IHC expression of p16 can be used as a surrogate marker of HPV. 2. Alsbeih G, Al-Harbi N, Bin Judia S, Al-Qahtani W, Khoja H, El-Sebaie M, Tulbah A. 2017 May/Jun;25(5):366-373. doi: 10.1097/PAI.0000000000000309. The commonest site of involvement in our study was the oral cavity (79% cases). This was in accordance with the study conducted by Ai et al. [12,16,17] while in study by Shinohara et al., there was a significant correlation between p16 expression and age (P = 0.03).[15]. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas. Ralli M, Singh S, Yadav SP, Sharma N, Verma R, Sen R. Assessment and clinicopathological correlation of p16 expression in head and neck squamous cell carcinoma. Formalin fixation leads to robust, easily interpretable p16 staining in cell blocks. Routine Use of Adjunctive p16 Immunohistochemistry Improves Unauthorized use of these marks is strictly prohibited. A similar distribution of tumors was seen in the study by Boslooper et al.,[18] while the larynx was the most common site of involvement in most of the studies. These differences could also be attributed to the difference in geographic distribution of tumor, sample size, scoring criteria and different types of antibodies used by different authors. Out of 60 cases with p16 positivity, 43 (70.2%) were <50 years of age, 47 (78.33%) were males and 53 (88.33%) had cancer in the oral cavity. The LAST and 2014 WHO terminology that incorporates Bethesda terminology was simplified to the CIN grade: CIN1 indicates LSIL, CIN2 indicates high-grade squamous intraepithelial lesions (HSIL) (CIN2), and CIN3 indicates HSIL (CIN3). Readers were blinded to round 1 reading results. These effects are displayed graphically in Figure 2, where PPA (sensitivity) is plotted against 1NPA (1specificity) for all of the ISPs using either H&E (ISPH&E; blue circles), or H&E plus p16 according to LAST (ISPH&E+p16/LAST; red circles). Conclusions: Clipboard, Search History, and several other advanced features are temporarily unavailable. Expanding the use of p16 into non-LAST cases would lead to a comparable improvement in sensitivity within this subgroup of biopsies, at the cost of a minimal, but statistically significant difference in specificity. Along with it, trials should be performed to get a proper treatment regime for HPV-positive and HPV-negative HNSCC in order to provide better treatment and lower relapse rates. The mean sensitivity and specificity for consensus CIN2+ of . The mean sensitivity and specificity for consensus CIN2+ of p16 IHC as scored by the readers were 88% and 87%, respectively, versus an overall sensitivity and specificity by the pathologist of 96% and 92%, respectively. The ISPs who have a diagnostic approach that is balanced between sensitivity and specificity have an 10% difference in PPA with the use of p16 and this also is only minimally impacted by whether or not they requested p16. Moreover, the average differences in PPA were either identical or very similar for LAST cases and non-LAST cases within all 3 tertiles. All 70 ISPs who participated in this study were (i) board-certified in anatomic pathology, (ii) licensed and currently practicing medicine in the United States, and (iii) evaluate cervical histology specimens as part of their routine clinical practice. Association of p16 overexpression with various clinicopathologic parameters including T-stage, N-stage, grade, recurrence status, and risk factors was evaluated. p53 in head and neck cancer: Functional consequences and environmental implications of TP53 mutations. Simoens C, Goffin F, Simon P, et al. . Table 1 illustrates the correlation of p16 expression with various clinical parameters. government site. Majority of the tobacco users, paan users and alcohol consumers were males. Singh C, Manivel JC, Truskinovsky AM, Savik K, Amirouche S, Holler J, Thyagarajan B, Gulbahce HE, Pambuccian SE. A significant association was seen between p16 expression and history of abnormal sexual habits (P = 0.02) in our study. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Scoring of p16INK4a immunohistochemistry based on independent - Nature Please enable it to take advantage of the complete set of features! 7. Conclusions: On the basis of PPA and NPA for CIN2+ on H&E-stained slides compared with the CPR, the 70 ISPs were divided into tertiles. 