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作者：Caroline Helwick  
出處：WebMD醫學新聞

　　【24drs.com】November 3, 2009 (芝加哥) — 頭頸部鱗狀細胞癌(head and neck squamous cell carcinoma，HNSCC)病患中，p16抗體值高可能代表感染了高風險的人類乳突病毒(human papillomavirus，HPV)。阿拉巴馬大學的研究者在美國臨床病理協會2009年會中報告指出，若經確認，它可作為其他昂貴檢查的替代方案且所費低廉。
　　
　　最近，發現高風險血清型HPV與某種HNSCC有關。檢測組織中HPV的常用方法包括原位雜交技術(in situ hybridization，ISH)以及聚合酶連鎖反應(PCR)。
　　
　　第一作者、阿拉巴馬大學的Elizabeth Kerr醫師表示，目前的研究評估採用免疫組織化學(IHC)檢測HPV和p16的好處，p16是代表HPV感染的標記，希望可以取代ISH和PCR，成為較具成本效益的替代方法。
　　
　　她報告指出，該研究中，HNSCC病患有73%為高風險HPV陽性。我們的樣本使用IHC檢測都是HPV陰性，但是，p16 (3+)代表與高風險HPV有強烈關聯。
　　
　　Kerr醫師的團隊搜尋阿拉巴馬大學的資料庫中，2008年1月至2009年7月的口咽發育不良與腫瘤案例。她們只選擇經外部參考實驗室以PCR確認HPV狀態的案例。HPV 檢測結果未對參與的病理專家公告。
　　
　　樣本包括16名病患(13名男性與3名女性)，年紀中位數為50歲。使用免疫組織化學染色對組織的p16和HPV抗體染色。鱗狀細胞的細胞核p16染色結果分為陰性(沒有染色或染色的細胞<10%)、1+ (染色的細胞11%-30%)、2+ (染色的細胞31%-50%)或3+ (染色的細胞>50%)。鱗狀細胞核染色超過10%被視為HPV陽性。 此外，以內部實驗室的ISH分析(使用HPV III探針)檢測樣本的HPV。
　　
　　將IHC檢測HPV和p16的結果與PCR和ISH的結果相連結。
　　
　　16個病灶中有9個為p16 (3+)。所有病灶都是鱗狀細胞腫瘤— 8個來自扁桃腺或口咽，1個來自鼻咽。鱗狀乳頭狀瘤之一顯示為p16 (2+)，其他顯示為p16 (1+)。IHC都沒有顯示這些病灶為HPV陽性。
　　
　　根據內部實驗室的ISH分析，8個病灶為高風險HPV陽性。全部都是鱗狀細胞腫瘤且來自扁桃腺或口咽。Kerr醫師報告指出，p16 (3+) IHC和ISH-偵測出高風險HPV之間有強烈關聯。
　　
　　ISH-偵測高風險HPV陽性的這8個病灶，PCR-偵測高風險HPV也是陽性。有4個鱗狀乳頭狀瘤(來自喉頭、聲門與氣管)為PCR-偵測低風險HPV。
　　
　　Kerr醫師指出，IHC偵測p16 (3+) 的案例與高風險HPV PCR的關聯顯示有100%敏感度與87.5%專一度。內部實驗室的ISH-偵測高風險HPV與PCR-偵測高風險HPV的關聯，也顯示有100%敏感度與100%專一度。
　　
　　作者們結論表示，因為p16 (3+)案例與PCR-偵測高風險HPV和ISH-偵測高風險HPV有強烈關聯，p16可以作為HPV感染的替代指標，也是可取代昂貴的PCR和ISH分析的替代方法且所費低廉。
　　
　　未參與本研究的阿拉巴馬大學病理學教授Isam A. Eltoum醫師向Medscape Pathology表示，這是一個很好的初步研究，特別之處在於回顧者也不知情，但還需要以更大型的系列研究進一步確認。
　　
　　HPV感染專家Eltoum醫師表示，如果p16成為有用的替代物，對病理科醫師來說很有幫助，因為是我們例行性操作的項目，不像PCR得在分子實驗室進行。藉此，病理學家可以開立p16檢驗單且立即判斷病灶是否與HPV有關，病理學家可以全盤掌握。
　　
　　Kerr醫師與 Eltoum醫師皆宣告沒有相關財務關係。
　　
　　美國臨床病理協會(ASCP)2009年會：摘要84。發表於2009年10月30日。

High p16 Antibody Levels May Signal HPV Infection in Head and Neck Cancer

By Caroline Helwick
Medscape Medical News

November 3, 2009 (Chicago, Illinois) — In patients with head and neck squamous cell carcinoma (HNSCC), high p16 antibody expression might serve as a marker for infection with high-risk human papillomavirus (HPV). If validated, it could serve as a cost-effective alternative to more expensive tests, University of Alabama researchers reported here at the American Society for Clinical Pathology 2009 Annual Meeting.

