p16 immunohistochemistry positive

Interestingly, few nondiseased controls were also detected to have p16 mutations. 8600 Rockville Pike PMC The percentage that was p16 IHC positive increased with higher-risk HPV groups for each diagnosis (P trend < .001). Pathol. 1B) include the following: Abnormalities of squamous cell nuclei; Undifferentiation of cytoplasm in the upper 2/3 layer of squamous epithelium; mitotic figures can occur in the upper 2/3 layer of squamous epithelium; pathological mitosis at any level. In the CERvical Tissue AdjunctIve aNalysis (CERTAIN) study, we systematically analyzed the impact of adjunctive p16 IHC on the accuracy (agreement with reference pathology results) of diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) in the United States. Chang and Cassarino69 evaluated atypical cellular blue nevi, including cases with mild, moderate, and severe atypia, versus melanoma (including cases of malignant cellular blue nevi). Accessibility Incorporation of p16 immunohistochemistry for the diagnosis of melanocytic lesions is of limited use, especially for the purpose of differentiating benign from malignant lesions. Free E2F then acts to progress cell cycle progression by the transcription of genes required for mitotic S phase entry and DNA synthesis.1618, There are 2 families of CDKIs.17 The CIP/KIP family of kinase inhibitors includes p21, p27, and p57. c, Primary invasive melanoma showing weak cytoplasmic staining with negative nuclear staining (yellow arrow), cytoplasmic staining with negative nuclear staining (red arrow), and strong cytoplasmic and strong nuclear staining (green arrow) (p16 immunohistochemistry, original magnification 60 objective). Sci Rep 12, 7613 (2022). This system most commonly pertains to squamous cell carcinomas that tested negative for p16, an immunohistochemical proxy for HPV infection, or were not tested. In our study, we found that Ki67 was primarily expressed in the basal and parabasal layers in the normal cervical squamous epithelium (Fig. In this example, if only nuclear staining is considered within this illustrated field, then positivity may be interpreted as being around 5%. Fishers exact test and chi-squared test were used to assess the correlation between the histological diagnosis and the immunohistochemical expression patterns of p16 and Ki67. Epub 2009 Mar 3. 1D). As a CDK inhibitor, p16 can slow down the progression of the cell cycle by inactivating the CDK that phosphorylates the retinoblastoma protein, which is also a tumor suppressor protein that regulates the cell circle. With this study we assessed the impact of p16 immunohistochemistry on CIN grading in an hrHPV-based screening setting. Pathol. Abstract Background p16 is a tumor suppressor gene, over expression of which is considered as a surrogate marker of oncogenic human papillomavirus (HPV) infection. The .gov means its official. 2014 Dec;142(6):767-72. doi: 10.1309/AJCP3TPHV4TRIZEK. Analysis of multiple studies shows a wide range of results, as previously discussed. When it is used in a panel of other melanocytic markers, however, the possibility for diagnostic utility is likely increased.8 Perhaps other potential markers similar to p16 might provide better use for distinguishing benign from malignant melanocytic lesions in the future, such as with the recent report72 of p15 immunohistochemistry in melanocytic lesions. J. Surg. Liu, Y. et al. p16 plays an important role in regulating the cell cycle. What does p16 positive mean? - Studybuff.com (E) Histological picture of HSIL (F) In HSIL ,Ki67 was not only expressed in basal layer and parabasal layer, but also expressed in 2 / 3 of squamous epithelium. The potentially high rates of misdiagnosis and the possibility that they may contribute to an unfavorable outcome are of great concern to dermatologists and pathologists. 16, 205 (2012). Liu, J., Su, S. & Liu, Y. (A) Histologically interpreted as suspicious LSIL (B) P16 staining shows diffuse and strong positive staining in the lower part of the squamous epithelium (C) Morphology is difficult to determine whether it is LSIL or HSIL (D) P16 showed moderate positive in some areas and weakly positive in some areas (E) Histologically interpreted as LSIL (F) P16 shows uneven positivity of moderate intensity (G) The glandular epithelium showed obvious atypia (H) P16 shows uneven positivity of moderate intensity. PubMed Central Abstract Background In the human papillomavirus (HPV) era, the best way to assess oropharyngeal squamous carcinomas (SCC) for risk stratification is not clear. The main aim of this study was to evaluate the discrepancy of p16 IHC expression relatively to HPV RNA ISH in penile cancer tissue. Immunohistochemistry (IHC), determination of human papilloma virus (HPV) status, by p16 staining or by in situ hybridization (ISH), and next-generation gene sequencing can guide us regarding probable primary sites and tumor biology. The lower anogenital