Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma.
Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma.
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发表时间：
1998
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通讯作者：
S. Wilczynski;B. T. Lin;Yuan Xie;Benjamin Pazt
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作者：
S. Wilczynski;B. T. Lin;Yuan Xie;Benjamin Pazt
大约 15% 的头颈部鳞状细胞癌 (SCC) 中检测到人乳头瘤病毒 (HPV) DNA。最近的研究表明，HPV 在某些解剖部位（尤其是扁桃体区域）有优势，在 Waldeyer 扁桃体环的约 60% 的鳞状细胞癌中发现了病毒 DNA。本研究旨在确定扁桃体鳞状细胞癌中检测到和未检测到 HPV DNA 时形态或癌基因表达是否存在差异。使用共有引物组 (My09/My11) 和类型特异性引物，通过聚合酶链反应 (PCR) 分析扁桃体 22 个 SCC 中 HPV DNA 的存在。通过RNA原位杂交在原发性和转移性肿瘤中建立病毒转录。侵袭性鳞状细胞癌的形态分为三种亚型：角化良好（K-SCC）、角化中等（I-SCC）和角化不良（P-SCC）。通过免疫组织化学研究 p53、pRB 和细胞周期蛋白 D1 (bcl-1) 的表达。在这些病例（6 例 K-SCC、2 例 I-SCC 和 14 例 P-SCC）中，14 例（64%）检测到 HPV DNA，其中 11 例含有 HPV-16（10 例 P-SCC、1 例 I-SCC 和 0 例 K-SCC），各 1 例含有 HPV-33、HPV-59 和未分类的 HPV 型（所有 P-SCC）。在 7 个 HPV-16 阳性肿瘤中的 7 个中证实了病毒癌蛋白 E6/E7 转录。在大多数 HPV 阴性肿瘤（8 个病例中的 7 个）中检测到 Cyclin D1 蛋白过度表达，而在 13 个 HPV 阳性肿瘤中则很少或不表达。在 3 个 HPV 阴性 K-SCC 中检测到 p53 蛋白过度表达。在 HPV 阳性肿瘤中，表达 pRB 的恶性细胞较少，并且染色强度低于 HPV 阴性癌症。 HPV DNA 和 E6/E7 表达，尤其是 HPV-16，在大多数扁桃体鳞状细胞癌中均可检测到，并且几乎完全与角化不良的肿瘤组织学相关。带有 HPV DNA 的肿瘤中细胞周期蛋白 D1、pRB 和 p53 表达的减少与病毒癌蛋白对细胞蛋白的已知影响一致。 HPV阳性肿瘤的形态表明HPV可能偏爱非角化鳞状细胞群，或者病毒转化的细胞抑制肿瘤细胞的角化。角化良好的扁桃体鳞状细胞癌缺乏 HPV DNA，并与细胞周期蛋白 D1 蛋白和/或 p53 的过度表达相关，这表明通过与病毒癌蛋白相互作用或通过细胞蛋白本身的变化来改变细胞周期调节蛋白的机制对于扁桃体鳞状细胞癌的肿瘤发生至关重要。
Human papillomavirus (HPV) DNA has been detected in approximately 15% of squamous cell carcinomas (SCCs) of the head and neck. Recent studies have shown a predilection of HPV for certain anatomical sites, especially the tonsillar region, with viral DNA identified in approximately 60% of SCCs of the Waldeyer's tonsillar ring. This study was undertaken to determine whether there are differences in morphology or in oncogene expression in SCC of the tonsil with and without detectable HPV DNA. Twenty-two SCCs of the tonsil were analyzed for the presence of HPV DNA by polymerase chain reaction (PCR) using both a consensus primer set (My09/My11) and type-specific primers. Viral transcription was established in both primary and metastatic tumors by RNA in situ hybridization. The morphology of invasive SCC was classified into three subtypes: well keratinized (K-SCC), intermediate keratinized (I-SCC), and poorly keratinized (P-SCC). Expression of p53, pRB, and cyclin D1 (bcl-1) were studied by immunohistochemistry. In these cases (6 K-SCCs, 2 I-SCCs, and 14 P-SCCs), HPV DNA was detected in 14 (64%), with 11 containing HPV-16 (10 P-SCCs, 1 I-SCCs, and 0 K-SCCs) and 1 each containing HPV-33, HPV-59, and an unclassified HPV type (all P-SCCs). Viral oncoprotein E6/E7 transcription was demonstrated in 7 of 7 HPV-16-positive tumors. Cyclin D1 protein overexpression was detected in the majority of HPV-negative tumors (7 of 8 cases), whereas it was minimal or absent in 13 HPV-positive tumors. Overexpression of p53 protein was detected in 3 HPV-negative K-SCCs. In the HPV-positive tumors, fewer malignant cells expressed pRB and the staining was less intense than in the HPV-negative cancers. HPV DNA and E6/E7 expression, especially HPV-16, is detected in the majority of tonsillar SCCs and is almost exclusively associated with a poorly keratinized tumor histology. Decreased expression of cyclin D1, pRB, and p53 in tumors with HPV DNA is consistent with the known effects of the viral oncoproteins on the cellular protein. The morphology of the HPV-positive tumors suggests that HPV may have a predilection for a population of nonkeratinizing squamous cells or that the virally transformed cells inhibit keratinization of the tumor cells. Well keratinized tonsillar SCCs lack HPV DNA and are associated with overexpression of cyclin D1 protein and/or p53, suggesting that mechanisms that alter the cell cycle regulatory proteins, either by interaction with viral oncoproteins or by changes in the cellular proteins themselves, is critical for tumorigenesis of tonsillar SCC.