Aberrant P53 Research Articles

Comprehensive Clinicopathological and Immunohistochemical Analysis of Human Papillomavirus-independent Squamous Cell Carcinoma and Adenosquamous Carcinoma of the Uterine Cervix.

Human papillomavirus-independent (HPVI) squamous cell carcinoma (SCC) and adenosquamous carcinoma (ASC) of the uterine cervix are extremely rare. The aim of this study was to comprehensively describe the clinicopathological features, patient outcomes, and immunophenotypes of HPVI SCC and ASC. We found four and two patients with HPVI SCC and ASC, respectively, and reviewed their electronic medical records and pathology slides. We also performed immunostaining for p16 and p53. All except one patient underwent surgery. Two, one, and one patients with HPVI SCC were diagnosed as having IIIC1, IVA, and IVB diseases, respectively. Two patients with HPVI SCC experienced recurrences, and died of disease within nine months after treatment initiation. Both patients with HPVI ASC developed lung metastasis at four months post-operatively. HPVI SCCs and the squamous component of HPVI ASCs showed keratinizing, condylomatous, or poorly differentiated morphology. The glandular component of HPVI ASCs was gastric-type endocervical adenocarcinoma. None of the six tumors exhibited block positivity for p16. Two HPVI SCCs and one HPVI ASC displayed aberrant p53 expression. HPVI SCC is a rare and aggressive cervical malignancy that presents initially as advanced-stage disease with poor prognosis. Although the patients with initial stage I and II HPVI ASC were treated with curative intent, distant metastases appeared in the lungs during the early course of treatment. Further investigations are necessary to clarify the association between histological features and clinical behavior of HPVI ASC.

Vulvar squamous cell carcinoma: The role of p53 and p16 immunohistochemistry

Vulvar squamous cell carcinomas (SCC) represent a heterogeneous group of patients with implications for prognosis and response to treatment. Human papillomavirus (HPV)-associated SCC is characterised by p16 positivity, whereas non-HPV SCC often shows aberrant p53 expression. We conducted a retrospective analysis involving 148 patients with vulvar SCC from two Gynecologic Oncology units from Sydney, Australia. Patients’ demographics, tumor characteristics, types of treatment and survival were analyzed and compared to p16 and p53 immunohistochemistry status. The p16-positive group was younger and included a higher prevalence of smokers, while the p53-positive group demonstrated greater comorbidity indices and was associated with tumor features that are independently related to poor prognosis. Compared to p16-positive patients our study has shown significantly higher recurrence rates and lower overall survival in the p53-positive group. Our findings support existing literature, emphasizing the prognostic significance of p16 and p53 in vulvar SCC. Despite the retrospective nature and variations in immunohistochemistry reporting, our study provides valuable insights into patient outcomes, particularly in a demographically diverse population. Future research, like the STRIVE trial, may determine if implementation of p16 and p53 stratified management algorithm will improve outcomes for women with vulvar SCC (McAlpine, 2024).

HPV-Independent Cervical Adenocarcinoma Discovered by Cytology-Based Screening: A case report of gastric type adenocarcinoma of the uterine cervix from cytopathology to histopathology

