Occult Nodal Disease and Occult Extranodal Extension in Patients With Oropharyngeal Squamous Cell Carcinoma Undergoing Primary Transoral Robotic Surgery With Neck Dissection
Caitlin P. McMullen, MD1; Jonathan Garneau, MD2; Emillie Weimar, MD3; et al Sana Ali, MD4; Joaquim M. Farinhas, MD, MBA4; Eugene Yu, MD3; Peter M. Som, MD5; Cathy Sarta, RN6; David P. Goldstein, MD, MSc1; Susie Su, MSc7; Wei Xu, PhD7; Richard V. Smith, MD6; Brett Miles, MD, DDS2; John R. de Almeida, MD, MSc1
Author Affiliations Article Information
JAMA Otolaryngol Head Neck Surg. Published online June 20, 2019. doi:10.1001/jamaoto.2019.1186
Key Points
Question What is the rate of occult extranodal extension and postoperative nodal upstaging in patients with pathologic T1-2 oropharyngeal squamous cell carcinoma treated by transoral robotic surgery and neck dissection?
Findings In this cohort study of 92 patients with oropharyngeal squamous cell carcinoma from 3 different centers, the rate of occult extranodal extension on final pathologic findings was 13%. In the entire cohort, the nodal category of 12 patients (13%) was upstaged postoperatively, and the nodal category of 12 (13%) was downstaged postoperatively.
Meaning These results suggest that preoperative prediction of nodal disease and extranodal extension remains a challenge for patients with localized oropharyngeal squamous cell cancer.
Abstract
Importance The historically reported rates of subclinical cervical nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) predate the emergence of human papillomavirus as the predominant causative agent. The rate of occult nodal disease with changing etiology of OPSCC is not known, and it is challenging to anticipate which patients will be upstaged postoperatively and will require adjuvant therapy.
Objective To assess the rate of nodal upstaging and occult extranodal extension (ENE) in a multi-institutional population of patients with pathologic (p)T1-2 OPSCC treated by transoral robotic surgery and neck dissection.
Design, Setting and Participants This retrospective, multicenter cohort study of 92 participants at 2 US institutions (Albert Einstein College of Medicine, Bronx, New York [n = 38], and Icahn School of Medicine at Mount Sinai, New York, New York [n = 39]) and 1 Canadian institution (Princess Margaret Hospital, Toronto [n = 15]) examined the rate of postoperative pathologic upstaging for 92 patients with pT1-2 OPSCC undergoing transoral robotic surgery with neck dissection from August 2007 to December 2016. A neuroradiologist at each site blinded to final pathologic diagnosis reviewed preoperative imaging; these findings were compared with operative pathology and applied for tumor staging using the eighth edition of the American Joint Committee on Cancer Cancer Staging Manual. The statistical analysis was performed on December 18, 2018.
Main Outcomes and Measures Occult pathologic nodal disease and change in nodal category postoperatively.
Results Of 92 patients who met the inclusion criteria, 76 (83%) were male, and they had a mean (SD) age at surgery of 59.5 (10.5) years; 70 patients (84%) with available p16 status were positive. Five of 18 patients (28%) who had no evidence of nodal disease on imaging had occult pathologic nodal disease. Seven of 32 patients (22%) presenting with no nodal disease or with a single metastatic node on imaging received pathologic upstaging because of multiple positive nodes, indicating implementation of additional adjuvant treatment not anticipated after a priori imaging. Changes included 12 patients (13%) who had pathologic nodal upstaging and 12 (13%) with pathologic nodal downstaging in the eighth edition of staging. In the cohort, 24 patients (27%) had pathologic ENE, and 5 of 39 patients (13%) had occult ENE in the absence of radiographic evidence.
Conclusions and Relevance Predicting pathologic staging preoperatively for patients with OPSCC undergoing transoral robotic surgery and neck dissection remains a challenge. Although nodal size, tumor size, and location do not help predict ENE, the presence of nodes on imaging and nodal category may help predict ENE. Our findings suggest a small proportion of patients might benefit from further adjuvant therapies not predicted by preoperative imaging based on occult nodal upstaging and ENE.
Introduction
Transoral surgical approaches, including transoral robotic surgery (TORS), with or without postoperative adjuvant treatment have become well-accepted alternatives to definitive chemoradiotherapy for select patients with oropharyngeal squamous cell carcinoma (OPSCC). The oncologic outcomes of these techniques, with or without adjuvant therapy, are comparable to definitive chemoradiotherapy alone, while early retrospective studies suggest a possible improvement in functional and quality of life outcomes.1-4 The neck is electively managed, even for localized OPSCC, since the historical rate of occult nodal disease in OPSCC was approximately 30%.5,6 These published rates predate the increased incidence of the human papillomavirus (HPV) as the predominant causative agent in OPSCC and the emergence of transoral approaches. The rate of occult nodal disease in the current era of OPSCC dominated by HPV is not definitively known.
Many patients undergoing TORS with neck dissection for OPSCC may receive triple-modality therapy with adjuvant chemoradiotherapy, particularly if extranodal extension (ENE) or positive margins are found on final pathological analysis.7,8 Despite advances in imaging modalities, it remains a challenge to estimate which patients have pathologic nodal metastases and ENE as well as which patients will be upstaged postoperatively and require adjuvant therapy. Knowledge of the likelihood of pathologic upstaging because of occult cervical disease or pathologic ENE would be valuable not only for counseling patients preoperatively about their potential need for adjuvant treatment, but also for determining who may benefit most from primary surgical approaches.
