Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas

Klußmann, Jens Peter; Weissenborn, Soenke J.; Wieland, Ulrike; Dries, Volker; Kolligs, Jutta; Jungehuelsing, Markus; Eckel, Hans Edmund; Dienes, Hans Peter; Pfister, Herbert; Fuchs, Pawel G.

doi:10.1002/1097-0142(20011201)92:11<2875::aid-cncr10130>3.0.co;2-7

Cited by 304 publications

(325 citation statements)

References 31 publications

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“…In this study, we found an HPV prevalence of 24.3% in our cohort, which is lower than the prevalence in OSCC and tonsillar cancer reported for the USA (45-83%) 4,5 or northern Europe (26-93%), 5,23,24 but comparable to data for central Europe (14-33%) [25][26][27] . We considered HPV-association of samples when high risk HPV-DNA was detected along with p16INK4a expression.…”

Section: Discussioncontrasting

confidence: 70%

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

et al. 2016

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Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OSCC) are clinical and biological distinct from their HPV-unrelated counterparts. Patients with HPV-related OSCC display improved prognosis and therefore we investigated possible immune cell infiltrations associated with this tumor phenotype. We retrospectively analyzed a randomly selected cohort of 140 OSCC for presence of immune cells and HPV by immunohistochemistry and PCR followed by beadbased hybridization (Luminex technology). HPV prevalence was 24.3% as determined by positive staining of p16INK4a and detection of high risk HPV-DNA. We found significantly higher numbers of CD56 positive (CD561) cells in tumor and surrounding microenvironment in HPV-associated compared to HPV-negative OSCC (t-test: p 5 0.004 and p 5 0.002). For the entire cohort presence of CD561 cells was associated with increased overall survival independent from HPV (Kaplan-Meier: p 5 0.002; Cox regression: p 5 0.042). Presence of CD561 cells also correlated with a better outcome in HPV-negative and especially in HPV-negative OSCC with alcohol consumption 2 standard drinks per day (Kaplan-Meier: p 5 0.05 and p 5 0.003). Immunofluorescence localization of granular Granzyme B (GZMB) within CD561 cells and coexpression of CD16 and CD56 suggests that detected CD561 cells mainly represent cytotoxic Natural Killer (NK) cells. The fraction of potentially cytotoxic NK cells was significantly higher in HPV-associated compared to HPV-negative OSCC (Mann-Whitney-U-Test: p 5 0.011). The elevated abundance and activity of cytotoxic NK cells in OSCC with HPV driven carcinogenesis might contribute to favorable outcome in HPV-related OSCC.Head and neck cancer (HNC, comprising cancers of the oral cavity, lip, pharynx, nasopharynx and larynx) is ranking at position seven of newly diagnosed cancers and cause of cancer death worldwide, with 4.8% of total cancer incidence and 4.6% of total cancer mortality. 1 In particular oropharyngeal squamous cell carcinomas (OSCC) are related to high risk human papillomavirus (HPV) infection, which is accepted to be causally connected to HNC. 2,3 A recently published metaanalysis demonstrates a rising incidence of HPV1 OSCC in the United States from 21% (pre-1990), to 51% (1990-1999), to 65% (2000-2013). 4 Patients with HPV-associated OSCC show lower levels of disease recurrence and progression compared to patients with HPV-negative OSCC. Even with good loco regional tumor control, patients with HPV-associated OSCC have similar rates of distant metastases as patients with HPVnegative OSCC. Further efforts are needed to understand clinical and biological features of this distinct disease. 2,5,6 Molecular basis of HPV-associated cancers differ from their HPVunrelated counterparts. 3 Pathways related to cell cycle control or apoptosis (commonly affected by mutations in HPVnegative cancers) are silenced at protein level by HPVoncoproteins (mainly E6 and E7). It has been speculated that lower levels of genetic alterations contribute to better treat...

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Section: Discussioncontrasting

confidence: 70%

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

et al. 2016

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“…The amount of cancer cells in a biopsy specimen may impact viral load quantitation, and substantial variability may exist in viral load measurements within a single tumor. 29 Additionally, it remains uncertain whether the measurement of viral load is the result of a few cells with greater number of HPV DNA copies, or many cells with few copies. Nonetheless, it seems that estimated viral load might contribute to defining the subset of HPV-positive oral and oropharyngeal cancers that are more likely the result of HPV infection.…”

Section: Discussionmentioning

confidence: 99%

HPV16 semiquantitative viral load and serologic biomarkers in oral and oropharyngeal squamous cell carcinomas

