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Detection of Human Papillomavirus in Cervical Lymph Nodes: a Highly Effective Strategy for Localizing Site of Tumor Origin

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Detection of Human Papillomavirus in Cervical Lymph Nodes: a Highly Effective Strategy for Localizing Site of Tumor Origin Vol. 9, 6469–6475, December 15, 2003 Clinical Cancer Research 6469 Detection of Human Papillomavirus in Cervical Lymph Nodes: A Highly Effective Strategy for Localizing Site of Tumor Origin Shahnaz Begum,1 Maura L. Gillison,2 the oropharynx, either directly by ISH or indirectly by M. Ali Ansari-Lari,1 Keerti Shah,3 and immunohistochemistry for p16 overexpression. William H. Westra1,4 Departments of 1Pathology, 2Oncology, 3Molecular Microbiology and INTRODUCTION Immunology, and 4Otolaryngology-Head and Neck Surgery, The Nearly 40,000 patients in the United States (1) and over Johns Hopkins Medical Institutions, Baltimore, Maryland 500,000 patients worldwide (2) are diagnosed with head and neck squamous cell carcinoma (HNSCC) each year. Despite ABSTRACT vast improvements in the diagnostic and therapeutic armament over the past several decades, mortality rates have not changed Purpose: Patients with head and neck squamous cell significantly. Patients tend to present with advanced disease carcinoma (HNSCC) often come to clinical attention with a when opportunities for cure are not optimal. Indeed, most pa- neck mass due to metastatic spread to lymph nodes. Treat- tients already have metastatic spread to regional lymph nodes at ment is dictated by the subsequent determination of primary the time of presentation (3); 13% of patients present with a neck tumor site and stage. However, the primary site remains mass as the first and only clinical manifestation (4), and 3% to elusive in some patients even after an exhaustive examina- 9% of the primary tumors continue to elude detection even after tion. Human papillomavirus type 16 (HPV-16) is an impor- clinical, radiographic, endoscopic, and histopathologic evalua- tant etiologic agent for HNSCCs that arise within the oro- tion (5). The treatment of patients with occult primary HNSCCs pharynx but less so for tumors from nonoropharyngeal sites. is challenging and controversial. One option is to blanket the Detection of HPV-16 or a surrogate marker may be useful in mucosa judged most at risk with wide-field radiation, but such localizing tumor origin in patients who present with meta- prophylactic treatment is associated with the risk of xerstomia, static HNSCC. mucositis, and other complications of radiation. Experimental Design: We performed in situ hybridiza- Human papillomavirus (HPV), particularly the tumorigenic tion (ISH) for HPV-16 on lymph node metastases from 68 16 subtype, has been confirmed recently as a causative agent in patients with HNSCC. P16 immunohistochemistry was also the development of a subset of HNSCCs (6). In particular, performed because HPV-16 integration disrupts the retino- HPV-16 is present in the majority of tumors arising in the blastoma pathway and induces an overexpression of p16. oropharynx, but in only a small percentage of HNSCCs arising Results: HPV-16 was detected in 22 of the 68 (32%) in nonoropharyngeal sites (6–8). In HPV-positive oropharyn- cases by ISH. When stratified by site of origin, HPV-16 was geal carcinomas, transcription of the viral oncoprotein E7 is detected in 22 of 31 (71%) metastases from the oropharynx, known to functionally inactivate the Retinoblastoma (Rb) gene but in none of the 37 (0%) metastases from other sites (P < product, causing a perturbation of other key components of the 0.001; Fisher’s exact). P16 expression was associated with Rb pathway (7, 9–11). As one example, functional inactivation the presence of HPV-16 by ISH: 21 of 22 HPV-16 positive of Rb by E7 is known to induce an up-regulation of p16 tumors exhibited p16 expression, whereas only 4 of the 46 expression (12, 13), reaching levels that can be readily detected HPV-16-negative tumors were p16 positive (95% versus 9%; by routine immunohistochemistry (IHC). Although p16 IHC has P < 0.001; Fisher’s exact). P16 expression in the node shown promise as an ancillary diagnostic tool in the recognition metastases also correlated with site of tumor origin: 24 of 31 of HPV-induced neoplasia of the female genital tract (14–16), oropharyngeal tumors were p16 positive, whereas only 1 of potential applications to tumors of the upper aerodigestive tract 37 nonoropharyngeal tumors was p16 positive (77% versus have yet to be defined. The purpose of the present study was to 3%; P < 0.001; Fisher’s exact). determine whether detection of HPV, by direct in situ hybrid- Conclusions: For patients with metastatic HNSCC, de- ization (ISH) or by immunohistochemical detection of p16 as a tection of HPV-16 is a reliable way to establish origin from surrogate marker, is helpful in pinpointing the site of tumor origin in those patients with cervical lymph node metastases. MATERIALS AND METHODS Received 4/30/03; revised 9/3/03; accepted 9/8/03. Patients. The surgical pathology files were searched for Grant support: NIH (1R01 DE13121-01A1). The costs of publication of this article were defrayed in