Unilateral vs Bilateral Transoral Surgery for Tonsillar Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

Andrew M Peterson; Lucas Cruz; Michael P Wu; Spencer R Bockover; Dorina Kallogjeri; Lauren H Yaeger; Alex Harbison; Paul Zolkind; Jason T Rich; Patrik Pipkorn; Randal C Paniello; Sidharth V Puram; Ryan S Jackson

doi:10.1001/jamaoto.2025.2235

. 2025 Aug 14;151(12):1148–1156. doi: 10.1001/jamaoto.2025.2235

Unilateral vs Bilateral Transoral Surgery for Tonsillar Squamous Cell Carcinoma

A Systematic Review and Meta-Analysis

Andrew M Peterson ^1,^2,^✉, Lucas Cruz ², Michael P Wu ^1,², Spencer R Bockover ^1,², Dorina Kallogjeri ^2,³, Lauren H Yaeger ⁴, Alex Harbison ^1,², Paul Zolkind ^1,², Jason T Rich ^1,², Patrik Pipkorn ^1,², Randal C Paniello ^1,², Sidharth V Puram ^1,², Ryan S Jackson ^1,²

¹Head and Neck Tumor Center at Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri

²Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri

³Statistics Editor, JAMA Otolaryngology–Head & Neck Surgery

⁴Bernard Becker Medical Library, Washington University School of Medicine, St Louis, Missouri

Accepted for Publication: June 5, 2025.

Published Online: August 14, 2025. doi:10.1001/jamaoto.2025.2235

^✉

Corresponding Author: Andrew M. Peterson, MD, MSCI, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8115, St Louis, MO 63110 (pandrew@wustl.edu).

Author Contributions: Drs Peterson and Jackson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Peterson, Harbison, Jackson.

Acquisition, analysis, or interpretation of data: Peterson, Cruz, Wu, Bockover, Kallogjeri, Yaeger, Zolkind, Rich, Pipkorn, Puram, Jackson, Paniello.

Drafting of the manuscript: Peterson.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Peterson, Cruz, Kallogjeri.

Administrative, technical, or material support: Peterson, Bockover, Yaeger, Puram.

Supervision: Wu, Harbison, Pipkorn, Jackson.

Conflict of Interest Disclosures: Dr Kallogjeri reported receiving personal fees from JAMA Otolaryngology–Head & Neck Surgery for serving as statistics editor outside the submitted work. Dr Jackson reported receiving honoraria from Intuitive outside the submitted work. No other disclosures were reported.

Disclaimer: Dr Kallogjeri is statistics editor of JAMA Otolaryngology–Head & Neck Surgery, but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Meeting Presentation: This study was presented at the Combined Otolaryngology Spring Meetings; May 15, 2025; New Orleans, Louisiana.

Data Sharing Statement: See Supplement 2.

^✉

Corresponding author.

PMCID: PMC12355387 PMID: 40810933

Key Points

Question

Among patients with tonsillar squamous cell carcinoma (SCCa), what are the second primary tumor rates, oncologic survival, functional outcomes, and complications between patients undergoing bilateral vs unilateral transoral surgery?

Findings

This systematic review and meta-analysis of 11 studies including 1486 patients found that the synchronous contralateral tonsil second primary rate for patients undergoing bilateral surgery was 4% (95% CI, 2%-5%) and that the metachronous contralateral tonsil second primary rate for patients undergoing unilateral surgery was 0.1% (95% CI, 0%-1%). There were no differences in overall survival, disease-free survival, gastrostomy tube dependence, and postoperative oropharyngeal hemorrhage rates.

Meaning

This study suggests that omission of contralateral elective extracapsular tonsillectomy in tonsillar SCCa is safe; there are no clear benefits to performing bilateral surgery for unilateral tonsillar SCCa.

Abstract

Importance

Transoral surgery via a radical tonsillectomy followed by pathology-guided adjuvant therapy is standard of care for tonsillar squamous cell carcinoma (SCCa). There is significant variation in the management of the contralateral tonsil without clinical evidence of disease.

Objective

To assess the second primary tumor rates, oncologic survival, functional outcomes, and complications between bilateral and unilateral transoral surgery for tonsillar SCCa.

