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Molecular Characterization of Invasive and in Situ Squamous Neoplasia of the Vulva and Implications for Morphologic Diagnosis and Outcome

Modern Pathology(2020)SCI 1区

Vancouver General Hospital and University of British Columbia | Molecular Oncology | Contextual Genomics | Genetic Pathology Evaluation Centre | Department of Obstetrics and Gynecology

Cited 41|Views42
Abstract
Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC) is an aggressive clinical entity. Current diagnostic guidelines for premalignant lesions are ambiguous, and their molecular profile and progression events are still unclear. We selected 75 samples, from 40 patients, including 33 VSCC, 8 verrucous carcinomas (VC), 13 differentiated-type vulvar intraepithelial neoplasia (dVIN), 11 suspicious for dVIN (?dVIN), 6 differentiated exophytic vulvar intraepithelial lesions (DE-VIL), 2 vulvar acanthosis with altered differentiation (VAAD), and 2 usual-type vulvar intraepithelial neoplasia (uVIN/HSIL). Invasive and precursor lesions were matched in 29 cases. Clinical information, p16 immunohistochemistry, and mutation analysis were performed on all lesions. All dVIN, ?dVIN, DE-VIL, and VAAD were p16 negative, all uVIN/HSIL were p16 positive. In the HPV-independent group, mutations were identified in 6 genes: TP53 (n = 40), PIK3CA (n = 20), HRAS (n = 12), MET (n = 5), PTEN (n = 4), and BRAF (n = 1). TP53 mutations occurred in 73% (22/30) VSCC, 85% (11/13) dVIN, 70% (7/10) ?dVIN and no VC (0/8), DE-VIL (0/6) nor VAAD (0/2). Basal atypia was the only reliable feature of TP53 mutations. ?dVIN lesions that were non-acanthotic and atypical but obscured by inflammation, all harbored TP53 mutations. In lesions without TP53 mutations, PIK3CA (50% VC, 33% DE-VIL, 100% VAAD, 40% VSCC) and HRAS (63% VC, 33% DE-VIL, 0% VAAD, 20% VSCC) mutations were found. Mutational progression from in situ to invasive was seen (7/26, 27%) and usually involved TP53 (4/26, 15%). Cases with TP53 and PIK3CA co-mutations had the worse clinical outcomes (p < 0.001). We recommend testing for p53 in all HPV-independent lesions suspicious for dVIN, even in the presence of marked inflammation or non-acanthotic skin, particularly when close to a margin. VC, VAAD, and DE-VIL, were almost never mutated for TP53, but instead often harbored PIK3CA and HRAS mutations. In VSCC, combined TP53 and PIK3CA mutations may inform prognosis.
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Diagnostic markers,Oncogenesis,Medicine/Public Health,general,Pathology,Laboratory Medicine
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要点】:本文对侵袭性和原位外阴鳞状上皮肿瘤进行了分子特征分析,揭示了TP53和PIK3CA基因突变与临床结果的相关性,为形态学诊断提供了新的分子标记。

方法】:作者对75个样本进行了临床信息收集、p16免疫组化染色和基因突变分析。

实验】:实验使用了来自40名患者的75个样本,包括33个侵袭性外阴鳞状细胞癌(VSCC)、8个疣状癌(VC)、13个分化型外阴上皮内瘤变(dVIN)、11个疑似dVIN(?dVIN)、6个分化型外生性外阴上皮病变(DE-VIL)、2个外阴棘皮症伴分化不良(VAAD)和2个常见型外阴上皮内瘤变/高级别鳞状上皮内病变(uVIN/HSIL)。侵袭性和原位病变在29个案例中进行了匹配。实验结果显示,所有dVIN、?dVIN、DE-VIL和VAAD均为p16阴性,所有uVIN/HSIL均为p16阳性。在HPV独立组中,6个基因发生了突变:TP53(n = 40)、PIK3CA(n = 20)、HRAS(n = 12)、MET(n = 5)、PTEN(n = 4)和BRAF(n = 1)。TP53突变在VSCC中占73%(22/30)、dVIN中占85%(11/13)、?dVIN中占70%(7/10),而VC、DE-VIL和VAAD中未见。基底层非典型性是TP53突变的唯一可靠特征。在无TP53突变的病变中,PIK3CA(50% VC、33% DE-VIL、100% VAAD、40% VSCC)和HRAS(63% VC、33% DE-VIL、0% VAAD、20% VSCC)突变被发现。从原位到侵袭性的突变进展可见(7/26,27%),通常涉及TP53(4/26,15%)。TP53和PIK3CA共突变病例的临床结局较差(p < 0.001)。作者建议对所有疑似dVIN的HPV独立病变进行p53测试,尤其是在炎症明显或非角化皮肤的情况下,尤其是靠近边缘的病变。VC、VAAD和DE-VIL很少发生TP53突变,但常常携带PIK3CA和HRAS突变。在VSCC中,TP53和PIK3CA联合突变可能提供预后信息。