Methods
Study Cohort
Patients were identified through previously collected institutional review board–approved databases at each site (Princess Margaret Cancer Center, Toronto, Ontario, Canada; Icahn School of Medicine at Mount Sinai, New York, New York; and Montefiore Medical Center, New York, New York). Patients with pathologic (p)T1-2N0-3M0 OPSCC who completed TORS with concurrent or staged ipsilateral or bilateral neck dissections from August 2007 to December 2016, and who had imaging available for review were identified and included. Bilateral neck dissections were done at the discretion of the treating surgeon (D.P.G., R.V.S., B.M., J.D.A., and other surgeons at each institution) and were generally performed for patients with bilateral nodal disease or for disease considered to be at high risk for contralateral nodal involvement. Patients were excluded for the following reasons: previous treatment for head and neck cancer, previous neoadjuvant therapy, aborted TORS, nonoropharyngeal primary site, pathological findings other than SCC, transoral approaches with techniques other than TORS, mandibulotomy or other open approaches to oropharyngeal tumor, or no available medical records, imaging for review, operative notes, and complete pathology reports. Institutional databases were created at each institution for the purpose of head and neck cancer research before the inception of this study. Each participating institution obtained individual institutional review board approval. Informed consent was waived for this study because it was a retrospective review with privacy violation as the only serious risk to patients. Obtaining informed consent was also impractical because some patients may have died or were lost to follow-up.
Clinical Data Collection
Retrospective reviews of medical records were performed at each participating institution between September 1, 2016, and December 1, 2018. All data were deidentified and transferred to the University of Toronto, Toronto, Ontario, Canada, for compilation, and statistical analysis was performed on December 18, 2018.
Imaging
Once patients were identified through the respective clinical databases, preoperative scans were reviewed by a neuroradiologist at each individual site (Albert Einstein: S.A. and J.M.F.; Mount Sinai: P.M.S.; Toronto: E.W. and E.Y.). If both computed tomography (CT) and magnetic resonance imaging (MRI) were available, the CT findings were preferentially included for nodal disease status, and MRI findings were included for primary site information. If preoperative positron emission tomography with CT (PET-CT) was available, those findings were recorded and the final preoperative clinical staging incorporated these PET-CT findings. The ultimate radiographic stage incorporated all available radiographic information as it would in the clinical setting.
The following criteria characterized the presence of a suspicious node on imaging: (1) retropharyngeal nodes 0.8 cm or larger in the longest dimension in the axial plane; (2) jugulodigastric chain and level 1b nodes 1.5 cm or larger; (3) nodes in all other levels 1.0 cm or larger; (4) nodes with cystic or necrotic components of any size; (5) nodes with a rounded rather than ovoid shape of any size; and (6) asymmetric clustering of nodes and loss of fatty hilum. Enhancement with intravenous contrast material was not a definite consideration for suspicious adenopathy. Nodes suspicious for ENE would have 1 or both of the following characteristics: poorly defined peripheral margins, and/or the presence of matted nodes.
Pathology
Findings on the pathology report were collected from the medical record. Extranodal extension was recorded according to the findings on the pathologic analysis performed at the time of treatment, and p16-positivity was defined as at least 70% immunohistochemical staining of tumor cells. Patients with no measurable tumor on final pathology results were recorded as T0 or TX.
End Points and Statistical Analysis
The main outcome measures were the rate of occult ENE and the rate of occult nodal disease in patients with OPSCC undergoing TORS with neck dissection. The secondary outcome measure was the rate of pathologic nodal category change in patients with OPSCC undergoing TORS with neck dissection. Occult nodal disease was defined as the presence of pathologic nodal metastases of OPSCC after no preoperative evidence was noted on imaging of nodal disease. Statistical analyses were conducted using SAS, version 9.3 (SAS Institute Inc) and R, version 9 (SAS Institute Inc). To compare groups, the Fisher exact test was used for categorical variables and the Kruskal-Wallis test was used for continuous variables.
Results
Study Population
Of 92 patients who met the inclusion criteria, 76 (83%) were male and the mean (SD) age at surgery was 59.5 (10.5) years. Clinicopathologic features are reported in Table 1. Regarding tumor sites, 57 patients (62%) had a tonsil primary tumor, 32 patients (35%) had a base of tongue primary tumor, 2 (2%) had a soft palate tumor, and 1 (1%) had a pharyngeal wall tumor. Among the 92 patients, 70 (84%) were p16-positive, 42 (46%) were pT1, 48 (52%) were pT2, and 2 (2%) were pT0. Three patients did not have the presence or absence of ENE mentioned in the pathology report, and these 3 patients had radiographic findings suspicious for ENE preoperatively.
In this population, 18 patients (20%) were reported as radiographically N0, 53 (58%) had evidence of ENE on preoperative imaging, 32 (35%) underwent bilateral neck dissections, and 60 (65%) underwent ipsilateral neck dissection only. Twenty patients had PET-CT and CT imaging available for review; 3 had MRI and PET-CT; 2 had MRI alone; 2 had MRI, CT, and PET-CT; and the remainder had CT alone.
Extranodal Extension
In the cohort, 24 patients (27%) had pathologic ENE, and 5 of 39 patients (13%) had occult ENE in the absence of radiographic evidence. No patient with radiographic N0 disease had occult ENE. When the 3 patients with missing ENE data were excluded, the sensitivity was 79% (95% CI, 58%-93%) and the specificity was 52% (95% CI, 40%-65%) for pathologic ENE based on preoperative imaging. The positive predictive value was 38% (95% CI, 25%-53%) and the negative predictive value was 87% (95% CI, 73%-96%).
The presence of radiographic nodal positivity (odds ratio [OR], 12.3; 95% CI, 1.2 to infinity) and 1 or more suspicious nodes (OR, 11.0; 95% CI, 1.1 to infinity) were associated with occult pathologic ENE on univariate analysis. Higher radiographic (r) nodal category (vs rN0) was associated with the presence of pathologic ENE (OR: rN1, 17.4 [95% CI, 2.2 to infinity]; rN2, 20.6 [95% CI, 1.4 to infinity]; and rN3, 51.8 [95% CI, 3.6 to infinity]) (Table 2). Radiographic T category, primary subsite, p16 status, and size of the dominant node were not associated with occult ENE.