Kreimer

Clifford

Snijders

et al. 2005

Intl Journal of Cancer

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A considerable subset of oropharyngeal squamous cell carcinomas (SCCs) are positive for human papillomavirus (HPV); however, delineating etiologically-associated HPV infections from SCCs with concurrent HPV infection unrelated to tumorigenesis is challenging. Viral load assessment in biopsy specimens may help facilitate such differentiation. HPV16 viral load and serologic markers were assessed among oral and oropharyngeal cases from a multinational study conducted by the International Agency for Research on Cancer (IARC). HPV16 viral load, measured semiquantitatively by PCR-enzyme immunoassay, was dichotomized as high or low based on the median optical density value. Serologic antibodies to HPV16 virus-like particles (VLPs) and to HPV16 E6 and E7 proteins were measured by ELISA. Compared to HPV DNA-negative cases (n = 852), HPV16 DNA-positive cases with high viral load (n = 26) were significantly more likely to originate in the oropharynx (odds ratio [OR], 12.0; 95% confidence interval [CI], 5.2-27.5) and, after adjustment for tumor site (AdjOR), have antibodies against HPV16 VLPs (AdjOR, 14.6; 95% CI, 6.0-35.6), E6 (AdjOR, 57.6; 95% CI, 21.4-155.3) and E7 (AdjOR, 25.6; 95% CI, 9.3-70.8). HPV16 DNA-positive cases with low viral load (n = 27) were more commonly oropharyngeal (OR, 2.7; 95% CI, 1.1-6.2) and seropositive for HPV16 VLPs (AdjOR, 2.7; 95% CI, 1.1-6.9), E6 (AdjOR, 3.0; 95% CI, 0.7-14.0) and E7 (AdjOR, 3.5; 95% CI, 0.7-16.3), compared to HPV DNA-negative cases; the associations, however, were neither as strong nor as significant as the associations for high viral load. As there appears to be a strong association between HPV16 serologic markers and viral load, in the absence of data on serologic markers, HPV16 viral load may be used to help delineate the subset of HPV16 DNA-positive oral and oropharyngeal cancers that may be the consequence of HPV infection. ' 2005 Wiley-Liss, Inc.Key words: human papillomavirus; HPV16 viral load; oral cancer; oropharyngeal cancer Numerous studies have provided consistent evidence that human papillomavirus (HPV), the necessary cause of cervical cancer, is present in tumor biopsies from approximately 20-50% of oropharyngeal squamous cell carcinomas (SCCs) and a smaller subset of oral SCCs. 1-4 Among HPV DNA-positive oropharyngeal SCCs, 90% are positive for HPV16. 1-4 Nonetheless, HPV DNA detection in tumor biopsies may not be sufficient evidence of causation. HPV16 DNA from tumor specimens analyzed jointly with markers of expression of the viral oncogene E6, mutational patterns of the cancer suppressor gene TP53 and levels of allelic loss, have helped identify a subset of these cancers that may be the consequence of HPV infection. 1,2,[5][6][7][8] HPV viral load, a measure of the amount of viral DNA in biopsy specimens, alone or in conjunction with well-characterized HPV serologic assays, may clarify the role of HPV among oral and oropharyngeal cases. Antibodies against HPV E6 and E7 are markers of an invasive HPV-associated malignancy 9,10 and are rarely present among ind...

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“…9 It has been shown that there are several differences between HPV-positive and -negative headand-neck squamous cell carcinomas. Despite the fact that HPV positivity in head-and-neck squamous cell carcinomas is an indicator for favorable prognosis, from a clinical point of view these tumors are often poorly differentiated 4,6,[10][11][12] and metastasized to lymph nodes at presentation. 10,11 Furthermore, HPV-positive tumors are often smaller at first diagnosis (diameter r4 cm), 13 and associated with low/no exposure to alcohol and tobacco.…”

mentioning

confidence: 99%

“…Despite the fact that HPV positivity in head-and-neck squamous cell carcinomas is an indicator for favorable prognosis, from a clinical point of view these tumors are often poorly differentiated 4,6,[10][11][12] and metastasized to lymph nodes at presentation. 10,11 Furthermore, HPV-positive tumors are often smaller at first diagnosis (diameter r4 cm), 13 and associated with low/no exposure to alcohol and tobacco. 10,11 At the molecular level, the functional inactivation of two key tumor suppressor proteins, ie, p53 and pRb by the HPV-derived oncoproteins E6 and E7, often result in the downregulation of p53, pRb, cyclin D1, and a strong upregulation of p16 INK4A in HPVpositive tumors.…”

mentioning

confidence: 99%

“…10,11 Furthermore, HPV-positive tumors are often smaller at first diagnosis (diameter r4 cm), 13 and associated with low/no exposure to alcohol and tobacco. 10,11 At the molecular level, the functional inactivation of two key tumor suppressor proteins, ie, p53 and pRb by the HPV-derived oncoproteins E6 and E7, often result in the downregulation of p53, pRb, cyclin D1, and a strong upregulation of p16 INK4A in HPVpositive tumors. 5,7,[14][15][16] HPV-negative tumors, in contrast, often show inactivation of p16 INK4A , p53 overexpression as a result of gene mutations, cyclin D1 gene amplification and overexpression, as well as EGFR accumulation.…”

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confidence: 99%

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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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Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas

Cited by 304 publications

References 31 publications

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma

HPV16 semiquantitative viral load and serologic biomarkers in oral and oropharyngeal squamous cell carcinomas

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

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