Re: Human Papillomavirus in Oral Exfoliated Cells and Risk of Head and Neck Cancer
Re: Human Papillomavirus in Oral Exfoliated Cells
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Risk of Head
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Neck Cancer
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Journal of the National Cancer Institute
, Vol. 96, No. 15, August 4, 2004
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(1) Smith EM, Ritchie JM, Summersgill KF, Hoffman HT, Wang DH, Haugen TH,
et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Can- cer Inst 2004
;96:449 -55. (2) Herrero R, Castellsague X, Pawlita M, Lis- sowska J, Kee F, Balaram P,
et al. Human pap- illomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003
;95:1772- 83. (3) Gillison ML,
Shah KV. Human papillomavirus- associated head and neck squamous cell carci- noma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 2001
;13: 183- 8. (4) Kreimer AR, Alberg AJ, Daniel R, Gravitt PE, Viscidi R, Garrett ES, et al. Oral human pap- illomavirus infection in adults is associated with sexual behavior and HIV serostatus. J In- fect Dis 2004;189:686 -98. (5) Kutler DI, Wreesmann VB, Goberdhan A, Ben Porat L, Satagopan J, Ngai I,
et al. Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 2003
;95: 1718 -21. (6) Wadsworth JT, Somers KD, Cazares LH, Malik G, Adam BL, Stack BC Jr, et al. Serum
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CORRESPONDENCE
I read with interest the article by
Smith et al. (1) reporting an
association between human papillomavirus
(HPV) and head and neck
squamouscell carcinoma (HNSCC). Their study
is consistent with two previous reports
of the association of HPV with
HNSCCs and especially with tonsillar
and oropharyngeal cancers (2,3).
These three studies suggest that
approximately 25% of tonsillar and
oropharyngeal cancers are linked with
HPV-induced carcinogenesis. In
addition, all three studies found a
preponderance (i.e., 85% or more) of
HNSCCs with HPV type 16 (HPV16)
DNA, the type that causes
approximately 50% of cervical cancers. These
data are consistent with an etiologic
role for HPV in the development of a
subset of HNSCCs and the notion that
HPV16 is uniquely oncogenic.
However, Smith et al. (1) state that
HPV testing of an oral rinse may be
predictive of HPV-related head and
neck cancers. Such a statement
warrants caution. Although oral HPV DNA
was strongly associated with having
HNSCC compared with HPV DNA
negative control subjects (odds ratio
[OR] 11.5, 95% confidence interval
[CI] 5.2 to 25.7), the association was
substantially less than the more than
100-fold (odds ratio) associations
between HPV DNA in exfoliated cervical
cells and cervical cancer. This
order-ofmagnitude difference in strength of the
association is partly the result of the
non-HPV etiology of HNSCCs but also
of the weak concordance between oral
HPV status and HPV positivity of the
tumor ( 0.40, 95% CI 0.23 to
0.57). Oral HPV testing by Smith et al.
(1) was more accurate for that detection
of HNSCC than that previously
observed (2). Combining data from these
two studies (Table 1), was 0.33 (95%
CI 0.18 to 0.47). Unlike HPV testing
of exfoliated cervical specimens that can
be highly concordant with biopsy HPV
HPV DNA in tumor
No. negative (%)
No. positive (%)
HPV DNA in oral cells
No. negative (%)
No. positive (%)
Number pairs in parentheses represent the respective contributions from Smith et al. (1) and Herrero
et al. (2), respectively. Row percentages are provided (for all data, 0.33 [95% confidence interval {CI}
0.18 to 0.47]; 86.6% agreement [95% CI 83.5% to 89.4%] and 25.0% positive agreement [95% CI
0.18 to 0.47]; relative sensitivity 36.9% [95% CI 25.3% to 49.8%]; relative specificity 93.5%
[95% CI 90.9% to 95.5%]).
DNA (due to the proximity of the
sampling to the tumor), oral HPV DNA
status may reflect an exposure to HPV that
is often unrelated to having a cancer in
other anatomic locations of the head and
neck. A recent study found that the
prevalence of HPV DNA in oral rinses was
significantly higher than that in
transepithelial brush biopsy specimens of the
tonsillar region (4), suggesting that oral
HPV DNA status poorly reflects HPV
status elsewhere. Thus, the combination
of high prevalence of oral HPV DNA in
non-case subjects and poor agreement of
oral HPV DNA status in case subjects
will limit the usefulness of oral HPV
DNA testing for HPV-related HNSCCs,
except possibly among patients, such as
Fanconi anemia patients, who have a
predilection for these malignancies and
who are uniquely susceptible to
HPVinduced carcinogenesis and are at a high
risk of an HPV16-induced HNSCC (5).
Other biomarkers (e.g., p16INK4A
expression or 3q amplification) could be
considered for molecular diagnostics for
detection of HNSCC, but like HPV
DNA, these may require more invasive
cell collections from the tonsils and/or
oropharynx than simple oral collections
for diagnostic accuracy. Serum assays
for HPV16 oncoproteins E6 and E7 are
highly specific for HNSCC and better
correlate with HPV DNA sta (...truncated)