Abstract Introduction/Objective In recent years, the relative prevalence of adenocarcinoma has increased, comprising 20–25% of all cervical carcinomas in developed countries. Approximately 15% of cervical adenocarcinomas are unrelated to human papilloma virus (HPV) infection. With the shift toward HPV primary testing, an increased understanding of HPV-independent cervical adenocarcinomas becomes more important. Methods/Case Report This case report demonstrates a rare case of gastric-type adenocarcinoma (GAS) of the cervix discovered during a routine well-woman exam. Patient-reported episodes of vaginal spotting were noted prior to screening. HPV testing by PCR on the initial pap smear was negative. Cytology findings raised concerns about endocervical glandular cell abnormalities. Subsequent cervical biopsy revealed GAS, a finding supported by positive CK7, MUC5AC, CDX2, and aberrant (mutant) p53 expression by immunohistochemistry. HPV independence was further confirmed by negative results on mRNA ISH for high-risk HPV and HPV16/18. Results (if a Case Study enter NA) NA Conclusion Here we discuss the impact of cytology-based screening on HPV-independent cervical cancers, with focus on adenocarcinoma. While the move to primary HPV screening has been shown to be effective at identifying HPV-related neoplasms, it ineffectively addresses HPV-independent malignancies. In this particular population, cytology-based screening remains indispensable. The described case demonstrated subtle cytologic features consistent with endocervical glandular abnormality, ultimately correlating with subsequent histologic findings of HPV-independent GAS. Negative HPV results combined with subtle cytomorphologic changes displayed by some adenocarcinomas on PAP smear could present a significant diagnostic pitfall. Additionally, p16+ expression attributable to aberrant p53 pathways (rather than HPV) may further contribute to potential diagnostic errors. While further research into best practices for early detection of HPV-independent cervical neoplasias should be conducted, this team suggests both clinical survey and referral for cytologic screening following reports of abnormal vaginal bleeding and/or watery discharge and screener education focused on cervical GAS.

Lower expressions of MIR34A and MIR31 in colo-rectal cancer are associated with an enriched immune microenvironment

IntroductionMicroRNAs (MIRs) play a crucial role in colorectal cancer (CRC) development and metastasis by regulating immune responses. Tumour-infiltrating lymphocytes (TILs) are an important predictive factor in many cancers, but, their association with microRNAs have not been studied well in colorectal cancer. Three microRNAs (MIR34A, MIR31 & MIR21), the roles of which in tumorigenesis is well-studied and which also possess immunomodulatory effect, were identified by extensive literature search. Of these, MIR34A acts as a tumour suppressor, MIR21 is considered an onco-MIR, and MIR31 displays both tumour-suppressing and oncogenic properties, making it ambiguous. This study examines the relationship between these three micro-RNAs and TILs in CRC. Materials & methodsConducted over 18 months at a tertiary cancer care hospital in southern India, this unicentric observational study included 69 cases. These cases were analyzed for miR expression using q-RT-PCR, TILs density through hematoxylin & eosin(H&E) slide examination, and p53 and beta-catenin expression via immunohistochemistry (IHC). Correlations between non-parametric variables were assessed using Chi-square and Spearman correlation tests. ResultsThe study found significantly higher MIR34A expression in patients aged 60 years and less (26/41, p=0.024) and a higher prevalence of MIR21 in male patients (23/35, p=0.012). TILs at the tumour advancing front were categorized as low (≤10 %) or high (≥15 %). Among the 36 cases with low TILs, high MIR34A and high MIR31 expressions were observed in 24 cases (p=0.016) and 23 cases (p=0.03), respectively. Conversely, 21 of 33 cases with high TILs had low expressions of both MIR34A and MIR31. High TILs were more common in early-stage CRC (TNM stages I-IIIA), with 20 out of 28 cases, compared to 28 of 41 cases in later stages (IIIB-IVC) exhibiting low TILs (p=0.003). Aberrant p53 expression correlated with lower MIR34A levels, consistent with TCGA data. ConclusionLower MIR34A and MIR31 levels are associated with higher TILs density in CRC. Unlike other cancers where MIR34A has anti-tumour effects, there was no statistically significant correlation between its expression and the pT or TNM stages in this study. Increased TILs being a good prognostic indicator, this suggests MIR34A and MIR31 may help CRC cells evade immune surveillance. Aberrant p53 expression downregulates MIR34A, underscoring the therapeutic potential of miRs.

Utility of IMP3, p53, and S100P immunohistochemical stains in distinguishing reactive atypia from dysplasia in cholecystectomy specimens