Nodal Staging Changes
Results of preoperative imaging for the presence of nodal metastases (rN-positive vs pN-positive) were a sensitivity of 93% (95% CI, 85%-98%), specificity of 72% (95% CI, 47%-90%), positive predictive value of 93% (95% CI, 87%-97%), and negative predictive value of 72% (95% CI, 52%-86%).
Nodal category changes for the p16-positive cohort are provided in Table 3. In the entire cohort, changes included 12 patients (13%) with pathologic nodal upstaging and 12 (13%) with pathologic nodal downstaging. Of 18 patients, 5 (28%) with no evidence of nodal disease on imaging had occult pathologic nodal disease, including 2 patients with a single positive node and 3 with multiple positive nodes. Of 32 patients with radiographic findings of either no nodes or a single positive node, 7 (22%) were found to have multiple positive nodes. Nine of 43 patients (21%) with radiographic evidence of multiple positive nodes were pathologically downstaged to a single or no positive nodes.
Patients in the p16-Positive Subgroup
Of 70 patients who were p16 positive, 21 (30%) had a base of tongue primary site and 49 (70%) had tonsil primary sites; 50 (71%) were pENE negative, 18 (26%) were pENE positive, and the status of 2 patients (3%) was unreported. The occult nodal disease rate was 38% (3 pN-positive of 8 rN0 patients) in patients with radiographically node-negative results in this population. The occult ENE rate in the p16-positive population was 15% (4 pENE-positive of 27 rENE-negative patients). Of 70 patients, 8 (11%) were upstaged and 10 (24%) were downstaged for occult nodal disease postoperatively.
Discussion
Nodal disease plays an essential role in staging head and neck cancers. Accurate staging of disease is essential to select the optimal treatment regimen, particularly for patients treated surgically, and pathologic staging determines adjuvant therapies. Historical studies guiding our knowledge of the rates of occult nodal disease in OPSCC were based on a disease process primarily associated with tobacco use6,9; more recently, the disease process is primarily associated with a viral cause. The newest 8th edition of the Cancer Staging Manual distinguishes HPV-mediated OPSCC from non-HPV–related OPSCC.10 Despite a different clinicopathologic entity, our study found that the occult nodal disease rate in patients with radiographically node-negative necks was 28%, which is similar to reports predating the HPV era.5,6 In the subgroup of p16-positive patients in the present study, the occult nodal disease rate was higher (38%), but this rate could be attributed to the small number of patients who presented with radiographically node-negative necks (n = 8).
Beyond occult nodal disease in patients with radiographically node-negative necks, the postoperative discovery of a higher nodal category and occult ENE may necessitate unplanned adjuvant therapies. These findings may result in patient disappointment and treatments with higher morbidity, such as triple-modality treatment, when the alternative nonsurgical treatments would require only 2 modalities. A recent prospective cohort11 from a single institution reported a category change postoperatively in 26% of patients, thus potentially requiring a change in treatment plan. Change in category is a common problem that frequently affects treatment selection and patient expectations.
Imaging is the main modality other than physical examination to assess the extent of disease preoperatively, but the radiographic identification of ENE is not reliable and can be subjective. The reported sensitivity (33%-80%) and specificity (54%-98%) of preoperative CT for detecting ENE vary widely.12-14 Extranodal extension may even be present in a significant number of patients with clinically (c)N0 necks15 and may not correlate with nodal size, number of nodes, or p16 status.2
To improve the accuracy of preoperative imaging, radiographic factors associated with occult nodal disease and ENE have been explored. Geltzeiler et al16 reported that the presence of 3 or more suspicious lymph nodes on preoperative CT improved the predictive value of pENE in HPV-related OPSCC treated with TORS and neck dissection. Irregular borders and 3 or more suspicious nodes had a 91% positive predictive value for pENE.16 The overall ENE rate in their population was 39%, which was higher than our reported rate of 27%. The rate of occult pENE in patients in their study was 3.3%, which was lower than our rate of 13%.16
Use of PET-CT with fludeoxyglucose F 18 has been reported to increase the sensitivity and specificity of diagnosing regional disease17,18 but it may be less helpful for identifying occult disease.19 In cN0 head and neck cancers, Krabbe et al20 found the PET-CT sensitivity to be 50% and the specificity to be 87% for detection of pathologic nodal disease, indicating that 50% of patients with cN0 cancers had pathologic nodes that were not predicted by PET-CT.20 The addition of contrast material may enhance the detection of N-positive necks compared with the traditional low-dose CT without contrast, especially for necrotic and cystic nodes often observed in p16-positive OPSCC.21
In the present study, our findings reflect those of previous reports6,9 regarding the proportion of patients with a postoperative change in nodal category. In all, 26% of the patients had a change in nodal category on final pathologic analysis, and the change was equally upstaged or downstaged. This finding highlights the challenges of currently available imaging modalities for accurate prediction of disease extent and the subsequent selection of appropriate treatment regimens. The occult nodal positivity rate in patients with radiographically node-negative disease was similar to historical cohorts of patients with OPSCC that predated the emergence of HPV-associated disease.
In previous studies,16,19-21 authors usually included only a single imaging modality in their calculations. We adopted a pragmatic approach for this analysis and used a combination of available imaging modalities to assess nodal category for patients. For example, if CT with contrast material and PET-CT were available, both modalities were used. In the present study, the reported sensitivity (93%) and specificity (72%) of preoperative imaging for the prediction of nodal disease compared favorably with previous reports.17,20,21
A small number of patients would require additional, unanticipated adjuvant therapy based on nodal status. The 13% of patients with occult ENE would theoretically require unanticipated chemoradiotherapy. Of 32 patients with radiographically N0 or N1 disease who would potentially have received surgery alone, 22% received pathologic upstaging because of multiple positive nodes and likely would require unanticipated adjuvant radiotherapy.