Data Sources

A search of Embase, Ovid MEDLINE, Scopus, and Cochrane was performed on September 11, 2024.

Study Selection

Inclusion criteria were studies with more than 10 adults undergoing transoral surgery for unilateral tonsillar SCCa reporting at least 1 primary or secondary outcome. Screening of abstracts and full texts along with data extraction were performed in duplicate.

Data Extraction and Synthesis

The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline was followed. Data were pooled using a random-effects model.

Main Outcomes and Measures

The primary outcome measure was the synchronous and metachronous contralateral tonsil second primary tumor rates. Secondary outcome measures were between-group differences in oropharyngeal hemorrhage and gastrostomy tube dependence rates and 2-year and 5-year overall survival (OS) and disease-free survival (DFS).

Results

Of 136 unique citations identified, 11 studies were included, representing a total of 1486 patients (634 bilateral surgery, 852 unilateral surgery). The synchronous contralateral tonsil second primary tumor rate in the bilateral surgery group was 4.0% (95% CI, 2.0%-5.0%; I² = 0.05%). The metachronous contralateral tonsil second primary tumor rate in the unilateral surgery group was 0.1% (95% CI, 0%-1%; I² = 0.04%). There were no between-group differences in oropharyngeal bleeding rate (−0.2% [95% CI, −5.6% to 5.3%]) or gastrostomy tube dependence rate (−0.5% [95% CI, −5.2% to 4.3%]). The 2-year and 5-year pooled OS proportion differences between the bilateral surgery and unilateral surgery groups were 3.6% (95% CI, −2.2% to 9.4%) and 5.3% (95% CI, −3.8% to 14.4%), respectively. The 2-year and 5-year pooled DFS proportion differences between the bilateral surgery and unilateral surgery groups were −0.5% (95% CI, −6.5% to 5.4%) and 11.1% (95% CI, 1.6%-20.5%), respectively.

Conclusions and Relevance

This systematic review and meta-analysis suggests that omission of contralateral elective extracapsular tonsillectomy in tonsillar SCCa is safe with markedly low metachronous contralateral tonsillar second primary tumor rates and no compromise in survival. The decision to perform a simultaneous contralateral extracapsular tonsillectomy can be addressed via clinician-patient shared decision-making with consideration of its pros and cons.

This systematic review and meta-analysis assesses the second primary tumor rates, oncologic survival, functional outcomes, and complications between bilateral and unilateral transoral surgery for tonsillar squamous cell carcinoma (SCCa).

Introduction

The adoption of transoral laser microsurgery and transoral robotic surgery has significantly changed the management of oropharyngeal squamous cell carcinoma (SCCa). Patients and physicians often elect for transoral surgery with pathology-driven adjuvant therapy instead of primary chemoradiotherapy for surgically resectable SCCa in the modern era, particularly for human papillomavirus (HPV)–positive disease.^1,2,3,4,5,6 For tumors of the palatine tonsil, there is significant surgeon-to-surgeon and institutional variability in the management of the contralateral tonsil without clinical evidence of disease primarily because of the risk of a second contralateral tonsil primary tumor. Second primary malignant neoplasms are categorized as synchronous, which are tumors diagnosed at the same time or within 6 months of the original primary tumor, or metachronous, which are tumors diagnosed more than 6 months after the original tumor.⁷ Some surgeons recommend routine contralateral extracapsular tonsillectomy, citing an up to 10% synchronous bilateral tonsil second primary tumor rate,⁸ while others omit operating on the contralateral tonsil due to the potentially higher complication rate and worsened functional outcomes.

Studies on tonsillar SCCa have also had varied surgical recommendations, with some recommending routine bilateral transoral surgery^{8,9,10,11,12,13} and more recent studies recommending unilateral surgery alone.^14,15 A Triological “Best Practice” statement published in 2018 concluded that the contralateral tonsil should routinely be removed in cases of suspected or known unilateral HPV-positive tonsillar SCCa despite no clinical or radiographic evidence of disease in the contralateral tonsil.¹⁶ This statement emphasized the synchronous contralateral tonsil second primary tumor rates in bilateral surgery with little emphasis on functional outcomes, complication rates, oncologic survival, and the metachronous second primary tumor rates. The objective of this study was to systematically review the literature and meta-analyze the second primary tumor rates, oncologic survival, functional outcomes, and complications between bilateral and unilateral transoral surgery for tonsillar SCCa.