part by the patients with HNSCC who underwent neck dissections for car- payment of page charges. This article must therefore be hereby marked cinoma metastatic to regional lymph nodes between 1995 and advertisement in accordance with 18 U.S.C. Section 1734 solely to 2002. Medical records were reviewed to document the primary indicate this fact. site of tumor origin. The primary site was defined by histopatho- Requests for reprints: William H. Westra, The Weinberg Building, Room 2242, The Johns Hopkins Hospital, 401 North Broadway, Balti- logic confirmation of a mass detected on physical examination more, MD 21231-2410. Phone: (410) 955-2163; Fax: (410) 955-0115; by a head and neck surgeon. To facilitate comparison between E-mail: [email protected]. those tumors arising in the oropharynx and those tumors arising Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2003 American Association for Cancer Research. 6470 Human Papillomavirus Detection in Metastases from neighboring anatomical sites, cases were selected for ad- and -89) and ␤-globin (19, 20). Positive controls consisting of ditional analysis solely on the basis of primary tumor origin. The 10 and 100 HPV-16 (SiHa)- or HPV-18 (C4–2)-positive cells group of study cases included 31 metastatic HNSCCs from the diluted in a background of HPV-negative cells (K562) and a oropharynx and 37 metastatic HNSCCs from nonoropharyngeal negative control (K562 cells) were run within each assay. Sam- sites. HPV status of the primary tumors and their metastatic ples positive for ␤-globin were considered of sufficient quality implants was not known at the time of case selection. for analysis. In-situ hybridization (ISH). HPV-16 detection in formalin- Statistical Evaluation. Primary tumor location was cat- fixed and paraffin-embedded tissues was performed using the egorized as a dichotomous variable (oropharynx or nonorophar- ISH catalyzed signal amplification method for biotinylated ynx). Factors associated with oropharyngeal tumor location probes (DAKO GenPoint, Carpinteria, CA; Ref. 17). This cat- were evaluated by cross-tabulations and analyzed by use of the alyzed signal amplification system permits visualization of sin- Fisher’s exact test. The sensitivity value of a test was defined as gle copies of HPV-16 in infected cells (18). Briefly, 5-␮m tissue the percentage of oropharyngeal tumors that tested positive for sections underwent deparaffinization, heat-induced target re- HPV-16 by ISH or positive for p16 by IHC. The specificity trieval in citrate buffer, and digestion using Proteinase K (Roche value was defined as the percentage of nonoropharyngeal tu- Diagnostics, Indianapolis, IN). Slides were subsequently hy- mors that tested negative for HPV-16 by ISH or negative for p16 bridized with a biotinylated HPV-16 type-specific probe by IHC. Exact binomial confidence intervals were calculated. (DAKO). Signal amplification was performed by consecutive The ␬-statistic was used to measure agreement between HPV-16 application of streptavidin-horseradish peroxidase complex, bi- ISH and HPV PCR. Ps are two-sided unless otherwise specified. otinyl tyramide, and streptavidin-horseradish peroxidase com- Statistical analysis was conducted using STATA software, Ver- plex. Visualization of positive hybridization signals was per- sion 7 (STATA, College Station, TX). formed by incubation with the chromogenic substrate diaminobenzidine. Interpretation of staining was performed without knowledge of p16 immunohistochemical staining or RESULTS tumor origin. Of the 68 cases of metastatic squamous cell carcinoma to Immunohistochemistry (IHC). Five-␮m sections were cervical lymph nodes, 31 primary tumors were from the deparaffinized. Antigen retrieval was performed using heat- oropharynx, 21 were from the oral cavity, 11 were from the induced epitope retrieval with 10 mM citrate buffer. Tissue larynx, and 5 were from the hypopharynx. The results of HPV sections were incubated with a mouse monoclonal antibody detection using various detection strategies are summarized against p16 (MTM Laboratories, Heidelberg, Germany) at a in Table 1. 1:500 dilution. The p16 antibody was visualized using the By ISH, HPV-16 was detected in 22 of 31 (71%) me- avidin-biotin-peroxidase technique (DAKO LSAB kit; DAKO tastases from the oropharynx. In all of the HPV-16 positive Cytomation, Carpinteria, CA). cases, hybridization was visualized as a punctate signals Staining was regarded as positive if it was strong and within the nuclei. The signal varied from one or two incon- diffuse (Ͼ80% of tumor cells), and it was regarded as negative spicuous dots to many confluent dots (Fig. 1). Others have if absent or focal. Only strong, diffuse staining of the cytoplasm shown that the punctate pattern of hybridization correlates and nuclei, and not focal or weak staining, is associated with the with viral DNA integration and that the number of nuclear presence of high-risk HPV in neoplasia of the female genital dots correlates with the copy number of HPV DNA (21). In tract (14–16). Immunohistochemical interpretation was per- striking contrast, HPV-16 was not detected in any of the 37 formed without knowledge of HPV status or tumor origin.
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