Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil

Li, Wei; Thompson, Carol H.; O’Brien, Christopher J.; McNeil, Edward; Scolyer, Richard A.; Cossart, Yvonne E.; Veness, Michael J.; Walker, DM; Morgan, Gary J.; Rose, Barbara

doi:10.1002/ijc.11261

Cited by 208 publications

(178 citation statements)

References 38 publications

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“…51,52 Indeed, in HPV-positive cancer cells, p21 Cip1/WAF1 expression appears to be inducible, 53 although it remains unclear why under these conditions E7 cannot inactivate p21 Cip1/WAF1 by direct interaction. 14 Despite the strong association of p21 Cip1/WAF1 overexpression with HPV positivity in most tonsillar squamous cell carcinomas, we found p21 Cip1/WAF1 protein accumulation also in some HPV-negative tumors, which is in accordance with a study of Li et al 54 These authors examined 67 tonsillar squamous cell carcinomas for HPV involvement, but did not find p21 Cip1/WAF1 expression being associated with HPV positivity. An explanation for this paradox might be on the one hand the use of a different p21 Cip1/WAF1 -specific primary antibody and different criteria to assess p21 Cip1/WAF1 upregulation (420% of positive nuclei versus 410%) in comparison with our and other studies, 29,30,35,36 and on the other hand the use of only PCR to determine the presence of HPV.…”

Section: Discussionsupporting

confidence: 91%

“…Expression of p21 Cip1/WAF1 has also been associated with a favorable survival in patients with tongue squamous cell carcinomas, and in patients with ovarian, superficial bladder, gastric, colorectal, and esophageal cancers. 29,43,57,58 In one other study on tonsillar squamous cell carcinomas and two studies on laryngeal squamous carcinomas, no correlation was reported, 36,54,59 and in one study on head-and-neck squamous cell carcinomas derived from multiple head-and-neck localizations even a negative correlation with survival was described, 19 which may be explained by the heterogeneous tumor population. Other strong indicators for a favorable prognosis in our study include tumor diameter o4 cm, low/no expression of cyclin D1, and low/no tobacco consumption.…”

Section: Discussionmentioning

confidence: 98%

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P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16 INK4A, cyclin D1, pRb, p14 ARF , MDM2, p53, p21 Cip1/WAF1 , and p27 KIP1 . Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16 INK4A overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14 ARF (Po0.0001) and p21 Cip1/WAF1 (P ¼ 0.001), and downregulation of pRb (Po0.0001) and cyclin D1 (P ¼ 0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P ¼ 0.006), as well as for patients with T1-2 tumors (Po0.0001) or tumors showing low expression of cyclin D1 (P ¼ 0.028), presence of human papillomavirus and overexpression of p16 INK4A (P ¼ 0.01), p14 ARF (P ¼ 0.02) or p21 Cip1/WAF1 (P ¼ 0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21 Cip1/WAF1 , were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21 Cip1/WAF1 and p14 ARF overexpression and downregulation of pRb and cyclin D1. In particular p21 Cip1/WAF1 overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas. Modern Pathology ( Head-and-neck squamous cell carcinoma is the sixth most prevalent malignancy in the world, contributing 6% of new cancer cases annually worldwide. 1,2 These tumors have a 5-year survival rate of approximately 50%, which has not improved in the last two decades. 3 Well-recognized risk factors in the etiology of head-and-neck squamous cell carcinomas are extensive tobacco and alcohol consumption in B90% of cases, as well as oncogenic human papillomaviruses (HPVs), predominantly HPV type 16. 3,4 Interestingly, the association of HPV is strongest for tonsillar squamous cell carcinoma with a prevalence up to 50%. [5][6][7][8]

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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“…Finally, taking into account the oncogenic potential of HR HPV and the differences in clinical outcome, response to radiotherapy and prognosis for HPV-positive OSCCs, 21,22,33,[42][43][44][45] our data suggest that the presence of oral HPV infection should be determined in any OSCC along with the concomitant expression of survivin.…”

Section: Discussionmentioning

confidence: 89%

“…39,40 In a review on epidemiologic and molecular bases, Ha and Califano 41 attrib- uted to HR HPV a role in oral carcinogenesis but only in a small subset of cases, with differences reported in clinical outcome, response to radiotherapy and prognosis. 21,22,33,[42][43][44][45] In this context, it becomes important to identify this cluster principally on the basis of key immunohistochemical cell cycle markers that are inexpensive and reliable, such as PCNA, MIB-1 and survivin. Several reports have focused on the identification of useful markers such as molecules involved in the proliferation pathway or in the regulation of apoptosis, which may influence the cell death/cell viability balance toward cell proliferation or cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression of cell cycle markers and human papillomavirus infection in oral squamous cell carcinoma: Use of fuzzy neural networks