2005;55:74108. We therefore evaluated the characteristic and association of p16 and HPV in Thai patients with HNSCC. A statistically significant direct association was observed between p16 with age, site of the tumor, abnormal sexual habits and lymph node involvement. There are a number of caveats that should be made regarding our suggestion that pathologists might want to consider staining all cervical biopsies with p16 in order to avoid missing CIN2 lesions. Epub 2016 Nov 8. Solomon MC, Carnelio S, Gudattu V. Molecular analysis of oral squamous cell carcinoma: A tissue microarray study. The tissue block was sectioned at 45 m and the sections were stained for hematoxylin and eosin as per standard guidelines and examined. Beck TN, Smith CH, Flieder DB, Galloway TJ, Ridge JA, Golemis EA, Mehra R. Head Neck. 11,20,21 Recommendations . p53 expression but not p16(INK4A) correlates with human papillomavirus-associated esophageal squamous cell carcinoma in Kazakh population. Out of 60% positive cases, 23 (23%) showed Grade 1 (low expression) [Figure 6], 18 (18%) showed Grade 2 (moderate expression) [Figure 7] and 19 (19%) showed Grade 3 (strong expression) [Figure 8] p16 expression. Grade III: Poorly differentiated or anaplastic. A descriptive study was carried out for all the variables included in the study. p16ink4a immunohistochemical overexpression in premalignant and malignant oral lesions infected with human papillomavirus. Disclaimer. Correlation of P16 expression with various clinical factors. [2] More than 90% of HNCs are squamous cell carcinomas (HNSCC). Both outcomes have significant clinical consequences. Even the gynecologic pathologists of the CPR varied in how they interpreted the LAST criteria with one of the pathologists who reviewed all of the cases requesting p16 IHC for 19.0% of cases and the other for 31.9%. As it is impossible for a pathologist to know where their diagnostic approach fits in the spectrum of other pathologists unless they participate in a large analytical study such as CERTAIN, it can be argued that all pathologists should consider performing p16 IHC on all cervical biopsies. We demonstrated that nonpathologists can accurately diagnose CIN2+ using p16 IHC alone. eCollection 2020. Objective: Interpretation of results. This analysis has a number of strengths. As part of this project, a working group was tasked with developing recommendations for determining which, if any, biomarkers were useful in diagnosing HPV-associated lesions and in reducing diagnostic interobserver variability. Positive and negative controls were run simultaneously. Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: P16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization. The readers and the pathologist agreed on p16 IHC scoring for 42 (84%) of the 50 slides of CIN less severe than CIN2 and 37 (74%) of the 50 CIN2+ slides. and transmitted securely. National Library of Medicine Just as importantly, when p16 IHC was performed according to the LAST criteria, there was an improved correlation between the ISPs diagnosis of CIN2+ and the CPRs diagnosis of CIN2+, using either of the 2 reference diagnoses (CPRH&E or CPRH&E+p16) (Table 1). The IHC expression of p16 was classified according to nuclear and cytoplasmic positivity. According to Ralli et al., HNSCC was associated more with paan chewing and was more in nonalcoholics. are consultants to Ventana Medical Systems Inc (Roche Tissue Diagnostics), Roche Molecular Diagnostics, BD Lifesciences, and Inovio. Moreover, the ISPs were selected specifically to practice in different geographic regions of the United States and have a range of experience levels, specimen volumes, and employment settings (academic institution, hospital, private laboratory, or reference laboratory).11. In this report we further analyze data from the CERTAIN study to determine how restricting the use of p16 IHC to the subset of slides fitting the LAST criteria impacts the adjunctive use of p16 IHC. Trends of head and neck cancers in urban and rural India. Elango JK, Gangadharan P, Sumithra S, Kuriakose MA. Readers were grouped into tertiles based on their location on the receiver operating curve, which was estimated by inverse transformation of the linear regression line between the probit of PPA and the probit of 1NPA from all ISPs. During the first reading round on H&E-stained slides only, both ISPs as well as the gynecologic pathologists establishing the CPR-derived reference diagnoses were asked whether, based on their review on H&E, they would request adjunctive p16 IHC staining according to LAST criteria as follows: (i) an H&E morphologic differential diagnosis between precancer (CIN2 or CIN3) and a mimic of precancer, (ii) an H&E morphologic interpretation of CIN2 that is or was entertained, and (iii) an H&E morphologic interpretation of CIN1 but at high risk for missed high-grade disease, defined as a prior cytologic interpretation of HSIL, ASC-H, or AGC (not otherwise specified). your express consent. Gage JC, Schiffman M, Hunt WC, et al. Materials and methods: 3). [12,14], In our study, significant association was seen between p16 expression and sex of the patient (P = 0.004), while in study by Shinohara et al., there was no significant correlation between p16 expression and sex (P = 0.18). JAMA. As each case consisted of repeated measures from 17 or 18 ISPs, cases were treated as the respective sampling unit, and all observations belonging to a respective case were kept together when constructing resamples for the bootstrap CIs. and Singhi and Westra who observed that p16 expression significantly varies with tumor site,[12,21] while discordant with a study by Shinohara et al. Assessment of immunohistochemical expression of p16 in head and neck 2021 Oct 5;14:1419-1425. doi: 10.2147/CCID.S333376. Second Diagnostic Opinion by Experienced Dermatopathologists in the Setting of a Referral Regional Melanoma Unit Significantly Improves the Clinical Management of Patients With Cutaneous Melanoma. Castle PE, Adcock R, Cuzick J, et al. Essential information from each study (number of samples, antibody used, collection dates, overall p16 immunohistochemistry results, and general method of interpretation) was tabulated and analyzed. Figure 1. p16 expression in squamous cell, Figure 1. p16 expression in squamous cell carcinoma of the oral cavity, Figure 2. -. 