Immunohistochemical Staining For P53 Research Articles

Clinicopathological Findings and Comprehensive Review of Buschke-Lowenstein Tumors Based on a Case Study.

The Buschke-Löwenstein tumor (BLT), also known as giant condyloma acuminatum, is a rare, exophytic tumor, arising from pre-existing warty lesions associated with human papillomavirus (HPV) infection, particularly strains 6 and 11, which are considered to have low oncogenic potential. BLT presents as a large, cauliflower-like growth typically affecting the penis, vulva, vagina, perineum, scrotum, anus, and perianal area. Despite being a benign lesion, BLT is locally aggressive with a high recurrence rate, and can potentially undergo malignant transformation into squamous cell carcinoma, contributing to an overall mortality rate of 20-30%. The primary treatment is complete surgical excision with wide margins, frequently requiring complex reconstructive techniques for defect coverage. We report on a 68-year-old patient, with multiple comorbidities, who presented with a two-year history of a large exophytic tumor in the genital region, affecting the penis, along with progressive erectile dysfunction and urinary problems. The tumor was surgically excised with oncological safety margins, and reconstruction was performed using advancement and rotation flaps from the scrotum and intact penile skin. Histopathological examination confirmed the diagnosis of Giant Condyloma (Buschke-Löwenstein tumor), showing acanthosis, papillomatosis, parakeratosis, and koilocytic cell collections, with positive immunohistochemical staining for p16, p63, and ki67. Postoperatively, the patient had a good clinical outcome and a complete surgical cure. This case highlights the critical need for timely intervention and comprehensive management strategies in treating giant condyloma, given its potential for local invasion and substantial impacts on patient quality of life. Early diagnosis and thorough surgical excision are crucial for effective management and to reduce the high recurrence, morbidity and malignant transformation risk associated with this condition.

Molecular classification of endometrial carcinoma on endometrial biopsy: an early prognostic value to guide personalized treatment

ObjectiveMolecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the...

Human papillomavirus prevalence, genotype distribution, and prognostic factors of vaginal cancer.

We aimed to investigate human papillomavirus (HPV) prevalence and genotype distribution and prognostic factors in vaginal cancer (VC). VC patients who received treatment between 1989 and 2020 were retrospectively reviewed. L1 general polymerase chain reaction (PCR) followed by HPV Blot (King Car, I-Lan, Taiwan) and E6 type-specific-PCR were performed for genotyping firstly. P16 and p53 immunohistochemistry staining was performed. Univariate and multivariate analyses identified predictors of clinical outcomes.79 VC patients were eligible for analysis. 73 patients (92.4%) were squamous cell carcinoma (SCC) and 6 (7.6%) as non-SCC. The median follow-up time was 134.3 months (range 0.9-273.4). Among nine initially HPV-negative cases, seven were identified as being positive through HPV16/18/45/52/58 whole-genome amplification followed by Sanger sequencing (WGASS). HPV DNA sequences were detected in 98.6% of SCC and 83.3% of non-SCC, respectively, with HPV16 (49.4%), HPV52 (15.2%) and HPV58 (8.9%) being predominant. Patients with paraaortic lymph node (LN) metastasis had a 5-year cancer-specific survival (CSS) rate of 0%. Multivariate analysis revealed that only p16 and stage were significantly correlated with prognosis. Variables with strong correlations (p16- and HPV-positivity, LN metastasis and stage), were included in models 2-5 alternatively. Stage III/IV (hazard ratio [HR] = 3.64-4.56) and LN metastasis (HR = 2.81-3.44) were significant negative predictors of CSS, whereas p16-positivity (HR = 0.29-0.32) and HPV-positivity (HR = 0.14) were related to better prognosis. In conclusion, 97.5% of VCs were HPV-positive with WGASS. Stage III/IV and LN metastasis were significant negative predictors, whereas p16- and HPV-positivity were significantly associated with better prognosis.

Correlation between immunohistochemical staining and clinicopathological findings in endometrial carcinoma.

