p16 is a tumor suppressor protein that plays an important role in regulating the cell circle. J. Pathol. 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. Atypical/dysplastic nevi were also analyzed and had a lesser rate of p16 mutations compared with melanomas.23, The role of p16 in cellular senescence, particularly in melanocytes, is also of great importance, because senescence is considered to be a critical barrier for tumorigenesis or progression of melanoma.24 In vitro cell culture studies further support this view. Sometimes more than one cancer can occur in the oropharynx and in other parts of the oral cavity, nose, pharynx, larynx (voice box), trachea, or esophagus at the same time. A more variable staining pattern is illustrated in primary invasive cutaneous melanoma, in which there is mostly cytoplasmic staining of the invasive cells (Figure 1, d), versus negative staining (Figure 1, f), versus cases in which there is heterogenous positive and negative staining of the invasive cells (Figure 1, h). The use of biomarkers and HPV genotyping to improve diagnostic accuracy in women with a transformation zone type 3, Characterization of cervical biopsies of women with HIV and HPV co-infection using p16ink4a, ki-67 and HPV E4 immunohistochemistry and DNA methylation, HPV-negative tumors of the uterine cervix, MCM-2, Ki-67, and EGFR downregulated expression levels in advanced stage laryngeal squamous cell carcinoma, RETRACTED ARTICLE: Cervical adenosquamous carcinoma: detailed analysis of morphology, immunohistochemical profile, and clinical outcomes in 59 cases, A prognostic value of CD45RA+, CD45RO+, CCL20+ and CCR6+ expressing cells as immunoscore to predict cervical cancer induced by HPV, Immunohistochemical and genetic characteristics of HPV-associated endocervical carcinoma with an invasive stratified mucin-producing carcinoma (ISMC) component, Cervical carcinomas with serous-like papillary and micropapillary components: illustrating the heterogeneity of primary cervical carcinomas, Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study, https://doi.org/10.1016/j.ygyno.2007.07.064, https://doi.org/10.1097/01.RCT.0000157092.44680.25, https://doi.org/10.1097/PAS.0000000000000494, https://doi.org/10.1038/modpathol.2015.126, https://doi.org/10.1016/j.humpath.2017.06.014, https://doi.org/10.30699/ijp.2020.112421.2208, http://creativecommons.org/licenses/by/4.0/. By submitting a comment you agree to abide by our Terms and Community Guidelines. The .gov means its official. From January 2019 to January 2021, among the women who presented to the Obstetrics and Gynaecology Clinic of the First Hospital of Jilin University, all who underwent biopsy were retrospectively included in this study. What does p16 positive mean? - Studybuff.com p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Making an accurate diagnosis for melanocytic lesions has always been challenging for pathologists, especially when dealing with difficult-to-diagnose cases. (A) P16 immunohistochemical staining showed negative (B) P16 immunohistochemical staining showed local weak positive(C) P16 immunohistochemical staining showed diffuse and strong positive (D) Histology shows the performance of LSIL (E) P16 immunohistochemical staining showed diffuse and strong positive over 1/3 layer of squamous epithelium. 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. 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. In distinguishing between LSIL and HSIL, p16 positivity was defined as a combination of strong positive diffuse nuclear and cytoplasmic staining in more than 2/3 of the layers of the cervical squamous epithelium2. Both cytoplasmic staining and nuclear staining were required for tumor cells to be considered positive. Examples of representative cases showing p16 immunostaining pattern are also illustrated. Internet Explorer). It measures the presence of two specific proteins, p16 and Ki-67, in a sample of cervical cells. 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. LAST classification of "HSIL" diagnosis, which includes p16 IHC-positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (<30 years) women diagnosed with CIN2 for whom surveillance rather than treatment is recommended. Relationships of p16 Immunohistochemistry and Other Biomarkers - PubMed 3H). government site. Google Scholar. 4GH). Tract Dis. Oropharyngeal (p16-) cancer staging refers to TNM staging of carcinomas originating in the oropharynx that are not human papillomavirus (HPV)-associated. Patients were considered p16 positive by p16 IHC if there was strong and diffuse nuclear and cytoplasmic staining in at least 70% of tumour cells. To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses. 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). Reanalysis was performed by separating studies depending on whether nuclear alone or nuclear and cytoplasmic staining was considered positive for p16 staining (Table). Misdiagnosis of melanoma, mainly underdiagnosis, constitutes 13% of total pathology-related medical malpractice lawsuits, the second largest group of malpractice claims.2 Recurrent problems include melanoma misdiagnosed as a melanocytic nevus (without disclosure of diagnostic doubt), chronically inflamed nevus, Spitz nevus, and dysplastic/atypical nevus.24 These lesions are often difficult to diagnose, and interpretation may be subjective, leading to a range of diagnoses from different pathologists, including expert dermatopathologists. However, both previous studies and our study suggest that there are some problems in the interpretation of p16 immunohistochemical staining in a few cases. PubMed Haematoxylin and eosin-stained slides of all biopsy samples were reviewed by two pathologists(Consultant) and classified according to the criteria outlined by the LAST project1. Contrarily, p16 interpretation may be problematic. 