Methods

This systematic review and meta-analysis was conducted and reported in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline.¹⁷ This review was exempt from the Washington University institutional review board because no identifiable patient data were used.

Eligibility Criteria

The PICO (Population, Intervention, Comparator, Outcome) format was used to design the meta-analysis research question. The population was adults with unilateral tonsillar SCCa. The intervention and comparator were bilateral or unilateral primary transoral surgery (including either transoral laser microsurgery or transoral robotic surgery). The primary outcome measure was the synchronous and metachronous contralateral tonsil second primary tumor rates. Secondary outcome measures included between-group combined differences of postoperative oropharyngeal hemorrhage rates, long-term gastrostomy tube dependence rates, and 2-year and 5-year overall survival (OS) and disease-free survival (DFS). Long-term gastrostomy tube dependence was defined as gastrostomy tube use for more than 1 year after surgery.

The inclusion criteria were case series, case-control studies, cohort studies, and clinical trials with more than 10 adult patients that reported at least 1 primary or secondary outcome of interest for patients undergoing transoral surgery for unilateral tonsillar SCCa. Exclusion criteria were studies including histopathology other than SCCa, systematic reviews, studies that did not specify their surgical approach, or studies that did not report data specific to the patients from the palatine tonsil subsite of the oropharynx. Published conference abstracts without full text that had sufficient information to aid in a pooled analysis were also included.

Search Strategy

A medical librarian (L.H.Y.) searched the literature for records including the concepts of tonsillar SCCa, transoral surgery, tonsillectomy, bilateral, unilateral, and contralateral. The librarian created search strategies using a combination of keywords and controlled vocabulary in Embase (starting in 1947), Ovid MEDLINE (starting in 1946, Scopus (starting in 1823), Cochrane Central Register of Controlled Trials (starting in 1997), The Cochrane Database of Systematic Reviews (starting in 1997), and ClinicalTrials.gov (starting in 1997). All search strategies were completed September 11, 2024, with no added limits, and studies were deduplicated using previously described deduplication processes.¹⁸ Fully reproducible search strategies for each database can be found in the eAppendix in Supplement 1. Reference lists were also reviewed for any additional relevant citations not retrieved by the search strategy. The corresponding authors of all studies with survival outcomes were contacted requesting deidentified patient data to aid in analysis, but we were unable to obtain the individual patient data.

Data Collection and Assessment of Data Quality

All stages of the review (title and abstract screening, full-text screening, and data extraction) were performed in duplicate by 2 independent reviewers, which included 1 otolaryngology resident physician (A.M.P), 1 head and neck surgical oncology fellow (M.P.W.), and 2 trainees with advanced clinical research training (L.C. and S.R.B.). Each reviewer was blinded to the other reviewer’s results. Discrepancies at each stage of the review were resolved by the head and neck fellow and senior author (M.P.W. and R.S.J.). The quality of observational studies was assessed by 2 independent blinded reviewers (A.M.P and L.C.) using the Methodological Index for Non-Randomized Studies (MINORS), which has a maximum sum score of 16 for noncomparative studies and 24 for comparative studies.¹⁹ Kaplan-Meier curves without corresponding quantitative data were assessed using a validated image analyzer that has been used in previous systematic reviews to extract data points for the pooled survival analysis.^20,21

Statistical Analysis

Standard descriptive statistics were used to describe the study population, baseline demographic characteristics, pathologic T stage (pT), pathologic N stage (pN), and p16 or HPV status. Primary and secondary outcomes presented as proportions were pooled using a random-effects model of proportions via the method of DerSimonian and Laird. Pooled 2-year and 5-year OS and DFS were calculated. Publication bias was assessed by creating a funnel plot and using the Egger test for small-study effects. Data analysis was performed from October 22 through November 14, 2024, using Stata, version 18 (StataCorp LLC) and SPSS, version 29.0 (IBM Corp). The statistical significance threshold was P = .05.