To analyze the immunohistochemical staining pattern of mismatch repair (MMR) proteins and p53 in endometrial carcinoma cases, including different subtypes and stages, to gain insights into their role in the pathogenesis and clinical behaviour of this malignancy. In this study, we investigate the association between MMR deficiency, p53 mutational status, and clinical outcomes in various subtypes of endometrial carcinoma. The immunohistochemical staining pattern of MMR proteins in 96 cases of endometrial carcinoma have been analyzed, including 72 endometrioid, 14 papillary serous, 5 clear cell, and 5 mixed Müllerian tumor. The results showed that 36 cases were MMR deficient, with the majority being of endometrioid subtype. The p53 immunostain showed a mutational pattern in a subset of cases, with a documented dismal prognosis. However, aforementioned stains failed to predict synchronous or metachronous cancers in 5 patients. These findings highlight the importance of MMR and p53 immunohistochemical staining in the classification, and prognosis of endometrial carcinoma.

High-Risk HPV CISH Detection in Cervical Biopsies with Weak and/or Focal p16 Immunohistochemical Positivity.

In cervical biopsies, for diagnosis of Human Papilloma Virus (HPV) related conditions, the immunohistochemical staining for p16 has a diagnostic value only if diffusely and strongly positive, pattern named "block-like". "Weak and/or focal (w/f) p16 expression" is commonly considered nonspecific. In our previous study, we demonstrated the presence of high-risk HPV (hrHPV) DNA by LiPa method in biopsies showing w/f p16 positivity. The aim of the present study was to investigate the presence of hrHPV-DNA by CISH in the areas showing w/f p16 expression. We assessed the presence of hrHPV16, 18, 31, 33, 51 by CISH in a group of 20 cervical biopsies showing w/f p16 expression, some with increased Ki67, and in 10 cases of block-like expression, employed as control. The immunohistochemical p16 expression was also assessed by digital pathology. hrHPV-CISH nuclear positivity was encountered in 12/20 cases of w/f p16 expression (60%). Different patterns of nuclear positivity were identified, classified as punctate, diffuse and mixed, with different epithelial distributions. Our results, albeit in a limited casuistry, show the presence of HPV in an integrated status highlighted by CISH in w/f p16 positive cases. This could suggest the necessity of a careful follow-up of the patients with "weak" and/or "focal" immunohistochemical patterns of p16, mainly in cases of increased Ki67 cell proliferation index, supplemented with molecular biology examinations.

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Abstract B013: Development of oropharyngeal tumor organoids for disease modeling and high throughput drug screening

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with approximately 550,000 new cases diagnosed each year. The oropharynx is one of the most common sites of occurrence, and disease in this region most often presents in the palatine tonsil, followed by the base of tongue and soft palate. Human papilloma virus (HPV) is a common cause of HNSCC, giving rise to a distinct subset of tumors with a different clinical presentation, disease course, and response to treatment. In order to further characterize HPV+ HNSCC tumors and their therapy response, we have leveraged our high throughput 3D tumor organoid screening platform. Our approach entails seeding tumor cells in extracellular matrix gels deposited around the perimeter of tissue culture wells in ring-like structures, with screening results available within a week from surgery (Phan et al, 2019; Al Shihabi et al, 2022; Nguyen et al, 2022; Al Shihabi et al 2023). We particularly focused on tonsil tumors, and develop organoids from both HNSCC and contralateral normal tonsil tissue. Thus far, we have procured tonsil samples from 31 patients to develop organoids, perform high throughput drug screening, and immunohistochemical characterization including H&E staining, Ki67, p16 and p53 immunohistochemical staining. We have leveraged dynamic optical contrast imaging (DOCI), a label-free tissue autofluorescence imaging method that is being investigated clinically (Kim et al, 2017), to assist in distinguishing tumor organoids from normal tissue organoids. Lastly, given the importance of radiation as a treatment modality for HPV+ HNSCC, we have also optimized a chemoradiation pipeline to test possible combinatorial effects. Taken together, our results demonstrate that 3D organoids of HNSCC generated from patient samples can successfully preserve native tissue characteristics and can be used for high throughput drug screening and radiation de-escalation testing, affording critical insight into the management of HNSCC in patients. Citation Format: Krishna K. Bommakanti, Luda Lin, Yazeed Alhiyari, Andreanne Sannajust, Brandon Mo, Lauran Evans, Peyton Tebon, Maie St. John, Alice Soragni. Development of oropharyngeal tumor organoids for disease modeling and high throughput drug screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B013.

