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Second Primary Tumors in Patients Presenting With Unilateral
HPV-Associated Tonsillar Squamous Cell Carcinoma
Ryan A. McMillan, MD ; Kathryn M. Van Abel, MD ; Linda X. Yin, MD ; David M. Routman, MD ;
Daniel J. Ma, MD; Michelle A. Neben Wittich, MD; Daniel L. Price, MD; Jan L. Kasperbauer, MD ;
Katharine R. Price, MD; Ashish V. Chintakuntlawar, MD; Eric J. Moore, MD
Objective: To describe and compare rates of metachronous and synchronous second primaries of the contralateral tonsil
in patients with primary HPV(+) tonsillar squamous cell carcinoma (SCC).
Study Design: Retrospective cohort study.
Materials and Methods: This is a single tertiary care center retrospective case series, from 2006 to 2019, of HPV(+) ton-
sillar SCC patients who underwent primary surgical resection with unilateral wide-field tonsillectomy or bilateral tonsillectomy
for diagnostic or therapeutic purposes. A metachronous second primary is one diagnosed >6 months after completion of surgi-
cal treatment. A synchronous second primary is one diagnosed during bilateral tonsillectomy for unilateral HPV(+) tonsillar
SCC. Rates of second primary and patient characteristics were compared using chi-square tests.
Results: About 303 patients underwent unilateral surgical resection +/� adjuvant therapy for HPV(+) tonsillar SCC. One
(0.3%) developed a metachronous second primary in the contralateral tonsil 11.9 years following treatment. Fifty-seven
patients with HPV(+) tonsillar SCC underwent bilateral tonsillectomy, and 37/57 (65%) had no clinical signs for contralateral
disease. Of these, only 1/37 (2.7%) was incidentally found to have a synchronous second primary. Twenty patients underwent
bilateral tonsillectomy due to clinical concern for contralateral disease. Of these, 3/20 (15%) were found to have a synchro-
nous HPV(+) SCC in the contralateral tonsil.
Conclusions: The prevalence of metachronous second primary after appropriate treatment of HPV(+) tonsillar SCC is
very low (0.3%) and so is the chance of incidentally discovering a synchronous second primary during bilateral tonsillectomy
(2.7%). We do not recommend bilateral tonsillectomy as a part of the routine algorithm in the surgical management of these
patients.
Key Words: Human papillomavirus, transoral robotic surgery, oropharynx carcinoma, tonsillectomy.
Level of Evidence: 3
Laryngoscope, 00:1–7, 2021
INTRODUCTION
Historically, second primary malignancies have been
regarded as the leading cause of long-term mortality in
patients with head and neck cancer.1 In the 1970s and
1980s, oropharyngeal cancers carried the highest risk of a
second primary in head and neck cancer patients.2 Many
of these were thought to be driven by field cancerization,
a concept popularized by Slaughter et al. that states that
any epithelium exposed to persistent carcinogens is under
similar risk for developing independent cancers.3 Today,
in the era of human papillomavirus (HPV)-driven
carcinogenesis, the oropharynx now has the lowest rate of
second primaries among head and neck subsites.4 Despite
this, the concern that the HPV infection within one site of
the oropharynx may herald field cancerization within
other subsites of Waldeyer’s ring still exists. Whether this
tissue remains at risk for the development of a second
HPV driven primary is largely unknown.
Recently, there has been a resurgent interest in
bilateral tonsillectomy for patients presenting with uni-
lateral HPV associated tonsillar squamous cell carcinoma
(HPV(+) tonsillar SCC). While some argue that this
approach may decrease the delayed diagnosis of second
primary tumors, others argue that it increases surgical
morbidity for a small mitigation in risk of a second pri-
mary and fails to address all of the at-risk oropharyngeal
tissue in Waldeyer’s ring.5–10 To weigh the benefits and
dangers of bilateral tonsillectomy in patients presenting
with unilateral HPV(+) tonsillar SCC, we must have a
thorough understanding of risk for second primary
tumors in the contralateral tonsil.
The prevalence of a metachronous second primary
diagnosed after treatment in patients undergoing unilat-
eral wide-field tonsillectomy has not been compared to
the prevalence of a synchronous second primary diag-
nosed in patients undergoing bilateral tonsillectomy for
From the Department of Otolaryngology-Head and Neck Surgery
(R.A.M., K.M.V.A., L.X.Y., D.L.P., J.L.K., E.J.M.), Mayo Clinic, Rochester,
Minnesota, U.S.A.; Department of Radiation Oncology (D.M.R., D.J.M., M.A.