Because of the uncertainty of preoperative imaging when assessing pathologic nodal disease and ENE, alternative methods for staging and treatment selection have been explored. Spellman et al22 recently advocated for a staging neck dissection upfront for cT1-2cN0 oropharyngeal cancers. They first performed the neck dissection, then allocated patients found to have pN2-3 disease or ENE on final results of pathologic analysis to chemoradiotherapy instead of completing TORS for management of the primary site.22 Of 19 patients examined, 5 (26%) were triaged postoperatively to radiotherapy or chemoradiotherapy for at least pN2 disease or pENE. Five of the 14 (36%) surgically triaged patients were upstaged from cN0 to pN1 without a change in management. Spellman et al22 reported that this methodology accurately categorized patients and appropriately selected those ideal for primary surgical therapy.
Because ENE plays an important role in the eighth edition of the Cancer Staging Manual of HPV-associated OPSCC, it is unclear whether ENE is associated with outcomes in this patient population. Some authors23,24 have found that ENE does not significantly affect most oncologic outcomes, whereas others have found it to be a significant indicator of outcomes, in particular of distant disease failure.25,26 Specifically regarding radiographic ENE, some studies27,28 have found radiographic ENE to correlate with outcomes in HPV-associated OPSCC, while others have not. These studies are mostly limited by their retrospective design. The National Cancer Center Network Guideline for the treatment of OPSCC indicates the addition of chemotherapy postoperatively for ENE in accordance with the results of the European Organization for Research Therapy Oncology Group Trial (EORTC trial 22931)7 and the Radiation Therapy Oncology Group 9501 trial.8 Grading of ENE, and specifically higher-grade ENE, may correlate better with outcomes in the HPV-associated OPSCC population compared with simply a binary system.29 Our study did not extend to the determination of oncologic outcomes based on pathologic findings.
Limitations
This study had a number of limitations, including those associated with its retrospective, multi-institutional nature. Unfortunately, 3 patients did not have the presence or absence of ENE mentioned specifically in the pathology reports. Images at each site were reviewed separately, and interinstitutional variability was not measured. In contrast to the criteria for suspicious adenopathy used in our study, some authors30-32 used different measurements, such as 3 or more borderline nodes, central radiolucency, and nonfat low-density areas within the node. Variations in criteria for suspicious adenopathy would affect the risk of occult nodal disease. In addition, the images were reviewed retrospectively, and results may have varied from the original reports at the time of treatment.
This study excluded locally advanced primary tumors on final pathology findings, but clinical decision making does not have this information available preoperatively and can only be estimated from imaging and physical examination findings. The scope of this study was limited to radiographic assessment and did not extend into adjuvant therapy and prediction of outcomes. Future directions of this work may include the implications of these findings on treatment regimens and outcomes.
Conclusions
In this multicenter study, 26% of patients had a postoperative change in nodal category, although only 13% had unanticipated ENE, potentially indicating a need for adjuvant chemotherapy. Our study’s results suggest that radiographically positive nodes and a more advanced nodal category may be associated with ENE, whereas the T category, size of the largest node, and tumor location may not. The occult nodal disease rate was 28%, which is comparable to historically reported rates in oropharyngeal cancers. Combining imaging modalities may slightly improve the sensitivity and specificity of preoperative imaging in assessing association with nodal disease. This study highlights the continued challenges when using radiographic criteria to assess which patients would benefit from either primary surgical or nonsurgical treatment of OPSCC.
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Article Information
Accepted for Publication: April 11, 2019.
Corresponding Author: John R. de Almeida, MD, MSc, Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Princess Margaret Cancer Center, 610 University Ave, Office 3-955, Toronto, ON M5G 2M9, Canada (john.dealmeida@uhn.ca).
Published Online: June 20, 2019. doi:10.1001/jamaoto.2019.1186
Author Contributions: Drs McMullen and de Almeida 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: McMullen, Garneau, Yu, Xu, Miles, de Almeida.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: McMullen, Su, de Almeida.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: McMullen, Su, Xu.
Administrative, technical, or material support: Garneau, Farinhas, Sarta, Smith, Miles.
Supervision: Farinhas, Yu, Som, Miles, de Almeida.
Conflict of Interest Disclosures: Dr Smith reported receiving a stipend as education coordinator from the American Academy of Otolaryngology–Head and Neck Surgery and reported receiving editor and author royalties from UpToDate not associated with this topic.
References
1.
Chen AM, Daly ME, Luu Q, Donald PJ, Farwell DG. Comparison of functional outcomes and quality of life between transoral surgery and definitive chemoradiotherapy for oropharyngeal cancer. Head Neck. 2015;37(3):381-385. doi:10.1002/hed.23610PubMedGoogle ScholarCrossref
2.
Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck. 2011;33(12):1683-1694. doi:10.1002/hed.21669PubMedGoogle ScholarCrossref
3.
Weinstein GS, Quon H, Newman HJ, et al. Transoral robotic surgery alone for oropharyngeal cancer: an analysis of local control. Arch Otolaryngol Head Neck Surg. 2012;138(7):628-634. doi:10.1001/archoto.2012.1166
ArticlePubMedGoogle ScholarCrossref
4.
de Almeida JR, Byrd JK, Wu R, et al. A systematic review of transoral robotic surgery and radiotherapy for early oropharynx cancer: a systematic review. Laryngoscope. 2014;124(9):2096-2102. doi:10.1002/lary.24712PubMedGoogle ScholarCrossref
5.
Pitman KT, Johnson JT, Myers EN. Effectiveness of selective neck dissection for management of the clinically negative neck. Arch Otolaryngol Head Neck Surg. 1997;123(9):917-922. doi:10.1001/archotol.1997.01900090023004
ArticlePubMedGoogle ScholarCrossref
6.
Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990;160(4):405-409. doi:10.1016/S0002-9610(05)80554-9PubMedGoogle ScholarCrossref
7.
Bernier J, Domenge C, Ozsahin M, et al; European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945-1952. doi:10.1056/NEJMoa032641PubMedGoogle ScholarCrossref
8.
Cooper JS, Pajak TF, Forastiere AA, et al; Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937-1944. doi:10.1056/NEJMoa032646PubMedGoogle ScholarCrossref
9.