squamous terminology standardization project for HPV-associated lesions: Background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. p16 is a tumor suppressor protein that inhibits cyclin-dependent kinase 4A. Although most p16 results are distinctly positive or negative, certain ones are ambiguous: they meet some but not all requirements for the Antecedent cytologic interpretations were also available. As such, it is usually absent in head and neck SCC, the gene being mutated or deleted or the expression being abrogated by other mechanisms. p16 and Ki67 are immunohistochemical markers related to cervical squamous intraepithelial lesions. Because studies considering only nuclear immunohistochemical p16 staining as positive appeared to show more consistent results, limiting the interpretation to nuclear p16 staining may prove to be more accurate, and may improve interobserver variability, thus potentially making it more useful in the routine distinction of benign versus malignant melanocytic lesions. Mills, A. M. et al. The practical application of p16 staining is still problematic. c and d, Primary invasive melanoma with corresponding p16 staining. Article Google Scholar. CAS Consort diagram of specimen inclusions and, Consort diagram of specimen inclusions and exclusions. National Library of Medicine Longatto Filho, A. et al. Conversely, tumors with more than 1% immunopositivity were considered to be p16 positive (retained expression). Using p16 immunohistochemistry to classify morphologic cervical intraepithelial neoplasia 2: Correlation of ambiguous staining patterns with HPV subtypes and clinical outcome. Therefore, we divided these cervical biopsies into five groups: normal, uncertain LSIL, LSIL, HSIL and uncertain HSIL. In a study5 wherein 11 expert pathologists reviewed 37 classic melanocytic lesions, there was total agreement in only 30% of cases. Correspondence to 39, 17081718 (2015). The reported percentage of benign nevus cases staining positive ranged from 61% to 100%. The results indicated that p16 expression was significantly different among normal, LSIL and HSIL specimens. Consort diagram of specimen inclusions and exclusions. Among 217 specimens whose histological diagnosis was normal, 158 were negative for p16 expression, 59 were weakly positive and 0 were diffusely positive. HMB45 and Ki-67, nevertheless, have been used for some time, and there is substantial literature supportive of their use with difficult melanocytic lesions. Mason et al64 showed no difference in p16 staining in Spitz nevi and spitzoid melanomas, concluding that p16 was not a useful marker to distinguish the two. The glandular epithelium exhibited obvious atypia (Fig. The high positivity rate of Ki67 immunohistochemistry suggests a high proliferation index and a high degree of malignancy. However, p16 negativity is sufficient to rule out HPV. p16 IHC-positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC-negative, CP-diagnosed CIN2 biopsies (P < .001). Presented at the 16th Spring Seminar of the Korean Pathologists Association of North America (KOPANA); March 3, 2017; San Antonio, Texas. Therefore, we excluded those cases with uncertain histological diagnosis, including 68 cases of indeterminate LSIL and 128 cases of indeterminate HSIL. Among 68 specimens with a histological diagnosis of uncertain LSIL, 57 were negative for p16 expression, 9 were weakly positive and 2 were diffusely positive. The p16 immunopositive cases were further divided into focal expression (if . Characterization of cervical biopsies of women with HIV and HPV co-infection using p16. https://doi.org/10.1016/j.humpath.2017.06.014 (2017). Article suggests that 1/3 of CIN2 cases are diagnosed as CIN1 by some pathologists and that CIN1 cases are often not recommended for p16 immunohistochemical staining. Ki67 immunohistochemical staining is of high value in distinguishing cervical squamous intraepithelial lesions from benign lesions (atrophic cervical squamous epithelium) because Ki67 exhibits higher expression in the former, but Ki67 staining cannot distinguish between dysplasia and immature squamous metaplasia12,13. All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group (Ptrend < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies (P < .001). In addition, cervical squamous intraepithelial lesions often appear in the transformation zone, and the glands may also exhibit morphological changes. We obey the principles of the 1983 Declaration of Helsinki. The value of Ki67 for the diagnosis of LSIL and the problems of p16 in The p16 immunohistochemical (IHC) marker has been used increasingly as an adjunct to morphologic assessment of cervical biopsies in which the differential diagnoses include high-grade squamous intraepithelial lesion (HSIL) and its mimics. p16 - Wikipedia Results.: Immunohistochemical positivity commonly considered a surrogate marker for oncogenic HPV infection Inactivation of Rb by the viral E7 oncoprotein following viral integration into host genome leads to overexpression of p16 ( Arch Pathol Lab Med 2007;131:1343 ) Lower Anogenital Squamous Terminology (LAST) standardization recommended p16INK4a immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs). p16 is a tumor suppressor protein that plays an important role in regulating the cell circle. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. PubMed Immunohistochemistry was performed using an anti-p16 mouse monoclonal antibody (clone 16P04/JC2; GeneTech, Shanghai, China) and an anti-Ki67 mouse monoclonal antibody (clone UMAB107; ZSGB-BIO, Beijing, China). 29(1), 5159. HPV persistence can occur for up to 10 to 15 years; therefore, it is possible for a partner to have contracted HPV from a previous partner and transmit it to a current partner. Excluded were studies that used a scale or grading-type system in reporting their p16 immunohistochemistry results, because they did not clearly distinguish a positive versus negative result but rather a gradient of staining patterns or relative expression. The INK4 family of CDKIs include p15INK4b, p16INK4a (referred to herein as p16), p18INK4c, and p19INK4d. Adjunctive use of p16 immunohistochemistry for optimizing management of HHS Vulnerability Disclosure, Help Many independent groups have therefore studied the possible incorporation of p16 immunohistochemistry for the purpose of distinguishing benign from malignant melanocytic lesions, particularly in sporadic melanoma cases. Therefore, we excluded those cases with uncertain histological diagnosis, including 68 cases of indeterminate LSIL and 128 cases of indeterminate HSIL. Tract Dis. Multiple other stimuli for upregulation of p16 have also been proposed, such as response to DNA damage.1619, Among the CDKIs, there has been great interest in studying the relation of p16 with melanoma. a and b, Nevus with corresponding p16 staining. These cases do not meet the diagnostic recommendations of p16 positivity proposed by the LAST project. 39, 611617 (2015). doi: 10.1136/bmjopen-2021-059593. p16 can show diffusely and strongly positive expression in a small portion of LSILs. p16 immunohistochemistry in oropharyngeal squamous cell - Nature Hebbar, A. Positive (either PPIB or UBC) . Int J Gynecol Pathol. A few immunohistochemical markers have been proposed and used to assist the pathologist with melanocytic lesions.813 Currently, a panel comprising HMB45, Ki-67, and p16 is commonly used to seek assistance in distinguishing benign from malignant lesions.8 Although the panel may be helpful in some cases, it variably lacks the confidence to provide definitive answers sought by the pathologist. Discrepancy in p16 expression in patients with HPV-associated head and The most studied among these are p21 and p16.16 It is thought that induction of cellular senescence is established and/or maintained by either or both of the p53/p21 and p16/pRb pathways.1922 The upregulation of p16 has been shown to respond to hypermitogenic/oncogenic signals such as overexpression of RAS, MAP kinases, or Myc. One of the alterations in behavior included ordering additional tests.7 Immunohistochemistry is likely the most common additional test used by pathologists to assist in the distinction between benign and malignant melanocytic lesions. Product Description. Cyclin-dependent kinase inhibitors (CDKIs) are essential proteins involved in withdrawing from cell cycle progression. Unfortunately, however, the wide variation in the numerous studies appears to undermine the possible value of p16 immunohistochemistry in its application for melanocytic lesions. A comparison of high-grade cervical abnormality risks in women living with and without human immunodeficiency virus undergoing routine cervical-cancer screening. Correlation of p16 immunohistochemistry with clinical and epidemiological features in oropharyngeal squamous-cell carcinoma Chrystiano de C. Ferreira , Rozany Dufloth , Ana C. de Carvalho , Rui M. Reis , Iara Santana , Raiany S. Carvalho , Ricardo R. Gama Higher magnification of p16 staining provided as inset on lower right corner of b illustrates a clearer view of strong and diffuse nuclear and cytoplasmic staining of dermal nevus cells. When the squamous epithelium has papillary hyperplasia, Ki67 is also expressed around the vascular axis (Fig. 1C). An official website of the United States government. PubMed Central This article suggests that cervical squamous intraepithelial lesions should be diagnosed using histological morphology. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Therefore we aimed to evaluate the association of p16 and p53 overexpression in triple negative breast cancer with various prognostic parameters. For baseline comparison, a nevus with corresponding p16 immunohistochemistry characteristically shows strong and diffuse staining pattern of nevocytes (Figure 1, b). https://doi.org/10.1097/01.RCT.0000157092.44680.25 (2005). and S.S.contributed to operation of the experiment, and revision of the manuscript; All authors issued final approval for the version to be submitted. What is p16 in HPV? Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Discrepancy of p16 immunohistochemical expression and HPV RNA in penile Expression of p16 INK4A (p16 positive) is highly correlated with human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC), however, p16-positivity is not limited to HPV positive tumors and therefore, not a perfect surrogate for HPV. Correlation of p16 immunohistochemistry with clinical and - PLOS However, a small portion of the specimens, whose morphology was between LSIL and HSIL, demonstrated uncertain cytoplasmic differentiation in the middle or upper third of the epithelium (Fig. Therefore, herein we review p16 immunohistochemistry as a marker for diagnostic use, particularly for the distinction of nevi from melanoma. Surgical resection is curative early in the disease, but chemotherapy, biotherapy, and immunotherapy remain ineffective for more advanced melanoma, with mean survival from first detection of metastases being only 6 to 9 months.1 Accurate pathologic identification of the primary melanoma is critical for optimal clinical management. It is worth considering whether these cases should be diagnosed as HSIL9. Multiple studies have also incorporated specialized types of melanocytic lesions, such as Spitz lesions,5861,64,66,68 desmoplastic melanomas,58,67,71 blue nevusrelated lesions,69,71 and mucosal melanocytic lesions41,49,62,63; 2 studies43,70 focused on nodal metastases, and a recent study (S. S. Koh, unpublished data, 2018) compared nevi of pregnancy and nevoid melanomas. Melanoma is the most fatal cutaneous neoplasm. Positive staining is defined as block staining: strong nuclear and cytoplasmic expression in a continuous segment of cells (at least 10 20 cells); in squamous epithelium, block positivity needs to involve basal and parabasal layers. The authors have no relevant financial interest in the products or companies described in this article. 35, 210220 (2009). The p16 (CDKN2a/INK4a) gene is an important tumor-suppressor gene, involved in the p16/cyclin-dependent kinase/retinoblastoma gene pathway of cell cycle control. We also used the chi-squared test to compare the differences in Ki67 expression between normal cervix and LSIL. Google Scholar. Many recommend use of both p16 immunohistochemistry and HPV in situ hybridization (ISH). https://doi.org/10.4103/0974-2727.199630 (2017). However, in our study, some cases exhibited morphology between that of LSIL and HSIL. References 2931, 34, 35, 43, 44, 46, 50, 5254, 61. p16 IHC-positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. PubMedGoogle Scholar. Immunohistochemistry was performed using the Autostainer Link 48 automated system (Dako Co., Carpinteria, CA, USA) and the EnVision system (Dako). Bethesda, MD 20894, Web Policies Written informed consent for the publication of the clinical details and images was obtained from the patient. You are using a browser version with limited support for CSS. 4AB). p16 Immunohistochemical Expression in Head and Neck Squamous Cell E6, on the other hand, acts by degrading p53, preventing apoptosis.27,28. It is a specific inhibitor of cdk4/cdk6. In general, however, there does appear to be a decreasing trend of p16 staining going from benign to advanced melanoma (especially metastatic lesions). However, in daily clinical practice, the distinction of HSIL and LSIL using p16 immunohistochemical staining is difficult in some special cases. p16 IHC-positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL+ cytology, or to be diagnosed as CIN3+ by the EP (P < .001 for all). Prev Med. The p16 IHC analysis yielded positive results for five cases where there was an absence of detectable HPV mRNA by ISH. p16 was diffusely and strongly positive in some LSILs, and some problems were encountered in the interpretation of p16 staining. 3GH). In 2012, the LAST project published a consensus and suggested that cervical squamous intraepithelial lesions caused by human papillomavirus (HPV) should be divided into two categories: low-grade cervical squamous intraepithelial lesions (LSIL) and high-grade cervical squamous intraepithelial lesions (HSIL). Damgaard RK, Jenkins D, de Koning MN, Quint WG, Stoler MH, Doorbar J, Kahlert J, Gravitt PE, Steiniche T, Petersen LK, Hammer A. BMJ Open. The phosphorylation of Rb releases the bound E2F. p16INK4A (henceforth referred to as p16) immunohistochemistry (IHC) is a good surrogate test for the presence of a potentially transforming human papillomavirus (HPV) infection in anogenital carcinomas and premalignant lesions1. Pathology Outlines - p16 Federal government websites often end in .gov or .mil. However, HPV infections often clear on their own within a year or two. Epub 2022 Sep 20. 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