Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vulvar Intraepithelial Neoplasia (VIN) is the precursor lesion of Vulvar Squamous Cell Carcinoma (VSCC), and the differentiated type (dVIN) is more frequently observed in relation to VSCC. In contrast to usual-type VIN (uVIN), which is related to infection by human papillomavirus (HPV), a germline mutation in the p53 gene is thought to be associated with ~90% of dVIN cases. To date, no infectious agent has been identified in association with dVIN, and studies investigating this possibility have been hindered by the difficulty in accurately diagnosing dVIN from small biopsies. Here, we used immunostaining for p16ink4a), a biomarker for HPV infection, to study 14 uVIN high-grade VIN and 14 dVIN cases, and to select 10 dVIN cases to broadly screen for all kn(own viruses using a pan-viral microarray platform (ViroChip). All of the uVIN tissue samples, including 8 warty and 6 basaloid cases, showed positivity with the p16(ink4a) immunostain. The staining pattern was full-thickness for all except two cases in which positive staining was localized in the lower 1/3 of the epidermis. In contrast, immunostaining for p16(ink4a) was negative in all dVIN cases. ViroChip analysis of 10 pure dVIN samples confirmed the absence of human papillomavirus subtypes or any other virus with the exception of a single sample that showed a weak microarray signature to a porcine herpesvirus. Follow-up PCR testing of the sample was negative for herpesvirus, and in-depth metagenomic next-generation sequencing revealed only sequences corresponding to non-pathogenic viral flora and bacterial contamination. In this study, we demonstrated lack of a virus association in 10 dVIN cases. Alternative pathways for carcinogenesis such as the p53 mutation should be considered for investigation of potential treatment options in dVIN.
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PMID:No viral association found in a set of differentiated vulvar intraepithelial neoplasia cases by human papillomavirus and pan-viral microarray testing. 2589 43

The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status. The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon. This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation. To address this problem, we sought to compare p53 IHC patterns with TP53 mutation status. We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]). IHC for p16 and p53, and sequencing of TP53 exons 4-9 were performed. HPV in situ hybridization (ISH) was performed in selected cases. We identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression. These IHC patterns were consistent with TP53 mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions. Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused. The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH. This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53 mutational status in both VSCC and vulvar in situ lesions.
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PMID:Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status. 3220 95

Squamous cell carcinoma of the vulva can arise through 2 pathways: human papillomavirus (HPV)-dependent high-grade squamous intraepithelial lesions (previously termed usual vulvar intraepithelial neoplasia) or HPV-independent (differentiated vulvar intraepithelial neoplasia, dVIN). Distinguishing between the 2 types can be clinically and histologically difficult. A subset of high-grade squamous intraepithelial lesions with superimposed chronic inflammation mimicking dVIN has recently been reported; p53 shows characteristic mid-epithelial staining (with basal sparing) in such cases. The pathology databases of 2 academic institutions were searched for vulva specimens with corresponding p53 and p16 immunohistochemical stains, yielding 38 specimens (from 27 patients). In situ hybridization and multiplex polymerase chain reaction-MassArray for high-risk HPV were performed on at least 1 block from each patient. All cases resembled dVIN or lichen sclerosus morphologically, but with a higher degree of atypia. All but 1 case demonstrated mid-epithelial p53 staining with basal sparing by immunohistochemistry. All cases showed block positivity for p16 and at least patchy positivity by HPV in situ hybridization. Of the 23 cases with valid HPV DNA polymerase chain reaction results, 15 were positive and 8 were negative. Of the positive cases, HPV16 was identified in 10 cases, with other high-risk types in the remaining 5. To our knowledge, this is the largest cohort of high-grade squamous intraepithelial lesions mimicking dVIN reported to date. Prior studies reported positivity for HPV16 in all cases tested, however, we found HPV16 in only 67% of HPV positive cases. This case series highlights the importance of immunohistochemistry, and occasionally HPV in situ hybridization, for accurate diagnosis, and expands the spectrum of associated HPV types.
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PMID:Expanding the Morphologic, Immunohistochemical, and HPV Genotypic Features of High-grade Squamous Intraepithelial Lesions of the Vulva With Morphology Mimicking Differentiated Vulvar Intraepithelial Neoplasia and/or Lichen Sclerosus. 3292 43