Candela FC, Kothari K, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck. 1990;12(3):197-203.PubMedGoogle ScholarCrossref
10.
Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137. doi:10.3322/caac.21389PubMedGoogle ScholarCrossref
11.
Smith RV, Schiff BA, Garg M, Haigentz M. The impact of transoral robotic surgery on the overall treatment of oropharyngeal cancer patients. Laryngoscope. 2015;125(suppl 10):S1-S15. doi:10.1002/lary.25534PubMedGoogle ScholarCrossref
12.
Chai RL, Rath TJ, Johnson JT, et al. Accuracy of computed tomography in the prediction of extracapsular spread of lymph node metastases in squamous cell carcinoma of the head and neck. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1187-1194. doi:10.1001/jamaoto.2013.4491
ArticlePubMedGoogle ScholarCrossref
13.
Souter MA, Allison RS, Clarkson JH, Cowan IA, Coates MH, Wells JE. Sensitivity and specificity of computed tomography for detection of extranodal spread from metastatic head and neck squamous cell carcinoma. J Laryngol Otol. 2009;123(7):778-782. doi:10.1017/S0022215109004332PubMedGoogle ScholarCrossref
14.
Prabhu RS, Magliocca KR, Hanasoge S, et al. Accuracy of computed tomography for predicting pathologic nodal extracapsular extension in patients with head-and-neck cancer undergoing initial surgical resection. Int J Radiat Oncol Biol Phys. 2014;88(1):122-129. doi:10.1016/j.ijrobp.2013.10.002PubMedGoogle ScholarCrossref
15.
Coatesworth AP, MacLennan K. Squamous cell carcinoma of the upper aerodigestive tract: the prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck. Head Neck. 2002;24(3):258-261. doi:10.1002/hed.10020PubMedGoogle ScholarCrossref
16.
Geltzeiler M, Clayburgh D, Gleysteen J, et al. Predictors of extracapsular extension in HPV-associated oropharyngeal cancer treated surgically. Oral Oncol. 2017;65:89-93. doi:10.1016/j.oraloncology.2016.12.025PubMedGoogle ScholarCrossref
17.
Adams S, Baum RP, Stuckensen T, Bitter K, Hör G. Prospective comparison of 18F-FDG PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head and neck cancer. Eur J Nucl Med. 1998;25(9):1255-1260. doi:10.1007/s002590050293PubMedGoogle ScholarCrossref
18.
Branstetter BF IV, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT more accurate than PET or CT alone? Radiology. 2005;235(2):580-586. doi:10.1148/radiol.2352040134PubMedGoogle ScholarCrossref
19.
Stoeckli SJ, Steinert H, Pfaltz M, Schmid S. Is there a role for positron emission tomography with 18F-fluorodeoxyglucose in the initial staging of nodal negative oral and oropharyngeal squamous cell carcinoma. Head Neck. 2002;24(4):345-349. doi:10.1002/hed.10057PubMedGoogle ScholarCrossref
20.
Krabbe CA, Dijkstra PU, Pruim J, et al. FDG PET in oral and oropharyngeal cancer: value for confirmation of N0 neck and detection of occult metastases. Oral Oncol. 2008;44(1):31-36. doi:10.1016/j.oraloncology.2006.12.003PubMedGoogle ScholarCrossref
21.
Haerle SK, Strobel K, Ahmad N, Soltermann A, Schmid DT, Stoeckli SJ. Contrast-enhanced 18F-FDG-PET/CT for the assessment of necrotic lymph node metastases. Head Neck. 2011;33(3):324-329.PubMedGoogle Scholar
22.
Spellman J, Sload R, Kim P, Martin P, Calzada G. Staging neck dissection and transoral robotic surgery treatment algorithm in palatine tonsil cancer. Otolaryngol Head Neck Surg. 2018;158(3):479-483. doi:10.1177/0194599817742615PubMedGoogle ScholarCrossref
23.
Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer. 2013;119(18):3302-3308. doi:10.1002/cncr.28169PubMedGoogle ScholarCrossref
24.
Kharytaniuk N, Molony P, Boyle S, et al. Association of extracapsular spread with survival according to human papillomavirus status in oropharynx squamous cell carcinoma and carcinoma of unknown primary site. JAMA Otolaryngol Head Neck Surg. 2016;142(7):683-690. doi:10.1001/jamaoto.2016.0882
ArticlePubMedGoogle ScholarCrossref
25.
An Y, Park HS, Kelly JR, et al. The prognostic value of extranodal extension in human papillomavirus–associated oropharyngeal squamous cell carcinoma. Cancer. 2017;123(14):2762-2772. doi:10.1002/cncr.30598PubMedGoogle ScholarCrossref
26.
Shevach J, Bossert A, Bakst RL, et al. Extracapsular extension is associated with worse distant control and progression-free survival in patients with lymph node–positive human papillomavirus–related oropharyngeal carcinoma. Oral Oncol. 2017;74:56-61. doi:10.1016/j.oraloncology.2017.09.014PubMedGoogle ScholarCrossref
27.
Kann BH, Buckstein M, Carpenter TJ, et al. Radiographic extracapsular extension and treatment outcomes in locally advanced oropharyngeal carcinoma. Head Neck. 2014;36(12):1689-1694. doi:10.1002/hed.23512PubMedGoogle ScholarCrossref
28.
Liu JT, Kann BH, De B, et al. Prognostic value of radiographic extracapsular extension in locally advanced head and neck squamous cell cancers. Oral Oncol. 2016;52:52-57. doi:10.1016/j.oraloncology.2015.11.008PubMedGoogle ScholarCrossref
29.
Sinha P, Lewis JS Jr, Piccirillo JF, Kallogjeri D, Haughey BH. Extracapsular spread and adjuvant therapy in human papillomavirus–related, p16-positive oropharyngeal carcinoma. Cancer. 2012;118(14):3519-3530. doi:10.1002/cncr.26671PubMedGoogle ScholarCrossref
30.