Results

Baseline Characteristics of Included Studies

A total of 202 studies from electronic databases were identified. After excluding 66 duplicates, a total of 136 abstracts were reviewed. After applying the inclusion and exclusion criteria, 15 studies remained for full-text review. Two of the abstracts^22,23 from conferences were published as abstracts only but were deemed to have adequate information to meet inclusion criteria for the qualitative and quantitative synthesis. Nine other full texts^{8,9,10,11,12,13,14,15,24} met inclusion and exclusion criteria, resulting in a total of 11 studies included, representing a total of 1486 patients (634 bilateral surgery, 852 unilateral surgery) (Figure 1). A total of 1206 patients from 7 studies^{8,12,13,14,15,23,24} had p16 or HPV status reported, which was positive in 1117 patients (92.6%). Study characteristics and total MINORS score for each included study are shown in Table 1.^{8,9,10,11,12,13,14,15,22,23,24}

Figure 1. — SCCa indicates squamous cell carcinoma.

^aTwo abstracts were presented at conferences as abstracts only without subsequent full-text publication. Each of these abstracts included enough data and detail to include in the final qualitative and quantitative analysis and are noted in Table 1.

Table 1. Baseline Characteristics of the Included Studies.

Source	Study type	Patients undergoing transoral surgery for tonsillar SCCa, No.		Age, mean (SD), y^a		Women per group, No. (%)		pT Stage by group, stage (No.)		pN Stage by group, stage (No.)		p16 or HPV positive, No. (%)	MINORS criteria score
Source	Study type	Unilateral	Bilateral	Unilateral	Bilateral	Unilateral	Bilateral	Unilateral	Bilateral	Unilateral	Bilateral	p16 or HPV positive, No. (%)	MINORS criteria score
Comparative unilateral vs bilateral transoral surgery studies
McQuone et al,⁹ 1998	Case series	7	16	55 (NR)	55 (NR)	7 (19)	7 (19)	NR	NR	N1 (2), N2 (7)	N1 (2), N2 (7)	NR	10
Wysocka et al,²³ 2012 (abstract only)	Case series	96	63	NR	NR	NR	NR	NR	NR	NR	NR	36 (82)^b	9
Dziegielewski et al,⁸ 2017	Cohort	49	30	58 (10)	58 (10)	11 (37)	7 (14)	T1 (17), T2 (27), T3 (4) T4 (1)	T1 (14), T2 (14), T3 (1), T4 (1)	Nx (1), N0 (3), N1 (18), N2 (27)	Nx (0), N0 (2), N1 (12), N2 (16)	p16: 61 (77), HPV: 52 (66)	16
Parhar et al,¹⁴ 2021	Cohort	295	16	58 (8.5)	NR	48 (16)	NR	T1 (95), T2 (168), T3 (24), T4 (2)	NR	Nx (0), N0 (39), N1 (213), N2 (43)	NR	295 (100)	16
McMillan et al,¹⁵ 2022	Cohort	303	57	57 (9.5)	55 (8.3)	40 (13)	14 (25)	T1 (97), T2 (149), T3 (26), T4 (31)	T1 (23), T2 (22), T3 (0), T4 (2)	Nx (0), N0 (46), N1 (211), N2 (46)	Nx (0), N0 (7), N1 (34), N2 (6)	360 (100)	16
Peterson et al,²⁴ 2025	Cohort	106	52	60 (10)	60 (10)	14 (13)	5 (10)	T1 (39), T2 (53), T3/4 (14)	T1 (23), T2 (25), T3/4 (4)	Nx (1), N0 (10), N1 (75), N2 (20)	Nx (0), N0 (3), N1 (40), N2 (9)	158 (100)	17
Bilateral transoral surgery only
Koch et al,¹⁰ 2001	Case series	0	16	NA	NR	NA	NR	NA	NR	NA	NR	NR	8
Kothari et al,¹¹ 2008	Case series	0	22	NA	NR	NA	NR	NA	NR	NA	NR	NR	8
Saunders et al,²² 2013 (abstract only)	Case series	0	120	NA	NR	NA	NR	NA	NR	NA	NR	NR	9
Rokkjaer et al,¹² 2018	Case series	0	211	NA	59 (14)	NA	53 (25)	NA	NR	NA	NR	156 (74)	9
Mahmood et al,¹³ 2022	Case series	0	59	NA	60.8 (NR)	NA	14 (23.7)	NA	T1, 2 (36), T3, 4 (13), Tx (10)	NA	N0 (17); N1, 2 (42)	51 (86)	9

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Abbreviations: HPV, human papillomavirus; MINORS, Methodological Index for Non-Randomized Studies; NA, not applicable; NR, not reported; SCCa, squamous cell carcinoma.