1. pRb and CyclinD1 Complement p16 as Immunohistochemical Surrogate Markers of HPV Infection in Head and Neck Cancer. Highlights Testing for p16 status is clinically important for oropharyngeal carcinomas. Figure 1 shows the distribution of the average frequencies at which the 70 ISPs requested adjunctive p16 staining during round 1. BMC Res Notes. They may however show patchy non-block-type staining. 20. Two studies 25, 26 provided results for p16 INK4a interpretation as p16 INK4a positive or negative, . Zoroquiain P, Fernandes BF, Gonzlez S, Novais GN, Schalper KA, Burnier MN Jr. Int J Surg Pathol. Dass SE, Huizenga T, Farshchian M, Mehregan DR. Clin Cosmet Investig Dermatol. IHC p16 Score 0, 0%5% of nuclei and cytoplasm positive (IHC, 200), Immunohistochemical p16 Score 1, Sporadic (5%10% of nuclei and cytoplasm with weak and scattered positivity) (IHC, 400), Immunohistochemical p16 Score 2, focal (>10%30% of nuclei and cytoplasm strongly positive, spreading in one tissue area) (IHC, 400), Immunohistochemical p16 Score 3, diffuse (>30%85% of cells with strong positivity, spreading in several tissue areas) (IHC, 400). Others are quite uncommon types which include lymphoma and adenoid cystic carcinoma. The negative impact of staining all cervical biopsies with p16 is largely economic. Abstract Context: Misdiagnosis of melanoma and melanocytic lesions in general has tremendous medical-legal implications, often leading to unnecessary and excessive use of adjunctive tests. When restricted to LAST cases, the average difference in PPA between when the ISP used p16 versus when they did not was almost 6-fold greater for the tertile favoring specificity over sensitivity compared with the tertile favoring sensitivity over specificity (21.0% increase in PPA vs. 3.6%, respectively; Table 5). 3. Qualitative and Quantitative Diagnosis in Head and Neck Cancer. Correlation of P16 expression with histological grading, WDSCC: Well-differentiated squamous cell carcinoma, MDSCC: Moderately differentiated squamous-cell carcinoma, PDSCC: Poorly differentiated squamous cell carcinoma. [22] Ralli et al. Unable to load your collection due to an error, Unable to load your delegates due to an error. When evaluating the effect of adjunctive p16 within the subset of LAST cases only, both PPA and NPA increased significantly comparing the ISPs reading results without or with p16 to either of the reference diagnoses (Table 4). ISPs who favor specificity over sensitivity show an overall 0.2% difference in NPA, which varies from 1.9% to 1.1% depending on whether or not they requested a p16 using the LAST criteria, respectively. government site. 2008;9:425434. During the first reading round, only H&E-stained slides were used to establish the individual ISPs diagnoses (ISPH&E). All rights reserved. Boslooper K, Lam AK, Gao J, Weinstein S, Johnson N. The clinicopathological roles of alpha-B-crystallin and p53 expression in patients with head and neck squamous cell carcinoma. Accessibility HHS Vulnerability Disclosure, Help Please enable it to take advantage of the complete set of features! Cytological interpretation of p16 immunohistochemistry in head and neck We demonstrated that nonpathologists can accurately diagnose CIN2+ using p16 IHC alone. Clark JL, Lu D, Kalir T, et al. Galgano MT, Castle PE, Atkins KA, et al. We believe these results are representative of the general practice of surgical pathology in the United States. Hashmi AA, Hussain ZF, Hashmi SK, et al. Study of p16 expression may provide clinicians with more exact information in order to evaluate tumor aggressiveness, treatment modalities and can provide support for vaccination program in a high-risk group. p16 Immunohistochemical Expression in Head and Neck Squamous Cell Of the 100 cases, in 74 patients lymphadenopathy was absent at the time of presentation and amongst them 50 (67.56%) cases showed positive grade p16 expression. Careers, Unable to load your collection due to an error. Smeets SJ, Plas M, Schaaij-Visser T, Veen E, Meerloo J, Braakhuis B, et al. head and neck squamous cell carcinoma; hpv; oropharyngeal squamous cell carcinoma; p16. Routine use of adjunctive. Accessibility 2019 Jun 13;11(6):820. doi: 10.3390/cancers11060820. [3,14,19,20,27], In the present study, p16 expression had