Som PM. Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. AJR Am J Roentgenol. 1992;158(5):961-969. doi:10.2214/ajr.158.5.1566697PubMedGoogle ScholarCrossref
31.
Stoeckli SJ, Haerle SK, Strobel K, Haile SR, Hany TF, Schuknecht B. Initial staging of the neck in head and neck squamous cell carcinoma: a comparison of CT, PET/CT, and ultrasound-guided fine-needle aspiration cytology. Head Neck. 2012;34(4):469-476. doi:10.1002/hed.21764PubMedGoogle ScholarCrossref
32.
van den Brekel MW, Stel HV, Castelijns JA, et al. Cervical lymph node metastasis: assessment of radiologic criteria. Radiology. 1990;177(2):379-384. doi:10.1148/radiology.177.2.2217772PubMedGoogle ScholarCrossref
Caitlin P. McMullen, MD1; Jonathan Garneau, MD2; Emillie Weimar, MD3; et al Sana Ali, MD4; Joaquim M. Farinhas, MD, MBA4; Eugene Yu, MD3; Peter M. Som, MD5; Cathy Sarta, RN6; David P. Goldstein, MD, MSc1; Susie Su, MSc7; Wei Xu, PhD7; Richard V. Smith, MD6; Brett Miles, MD, DDS2; John R. de Almeida, MD, MSc1
Author Affiliations Article Information
JAMA Otolaryngol Head Neck Surg. Published online June 20, 2019. doi:10.1001/jamaoto.2019.1186
Key Points
Question What is the rate of occult extranodal extension and postoperative nodal upstaging in patients with pathologic T1-2 oropharyngeal squamous cell carcinoma treated by transoral robotic surgery and neck dissection?
Findings In this cohort study of 92 patients with oropharyngeal squamous cell carcinoma from 3 different centers, the rate of occult extranodal extension on final pathologic findings was 13%. In the entire cohort, the nodal category of 12 patients (13%) was upstaged postoperatively, and the nodal category of 12 (13%) was downstaged postoperatively.
Meaning These results suggest that preoperative prediction of nodal disease and extranodal extension remains a challenge for patients with localized oropharyngeal squamous cell cancer.
Abstract
Importance The historically reported rates of subclinical cervical nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) predate the emergence of human papillomavirus as the predominant causative agent. The rate of occult nodal disease with changing etiology of OPSCC is not known, and it is challenging to anticipate which patients will be upstaged postoperatively and will require adjuvant therapy.
Objective To assess the rate of nodal upstaging and occult extranodal extension (ENE) in a multi-institutional population of patients with pathologic (p)T1-2 OPSCC treated by transoral robotic surgery and neck dissection.
Design, Setting and Participants This retrospective, multicenter cohort study of 92 participants at 2 US institutions (Albert Einstein College of Medicine, Bronx, New York [n = 38], and Icahn School of Medicine at Mount Sinai, New York, New York [n = 39]) and 1 Canadian institution (Princess Margaret Hospital, Toronto [n = 15]) examined the rate of postoperative pathologic upstaging for 92 patients with pT1-2 OPSCC undergoing transoral robotic surgery with neck dissection from August 2007 to December 2016. A neuroradiologist at each site blinded to final pathologic diagnosis reviewed preoperative imaging; these findings were compared with operative pathology and applied for tumor staging using the eighth edition of the American Joint Committee on Cancer Cancer Staging Manual. The statistical analysis was performed on December 18, 2018.
Main Outcomes and Measures Occult pathologic nodal disease and change in nodal category postoperatively.
Results Of 92 patients who met the inclusion criteria, 76 (83%) were male, and they had a mean (SD) age at surgery of 59.5 (10.5) years; 70 patients (84%) with available p16 status were positive. Five of 18 patients (28%) who had no evidence of nodal disease on imaging had occult pathologic nodal disease. Seven of 32 patients (22%) presenting with no nodal disease or with a single metastatic node on imaging received pathologic upstaging because of multiple positive nodes, indicating implementation of additional adjuvant treatment not anticipated after a priori imaging. Changes included 12 patients (13%) who had pathologic nodal upstaging and 12 (13%) with pathologic nodal downstaging in the eighth edition of staging. In the cohort, 24 patients (27%) had pathologic ENE, and 5 of 39 patients (13%) had occult ENE in the absence of radiographic evidence.
Conclusions and Relevance Predicting pathologic staging preoperatively for patients with OPSCC undergoing transoral robotic surgery and neck dissection remains a challenge. Although nodal size, tumor size, and location do not help predict ENE, the presence of nodes on imaging and nodal category may help predict ENE. Our findings suggest a small proportion of patients might benefit from further adjuvant therapies not predicted by preoperative imaging based on occult nodal upstaging and ENE.
Introduction
Transoral surgical approaches, including transoral robotic surgery (TORS), with or without postoperative adjuvant treatment have become well-accepted alternatives to definitive chemoradiotherapy for select patients with oropharyngeal squamous cell carcinoma (OPSCC). The oncologic outcomes of these techniques, with or without adjuvant therapy, are comparable to definitive chemoradiotherapy alone, while early retrospective studies suggest a possible improvement in functional and quality of life outcomes.1-4 The neck is electively managed, even for localized OPSCC, since the historical rate of occult nodal disease in OPSCC was approximately 30%.5,6 These published rates predate the increased incidence of the human papillomavirus (HPV) as the predominant causative agent in OPSCC and the emergence of transoral approaches. The rate of occult nodal disease in the current era of OPSCC dominated by HPV is not definitively known.
Many patients undergoing TORS with neck dissection for OPSCC may receive triple-modality therapy with adjuvant chemoradiotherapy, particularly if extranodal extension (ENE) or positive margins are found on final pathological analysis.7,8 Despite advances in imaging modalities, it remains a challenge to estimate which patients have pathologic nodal metastases and ENE as well as which patients will be upstaged postoperatively and require adjuvant therapy. Knowledge of the likelihood of pathologic upstaging because of occult cervical disease or pathologic ENE would be valuable not only for counseling patients preoperatively about their potential need for adjuvant treatment, but also for determining who may benefit most from primary surgical approaches.