^{^a}

Estimated mean (SD) values were used when only median (range) values were provided.

^{^b}

Only 44 of 159 possible patients underwent p16 testing from this study.

Primary Outcome Measure: Synchronous and Metachronous Second Primary Tumor Rates

For the 634 patients who underwent bilateral transoral surgery from all 11 included studies,^{8,9,10,11,12,13,14,15,22,23} the combined synchronous contralateral tonsil second primary tumor rate was 4.0% (95% CI, 2.0%-5.0%; I² = 0.05%) (Figure 2A). For the 852 patients who underwent unilateral transoral surgery from a total of 6 studies,^8,9,14,15,23 the combined metachronous contralateral tonsil second primary tumor rate was 0.1% (95% CI, 0%-1%; I² = 0.04%) (Figure 2B). All 6 studies including unilateral patients except for one²³ reported length of follow-up with a median length of follow-up ranging from 11 to 50 months. Given that the ability to identify a metachronous second primary tumor is expected to be dependent on length of follow-up, a sensitivity analysis was performed for studies reporting length of follow-up of at least 24 months and again for studies reporting length of follow-up of at least 48 months. The pooled metachronous contralateral tonsil second primary tumor rate for the 4 studies^9,14,15,24 with at least 24 months of median follow-up was 0.1% (95% CI, 0%-1%; I² = 0.00%) (eFigure 1A in Supplement 1). The pooled metachronous contralateral tonsil second primary tumor rate for the 2 studies^14,15 with at least 48 months of median follow-up was 0.3% (95% CI, 0%-1%; I² = 0.06%) (eFigure 1B in Supplement 1). Additional sensitivity analyses were performed to calculate the synchronous and metachronous second primary tumor rates with exclusion of the 2 studies that had only an abstract published. The pooled synchronous contralateral tonsil second primary tumor rate was 6% (95% CI, 3%-11%; I² = 53.6%) (eFigure 2A in Supplement 1), and the pooled metachronous contralateral tonsil second primary tumor rate was 0.1% (95% CI, 0%-1%; I² = 0.00%) (eFigure 2B in Supplement 1). All extracted data are in Table 2.^{8,9,10,11,12,13,14,15,22,23,24}

Figure 2. — Data with wide variability have smaller data markers, while more precise estimates have larger data markers.

Table 2. Data Extraction for Outcomes of UL vs BL Transoral Surgery for Tonsillar Squamous Cell Carcinoma.

