Probes for TP53

Human papillomavirus (HPV)-independent primary endometrial squamous cell carcinoma (PESCC) is a rare but aggressive subtype of endometrial carcinoma for which little is known about the genomic characteristics. Traditional criteria have restricted the diagnosis of PESCC to cases without any cervical involvement. However, given that modern ancillary techniques can detect HPV and characteristic genetic alterations that should identify the more common mimics in the differential diagnosis, including endometrial endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma, those criteria may benefit from revision. To further characterize PESCC, we identified 5 cases of pure squamous cell carcinoma dominantly involving the endometrium that had the potential to be PESCC: 1 case involving only the endometrium and 4 cases with some involvement of the cervix. Clinicopathologic features were assessed and immunohistochemical analysis (p16, estrogen receptor, progesterone receptor, and p53), HPV RNA in situ hybridization (high-risk and low-risk cocktails and targeted probes for 16 and 18), and molecular studies were performed. All tumors showed aberrant/mutation-type p53 expression, were negative for estrogen receptor, progesterone receptor, and p16, and had no detectable HPV. Per whole-exome sequencing, 4 of the 5 tumors demonstrated comutations in TP53 and CDKN2A (p16). Four patients died of disease within 20 months (range, 1 to 20 mo; mean, 9 mo), and 1 patient had no evidence of disease at 38 months. PESCC represents a unique, clinically aggressive subtype of endometrial cancer with TP53 and CDKN2A comutations. This characteristic profile, which is similar to HPV-independent squamous cell carcinoma of the vulva, is distinct from endometrioid carcinoma with extensive squamous differentiation and HPV-associated primary cervical squamous cell carcinoma and can be used to distinguish PESCC from those mimics even when cervical involvement is present. Diagnostic criteria for PESCC should be relaxed to allow for cervical involvement when other pathologic features are consistent with, and ancillary techniques are supportive of classification as such.

Background Differentiated vulvar intraepithelial neoplasia (dVIN) is a non-human papilloma virus (HPV)-related high-grade precursor lesion to vulvar squamous cell carcinoma (vSCCa). Although TP53 gene mutations have been identified in 80% of dVIN, its role in dVIN pathogenesis as well as malignant transformation is still being poorly understood. Poor reproducible diagnostic criteria and ambiguous p53 immunostaining patterns, along with morphologic discordance still pose a diagnostic challenge. Methods A series of 60 cases of dVIN-related vSCCa along with adjacent dVIN were evaluated. Clinicopathological features as well as immunohistochemical results were recorded on the resection-confirmed dVIN-related vSCCa. Results The average age of the patients was 71 years. Thirty-five cases (58.4%) of dVIN-related vSCCa were moderately differentiated, fourteen cases (23.3%) were poorly differentiated, and the remaining eleven cases (18.3%) were well-differentiated. Twenty-nine cases (48.3%) were found to have lichen sclerosus adjacent to dVIN. In terms of p53 and p16 expression in dVIN-related vSCCa and the adjacent dVIN, fifty-five (91.7%) dVIN showed mutant p53 immunostaining pattern with strong positive expression in 80% cases (basal/para-basal expression) and null pattern expression in 11.7% cases. Five (8.3%) dVIN showed p53 wild-type staining pattern. The wild-type pattern were seen in 5% of vSCCa and p53 null pattern were seen in 13.3% vSCCa. Six cases demonstrated atypical staining patterns: two cases showed p53 null expression in dVIN but p53 overexpression in invasive carcinoma; three cases exhibited p53 null expression in invasive carcinoma, with the adjacent dVIN showing basal and para-basal mutant (2 cases) and wild-type (1 case) p53 expression patterns. A single case demonstrated p53 wild-type pattern in dVIN and overexpression in invasive carcinoma. In addition, 65% dVIN were p16 negative and 31.7% dVIN had patchy p16 staining. Conclusion: Clinical and prognostic value of the ambiguous/inconsistent patterns are uncertain and molecular studies are needed for further characterization.

The number of deaths due to oral squamous carcinoma (OSCC), a malignant tumor of the oral cavity, is on the increase. We examined fibrinogen (FIB) expression in patients with OSCC and developed novel immunoprofile classification methods that include FIB. The plasma FIB level in patients with OSCC was elevated compared with that in patients with non-tumor oral disease (non-T); using a cut-off point of 342 mg/dL, we found the area under the curve-receiver operating characteristic level for OSCC was 0.745. Similarly, FIB expression in OSCC tissues was significantly higher compared with that in non-T tissues. Hierarchical clustering based on the immunoprofile of several markers including FIB, p53, and p16 revealed four groups that could be used to categorize OSCC cases (referred to as immunoprofile subtypes, [IPS], I-IV). Tumors in IPS-II, which were FIB+/p53+, were associated with a significantly worse overall survival (OS) when compared with the other subtypes. We conclude that our IPS classification system can facilitate prognostic evaluation in OSCC, and that quantification of FIB is an important component of the classification strategy for this disease.