BackgroundDistinguishing reactive atypia from dysplasia in cholecystectomy specimens can be histologically challenging. The aim of this study was to evaluate the utility of IMP3, p53, and S100P immunostains in differentiating reactive atypia from dysplasia in cholecystectomies.MethodsFifty-four cholecystectomies were reviewed and characterized into 5 groups: 2 normal, 29 reactive atypia, 16 low-grade dysplasia, 2 high-grade dysplasia, and 5 adenocarcinoma. IMP3, p53, and S100P immunostains were performed and evaluated. IMP3 (nuclear) and S100P (nuclear or nuclear/cytoplasmic) were categorized into negative or positive expression, and p53 was categorized into wild-type and aberrant/mutant expression. Chi-square test was used for statistical analysis.ResultsThe patients were mostly middle-aged women (mean 44, range 19–87 years, 81% female), with predominantly Hispanic White ethnicity (80%). The majority of the normal and reactive atypia cases showed negative IMP3 (100% and 75.9%, respectively) and wild-type p53 (100% and 89.7%, respectively) staining. Over half (56.3%) of the low-grade dysplasia and all the high-grade dysplasia cases showed IMP3 positivity. Aberrant p53 staining pattern was seen in half of both low and high-grade dysplasia cases. Adenocarcinoma showed IMP3 positivity in 80% and p53 aberrancy in all cases. S100P showed no statistical significance among the diagnostic categories. Significant differences in staining patterns were found between reactive atypia vs. low-grade dysplasia, and reactive atypia vs. low-grade + high-grade dysplasia using a combination of IMP3 and p53 stains (all p < 0.05).ConclusionsIn challenging cholecystectomies, IMP3 positivity or aberrant p53 expression may serve as a useful adjunct to support a diagnosis of dysplasia over reactive atypia.

Aberrant p53 immunostaining patterns in breast carcinoma of no special type strongly correlate with presence and type of TP53 mutations

Recent studies have revealed an association between TP53 mutations and endocrine resistance in hormone receptor-positive, HER2-negative breast cancer (HR + HER2 −BC). Aberrant p53 immunostaining (IHC) patterns may provide a surrogate marker for TP53 mutations. Building upon a ternary algorithm of aberrant staining patterns, this study evaluates the reliability of p53 IHC as screening tool for TP53 mutations in BC (NST). Furthermore, it describes the histopathological and molecular characteristics of TP53-mutated cases, along with the mutational status of PIK3CA. This study comprised 131 early-stage, node-negative BCs with available core biopsies and resection specimens. Cases were categorized as follows: HR + HER2 − (85 cases), HER2 + (21 cases) and triple negative (TN, 25 cases). Aberrant IHC staining patterns for p53 were defined as overexpression (OE), complete absence (CA) and cytoplasmic (CY). In addition, targeted sequencing of TP53 and PIK3CA genes was performed. TP53 mutations were identified in 53 of 126 cases (42.1%). Within HR + HER2 − cases, TP53 mutations were found in 17 of 80 cases (21.3%). IHC accurately predicted TP53 mutation in 96.2% of cases with a specificity of 100%. Additionally, there was a significant agreement between missense mutations and OE, as well as between truncating mutations and CA (κ 73% and 76%). CY was observed in two TN cases with truncating mutations within the nuclear localization signalling domain of p53. TP53-mutated cases exhibited higher grade, greater nuclear pleomorphism and higher Ki-67 proliferation index and were associated with the PIK3CA wild-type status (p < 0.001). p53 IHC may provide a useful screening tool for identifying TP53-mutated BC of NST.

Inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1: a case report

BackgroundInflammatory rhabdomyoblastic tumors are relatively recently recognized soft tissue tumors with a low malignant potential. Here, we present a case of concurrent inflammatory rhabdomyoblastic tumor (IRMT), adrenal pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1 (NF1). To our knowledge, this is the first time that this constellation of tumors has been described in the literature.Case presentationA female patient in her late 20s with known NF1 was diagnosed with an inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a short succession. IRMT was found to harbor a near-haploid genome and displayed a typical immunohistochemical profile as well as a focal aberrant p53 expression pattern.ConclusionsThis case report strengthens the theory that defects in the tumor suppressor NF1 play a central role in the pathogenesis of inflammatory rhabdomyoblastic tumors and that IRMT may be part of the spectrum of neurofibromatosis type 1 related tumors.