Immunohistochemical and molecular pattern of p53 in epithelial ovarian cancers negative for germline BRCA1/2 variants

Epithelial ovarian cancers (EOC) associated with germline or somatic BRCA pathogenetic variants have a significantly higher rate of TP53aberrations. The majority of TP53 mutations are detectable by immunohistochemistry and several studies demonstrated that an abnormal p53 pattern characterized high-grade EOCs. An abnormal p53 immunohistochemical staining in fallopian tube (serous tubal intraepithelial carcinoma (STIC) and “p53 signature” is considered as a precancerous lesion of high-grade EOCs and it is often found in fallopian tube tissues of BRCA germline mutated patients suggesting that STIC is an early lesion and the TP53 mutation is an early driver event of BRCA mutated high-grade EOCs. No relevant data are present in literature about the involvement of p53 abnormal pattern in EOC carcinogenesis of patients negative for germline BRCA variants. We describe TP53 mutation results in relationship to the immunohistochemical pattern of p53 expression in a series of EOCs negative for BRCA1 and BRCA2 germline mutations. In addition, we also investigated STIC presence and “p53 signature” in fallopian tube sampling of these EOCs. Our results demonstrate that TP53 alterations are frequent and early events in sporadic EOCs including also low-grade carcinomas. Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status.

In Response to p53 Immunohistochemical Staining and TP53 Gene Mutations in Endometrial Cancer: Does Null Pattern Correlate With Prognosis?

In Response to p53 Immunohistochemical Staining and TP53 Gene Mutations in Endometrial Cancer: Does Null Pattern Correlate With Prognosis?

Incidence and Risk Factors for Recurrence and Progression of HPV-Independent Vulvar Intraepithelial Neoplasia.

Human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. Patients with HPV-independent VIN between 1991 and 2019 in a selected region were identified from the Dutch Nationwide Pathology Databank (Palga). Data were collected from the pathology reports. Crude and European age-standardized incidence rates were calculated for 10-year periods. Kaplan-Meier analyses were performed to determine the cumulative recurrence and cancer incidence, followed by Cox regression analyses to identify associated risk factors. A total of 114 patients were diagnosed with solitary HPV-independent VIN without prior or concurrent vulvar cancer. The European age-standardized incidence rate increased from 0.09 to 0.69 per 100,000 women-years between 1991-2010 and 2011-2019. A cumulative recurrence and cancer incidence of 29% and 46% were found after 8 and 13 years of follow-up, respectively. Nonradical surgery was identified as the only independent risk factor for recurrent HPV-independent VIN. Risk factors associated with progression to cancer were increasing age and a mutant p53 immunohistochemical staining pattern. The incidence of detected HPV-independent VIN has substantially increased the last decade and the subsequent recurrence and vulvar cancer risks are high. Although HPV-independent VIN may present as a wide morphologic spectrum, surgical treatment should aim for negative resection margins followed by close surveillance, especially for p53 mutant lesions.

Expression of p16 protein in breast cancer.

Breast cancer is themost common cancer and aleading cause ofdeath in women in Saudi Arabia. P16 is atumour suppressor gene that plays acrucial role in regulating cell cycle. Several studies have investigated thesignificance ofp16 expression in various cancer types. However, thesignificance ofp16 in breast cancer remains controversial and insufficiently studied. Thepresent study aims to examine theassociation between p16 expression and clinicopathological factors in breast cancer using immunohistochemistry staining. Thestudy utilised 475 prospectively collected tissue samples from 475 women with breast cancer in Saudi Arabia. Nuclear and cytoplasmic immunohistochemical staining ofp16 was observed in 338 (71%) ofthecases and showed significant direct associations with adverse tumour features, including high tumour grade (p < 0.0001), negative oestrogen receptor/progesterone receptor status (p < 0.001), and lymph node metastasis (p = 0.02). Our study revealed asignificant association between p16 protein expression and theestablished negative prognostic parameters in breast carcinoma including tumour grade, lymph node metastasis, and oestrogen receptor and progesterone receptor status.

