【中咽頭】HPV陽性扁平上皮癌の代替マーカーとして p16 は有用：適正なカットオフ値は 75%（ただし block-positive）

p16 Immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma

Head Neck Pathol. 2012 Jul; 6(Suppl 1): 75–82.

Abstract
It is widely acknowledged that human papillomavirus (HPV)-related oropharyngeal carcinoma is a biologically unique form of head and neck cancer that should be singled out and treated differently. It is now incumbent to find a test (or combination of tests) that accurately identifies cancers with the associated favorable prognosis for proper patient counseling and management and for placing patients in the correct treatment arms in the emerging clinical trials that are attempting to establish unique treatment types and approaches. The test (or combination of tests) that are utilized must be widely available, reliable, easy to interpret, and well-validated. While HPV-specific testing seems completely logical to use as a single test or one of a combination of tests, it turns out to be quite complicated in practice. Because of the different forms of the virus, the differing types of HPV-specific tests can give different information. HPV DNA, RNA, and protein assays have varying sensitivities for virus detection and also varying availability from formalin-fixed, paraffin-embedded tissue. Since p16 protein over expression is very sensitive for the presence of transcriptionally-active HPV and since it correlates strongly with patient outcomes, is widely available, and easy to interpret, it appears to currently be the single test that combines all of the desired attributes in a risk stratification marker for widespread implementation in clinical and research study settings. This article will review the literature on p16 immunohistochemistry and its relation to HPV-specific testing, discuss some practical issues related to its implementation, and present the case for why it should be the single test used for this purpose.

少し古いが、中咽頭癌の HPV（ヒトパピローマウイルス）の感染状態について p16 の免疫組織化学染色（IHC：immunohistochemistry）の有用性と適正なカットオフ設定を示した論文である。

まず、基礎知識として、HPV 陽性の扁平上皮癌は、子宮頸部で有名であるが、膣、外陰、男性外性器、肛門および肛門周囲、皮膚（特に爪）でも散見され、さらに、中咽頭をはじめとした頭頸部領域（口腔、上・下咽頭、喉頭、鼻腔など）でも発生する。

なお、一般に、同じ臓器で比較すると HPV 陽性癌は HPV 陰性癌よりも放射線療法などの治療が効きやすく、予後良好である。

HPV は DNA ウイルスなので、宿主 DNA に組み込まれ（integration）、E6 や E7 と称されるウイルス蛋白の作用により癌化を生じる。HPV が宿主細胞内に局在していることは、核酸（DNA）を直接可視化する ISH（in situ hybridization）法で確認できるが、コストが高い。そこで、p16INK4a の IHC が HPV 感染の優秀な surrogate marker として用いられている。p16 自体は悪性腫瘍の半分程度で非特異的に異常を示す蛋白であるが、HPV 感染では「核および細胞質のびまん性強陽性（block-positive）」であることが特徴的である。

この論文では p16 IHC と HPV-ISH を比較している。Free article なので、カットオフに関する肝になる部分を引用する。

A few studies appear to directly validate cutoffs of 50% or 75% as indicative of an HPV-related cancer. Schlecht et al. compared extent of p16 staining to RT-PCR for high-risk HPV E6/E7 on fresh tissue and found that all but one of 11 cases with >75% p16 staining harbored viral RNA and only 1 of 14 cases with partial p16 staining in <75% of tumor cells harbored viral RNA. In an analysis (accepted for publication) of 16 patients with partial p16
expression for whom we performed RT-PCR and RNA ISH for high-risk HPV E6/E7 mRNA on formalin-fixed, paraffin-embedded tissue, only 1 of 9 cases with <50% p16 staining harbored viral RNA (RNA ISH negative but RT-PCR positive with very low expression) while 3 of 5 cases with 50–75% p16 staining harbored viral RNA by both tests. The 2 cases with partial, but greater than 75% p16 staining both harbored viral RNA by both tests. As mentioned, from the larger oropharyngeal SCC patient database, of the 148 patients with >75% p16 expression, 147 (99%) were RNA ISH positive. Again, these studies help to validate that, in oropharyngeal SCC, a cutoff of 50%, or better yet 75%, of tumor cells staining for p16 is required to correlate with the presence of transcriptionally active HPV and improved patient outcomes.

【SANOTIC SUMMARY】
p16 陽性のカットオフは 75%（あるいは 50%）が適正（ただし、核および細胞質のびまん性強陽性（block-positive）を陽性として扱う）

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p16 Immunohistochemistry As a Standalone Test for Risk Stratification in Oropharyngeal Squamous Cell Carcinoma

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