Prabakaran PJ, Javaid AM, Swick AD, Werner LR, Nickel KP, Sampene E, Hu R, Ong IM, Bruce JY, Hartig GK, Wieland A, Canon J, Harari PM, Kimple RJ.
PMID: 28659312 | DOI: 10.1158/1078-0432.CCR-17-0969
Abstract
PURPOSE:
Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACC contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition. <p>Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient derived xenograft (PDX) which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiation (RT).</p> <p>Results: AMG 232 monotherapy induced modest tumor growth inhibition and RT monotherapy induced a transient tumor growth delay in a dose dependent fashion. Strikingly, combination treatment of AMG 232 with RT (including low dose RT of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates three months following treatment. Post treatment analysis revealed that while both AMG 232 and RT alone induced TP53 tumor suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.</p> <p>Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/RT combination may be warranted to improve local control in this challenging malignancy.
The American journal of surgical pathology
Hopkins, MR;Palsgrove, DN;Ronnett, BM;Vang, R;Lin, J;Murdock, TA;
PMID: 36069815 | DOI: 10.1097/PAS.0000000000001970
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.
Gynecology and Obstetrics Clinical Medicine
Wang, T;Baloda, V;Harinath, L;Jones, T;Zhang, H;Bhargava, R;Zhao, C;
| DOI: 10.1016/j.gocm.2023.01.004
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.