Ovarian carcinosarcomas: p53 status defines two distinct patterns of oncogenesis and outcomes.

Ovarian carcinosarcoma (OCS) is a rare and lethal type of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, we aim to evaluate the molecular features of OCS and elucidate their clinical significance. We examined 30 OCS by immunohistochemistry (IHC) and targeted panel sequencing collected from a single institution (2003-2013) as the initial molecularly characterized cohort (Cohort A). From November 2016 to April 2023, we collected an additional 67 OCS cases from three institutions across British Columbia and Alberta as the contemporary cohort (Cohort B) for clinical correlation. The Kaplan-Meier method was used to estimate overall and progression-free survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant. The majority of OCS (82%) in the initial Cohort A were p53-mutated, and the carcinomatous component displayed the histological and molecular features of a high-grade tubo-ovarian serous carcinoma (HGSC-like). In a minority of OCS, the epithelial components were characteristics of endometrioid or clear cell carcinomas, and IHC staining was wild type for p53. In the contemporary Cohort B, we observed the same histological findings related to the p53 IHC staining pattern. The median overall survival of the p53-mutated HGSC-like OCS (47 patients) was significantly higher (43.5 months) compared with that of the p53 wild-type OCS (10 patients, 8.8 months; P < 0.01). Pathogenic BRCA1/2 germline/somatic mutations were observed in 7 patients (17.5%) of HGSC-like OCS, and all these patients were alive at 3 years from diagnosis compared to a 51% 3-year survival among the patients with BRCA1/2 wild-type HGSC-like OCS (33 patients) (p = 0.022). Majority of patients (6/7) with BRCA1/2-mutated OCS received poly (ADP-ribose) polymerase inhibitor as maintenance therapy in this cohort. Most OCSs have a morphologic and molecular profile resembling HGSC; however, some OCSs display a molecular profile that suggests origin through non-serous oncogenic pathways. This molecular distinction has both prognostic and treatment (predictive) implications. These findings underscore the importance of routine p53 IHC testing on all OCS and BRCA1/2 testing on p53-mutated OCS.

Early Identification of TP53 mutation in Myelodysplastic Neoplasms and Acute Myeloid Leukemia Via Point-of-Care p53 Immunohistochemistry