Redefining aberrant P53 expression of gastric cancer and its distinct clinical significance among molecular-histologic subtypes

BackgroundNumerous studies have demonstrated a correlation between p53 overexpression and diminished survival in gastric cancer patients. However, conflicting findings exist, and we hypothesize that these discrepancies arise from the cancer's complexity and heterogeneity, coupled with a lack of consensus on aberrant p53 expression. MethodsWe enrolled a cohort of 187 patients with surgically resected gastric cancer. Patient categorization was based on Epstein–Barr virus (EBV), microsatellite instability (MSI), and Lauren classification (intestinal, diffuse and mixed). Utilizing an incremental algorithm, we evaluated p53 immunohistochemical (IHC) patterns in all 187 cases, while next-generation sequencing was successfully performed on 152 cases to identify TP53 mutations (mutTP53). ResultsMutTP53 was identified in 32 % of the 152 cases, comprising 36 missense, 5 nonsense, and 7 frameshift alterations. Missense mutations predominantly correlated with p53 overexpression, while nonsense and frameshifting alterations related to null expression. Trial calculations indicated that null expression and a p53 IHC cutoff at >40 % offered the best prediction of mutTP53 (kappa coefficient, 0.427), with the highest agreement (0.524) observed in diffuse type and the lowest (0.269) in intestinal type. Null expression and a p53 IHC cutoff at >10 %, but not mutTP53 per se, provided the optimal prediction of survival outcome (p = 0.043), particularly in diffuse type (p = 0.044). Multivariate analysis showed that aberrant p53 IHC expression was not an independent prognostic factor. ConclusionsP53 IHC patterns are predictive biomarkers for mutTP53 and gastric cancer outcomes, where a prerequisite involves a nuanced approach considering cutoff values and molecular-histologic subtyping.

Proposed diagnostic and prognostic markers of primary malignant hepatic vascular neoplasms

IntroductionPrimary malignant hepatic vascular tumors with various malignant potentials include epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), which may overlap pathologically. This study aimed to compare the pathological findings of hepatic EHE with those of AS, in association with patient outcomes.MethodsFifty-nine histologically confirmed patients with 34 EHE and 25 AS were admitted to a tertiary hospital from 2003 to 2020. Their EHE and AS pathological features were compared. Immunohistochemistry for CD31, ERG, CAMTA-1, TFE3, P53, and Ki-67 labeling was performed on paraffin-embedded blocks. Markers, along with histological findings, were analyzed for the purposes of diagnostic and prognostic significance by multivariate analysis.ResultsCAMTA-1 was 91.2% positive in EHE, but negative in AS (p = < 0.001). AS was significantly correlated to an aberrant p53 expression, high Ki-67 labeling, and high mitotic activity, compared to EHE (all, p = < 0.001). EHE can be classified as low grade (LG) and high grade (HG) using the prognostic values of mitotic activity and ki-67 labeling (sensitivity = 1, specificity = 1). Low grade-EHE showed significantly better overall survival than high grade-EHE (p = 0.020).ConclusionsImmunohistochemistry for CAMTA-1, P53, and Ki-67 labeling may help distinguish EHE and AS in histologically ambiguous cases, especially small biopsied tissue. Moreover, the combination of mitotic activity and Ki-67 labeling can be a prognostic factor for EHE with various clinical features.

Immunohistochemistry as an adjunct for challenging histological patterns of borderline Brenner tumors: An illustrative study of 4 cases

Borderline Brenner tumors (BBT) have a range of morphology that shows considerable overlap with that of malignant Brenner tumors (MBT). In particular, two histological patterns of BBT can be particularly challenging: 1) BBT with intraepithelial carcinoma (BBT-IEC) and 2) BBT with a small nested pattern (BBT-SNP). BBT-IEC is characterized by a tumor with the low-power non-infiltrative silhouette of a conventional BBT, but with increased cytological atypia and mitotic activity similar to that of MBT. Conversely, BBT-SNP is characterized by a complex proliferation of small tumor nests that closely resemble the infiltrative growth pattern of MBT, but without the obligate cytologic atypia and mitotic activity of MBT.We suggest that the combination of p16, p53 and Ki-67 may be helpful in distinguishing these 2 patterns of BBT from both conventional BBT and from MBT. While both conventional BBT and BBT-IEC show a null pattern of p16 expression, our case of BBT-IEC showed aberrant p53 overexpression, albeit with a maturation pattern similar to that described for TP53 mutant mucinous ovarian carcinoma and differentiated vulvar intraepithelial neoplasia (dVIN). Similarly, while BBT-SNP shows an infiltrative-like growth pattern similar to that of MBT, our case also showed a wild-type pattern of p53 expression and a Ki-67 proliferative index similar to areas with conventional BBT histology. In conclusion, in our small case series, we show that the use of immunohistochemistry for p53 and Ki-67 may help to distinguish challenging patterns of BBT from MBT. Further studies are needed to validate this finding in a larger case cohort.