no significant correlation with histological grade of the tumor (P = 0.36) which was in concordance with Yuen et al. Similarly, the overdiagnosis of HSIL can lead to unnecessary loop electrosurgical excision procedures, which can negatively impact subsequent pregnancies. doi: 10.4081/ejh.2011.e20. Eighty-six (86%) patients were tobacco users, intake being in the form of gutka or smoking, 24 (24%) were alcoholics, 60 (60%) were paan chewers and 24 (24%) had history of abnormal sexual habits. Lazarus P, Sheikh SN, Ren Q, Schantz SP, Sten JC, Richie JP, et al. Methods Barnes L, Eveson JW, Reichart P, Sidransky D, editors. Your message has been successfully sent to your colleague. You can read the full text of this article if you: Keywords 2017;25:17. Majority of our patients were tobacco users (86 patients), which 54 (62.79%) cases had positive p16 expression. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. 21. Wolters Kluwer Health This increase in the detection of histologic HSIL cases came at the cost of a slight, but statistically significant decrease in NPA (0.8%; 95% CI, 1.1 to 0.5; P<0.0001) when p16 was used in the subset of non-LAST cases in this study (Table 4; Fig. Its major function is to inhibit cyclin-dependent kinases (CDK4 and CDK6), which are required to phosphorylate the retinoblastoma protein (pRb). Agreement rates of ISPs diagnoses on H&E versus on H&E+p16/LAST with both CPR reference diagnoses dichotomized at the CIN2+ threshold are shown in Table 3. Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: A distinct clinicopathologic and molecular disease entity. A pathologist reviewed all 100 cases. Evaluation of multiple studies reveals a wide range of results. [10,11,21,22], Histological grading is a method of quantitating the degree of differentiation by applying a set of histopathological criteria. R24 TW007988/TW/FIC NIH HHS/United States, International Agency for Research on Cancer - Screening Group. We conducted a pilot study of whether nonpathologists could accurately diagnose cervical precancer in biopsies using only a basic light microscope, evaluating p16INK4a immunohistochemistry (p16 IHC) of biopsies, and video-based training for both. Supplemental Table S1 provides the similar data for the comparison to CPRH&E reference results, Supplemental Digital Content 1 (https://links.lww.com/PAS/B112). In general, poorly differentiated tumors are high-grade neoplasms, while well-differentiated tumors are low-grade lesions. However, the HPV status of tumors not staining strongly for p16 is difficult to interpret and may require the use of PCR, not available in all laboratories, as a final arbiter. Although the results of studies are contradictory, abnormal p16 immunohistochemistry does not reliably predict risk of progression of low grade cervical squamous lesions. It provides important additional information to clinical and pathologic staging. Relationships of. 2021 Feb 4;7:568946. doi: 10.3389/fmed.2020.568946. LAST cases were defined at the individual reader level, that is a case could be considered being a LAST case by a specific reader, and a non-LAST case by other readers. doi: 10.1002/hed.24604. For more information, please refer to our Privacy Policy. Most of the cases included in the present study were tobacco chewers (86%), paan chewers (60%), nonalcoholic (76%) and without multiple sexual partners (76%). Pena JC, Thompson CB, Recant W, Vokes EE, Rudin CM. no. The https:// ensures that you are connecting to the [5] Human papillomavirus (HPV) status is associated with p16 expression, and HPV-positive tumors are less likely to harbor p53 mutations. official website and that any information you provide is encrypted p16 Immunohistochemistry Interpretation by Nonpathologists as an The correlation of p16 expression with lymphadenopathy was found to be highly statistically significant (P = 0.009). Please try after some time. and Dragomir et al. This was found for OPA (ie, equivalent to accuracy), PPA (ie, equivalent to sensitivity), and NPA (ie, equivalent to specificity). National Library of Medicine Correlation of clinicopathological features with immunohistochemical expression of cell cycle regulatory proteins p16 and retinoblastoma: Distinct association with keratinisation and differentiation in oral cavity squamous cell carcinoma. Malpica A, Matisic JP, Niekirk DV, et al. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P<0.0001) and 3.5% (95% CI, 2.8-4.2; P<0.0001), respectively, using expert consensus diagnoses on hematoxylin and eosin+p16 as reference. Liu Y, Alqatari M, Sultan K, Ye F, Gao D, Sigel K, Zhang D, Kalir T. Hum Pathol. The .gov means its official. The mean sensitivity and specificity for consensus CIN2+ of p16 IHC as scored by the readers were 88% and 87%, respectively, versus an overall sensitivity and specificity by the pathologist of 96% and 92%, respectively. Correlation of p16 expression with lymphadenopathy. p16 INK4a Immunohistochemistry in Cervical Biopsy Specimens: A