N.W.), Mayo Clinic, Rochester, Minnesota, U.S.A.; and the Division of
Medical Oncology (K.R.P., A.V.C.), Mayo Clinic, Rochester,
Minnesota, U.S.A.
Editor’s Note: This Manuscript was accepted for publication on 26
June 2021.
Internal departmental funding was utilized without commercial
sponsorship or support. The authors have no other funding, financial rela-
tionships, or conflicts of interest to disclose.
Send correspondence to: Eric J. Moore, MD, Department of Otorhi-
nolaryngology, Mayo Clinic, 1 Rochester, MN 55905. E-mail: moore.
eric@mayo.edu
DOI: 10.1002/lary.29741
Laryngoscope 00: 2021 McMillan et al.: Second Primaries in HPV(+) Tonsillar SCC
1
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unilateral HPV(+) tonsillar SCC. In our study, we aim to
compare the prevalence of metachronous second pri-
maries after unilateral tonsillectomy to synchronous sec-
ond primaries after bilateral tonsillectomy for unilateral
HPV(+) tonsillar SCC with the goal of defining the risk of
developing a second primary tonsillar tumor in patients
with existing unilateral HPV(+) tonsillar SCC. Addition-
ally, we aim to determine the impact of bilateral tonsillec-
tomy on oncologic outcomes in this patient population.
METHODS
Patient Selection
After institutional review board approval (IRB 19–008331),
the departmental REDCap oropharyngeal cancer database was
queried to identify all patients with HPV(+) tonsillar SCC
treated at a tertiary care center. Inclusion criteria included a
date of diagnosis between January 1, 2006 and December
31, 2019, primary tonsillar SCC, HPV-positivity confirmed either
using p16 immunohistochemistry (>70% diffuse nuclear and cyto-
plasmic staining) or HPV DNA in situ hybridization (HPV16,
18, 31, 33, or 51), and primary surgical management � adjuvant
radiation therapy (RT) or chemoradiotherapy. The surgical
approach for margin clearing resection was a wide-field tonsil-
lectomy, defined as tonsillectomy with resection of the superior
pharyngeal constrictor, and complete frozen section margin
assessment. Tonsillectomies performed as a biopsy were typi-
cally completed as a routine tonsillectomy with frozen
section assessment, defined as excision of the palatine tonsil
leaving the superior constrictor intact, with assessment of mar-
gins as appropriate based on presence and size of malignancy.
Primary tonsillar SCC identified during HPV(+) unknown pri-
mary workup were included in the study. At our institution,
HPV(+) unknown primaries were approached with an ipsilat-
eral tonsillectomy and base of tongue resection, performed
sequentially based on highest clinical suspicion. If the primary
was found in the initial resection on intraoperative frozen
section analysis, the second subsite was not resected. Contra-
lateral base of tongue resection is performed rarely for the
workup of unknown primary at our institution. All patients
underwent primary treatment at our institution. Patients with
a prior head and neck SCC, metastatic disease at presentation,
other active malignancy, or patients receiving a de-escalated
dose of adjuvantradiation therapy (3 years after the completion of pri-
mary treatment. Synchronous second primaries were defined as
those diagnosed during primary management of HPV(+) tonsil-
lar SCC, and metachronous second primaries were defined as
those diagnosed >6 months after primary treatment.11 High-risk
bilateral tonsillectomy was defined as bilateral tonsillectomy per-
formed due to surgeon concern for a synchronous contralateral
primary based on symptomatology, physical examination, imag-
ing, or intraoperative findings. Low-risk bilateral tonsillectomy
was defined as bilateral tonsillectomy due to surgeon or patient
preference, with no concerning clinical findings to suggest contra-
lateral disease. Bilateral tonsillectomy was not performed in the
workup of HPV(+) unknown primary in this study.
Statistical Analysis
Categorical variables were summarized using frequencies
and percentages, and continuous variables were summarized
using means and standard deviations. Chi-square and Fisher’s
TABLE I.
Demographic, Clinical, and Tumor Characteristics of Patients
Undergoing Surgical Resection for Patients With HPV(+)tonSCC.