Source	No./total No. (%) at risk		Length of follow-up, median (range), mo	2-y OS		5-y OS		2-y DFS		5-y DFS		No./total No. (%) at risk							Surgical recommendation
	Metachronous contralateral tonsil second primary tumor rate	Incidental synchronous contralateral tonsil second primary tumor rate		UL	BL	UL	BL	UL	BL	UL	BL	Postoperative oropharyngeal bleeding rate		GT dependence at any point during postoperative course		GT dependence at last follow-up
	Metachronous contralateral tonsil second primary tumor rate			UL	BL	UL	BL	UL	BL	UL	BL	UL	BL	UL	BL	UL		BL
Comparative UL vs BL surgery studies
McQuone et al,⁹ 1998	0/3 (0)	1/8 (12.5)	34 (Mean)	100	NR	NR	NR	100	NR	NR	NR	NR	NR	NR	NR	NR		NR	Routine BL tonsillectomy
Wysocka et al,²³ 2012	0/96 (0)	5/63 (3.1)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR		NR	Routine BL tonsillectomy
Dziegielewski et al,⁸ 2017	0/49 (0)	3/30 (10)	11 (0-42)	NR	NR	NR	NR	NR	NR	NR	NR	1/49 (2)	1/30 (3)	10/49 (20)	7/30 (23)	1/49 (2)		1/30 (3)	Routine BL tonsillectomy
Parhar et al,¹⁴ 2021	1/295 (0.3)	2/16 (12.5)	48 (IQR, 30-62)	96	NR	90	NR	90	NR	85	NR	NR	NR	NR	NR	NR			UL radical tonsillectomy only
McMillan et al,¹⁵ 2022	1/303 (0.3)	1/37 (2.7)	50 (Unknown)	96	96	7	85	92	100	86	77	23/303 (8)	2/57 (4)	NR	NR	13/303 (4)		1/20 (5)	UL radical tonsillectomy only
Peterson et al,²⁴ 2025	2/106 (1.8)	1/52 (1.9)	31 (0-90)	94	89	88	74	94	87	83	73	8/106 (7)	8/52 (15)	14/106 (13)	9/52 (17)	9/106 (8)		4/52 (8)	UL radical tonsillectomy only
BL transoral surgery only
Koch et al,¹⁰ 2001	NA	2/16 (12.5)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR		Routine BL tonsillectomy
Kothari et al,¹¹ 2008	NA	5/22 (22.7)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR		Routine BL tonsillectomy
Saunders et al,²² 2013	NA	3/120 (2.5)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR		None
Rokkjaer et al,¹² 2018	NA	7/211 (3.3)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR		Routine BL tonsillectomy
Mahmood et al,¹³ 2022	NR	5/59 (8.5)	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR		Routine BL tonsillectomy

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Abbreviations: BL, bilateral; DFS, disease-free survival; GT, gastrostomy tube; NA, not applicable; NR, not reported; OS, overall survival; UL, unilateral.

Secondary Outcome Measures: Postoperative Hemorrhage, Swallowing Outcomes, and Survival

The oropharyngeal bleeding rate and long-term gastrostomy tube dependence rate were reported in 3 studies.^8,15 The pooled oropharyngeal bleeding rate was 6% (95% CI, 0%-13%; I² = 64.1%) for bilateral transoral surgery (eFigure 3 in Supplement 1) and 6% (95% CI, 2%-9%; I² = 61.7%) for unilateral transoral surgery (eFigure 4 in Supplement 1). There were no between-group proportional differences in the oropharyngeal bleeding rate (−0.2% [95% CI, −5.6% to 5.3%]) for bilateral vs unilateral surgery. The long-term gastrostomy tube dependence rate was 5% (95% CI, 1%-9%; I² = 0.01%) for bilateral transoral surgery (eFigure 5 in Supplement 1) and 4% (95% CI, 2%-7%; I² = 36.0%) for unilateral transoral surgery (eFigure 6 in Supplement 1). There were no between-group proportional differences in long-term gastrostomy tube dependence rates (−0.5% [95% CI, −5.2% to 4.3%]) in the bilateral vs unilateral surgery groups. Short-term swallowing outcomes were assessed by only 1 study, which found no between-group median difference in the time to nasogastric tube removal (0 days [95% CI, −1 to 1 day]) or between-group proportion difference in hospital discharge rate with a nasogastric tube (4.2% [95% CI, −11.5% to 19.9%]) in unilateral vs bilateral surgery.²⁴

Overall survival and DFS were reported in 3 studies^14,15,24 for the unilateral group and 2 studies^15,24 for the bilateral group, which included only patients with confirmed HPV-positive and/or p16-positive disease. The pooled bilateral vs unilateral group estimates were 94% vs 96% for 2-year OS, 78% vs 84% for 5-year OS, 93% vs 92% for 2-year DFS, and 74% vs 85% for 5-year DFS. The 2-year and 5-year pooled OS proportion differences between the bilateral and unilateral groups were 3.6% (95% CI, −2.2% to 9.4%) and 5.3% (95% CI, −3.8% to 14.4%), respectively. The 2-year and 5-year pooled DFS proportion differences between the bilateral and unilateral groups were −0.5% (95% CI, −6.5% to 5.4%) and 11.1% (95% CI, 1.6%-20.5%), respectively.