Methods
Study Cohort
Patients were identified through previously collected institutional review board–approved databases at each site (Princess Margaret Cancer Center, Toronto, Ontario, Canada; Icahn School of Medicine at Mount Sinai, New York, New York; and Montefiore Medical Center, New York, New York). Patients with pathologic (p)T1-2N0-3M0 OPSCC who completed TORS with concurrent or staged ipsilateral or bilateral neck dissections from August 2007 to December 2016, and who had imaging available for review were identified and included. Bilateral neck dissections were done at the discretion of the treating surgeon (D.P.G., R.V.S., B.M., J.D.A., and other surgeons at each institution) and were generally performed for patients with bilateral nodal disease or for disease considered to be at high risk for contralateral nodal involvement. Patients were excluded for the following reasons: previous treatment for head and neck cancer, previous neoadjuvant therapy, aborted TORS, nonoropharyngeal primary site, pathological findings other than SCC, transoral approaches with techniques other than TORS, mandibulotomy or other open approaches to oropharyngeal tumor, or no available medical records, imaging for review, operative notes, and complete pathology reports. Institutional databases were created at each institution for the purpose of head and neck cancer research before the inception of this study. Each participating institution obtained individual institutional review board approval. Informed consent was waived for this study because it was a retrospective review with privacy violation as the only serious risk to patients. Obtaining informed consent was also impractical because some patients may have died or were lost to follow-up.
Clinical Data Collection
Retrospective reviews of medical records were performed at each participating institution between September 1, 2016, and December 1, 2018. All data were deidentified and transferred to the University of Toronto, Toronto, Ontario, Canada, for compilation, and statistical analysis was performed on December 18, 2018.
Imaging
Once patients were identified through the respective clinical databases, preoperative scans were reviewed by a neuroradiologist at each individual site (Albert Einstein: S.A. and J.M.F.; Mount Sinai: P.M.S.; Toronto: E.W. and E.Y.). If both computed tomography (CT) and magnetic resonance imaging (MRI) were available, the CT findings were preferentially included for nodal disease status, and MRI findings were included for primary site information. If preoperative positron emission tomography with CT (PET-CT) was available, those findings were recorded and the final preoperative clinical staging incorporated these PET-CT findings. The ultimate radiographic stage incorporated all available radiographic information as it would in the clinical setting.
The following criteria characterized the presence of a suspicious node on imaging: (1) retropharyngeal nodes 0.8 cm or larger in the longest dimension in the axial plane; (2) jugulodigastric chain and level 1b nodes 1.5 cm or larger; (3) nodes in all other levels 1.0 cm or larger; (4) nodes with cystic or necrotic components of any size; (5) nodes with a rounded rather than ovoid shape of any size; and (6) asymmetric clustering of nodes and loss of fatty hilum. Enhancement with intravenous contrast material was not a definite consideration for suspicious adenopathy. Nodes suspicious for ENE would have 1 or both of the following characteristics: poorly defined peripheral margins, and/or the presence of matted nodes.
Pathology
Findings on the pathology report were collected from the medical record. Extranodal extension was recorded according to the findings on the pathologic analysis performed at the time of treatment, and p16-positivity was defined as at least 70% immunohistochemical staining of tumor cells. Patients with no measurable tumor on final pathology results were recorded as T0 or TX.
End Points and Statistical Analysis
The main outcome measures were the rate of occult ENE and the rate of occult nodal disease in patients with OPSCC undergoing TORS with neck dissection. The secondary outcome measure was the rate of pathologic nodal category change in patients with OPSCC undergoing TORS with neck dissection. Occult nodal disease was defined as the presence of pathologic nodal metastases of OPSCC after no preoperative evidence was noted on imaging of nodal disease. Statistical analyses were conducted using SAS, version 9.3 (SAS Institute Inc) and R, version 9 (SAS Institute Inc). To compare groups, the Fisher exact test was used for categorical variables and the Kruskal-Wallis test was used for continuous variables.
Results
Study Population
Of 92 patients who met the inclusion criteria, 76 (83%) were male and the mean (SD) age at surgery was 59.5 (10.5) years. Clinicopathologic features are reported in Table 1. Regarding tumor sites, 57 patients (62%) had a tonsil primary tumor, 32 patients (35%) had a base of tongue primary tumor, 2 (2%) had a soft palate tumor, and 1 (1%) had a pharyngeal wall tumor. Among the 92 patients, 70 (84%) were p16-positive, 42 (46%) were pT1, 48 (52%) were pT2, and 2 (2%) were pT0. Three patients did not have the presence or absence of ENE mentioned in the pathology report, and these 3 patients had radiographic findings suspicious for ENE preoperatively.
In this population, 18 patients (20%) were reported as radiographically N0, 53 (58%) had evidence of ENE on preoperative imaging, 32 (35%) underwent bilateral neck dissections, and 60 (65%) underwent ipsilateral neck dissection only. Twenty patients had PET-CT and CT imaging available for review; 3 had MRI and PET-CT; 2 had MRI alone; 2 had MRI, CT, and PET-CT; and the remainder had CT alone.
Extranodal Extension
In the cohort, 24 patients (27%) had pathologic ENE, and 5 of 39 patients (13%) had occult ENE in the absence of radiographic evidence. No patient with radiographic N0 disease had occult ENE. When the 3 patients with missing ENE data were excluded, the sensitivity was 79% (95% CI, 58%-93%) and the specificity was 52% (95% CI, 40%-65%) for pathologic ENE based on preoperative imaging. The positive predictive value was 38% (95% CI, 25%-53%) and the negative predictive value was 87% (95% CI, 73%-96%).