Background: Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) are heterogeneous diseases that often carry a poor prognosis. Once MDS or AML is diagnosed, first-line therapy choices include hypomethylating agent/venetoclax, induction chemotherapy, and/or targeted therapeutics as appropriate. Traditional “7+3” induction therapy has limited efficacy in in patients with TP53 disruption. Mutations in TP53 occur in at least 8% of de novo AML genomes, but turnaround time for next-generation sequencing (NGS) can be 10-14 days. Hence, it is possible that patients with TP53 mutation(s) will receive a regimen that will not be effective as it will not be known whether a patient has a TP53 mutation soon after diagnosis. Furthermore, health care disparities are amplified by the lack of readily available precision diagnostics in low- and middle-income countries (LMIC), leading to worse outcomes. Early identification of TP53 mutation through p53 immunohistochemistry (IHC) testing might allow for more timely prognostication and intervention. Methods: The UMass Chan Leukemia Registry and UMass Hematopathology archives identified patients with MDS or AML with TP53 disruption between 2011 and 2023. Immunohistochemical staining for p53 was performed on sections of bone marrow core biopsies by VENTANA CONFIRM anti-p53 (DO-7) primary antibody. Images were scored by manual counting by at least 2 separate hematopathologists. TP53 mutational analysis was performed as previously described (Patel SA , ..., Gerber JM. Leuk Lymphoma 2021; 62: 3348-60). For TP53 exome sequencing, the entire coding region from codons 1-393 of isoform A were covered, with coverage depth &amp;gt; 500X. The concordance between p53 IHC and the referent test ( TP53 mutational testing as the gold standard) was assessed. Results: Query of theUMass Leukemia Registry and UMass Hematopathology archives yielded 86 clinically annotated patients with MDS and AML with TP53 disruption. Among 42 patients with MDS (or its subentities) with TP53 disruption, 61 bone marrow biopsies had concurrently available data for p53 IHC and TP53 mutational testing. (Some cases were sequential biopsies from the same patient). Among 44 patients with AML (or its subentities) with TP53 disruption, 36 bone marrow biopsies had concurrently available data for p53 IHC and TP53 mutational testing. For patients with MDS with TP53 disruption, the sensitivity of p53 IHC testing was 68.1% and specificity was 93.3% (Panel A). For patients with AML with TP53 disruption, the sensitivity of p53 IHC testing was 75.8% and specificity was 100% (Panel B). Merged MDS and AML analysis showed sensitivity of 71.3% and specificity of 93.8%. When using a cutoff of ≥ 5% for p53 IHC testing, positive predictive value (PPV) was 100%. Conclusion: Our data show that p53 IHC testingdemonstrates high specificity and PPV but low sensitivity and negative predictive value (NPV), suggesting that IHC may be a valuable “rule-in” test. A cutoff value of ≥ 5% for IHC confers 100% PPV. This suggests that a positive IHC result may justify p53 IHC-adapted first-line choice of therapy, but a negative result does not exclude the possibility of TP53 mutation. IHC testing is a more cost-effective measure and is more readily available than NGS, which would make it an attractive alternative especially across global markets and in geographic regions marked by health care inequities, due to inability to access genomic testing. Limitations to our study include the relatively small sample size, as well as presence of TP53 mutations that prevent protein expression and thus prevent IHC positivity (i.e. stop codons and/or post-transcriptional modifications). Furthermore, results from our study may be distinct from other centers' studies given different inclusion criteria and non-uniform criteria for p53 staining analysis. However, our study retains value in that the use of a high-fidelity point-of-care p53 IHC staining method may lead to better outcomes with reduced financial toxicity and may inform first-line therapeutics if the IHC is positive. Further large-scale studies will be needed to confidently establish the p53 IHC staining method as the preferred surrogate for TP53 mutational testing. Additional work needs to be performed to assess the link between p53 staining pattern and TP53 allelic state. Earlier precision treatment may improve outcomes in this exceptionally high-risk population.

Evaluation of P53 immunostaining in patients with cutaneous melanoma.

P53 is a tumor suppressor gene that is mutated in numerous types of cancer. The aim of the present study was to determine the frequency of this mutation in cutaneous melanomas and to conduct clinicopathological characteristics and clinical outcome association analyses with the P53 mutation. P53 immunohistochemical staining was used as a surrogate marker for P53 mutation analysis to assess P53 status. In the present study, 50 pathological samples of cutaneous melanoma from 2012 to 2018 at Chulalongkorn University (Bangkok, Thailand), were subjected to anti-P53 immunohistochemistry, followed by an examination of the association between P53 statuses and clinical and pathological characteristics, along with clinical outcomes. A positive staining for anti-P53 antibody was detected in 30% of patients (15/50) with cutaneous melanomas. Positivity was significantly associated with female sex, nodular histological subtype and Breslow level 4. Cox regression analysis revealed that an age >65.5 years and Breslow grade 4 disease were associated with mortality. The Kaplan-Meier curve revealed a shorter duration of recurrence time in the P53 mutation than P53 wild type. In the present study, P53 mutations in specific cases of cutaneous melanoma were identified. Notably, patients who were older and/or had a Breslow score of 4 exhibited an increased risk of mortality. These findings suggested the potential involvement of P53 mutations in cutaneous melanoma, highlighting the necessity for further investigations to improve understanding of their roles.

Risk factors predicting pathological degradation after cervical excision in cervical intraepithelial neoplasia grade II P16-positive patients over 25 years old: a cross-sectional study.