Recently, infection with high-risk serotypes of HPV has been linked to a subset of HNSCC. The preferred methods for detecting HPV in tissue section are in situ hybridization (ISH) and polymerase chain reaction (PCR).

The current study evaluated the benefit of combining immunohistochemistry (IHC) for HPV and p16, a known surrogate marker for HPV infection, as a more cost-effective alternative to ISH and PCR in detecting HPV, said lead author Elizabeth Kerr, MD, from the University of Alabama at Birmingham.

"In this study, 73% of HNSCC [patients] were positive for high-risk HPV," she reported. "HPV detection by IHC was negative in all our samples, but p16 (3+) strongly correlated with high-risk HPV."

Dr. Kerr's team searched the University of Alabama's database for oral and pharyngeal dysplasia and carcinoma cases between January 2008 and July 2009. They selected only cases in which HPV status was confirmed on PCR by an outside reference lab. The HPV test results were undisclosed to the examining pathologists.

The sample consisted of 16 patients (13 men, 3 women), with a median age of 50 years. Tissue was immunohistochemically stained with the p16 and HPV antibodies. Nuclear staining of squamous cells for p16 was considered negative (no staining or <10% of cells stained), 1+ (11% to 30% of cells stained), 2+ (31% to 50% of cells stained), or 3+ (>50% of cells stained). Nuclear staining of more than 10% of squamous cells was considered positive for HPV. Additionally, samples were tested in-house for HPV with an ISH assay using the HPV?III family probe.

The results of the HPV and p16 IHC testing correlated with those obtained with PCR and ISH.

In 9 of 16 lesions, p16 (3+) expression was detected. All lesions were squamous cell carcinoma — 8 were from the tonsils or oropharynx and 1 was from the nasopharynx. One of the squamous papillomas showed p16 (2+) staining, and another showed p16 (1+) staining. None of the lesions stained positive for HPV with IHC.

Eight lesions were positive for high-risk HPV according to in-house ISH. All were squamous cell carcinoma and arose in the tonsils or oropharynx. There was a strong correlation between p16 (3+) IHC and ISH-detected high-risk HPV, Dr. Kerr reported.

The same 8 lesions that were positive for ISH-detected high-risk HPV were positive for PCR-detected high-risk HPV. There were 4 squamous papillomas (from the larynx, glottis, and trachea) that were positive for PCR-detected low-risk HPV.

"Those cases of p16 (3+) by IHC correlated with high-risk HPV PCR and showed 100% sensitivity and 87.5% specificity," Dr. Kerr noted. The in-house ISH-detected high-risk HPV also correlated with PCR-detected high-risk HPV and showed 100% sensitivity and 100% specificity.

The authors concluded that because p16 (3+) cases strongly correlated with PCR-detected high-risk HPV and ISH-detected high-risk HPV, p16 could be used as a surrogate marker for HPV infection, and would be a cost-effective alternative to the more expensive PCR and ISH assays.

Isam A. Eltoum, MD, professor of pathology at the University of Alabama at Birmingham, who was not involved in this study, told Medscape Pathology that "this is a good preliminary study, especially because the reviewers were blinded, but it needs to be confirmed in a larger series."

"If p16 can be confirmed as a useful surrogate, this would be helpful to the pathologist because it is routine in what we do, unlike PCR, which must be done by a molecular lab," said Dr. Eltoum, who is an expert in HPV infections. "Here, the same pathologist could order the p16 and see immediately whether the lesion is HPV-related. It would all be in the hands of the pathologist."

Dr. Kerr and Dr. Eltoum have disclosed no relevant financial relationships.

American Society for Clinical Pathology (ASCP) 2009 Annual Meeting: Abstract 84. Presented October 30, 2009.