Muzio

D’Angelo

Procaccini

et al. 2005

Intl Journal of Cancer

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Our aim was to evaluate in oral squamous cell carcinoma (OSCC) the relationship between some cell cycle markers and HPV infection, conditionally to age, gender and certain habits of patients, and to assess the ability of fuzzy neural networks (FNNs) in building up an adequate predictive model based on logic inference rules. Eighteen cases of OSCC were examined by immunohistochemistry for MIB-1, PCNA and survivin expression; presence of HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR (nPCR, MY09-MY11/GP5-GP6), and HPV genotype was determined by direct DNA sequencing. Data were analyzed by traditional statistics (TS) and FNNs. HPV DNA was found in 9/18 OSCCs (50.0 %) without any significant higher risk of HPV infection with respect to the sociodemographic variables considered ( p > 0.2), apart from tobacco smoking, reported in 44.4% of OSCC HPV-positive vs. 100% HPV-negative subjects ( p = 0.029). Regarding cell cycle markers, TS and FNN revealed that survivin was expressed significantly more in HPV-negative than in HPVpositive OSCC [root mean-square error (RMSE) = 5.89 3 10 -6 , % predicted 100.0]; furthermore, smoking played a protective role for survivin expression in HPV-positive cases (OR = 0.019, 95%CI 0.001-0.723, RMSE = 0.20, % of prevision 94.4). FNN, although on a small sample size, allowed us to confirm data by TS and to hypothesize a different cell cycle pattern for HPV-positive vs. HPV-negative OSCC. In the latter cases, the relevance of apoptotic vs. proliferative markers suggested that they may be related to the different supposed outcome of HPV-negative OSCC and that HPV may have a protective role in the expression level of survivin, especially in tobacco smokers. ' 2005 Wiley-Liss, Inc.Key words: human papillomavirus; survivin; oral squamous cell carcinoma; fuzzy neural network; carcinogenesis OSCC is rapidly increasing in incidence and represents the most frequent malignant oral tumor. The incidence of metastasis depends on the degree of cellular differentiation, deep invasion and site of the primary tumor; however, outcome is difficult to predict if only standard clinicopathologic parameters are taken into account. Biologic markers that can help to identify lesions with an aggressive phenotype and worse prognosis need to be identified.Since the majority of human neoplasms are characterized by an imbalance of the regulatory cell cycle control processes, the study of OSCC using the expression of proteins involved in the critical checkpoints of cell apoptosis and growth starts by elucidating the processes of carcinogenesis and appears to have good prognostic value. 1 Indeed, we know that apoptosis, or programmed cell death, and its suppression are involved in the carcinogenesis of several tumors; this process, mediated by caspases and cysteine proteinases present as proenzymes, is inhibited by several proteins, such as those of the Bcl-2 and IAP families. Survivin is an IAP protein, which is abundantly expressed in most solid and hematologic malignancies but undetectable in ...

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“…Epstein Barr Virus (EBV) has long been associated with nasopharyngeal cancers, and other data to supporting this concept are emerging from Human Papilloma Virus (HPV) related studies [6]. For instance, in addition to differences in HPV involvement of separate anatomic sites, with common involvement of the oropharynx, it is becoming apparent that HPV related carcinomas have an improved outcome compared to HPV negative carcinomas when adjusted for anatomic site and clinicopathologic stage [7,8]. Additionally, the heterogeneity of oncogene alteration among head and neck tumors supports such differences [9].…”

Section: Introductionmentioning

confidence: 99%

Site-Specific Molecular Signatures Predict Aggressive Disease in HNSCC

Belbin

Smith

Adrien

et al. 2008

Head and Neck Pathol

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It is known that head and neck squamous cell carcinomas (HNSCC) originating from different anatomic locations can exhibit varying behavior that is not predictable by histopathology of the primary tumor. Using a microarray containing 27,323 cDNA clones, we generated sets of gene expression profiles for 36 HNSCC primary tumors (12 oral cavity, 12 oropharynx, and 12 larynx/ hypopharynx). From these datasets, we ranked genes according to their ability to differentiate between patients whose disease progressed within a 24 month period (aggressive phenotype) and those that did not (nonaggressive phenotype) based on levels of gene expression. A merging of datasets from the three sites revealed that only a fraction of identified genes were shared between any two sites. This contrasted greatly with the significant overlap (approximately 50%) in down-regulated genes identified in tumor/normal comparisons using cases both from oropharynx and larynx/hypopharynx. From these data, we conclude that HNSCC tumors originating from different anatomic sites share consistent changes in gene expression when comparing primary tumors to normal adjacent mucosa; these common changes most likely reflect alterations required for tumor development. In contrast, once a tumor has developed, tumor-host interactions at the different anatomic sites are likely responsible for the site-specific signatures associated with aggressive versus non-aggressive disease. Predictions of outcome based on gene expression profiling are therefore heavily influenced by the anatomic site of the primary tumor.

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Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil

Cited by 208 publications

References 38 publications

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

Expression of cell cycle markers and human papillomavirus infection in oral squamous cell carcinoma: Use of fuzzy neural networks

Site-Specific Molecular Signatures Predict Aggressive Disease in HNSCC

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