Cervical intraepithelial neoplasia (CIN) is a collective term for pre-cancerous lesions associated with cervical invasive carcinoma. Treatment options depend on the development and progression of the disease. Especially for patients with CINII grade who are aged 25 years and older and have fertility requirements, it is a clinical challenge to determine whether to proceed with conservative or excisional treatment. Excisional treatment increases the risk of overtreatment outcomes, such as cervical insufficiency, preterm labor, miscarriage, and premature rupture of membranes, in young women with childbearing potential. P16 immunohistochemical staining has greatly improved the consistency of CINII patient's diagnosis. The aim of this study was to analyze the risk factors predicting pathological degradation after cervical excision in cervical intraepithelial neoplasia grade II P16-positive patients over 25 years old, and to provide information to help optimize clinical treatments patients with CINII disease. Single-factor and logistic regression models were used to analyze the risk factors for pathological downgrading in the CINII/P16-positive (+) group. The predicted probability of pathological downgrading in the CINII/P16(+) group of patients was calculated according to the logistic regression model to generate a new variable multi-indicator association for receiver operating characteristic (ROC) curve plotting to determine the predictive ability. A total of 248 women who met the inclusion and exclusion criteria were included. Statistical analysis showed that the CINII/P16(+) group had a higher pathological downgrading rate compared with the CINIII group after cold knife conization (CKC) (χ2=6.26, P=0.012). Univariate factors showed that the differences were statistically significant when comparing age, number of biopsy-involved quadrants, menopausal status, and involvement of glands, respectively (P<0.05). In contrast, the differences were not statistically significant when comparing cytological findings, type of transformation zone, high-risk human papilloma virus (HR-HPV) testing, abortion status, pregnancy frequency, time from diagnosis to CKC and Ki67 percentage between the two groups. Multifactorial logistic regression showed that the extent of biopsy CINII involvement [odds ratio (OR), 1.589], menopausal status (OR, 4.031), and glandular involvement (OR, 5.549) were all independent risk factors for pathological downgrading in the CINII/P16(+) patient group (P<0.05). The order of significance of the areas under the ROC curve (AUCs) was as follows: combined multiple indicators (AUC 0.716) > gland involvement (AUC 0.625) > biopsy CINII involvement extent (AUC 0.614) > menopausal status (AUC 0.565). A higher rate of pathological downgrading after CKC was found in CINII/P16-positive patients who were aged over 25 years. Overtreatment exists in patients with CINII/P16-positive diagnosis. Independent factors for pathological downgrading were identified by the factors including if the lesion involved the gland, the extent of CINII involvement on biopsy, and menopausal status.

Accurate interpretation of p53 immunohistochemical patterns is a surrogate biomarker for TP53 alterations in large B-cell lymphoma

BackgroundTo clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations.MethodsA total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists.ResultsForty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility.ConclusionsThe p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Sodium orthovanadate exhibits anti-angiogenic, antiapoptotic and blood glucose-lowering effect on colon cancer associated with diabetes.

The presence of type 2 diabetes mellitus increases the risk of developing the colon cancer. The main objective of this study was to determine the role of sodium orthovanadate (SOV) in colon cancer associated with diabetes mellitus by targeting the competitive inhibition of PTP1B. For in vivo study, high fat diet with low dose streptozotocin model was used for inducing the diabetes mellitus. Colon cancer was induced by injecting 1,2-dimethylhydrazine (25mg/kg, sc) twice a week. TNM staging and immunohistochemistry (IHC) was carried out for colon cancer tissues. In vitro studies like MTT assay, clonogenic assay, rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry were performed on HCT-116 cell line. CAM assay was performed to examine the anti-angiogenic effect of the drug. Sodium orthovanadate reduces the blood glucose level and tumor parameters in the animals. In vitro studies revealed that SOV decreased cell proliferation dose dependently. In addition, SOV induced apoptosis as depicted from rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry as well as p53 IHC staining. SOV showed reduced angiogenesis effect on eggs which was depicted from CAM assay and also from CD34 and E-cadherin IHC staining. Our data suggest that SOV exhibits protective role in colon cancer associated with diabetes mellitus. SOV exhibits anti-proliferative, anti-angiogenic and apoptotic inducing effects hence can be considered for therapeutic switching in diabetic colon cancer.