HER2-low and Overexpression in Mucinous Ovarian Cancer: Analysis of ASCO/CAP and ToGA Immunohistochemical Scoring.

Mucinous ovarian carcinoma is an uncommon malignancy characterized by resistance to chemotherapy and poor survival in the metastatic setting. HER2 amplification is a frequent late event in carcinogenesis, yet the incidence of HER2-low in mucinous ovarian carcinoma is unknown. Further, the optimal method for determining overexpression in these tumors is not established. We sought to assess the ASCO/CAP and ToGA trial scoring methods for HER2 IHC with correlation to FISH, p53, and mismatch repair protein status and to determine the incidence of HER2-low in mucinous ovarian carcinoma. A total of 29 tumors from 23 patients were included. Immunohistochemistry for HER2, p53, MLH1, PMS2, MSH2, and MSH6 was performed. Scoring was performed according to the ASCO/CAP and ToGA trial criteria. HER2 FISH was performed and scored according to the ASCO/CAP criteria. The proportion of HER2-low, defined as 1+ or 2+ staining with negative FISH, was determined. Using ASCO/CAP, 26% demonstrated 3+ while 35% demonstrated 2+ staining. Using ToGA, 30% demonstrated 3+ while 57% demonstrated 2+ staining. By FISH, 26% were positive for HER2 amplification. Both systems captured all FISH-positive cases; the use of ASCO/CAP resulted in fewer equivocal and false-positive cases. Among HER2-negative cases, 88% were HER2-low. Aberrant p53 expression was detected in 55% of cases; mismatch repair deficiency was not identified in any cases. ASCO/CAP guidelines are accurate and resource-effective in determining HER2 overexpression in mucinous ovarian carcinoma. HER2-low is common in these tumors; further studies to determine the role of HER2-targeted therapy including antibody-drug conjugates are indicated.

Gastric Type Endocervical Adenocarcinoma With Concurrent High-Grade Squamous Intraepithelial Lesion: A Clinicopathologic Study of Three Patients.

We investigate gastric-type endocervical adenocarcinoma (ECA), a prominent HPV-independent adenocarcinoma, and its coexistence with high-grade squamous intraepithelial lesion (HSIL) through the examination of three such tumors. In this study, we conducted an in-depth review of three patients with gastric-type ECA, each associated with high-risk HPV infection as detected on Pap smears. We detailed the clinical and pathological features of each patient and utilized RNAscope for high-risk HPV testing to ascertain HPV status in both gastric-type ECA and HSIL components. Immunohistochemistry with p16, p53, and other biomarkers was also applied. The gastric-type ECA component, characterized by well-differentiated glands with abundant, clear to eosinophilic cytoplasm, distinct cellular borders, and pale nuclei with conspicuous nucleoli, tested negative for both p16 and high-risk HPV, unlike the concurrent HSIL components which were positive. Additionally, two tumors showed aberrant p53 protein expression in the gastric-type ECA areas, and elevated carbohydrate antigen19-9 levels were noted in two patients. Treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy, supplemented by chemotherapy and/or radiation, with disease-free intervals of 24, 12, and 40 months post-treatment, respectively. This study highlights the critical need for meticulous diagnostic protocols that combine morphological examination, immunohistochemistry, and HPV RNA in situ hybridization. The rarity of gastric-type ECA coexisting with HPV infection underscores the necessity for continuous research and vigilant monitoring in the field of gynecological oncology.