Publication Bias

The synchronous contralateral tonsil second primary tumor rate was used as the outcome to assess publication bias because all 11 included studies reported this outcome.^{8,9,10,11,12,13,14,15,22,23} Publication bias was identified by creating a funnel plot (Figure 3), which showed no studies with a small sample size reporting a synchronous second primary tumor rate below the pooled estimate of 4%, which was confirmed by a statistically significant (P = .001) Egger test for small-study effects. Larger studies reported lower rates of synchronous second primary tumors closer to the pooled estimate of 4%.

Discussion

In this study, we found that patients undergoing unilateral transoral surgery for tonsillar SCCa have metachronous contralateral tonsil second primary tumor rates that are clinically negligible, with an estimate of 0.1%. The rate of simultaneous synchronous bilateral tonsillar SCCa for patients undergoing bilateral surgery was 4%, lower than the often-cited rate of 10%.⁸ There was no compromise in survival with the unilateral technique.

To date, the primary focus of articles advocating for bilateral surgery is the risk of a synchronous second primary tumor, with little emphasis or discussion on the comparative risk of a metachronous contralateral tonsil second primary tumor should the patient undergo unilateral surgery alone. Using our data to drive clinical care, we anticipate patients to react differently if they are presented with a 4% bilateral tonsil SCCa rate at the time of surgery compared with a contralateral tonsillar SCCa rate of 0.1% if unilateral surgery alone is performed with long-term follow-up. This conundrum highlights the importance of clear communication with patients.

We hypothesize 2 reasons why the metachronous primary tumor rates are consistently lower than synchronous primary tumor rates over multiple studies: (1) the immune system may have the ability to eliminate early cancers and (2) adjuvant radiotherapy and/or chemotherapy likely has some therapeutic effect on early tumors. Therefore, these contralateral tumors are more likely to become clinically undetectable, sparing the need for definitive treatment of the contralateral tonsil. If the patient undergoes close long-term surveillance, the rare metachronous contralateral tonsil second primary tumor is expected to be identified early and to be treatable with very high survival. Furthermore, there is no sound scientific reason to perform a contralateral extracapsular tonsillectomy but not address the remainder of the oropharyngeal subsites, such as the lingual tonsils. The contralateral palatine tonsil is arbitrarily chosen likely secondary to ease of access and expectation of decreased morbidity in comparison with the addition of an elective lingual tonsillectomy. However, previous data on HPV-positive oropharyngeal SCCa found that rates of second metachronous primary tumors at any oropharyngeal subsite were overall very low at 2.2% and these secondary tumors were slightly more likely to be found in the base of tongue than the palatine tonsil.²⁵ Although metachronous second oropharyngeal primary tumors tend to occur more often in those who receive surgery alone without radiotherapy, it is possible that the incidence of metachronous second primary tumors may increase over time in the radiotherapy deintensification era for HPV-positive oropharyngeal SCCa.²⁵

With the establishment of very low metachronous contralateral tonsil second primary tumor rates and no difference in oncologic survival, the focus of the debate can shift to functional outcomes and postoperative complications. Although an extracapsular tonsillectomy may seem somewhat trivial in the scope of a patient’s cancer care, the risk of postoperative hemorrhage and significant pain and dehydration are theorized to be higher with more extensive surgery. Compared with second primary tumor rates, very few studies assessed swallowing outcomes and oropharyngeal bleeding rates. We hypothesize that on further study, bilateral transoral surgery will have higher postoperative oropharyngeal hemorrhage rates given the greater raw oropharyngeal surface area postoperatively. However, it is likely the incidence of severe or life-threatening postoperative airway bleeding is similar between the approaches, given that the most severe arterial bleeding is expected to be from the radical tonsillectomy site. Nevertheless, the risk of pain and dehydration, oropharyngeal hemorrhage, and both short-term and long-term swallowing dysfunction warrant further study and discussion between the 2 surgical approaches.