The fading guardian: clinical relevance of TP53 null mutation in high-grade serous ovarian cancers.

we evaluated the concordance between immunohistochemical p53 staining and TP53 mutations in a series of HGSOC. Moreover, we searched for prognostic differences between p53 overexpression and null expression groups. patients affected by HGSOC were included. For each case p53 immunohistochemical staining and molecular assay (Sanger sequencing) were performed. Kaplan-Meier survival analyses were undertaken to determine whether the type of TP53 mutation, or p53 staining pattern influenced overall survival (OS) and progression free survival (PFS). 34 HGSOC were considered. All cases with a null immunohistochemical p53 expression (n=16) showed TP53 mutations (n=9 nonsense, n=4 in-frame deletion, n=2 splice, n=1 in-frame insertion). 16 out of 18 cases with p53 overexpression showed TP53 missense mutation. Follow up data were available for 33 out of 34 cases (median follow up time 15 month). We observed a significant reduction of OS in p53 null group [HR = 3.64, 95% CI 1.01-13.16]. immunohistochemical assay is a reliable surrogate for TP53 mutations in most cases. Despite the small cohort and the limited median follow up, we can infer that HGSOC harboring p53 null mutations are a more aggressive subgroup.

P53 Immunohistochemical Staining and TP53 Gene Mutations in Endometrial Cancer: Does Null Pattern Correlate With Prognosis?

Whether immunohistochemistry (IHC) of p53 accurately reflects the TP53 mutational status of endometrial carcinoma (EC) has not yet been established. This study aimed to clarify the relationship between p53 IHC and TP53 mutations in EC and to examine whether p53 IHC can be a more convenient prognostic marker than TP53 mutation in EC. We performed p53 IHC staining of EC samples obtained via surgery and genetic analyses using next-generation sequencing. p53 IHC results showed that of the 101 cases, 71 (70%) were wild-type (WT), 12 (12%) were overexpression (OE), and 18 (18%) were in the null group. Missense mutations were found in 9 cases (47.4%) in OE, 2 (10.5%) in null, and 8 (42.1%) in the WT group. Truncating mutations were found in 1 case (8.3%) in OE, 6 (50%) in null, and 5 (41.7%) in the WT group. The 5-year progression-free survival was 0% in OE, 74.8% in null, and 79.0% in the WT group. In the prognosis for each type of TP53 mutation, the 5-year progression-free survival was missense (32.2%), truncating (65.6%), and WT (79.7%). These survival comparisons showed that the p53 IHC OE had the poorest prognosis. These results suggest that the p53 IHC OE is an independent poor prognostic factor for EC and can be used as a simple and rapid surrogate marker for TP53 mutations. Contrastingly, the complete absence of p53 IHC-the null staining pattern-may not accurately predict a TP53 mutation in EC, and it is necessary to be more careful in making the diagnosis of "abnormal."

Rearrangement of KMT2A Characterizes a Subset of Pediatric Parotid Mucoepidermoid Carcinomas Arising Metachronous to Acute Lymphoblastic Leukemia

Introduction: Metachronous mucoepidermoid carcinomas (MMEC) may occur in association with childhood leukemias and lymphomas. We compared molecular abnormalities of MMEC in patients with ALL with the abnormalities found in primary mucoepidermoid carcinomas (MECs) in pediatric cases and young adults. Materials and methods: Immunohistochemical stains for p63 and SOX10, molecular alterations in MAML2 and KMT2A genes detected by FISH and/or next-generation sequencing were studied in 12 pediatric MMECs secondary to ALL and six primary MECs in pediatric patients and young adults. Follow-up information of patients in both groups was obtained. Results: KMT2A rearrangements were detected in pediatric MMECs, and they were associated with remarkable histomorphological changes, including deposits of abundant stromal collagen and intratumoral lymphoid proliferations. No KMT2A rearrangements were found in primary MECs. The prognosis of MMEC in patients with ALL, especially in KMT2A-rearranged cases, was worse than in primary MECs. Kruskal-Wallis test showed a statistically significant difference in overall survival between KMT2A-rearranged MMECs and KMT2A-intact MMECs in cases with ALL (p = 0.027). Conclusion: KMT2A-rearranged MMECs in ALL patients may have inherently more aggressive behavior, even when the histomorphology of MMEC suggests a low-grade malignancy.