Variable
Risk Group
P-Value
Low-Risk
Bilateral
High-Risk
Bilateral Unilateral
Age at diagnosis
in years, mean (SD)
55.1 (9.43) 53.5 (6.24) 57.3 (9.49) .10†
Sex, freq (%) .07
Female 10 (27.0%) 4 (20.0%) 40 (13.2%)
Male 27 (73.0%) 16 (80.0%) 263 (86.8%)
Smoking history,
freq (%)
.22
Never smoker 18 (64.3%) 13 (72.2%) 149 (49.2%)
Former smoker 3 (10.7%) 1 (5.6%) 37 (12.2%)
Current smoker 7 (25.0%) 4 (22.2%) 117 (38.6%)
ACE-27 Score,
freq (%)
.65
0—None 17 (51.5%) 11 (57.9%) 122 (40.5%)
1—Mild 9 (27.3%) 6 (31.6%) 113 (37.5%)
2—Moderate 6 (18.2%) 2 (10.5%) 56 (18.6%)
3—Severe 1 (3.0%) 0 (0.0%) 10 (3.3%)
Pathologic T*
classification,
freq (%)
.13
pT1 14 (50.0%) 9 (47.4%) 97 (32.0%)
pT2 12 (42.9%) 10 (52.6%) 149 (49.2%)
pT3 0 (0.0%) 0 (0.0%) 26 (8.6%)
pT4 2 (7.1%) 0 (0.0%) 31 (10.2%)
Pathologic N*
classification, freq (%)
.57
pN0 6 (21.4%) 1 (5.3%) 46 (15.2%)
pN1 18 (64.3%) 16 (84.2%) 211 (69.6%)
pN2 4 (14.3%) 2 (10.5%) 46 (15.2%)
Intent-to-cure treatment
modality, freq (%)
.12
Surgery alone 15 (40.5%) 2 (10.0%) 74 (24.4%)
Surgery + radiation 8 (21.6%) 7 (35.0%) 81 (26.7%)
Surgery + chemoradiation 14 (37.8%) 11 (55.0%) 148 (48.8%)
Overall pathologic
AJCC stage*,
freq (%)
.02
Stage 1 22 (75.9%) 17 (89.5%) 217 (71.6%)
Stage 2 5 (17.2%) 2 (10.5%) 68 (22.4%)
Stage 3 1 (3.4%) 0 (0.0%) 18 (5.9%)
Extranodal
extension,
freq (%)
8 (36.4%) 10 (52.6%) 160 (63.0%) .04
Positive final
margins,
freq (%)
4 (11.8%) 2 (10.0%) 11 (3.7%) .06
Bolded values indicate statistical significance, as defined
by P00: 2021 McMillan et al.: Second Primaries in HPV(+) Tonsillar SCC
3
synchronous primary (Table III, P 40 pack year smoking history. They
found no differences in complications, gastrostomy tube
rates or length of stay, and thus recommended that all
patients undergoing primary TORS for tonsillar cancers
undergo bilateral tonsillectomy to look for synchronous
disease.6 The largest retrospective review assessing the
status of the contralateral tonsil was performed by
Rokkjaer et al., in which in 180 patients underwent bilat-
eral tonsillectomy and 31 underwent contralateral tonsil
biopsy in the absence of high-risk features as part of stan-
dard practice. Seven of 211 (3.3%) patients had a synchro-
nous second primary in the contralateral tonsil, with 4 of
these being P16+. The authors in this study additionally
recommended bilateral tonsillectomy for those with
proven tonsillar SCC to avoid early recurrence.9
In contrast, a study by Parhar et al. of 295 patients
undergoing unilateral primary TORS for HPV(+) tonsil-
lar SCC demonstrated a metachronous second primary
rate of 0.3% in the contralateraltonsil. Additionally, their
study identified three patients that underwent bilateral
tonsillectomy due to high-risk imaging features and iden-
tified one patient (33%) that had a synchronous second
primary. There were no synchronous second primaries
identified in their low-risk bilateral tonsillectomy group,
and they recommend against routine bilateral tonsillec-
tomy in the absence of high-risk features.12 Our findings
lend strong support to the conclusions drawn by Parhar
et al. We similarly found a very low rate of metachronous
second primaries (0.3%) and a low rate of incidental syn-
chronous primaries on low-risk bilateral tonsillectomy
(2.7%). The low rate of second primaries in the orophar-
ynx has been shown to be true on a national level as well
through the Surveillance, Epidemiology, and End Results
(SEER) database.13 Strober et al. reported a second pri-
mary rate of approximately 1 cm of soft palate extension or base of tongue involve-
ment, or the presence of adverse nodal features.17 In our
cohort, 57% of patients received adjuvant radiotherapy to
the ipsilateral neck only. For patients receiving ipsilat-
eral photon beam RT, the contralateral tonsil does receive
a low dose of radiation. This is supported by using the
contralateral parotid gland as a surrogate marker for
the contralateral tonsillar tissue, which receives a mean
radiation dose of 10.9 Gy for those treated to the neck
and primary site and 9.7 Gy for the neck only.18 Further-
more, studies of definitive RT for primary tonsil cancers