3d, 3f). Epstein-Barr Virus, But Not Human Papillomavirus, Is Associated With Affiliations. Search for other works by this author on: From the Department of Pathology and Dermatopathology, Kaiser Permanente Anaheim Medical Center, Anaheim, California. The increase in E2F then leads to upregulation of p16 by a feedback mechanism. What is the ICD-10-CM code for skin rash. However, a conclusion about the role of Ki67 in the diagnosis of squamous intraepithelial lesions has not been established. 4AB). 25, 101120 (2006). Cervical changes that lead to cancer usually take several years often 10 years or more to develop. Similar to its use for diagnostics, p16 was found to have mixed results as to its role in prognostication. Although some studies incorporated atypical nevi in their studies, most did not analyze p16 immunohistochemistry staining characteristics based on grade of atypia. c and d, Primary invasive melanoma with corresponding p16 staining. https://doi.org/10.1016/j.ygyno.2007.07.064 (2007). Nuclear and cytoplasmic staining is seen in dysplastic squamous cervical epithelial cells infected with HPV, but not in normal cells. Antecedent cytologic interpretations were also available. Department of Pathology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China, You can also search for this author in Correlation of p16 immunohistochemistry with clinical and - PLOS Statistical analyses were conducted using SPSS 22 (SPSS, Chicago, IL, USA). For such difficult cases, new immune markers or other diagnostic methods need to be discovered in order to distinguish such lesions. 2C). 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 ) The value of Ki67 for the diagnosis of LSIL and the problems of p16 in the diagnosis of HSIL, https://doi.org/10.1038/s41598-022-11584-z. Ki67 expression in the middle and superficial one-third of the epithelium correlates well with the histopathological diagnosis of squamous intraepithelial lesions11. Immunohistochemistry is used by general pathologists and dermatopathologists as an adjunctive diagnostic tool primarily because of accessibility, turnaround time, and familiarity of interpretation. Two types of Ki67 expression have been defined, namely, basal and parabasal layer positivity and positivity in the upper two-thirds of the squamous epithelium. 3E), p16 demonstrated uneven positivity of moderate intensity (Fig. J. Surg. IHC for p16 was diffusely positive in the tumor cells, confirming the diagnosis of OPSCC (B, 200). For patients whose biopsy results do not support LSIL, the frequency of reexamination can be reduced to reduce the financial and psychological burden on patients. (A) Histological image of LSIL (B) Histological image of LSIL (C) Histological image of the cervix not infected by HPV (D) Cervical biopsy tissue showed some suspicious morphological features of LSIL (E) The morphology of cervical biopsy is between LSIL and HSIL. The percentage of Spitz nevi cases positive for p16 immunohistochemistry reported by multiple groups30,34,50,61,64 ranged from 0% to 100%. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Pathol. Lab. Pathology Outlines - p16 New Mexico HPV Pap Registry Steering Committee, See this image and copyright information in PMC. Article Among the 404 specimens whose histological diagnosis was HSIL, Ki67 immunohistochemical staining was observed in the basal and parabasal layers in 0 cases and in the upper two-thirds of the squamous epithelium in 404 cases (Table 1). Most pathologists would likely diagnose these cases as HSIL (72/128). Most studies did, however, show gradual loss of p16 with melanoma progression (see Table). Moreover, p16 over expression correlates with good prognosis in head and neck squamous cell carcinoma (HNSCC). Before 3C); p16 was moderately positive in some areas and weakly positive in others (Fig. The p16 immunopositive cases were further divided into focal expression (if . p16INK4a immunostaining in cytological and histological specimens from the uterine cervix: A systematic review and meta-analysis. National Natural Science Foundation of China (81902868). The prognostic significance of p16 expression pattern in diffuse ISSN 2045-2322 (online). Bookshelf Ghosh, A. M. N., Padmanabha, N. & Kini, H. Assessment of p16 and Ki67 immunohistochemistry expression in squamous intraepithelial lesion with cytohistomorphological correlation. Some35 have proposed that the gradual loss of p16 correlates with the progression of melanoma, but is not an initiating event. Relationships of p16 Immunohistochemistry and Other Biomarkers With The p16 IHC analysis yielded positive results for five cases where there was an absence of detectable HPV mRNA by ISH. Similar to spitzoid lesions, multiple studies analyzing nevi and primary invasive melanomas have also had mixed conclusions: some studies52,62 support p16 immunohistochemistry for diagnostic purposes (differentiating nevi from primary invasive melanoma), and some studies29,65 do not show convincing evidence. In a study5 wherein 11 expert pathologists reviewed 37 classic melanocytic lesions, there was total agreement in only 30% of cases. It is uncertain, though, whether this wide variation could be due to subjective interpretation, unstandardized laboratory techniques, source of the antibody, or other factors. 39, 611617 (2015). Histological diagnosis is used as a standard reference. Am. However, there appears to be some value for the use of p16 in distinguishing nodal nevi from metastatic melanoma within nodes. High discordance and low positive predictive rates of p16 were observed in HPV-associated OPSCC. (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. Although molecular testing is of much interest and there is great support for its development, currently, for most melanocytic lesions, immunohistochemical studies remain the most practical method for assistance in the routine diagnosis of melanocytic lesions for the average pathologist.