Clinicopathological Significance of Nucleosome Remodeling and Deacetylase Complex Expression in Endometrial Carcinoma.

Only a few studies have examined the expression of nucleosome remodeling and deacetylase complex in endometrial carcinoma (EC). The aim of this study was to analyze the expressions of histone deacetylase (HDAC1), HDAC2, and chromodomain helicase DNA-binding protein 4 (CHD4) in EC. Sixty cases of EC were categorized into two clusters based on the expression levels of the three proteins. Cluster 1 (C1) exhibited elevated expressions of HDAC2 and CHD4 compared with cluster 2 (C2). Notably, 75% of cases in C2 represented non-aggressive histological types, whereas 37.5% of cases in C1 manifested aggressive types. C2 exclusively comprised pathological tumor stage 1 (pT1) tumors, whereas C1 included pT2 and pT3 tumors. In C1, 25% of cases displayed aberrant p53 expression, contrasting with the absence of such expression in C2. Furthermore, only one patient in C2 experienced disease recurrence, whereas 20.8% of patients in C1 developed recurrent tumors. High HDAC2 and CHD4 expression may be associated with adverse clinicopathological characteristics in EC. Further studies are needed to validate these results.

O198: Cytosponge: Innovative technology in Barrett’s oesophagus surveillance

Abstract Introduction British Society of Gastroenterology guidance recommends oesophagogastroduodenoscopy (OGD) for Barrett’s oesophagus surveillance with quandrantic biopsies for every 2cm length of Barrett’s. The Covid pandemic led to delays in Barrett's surveillance and prolongation of surveillance intervals. This study assessed the potential role of Cytosponge, a novel cytology sampling device, in Barrett's surveillance. Methodology All patients due Barrett's surveillance in 2022/23 were identified and screened to assess suitability for Cytosponge. Cytology results and associated early clinical outcomes were assessed. Results 193 patients (77%) were suitable for Cytosponge, and 175 of these (90%) did not require OGD. 18 patients (10%) required urgent OGD for inadequate cytology samples (3), cellular atypia (8), aberrant p53 (3) or dysplasia (4). 2 patients had high grade dysplasia on subsequent OGD, successfully treated with radiofrequency ablation. No diagnosis of oesophago-gastric cancer was made during the follow-up period. By July 2023, 282 patients with Barrett’s oesophagus had completed Cytosponge assessment; minimum follow-up was 4 months and no patients had developed ‘inter-test’ malignancy. Conclusion These data are promising and suggest that endoscopy and biopsy may not be required for all Barrett’s surveillance. Cytology samples alone may be sufficient to assess for epithelial dysplastic and neoplastic change in Barrett’s surveillance, with judicious utilisation of endoscopy resources where indicated and necessary. Patients who received a Cytosponge in 2022 will be due for endoscopic surveillance in 2024 – these data will provide valuable additional information about the role of Cytosponge in Barrett’s surveillance and whether endoscopy can be replaced altogether.

STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response.

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

Abstract A051: Prior chlamydial infection and ovarian cancer risk by tumor p53 expression

Abstract A051: Prior chlamydial infection and ovarian cancer risk by tumor p53 expression

A Case of Aggressive Lung Squamous Cell Carcinoma With Aberrant Cytoplasmic p53 Aggregation.

Immunohistochemistry for p53 was a well-established method for cancer diagnosis in pathology. Aberrant cytoplasmic p53 positivity reflects the accumulation of p53 aggregates, which has been shown to be associated with chemoresistance and to be a predictive marker of a worse clinical course in ovarian cancer. A 65-year-old Japanese man was diagnosed with lung cancer, and surgical resection was performed. Multiple metastasis were found 21 months post-surgery. The lesions were resistant to chemotherapy, and he succumbed to the disease 29 months post-surgery. The resected primary lesion was pathologically diagnosed as squamous cell carcinoma, with notable cytoplasmic p53 positivity indicated by immunohistochemistry. Notable aberrant cytoplasmic accumulation of p53 aggregate was observed in the cancer cells of this case. Chemotherapy was ineffective for the recurrent lesions, suggesting a role of p53 aggregates in chemoresistance. Pathological analysis of p53 via immunohistochemistry may be useful in predicting chemoresistance of lung squamous cell carcinoma.

Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer.

The clinical features of sporadic mismatch repair deficiency (MMRd) and Lynch syndrome (LS) in Japanese patients with endometrial cancer (EC) were examined by evaluating the prevalence and prognostic factors of LS and sporadic MMRd in patients with EC. Targeted sequencing of five LS susceptibility genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) was carried out in 443 patients with EC who were pathologically diagnosed with EC at the National Cancer Center Hospital between 2011 and 2018. Pathogenic variants in these genes were detected in 16 patients (3.7%). Immunohistochemistry for MMR proteins was undertaken in 337 of the 433 (77.9%) EC patients, and 91 patients (27.0%) showed absent expression of at least one MMR protein. The 13 cases of LS with MMR protein loss (93.8%) showed a favorable prognosis with a 5-year overall survival (OS) rate of 100%, although there was no statistically significant difference between this group and the sporadic MMRd group (p = 0.27). In the MMRd without LS group, the 5-year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log-rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.

P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation.

The genes coding for the tumor suppressors p53 and retinoblastoma (Rb) are inactivated in the vast majority of small cell lung cancer (SCLC) tumors. Data support the notion that these two deleterious genetic events represent the initial steps in the development of SCLC, making them essential for a lung epithelial cell to progress toward the acquisition of a malignant phenotype. With the loss of TP53 and RB1, their broad tumor suppressive functions are eliminated and a normal cell is able to proliferate indefinitely, escape entering into cellular senescence, and evade death, no matter the damage it has experienced. Within this setting, lung epithelial cells accumulate further oncogenic mutations and are well on their way to becoming SCLC cells. Understanding the molecular mechanisms of these genetic lesions and their effects within lung epithelial cells is of paramount importance, in order to tackle this aggressive and deadly lung cancer. The present review summarizes the current knowledge on p53 and Rb aberrations, their biological significance, and their prospective therapeutic potential, highlighting completed and ongoing clinical trials with agents that target downstream pathways.

Immunohistochemistry in the Differential Diagnosis of Triple Negative Breast Carcinoma and High-grade Serous Carcinoma: Old and New Markers.

Distinction of metastasis to the breast from a breast primary, particularly high-grade triple-negative breast cancer (TNBC), can be challenging due to nonspecific morphology and immunohistochemical (IHC) profiles. Among metastases to the breast, high-grade serous carcinoma (HGSC) of müllerian origin is most likely to be misdiagnosed as TNBC. We assessed breast and müllerian markers on TNBC and HGSC, including keratin 7, keratin 20, GATA3, GCDFP15, mammaglobin, p53, PAX8 (MRQ50 and BC12 clones), TRPS1, SOX10, and WT1. Of 151 TNBC cases, TRPS1 had the highest sensitivity, showing expression in 149 (98.7%) cases, followed by SOX10 (110/151; 72.8%), GATA3 (102/151; 67.5%), GCDFP15 (29/151; 19.2%), and mammaglobin (27/151; 17.9%). PAX8 positivity was seen in 40.4% (61/151) of TNBC via the MRQ50 clone but was negative in all via the BC12 clone. Of 185 HGSC cases, PAX8 via the MRQ50 clone was the most sensitive (179/185; 96.8%), followed by WT1 (171/185; 92.4%) and PAX8 via the BC12 clone (164/185; 88.6%). In addition, TRPS1 positivity was seen in 75 HGSC cases (40.5%). Aberrant p53 patterns were seen in 64.9% (98/151) of TNBC and 94.1% (174/185) of HGSC. TRPS1 positivity in HGSC and PAX8 positivity via the MRQ50 clone in TNBC represent potential pitfalls in assessing high-grade carcinoma for which the differential diagnosis includes TNBC and HGSC. However, with this knowledge, utilization of a panel of breast and müllerian markers, including preferential use of the PAX8 BC12 clone, can facilitate accurate diagnosis.