treated with ipsilateral RT show low rates of contralat-
eral tonsillar failure.19 In our study, for the remaining
43% that received contralateral radiation to the neck
only, studies have demonstrated the tonsil tissue ipsilat-
eral to the neck being radiated for oropharyngeal SCC
will receive potentially clinically meaningful dose
(58.5 Gy) even when excluded from the treatment plan.18
Although it is likely that both ipsilateral and bilateral
adjuvant irradiation delivers some subclinical dose of
radiation to the contralateral tonsil, 74 patients in our
series underwent surgery alone without the development
of a metachronous second primary. Therefore, subclinical
non target dose to the contralateral tonsil is unlikely to
be responsible for the low rate of metachronous contralat-
eral tonsil primaries demonstrated here.
There are several limitations to this study that
deserve consideration. As this is a retrospective chart
review, assumptions were inevitably made when consid-
ering the rationale behind bilateral tonsillectomy. In
the absence of high-risk features, a bilateral tonsillec-
tomy was assumed to fall into the low-risk category and
the decision was considered surgeon preference. How-
ever, it is possible that the surgeon performing bilateral
tonsillectomy did have alternative rationale to per-
forming bilateral tonsillectomy that was not docu-
mented in the medical record. Given the lead time
advantage in patients diagnosed with a synchronous
second primary compared to those diagnosed with a
metachronous second primary, our survival analysis
must take lead-time bias into consideration. It is possi-
ble that if the patients with synchronous primaries
experienced delays in diagnosis and their contralateral
disease was found much later, they could have devel-
oped worse oncologic outcomes. Additionally, one must
note the relatively small number of bilateral tonsillecto-
mies performed at our institution when interpreting the
results. Finally, given differences in the length of follow-
up for patients undergoing unilateral tonsillectomy as a
part of primary treatment, it is possible that some
patients who were lostto follow-up did develop
metachronous second primaries unbeknownst to the
study team. This is less likely in the age of electronic
medical record sharing agreements, as even most
Laryngoscope 00: 2021 McMillan et al.: Second Primaries in HPV(+) Tonsillar SCC
6
patients that no longer receive long term oncologic sur-
veillance at this institution can be followed electroni-
cally via the medical record.
CONCLUSION
The prevalence of metachronous second primary after
unilateral treatment of HPV(+) tonsillar SCC is low (0.3%).
The chance of incidentally discovering a contralateral syn-
chronous second primary during bilateral tonsillectomy is
additionally low (2.7%). In contrast, 15% of patients with clini-
cal concern for contralateral disease had synchronous bilat-
eral HPV(+) tonsillar SCCs. Clinical vigilance with a
thorough preoperative head and neck examination and appro-
priate imaging will identify the majority of synchronous sec-
ond primaries in the contralateral tonsil. We strongly
recommend against bilateral tonsillectomy as a part of the
routine algorithm in the surgical management of patients
without clinical suspicion of a bilateral tonsil cancer. It is
important to note that if routine tonsillectomy is performed on
the contralateral tonsil and a synchronous primary is discov-
ered, the surgeon should be prepared to carry out an oncologic
margin clearing resection for the contralateral tumor.
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	 Second Primary Tumors in Patients Presenting With Unilateral HPV-Associated Tonsillar Squamous Cell Carcinoma
	INTRODUCTION
	METHODS
	Patient Selection
	Second Primary
	Statistical Analysis
	RESULTS
	Presenting Characteristics and Rate of Synchronous Primaries in Patients Undergoing Bilateral Tonsillectomy
	Radiotherapy
	Treatment Morbidity
	Oncologic Outcomes in Patients Undergoing Unilateral vs. Bilateral Tonsillectomy
	DISCUSSION
	CONCLUSION
	BIBLIOGRAPHY