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Page 10 of 13 Salas et al. J Cancer Metastasis Treat 2018;4:15 I http://dx.doi.org/10.20517/2394-4722.2017.66

We found a neck lymph node involvement rate of 24.4% and it has a trend associated with shorter survival
(P = 0.340). The traditional concept has been that SCC of the hard palate and maxillary alveolus exhibits a
low rate of occult metastasis [7,31,32] . However, our results suggest that regional lymph node involvement is also
frequent and relevant, and an elective treatment of the neck should be performed.

Regional recurrence rates in oral cancer have been described as between 30% and 47% in T1-2 carcinoma
with untreated N0 neck, and they produce a significant decrease in patient survival. Some studies, including
two prospective randomized trials, describe that neck recurrence rates decrease with the use of elective
neck dissection [22,33-35] . Regional recurrences in oral malignancies were associated with poor differentiation,
larger tumor size, positive lymph node, and extracapsular involvement [33,35] . A series of 114 cases with SCC
of the maxillary alveolus and hard palate report regional recurrence rates of 26% in the N0 cohort (n = 100),
and 35% of the patients had either initially N-positive neck or a later conversion from N0 to N-positive
neck. Neck recurrence was associated with diminished overall survival but not with larger tumor size
or postoperative radiation to the neck. Patients with initial diagnoses of N-positive and those who later
[36]
developed neck recurrences had similar OS .

Neck node recurrences occurred in 18 cases (23.1%) of our series and appeared at a mean time of 8.6 months;
this likely represents occult metastases at presentation. Therefore, we had 42.3% of neck node involvement
if we consider initial patients with positive nodes and N0 patients who developed neck recurrence. We also
found that 25.9% of cases without clinical evidence of neck involvement developed recurrences at the neck.
Neck recurrence had a trend to poor prognosis but did not achieve significance, probably because these cases
received effective treatment including surgery (44.4%) or chemoradiation (11.1%).

Large tumor size, PNI, and LVI have been extensively associated with nodal metastasis and with shorter
survival in HNSCC [37,38] . Evaluation of classical prognostic factors in our series confirmed that larger tumors (P
= 0.019), presence of PNI (P = 0.039), and LVI (P = 0.021) were associated with shorter OS, and LVI (P = 0.026)
was associated with shorter DFS.

HNSCCs associated with smoking or drinking alcohol has been associated with a poor prognosis and are
[39]
frequently located in laryngeal and hypopharyngeal cancer, respectively . Our analysis did not indicate
higher prevalence rates of these carcinogen agents and did not find an association with prognosis in the
upper maxilla.

Expression of p16 is a confident biomarker of HPV infection in OPSCC and both are associated with
better outcome [12,13,40-44] . In contrast to OPSCC, the rates of positive HPV in oral cancer are low, and recent
studies suggest a disparity between the detection of HPV DNA and p16 expression when the prevalence
[45]
of HPV is low . Evaluation of p16 staining in our series found that only 3 (7.4%) of upper maxilla SCC
cases were considered positive for p16 staining. The p16-positive cases had a trend to be younger (48.7 vs.
63.7 years, P = 0.067), and all 3 cases were free of neck recurrence and alive at 5 years. This is the first time
to our knowledge that p16 staining has been evaluated in upper maxilla SCC and could identify a group of
patients with specific behavior. However, our analysis has the weakness of its small sample size and it needs
to be confirmed by larger series (required size of series increases because of the low rates of p16-positive
status in non-OPSCC).

The results of this retrospective analysis reveal that tumors of the hard palate and upper alveolus are
associated with a high rate of neck node involvement and regional failure, which had a tendency to result
in poor survival. Expression of p16 has a low rate in this pathology and could be associated with specific
features.