning

confidence: 99%

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma

Alexander

Kum

et al. 2012

Modern Pathology

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Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a wellestablished association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.

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Section: Resultsmentioning

confidence: 99%

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma

Alexander

Kum

et al. 2012

Modern Pathology

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“…Because of this high-negative predictive value, demonstrated both in the literature (21,(33)(34)(35) and by our data, particularly in ASC-US cytology, the p16INK4a test should be included in the clinical diagnostic flow chart in order to identify patients with low or no risk of progression.…”

Section: ------------------------------------------------------------mentioning

confidence: 70%

Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease

Lukic

Sbenaglia

Carico

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. p16INK4a as a diagnostic marker of a cervical intraepithelial neoplasia of grade 2+ (CIN2+) in atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cytological samples has been analyzed, but has not yet been included in clinical routine practice. One hundred and ninety-one patients with an abnormal Pap test (84 ASC-US and 107 LSILs) who underwent colposcopy were selected for this study. At enrollment, 96 patients (Group 1) had a positive colposcopy and therefore underwent a cervical biopsy, while 95 (Group 2) had a negative colposcopy and were followed up for up to 1 year. Both groups were tested for p16INK4a using immunocytochemical methods, and the p16INK4a results were correlated with histology or follow-up outcome. In Group 1 ASC-US cases, 82% of lesions less than CIN2 were p16INK4a-negative and all CIN2 cases were p16INK4a-positive (p=0.00044). In Group 1 LSIL cases, 71% of lesions less than CIN2 were p16INK4a-negative and 87% of CIN2/3 were p16INK4a-positive (p= 0.00033). Seventy-seven percent of Group 2 ASC-US patients with a negative 1-year follow-up (NF-U) were p16INK4a-negative at enrollment, while all patients with positive follow-up (PF-U) were p16INK4a-positive (p=0.00113). In Group 2 LSIL cases, 83% of patients with NF-U were p16INK4a-negative, while 65% of patients with PF-U were p16INK4a-positive at enrollment (p=0.0014). In fact, 39% of the positive p16INK4a LSIL patients had CIN2+ histological lesions. The positive predictive value of p16INK4a for CIN2+ was 50% in ASC-US and 52% in LSIL cases; the negative predictive value was 100 and 94%, respectively. In conclusion, in our patients, a negative p16INK4a appears to be a marker of the absence of CIN3, while a positive p16INK4a can be correlated with the presence of histological CIN2+ found at enrollment or during the subsequent follow-up. Thus, its clinical predictive value is independent from the colposcopic aspect at enrollment. IntroductionIt has been proven that human papillomaviruses (HPVs) are strongly associated with pre-neoplastic and neoplastic lesions of the uterine cervix (1-3).According to present guidelines, patient treatment and followup vary according to the classification of the lesion (4-8). Patients with high-grade squamous intraepithelial lesions (HSILs) are referred for colposcopy and, when a cervical intraepithelial neoplasia of grade 2 or more is histologically confirmed (CIN2+), the lesion is treated with excisional procedures. However, the management of patients with low-grade squamous intraepithelial lesions (LSILs) and atypical squamous cells of undetermined significance (ASC-US) is still controversial. Therefore, the identification of patients that have CIN2+ lesions beneath a LSIL cytological superficial lesion is an important challenge in order to avoid under diagnosis and treatment.The aim to identify a specific triage test for women with ASC-US and LSILs has become increasingly crucial. The introduction of a biomarker that detects a CIN2+ cervi...

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“…The most carefully studied biomarker for the triage of women with equivocal cytological results is p16 INK4A . The studies that compared the accuracy of p16 INK4A with HC2 (Qiagen) for an underlying CIN2+ in women with ASC-US [60,61] or LSIL [61,62] were revisited in the p16 INK4A meta-analysis [23]. Although p16 INK4A in general showed lower or equal SE but higher SP compared to HC2, the authors concluded that the evidence was not enough to affirm that the immunomarker could outperform the viral testing in these diagnostic categories.…”

Section: Have the Main Questions About Biomarkers Been Answered?mentioning

confidence: 99%

Immunomarkers in Gynecologic Cytology: The Search for the Ideal ‘Biomolecular Papanicolaou Test’

Pinto¹,

Degen

Villa

et al. 2012

Acta Cytologica

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Harnessing the knowledge we have gained on the cell cycle disruption caused by human papillomaviruses (HPV) will likely lead to improved screening modalities for cervical cancer and its precursors. An easily applied biomarker that has high specificity and sensitivity would represent an attractive alternative or complement to cytology and HPV testing. To date, a number of promising markers have been investigated. These include p16^INK4A, MIB-1, BD-ProEx C, and L1. Newer possibilities involve a variety of gene products associated with aberrations of chromosome 3q, such as telomerase, p63, and PIK3CA, as well the combination of biomarkers such as p16^INK4A and MIB-1 in the same assay. Although none of them has yet been incorporated into screening algorithms or found its way into routine practice, their performance characteristics remain a focus of current investigations. This review summarizes what we know and where we hope to go in translating basic pathobiology into clinical practice.

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Is p16INK4A expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies

Cited by 68 publications

References 28 publications

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma

Prediction of clinical outcome using p16INK4a immunocytochemical expression in low-grade squamous intraepithelial lesions and high-risk HPV-positive atypical squamous cells of undetermined significance in patients with and without colposcopic evident cervical disease

Immunomarkers in Gynecologic Cytology: The Search for the Ideal ‘Biomolecular Papanicolaou Test’

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