An additional consideration in whether to perform unilateral or bilateral tonsillectomy is the symmetry of the oropharynx. Some surgeons argue that the asymmetry in the oropharynx after unilateral surgery may result in unnecessary worry and additional clinic visits, imaging, or invasive testing after the asymmetry is noted on examination by their primary care physician. However, with long-term follow-up with their head and neck surgical oncologist and quality documentation through the electronic medical record, the merit of this concern is likely low.

Strengths and Limitations

This study has some strengths, the largest of which is the large, pooled sample size with nearly 1500 patients allowing for precise synchronous and metachronous second primary tumor estimates that can immediately be clinically useful in counseling patients. This study also has some limitations. One limitation is the retrospective design of all studies included without any prospective or randomized studies conducted on the topic. There is expected heterogeneity in these studies, with a minority reporting the secondary outcomes of interest. In addition, 2 studies were included that were published as conference abstracts only without a corresponding full text^22,23; however, it was deemed that the benefit of including the second primary tumor data from these studies outweighed any risks or biases that contributed to their nonpublication. Furthermore, a sensitivity analysis was conducted after excluding these articles, with no changes in the estimate for the metachronous second primary tumor rate, although the synchronous second primary tumor rate was a higher and less precise estimate. Last, while most patients included in the analysis had confirmed HPV-related disease, there were at least some HPV-negative patients included, and some studies did not report HPV status. The difference in second primary tumor rates between the 2 distinct disease types is unknown, but certainly the carcinogenic mechanism behind alcohol and tobacco–related disease is different than that of HPV-related disease. Given that most patients in this study had HPV-positive disease, we expect our results to be generalizable primarily to the population with HPV-positive tonsillar SCCa, but subgroup analysis of patients with HPV-positive and HPV-negative SCCa could not be performed with the available data.

Conclusions

This systematic review and meta-analysis found that omission of contralateral elective extracapsular tonsillectomy in tonsillar SCCa is safe, with markedly low metachronous contralateral tonsillar second primary tumor rates and no compromise in survival. The decision to perform a simultaneous contralateral extracapsular tonsillectomy can be addressed via clinician-patient shared decision-making with consideration of its pros and cons.

Supplement 1.

eAppendix. Complete Search Strategy

eFigure 1A. Forest Plot of Metachronous Contralateral Tonsillar Second Primary Rate in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa With Median Follow-Up ≥ 24 Months

eFigure 1B. Forest Plot of Metachronous Contralateral Tonsillar Second Primary Rate in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa With Median Follow-Up ≥ 48 Months

eFigure 2A. Forest Plot of Synchronous Contralateral Tonsillar Second Primary Rate in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa With Exclusion of Abstract Only Papers (Sensitivity Analysis)

eFigure 2B. Forest Plot of Metachronous Contralateral Tonsillar Second Primary Rate in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa With Exclusion of Abstract Only Papers (Sensitivity Analysis)

eFigure 3. Forest Plot of Post-Operative Oropharyngeal Hemorrhage Rate in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa

eFigure 4. Forest Plot of Post-Operative Oropharyngeal Hemorrhage Rate in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa

eFigure 5. Forest Plot of Long-Term Gastrostomy Tube Rate in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa

eFigure 6. Forest Plot of Long-Term Gastrostomy Tube Rate in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa

eFigure 7A. Forest Plot of 2-Year Overall Survival in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa

eFigure 7B. Forest Plot of 2-Year Overall Survival in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa

eFigure 8A. Forest Plot of 5-Year Overall Survival in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa

eFigure 8B. Forest Plot of 5-Year Overall Survival in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa

eFigure 9A. Forest Plot of 2-Year Disease-Free Survival in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa

eFigure 9B. Forest Plot of 2-Year Disease-Free Survival in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa

eFigure 10A. Forest Plot of 5-Year Disease-Free Survival in Patients Undergoing Bilateral Transoral Surgery for Tonsillar SCCa

eFigure 10B. Forest Plot of 5-Year Disease-Free Survival in Patients Undergoing Unilateral Transoral Surgery for Tonsillar SCCa

jamaotolaryngolheadnecksurg-e252235-s001.pdf^{(1.1MB, pdf)}

Supplement 2.

Data Sharing Statement

jamaotolaryngolheadnecksurg-e252235-s002.pdf^{(15.4KB, pdf)}

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