The presence of radiographic nodal positivity (odds ratio [OR], 12.3; 95% CI, 1.2 to infinity) and 1 or more suspicious nodes (OR, 11.0; 95% CI, 1.1 to infinity) were associated with occult pathologic ENE on univariate analysis. Higher radiographic (r) nodal category (vs rN0) was associated with the presence of pathologic ENE (OR: rN1, 17.4 [95% CI, 2.2 to infinity]; rN2, 20.6 [95% CI, 1.4 to infinity]; and rN3, 51.8 [95% CI, 3.6 to infinity]) (Table 2). Radiographic T category, primary subsite, p16 status, and size of the dominant node were not associated with occult ENE.
Nodal Staging Changes
Results of preoperative imaging for the presence of nodal metastases (rN-positive vs pN-positive) were a sensitivity of 93% (95% CI, 85%-98%), specificity of 72% (95% CI, 47%-90%), positive predictive value of 93% (95% CI, 87%-97%), and negative predictive value of 72% (95% CI, 52%-86%).
Nodal category changes for the p16-positive cohort are provided in Table 3. In the entire cohort, changes included 12 patients (13%) with pathologic nodal upstaging and 12 (13%) with pathologic nodal downstaging. Of 18 patients, 5 (28%) with no evidence of nodal disease on imaging had occult pathologic nodal disease, including 2 patients with a single positive node and 3 with multiple positive nodes. Of 32 patients with radiographic findings of either no nodes or a single positive node, 7 (22%) were found to have multiple positive nodes. Nine of 43 patients (21%) with radiographic evidence of multiple positive nodes were pathologically downstaged to a single or no positive nodes.
Patients in the p16-Positive Subgroup
Of 70 patients who were p16 positive, 21 (30%) had a base of tongue primary site and 49 (70%) had tonsil primary sites; 50 (71%) were pENE negative, 18 (26%) were pENE positive, and the status of 2 patients (3%) was unreported. The occult nodal disease rate was 38% (3 pN-positive of 8 rN0 patients) in patients with radiographically node-negative results in this population. The occult ENE rate in the p16-positive population was 15% (4 pENE-positive of 27 rENE-negative patients). Of 70 patients, 8 (11%) were upstaged and 10 (24%) were downstaged for occult nodal disease postoperatively.
Discussion
Nodal disease plays an essential role in staging head and neck cancers. Accurate staging of disease is essential to select the optimal treatment regimen, particularly for patients treated surgically, and pathologic staging determines adjuvant therapies. Historical studies guiding our knowledge of the rates of occult nodal disease in OPSCC were based on a disease process primarily associated with tobacco use6,9; more recently, the disease process is primarily associated with a viral cause. The newest 8th edition of the Cancer Staging Manual distinguishes HPV-mediated OPSCC from non-HPV–related OPSCC.10 Despite a different clinicopathologic entity, our study found that the occult nodal disease rate in patients with radiographically node-negative necks was 28%, which is similar to reports predating the HPV era.5,6 In the subgroup of p16-positive patients in the present study, the occult nodal disease rate was higher (38%), but this rate could be attributed to the small number of patients who presented with radiographically node-negative necks (n = 8).
Beyond occult nodal disease in patients with radiographically node-negative necks, the postoperative discovery of a higher nodal category and occult ENE may necessitate unplanned adjuvant therapies. These findings may result in patient disappointment and treatments with higher morbidity, such as triple-modality treatment, when the alternative nonsurgical treatments would require only 2 modalities. A recent prospective cohort11 from a single institution reported a category change postoperatively in 26% of patients, thus potentially requiring a change in treatment plan. Change in category is a common problem that frequently affects treatment selection and patient expectations.
Imaging is the main modality other than physical examination to assess the extent of disease preoperatively, but the radiographic identification of ENE is not reliable and can be subjective. The reported sensitivity (33%-80%) and specificity (54%-98%) of preoperative CT for detecting ENE vary widely.12-14 Extranodal extension may even be present in a significant number of patients with clinically (c)N0 necks15 and may not correlate with nodal size, number of nodes, or p16 status.2
To improve the accuracy of preoperative imaging, radiographic factors associated with occult nodal disease and ENE have been explored. Geltzeiler et al16 reported that the presence of 3 or more suspicious lymph nodes on preoperative CT improved the predictive value of pENE in HPV-related OPSCC treated with TORS and neck dissection. Irregular borders and 3 or more suspicious nodes had a 91% positive predictive value for pENE.16 The overall ENE rate in their population was 39%, which was higher than our reported rate of 27%. The rate of occult pENE in patients in their study was 3.3%, which was lower than our rate of 13%.16
Use of PET-CT with fludeoxyglucose F 18 has been reported to increase the sensitivity and specificity of diagnosing regional disease17,18 but it may be less helpful for identifying occult disease.19 In cN0 head and neck cancers, Krabbe et al20 found the PET-CT sensitivity to be 50% and the specificity to be 87% for detection of pathologic nodal disease, indicating that 50% of patients with cN0 cancers had pathologic nodes that were not predicted by PET-CT.20 The addition of contrast material may enhance the detection of N-positive necks compared with the traditional low-dose CT without contrast, especially for necrotic and cystic nodes often observed in p16-positive OPSCC.21
In the present study, our findings reflect those of previous reports6,9 regarding the proportion of patients with a postoperative change in nodal category. In all, 26% of the patients had a change in nodal category on final pathologic analysis, and the change was equally upstaged or downstaged. This finding highlights the challenges of currently available imaging modalities for accurate prediction of disease extent and the subsequent selection of appropriate treatment regimens. The occult nodal positivity rate in patients with radiographically node-negative disease was similar to historical cohorts of patients with OPSCC that predated the emergence of HPV-associated disease.
In previous studies,16,19-21 authors usually included only a single imaging modality in their calculations. We adopted a pragmatic approach for this analysis and used a combination of available imaging modalities to assess nodal category for patients. For example, if CT with contrast material and PET-CT were available, both modalities were used. In the present study, the reported sensitivity (93%) and specificity (72%) of preoperative imaging for the prediction of nodal disease compared favorably with previous reports.17,20,21
A small number of patients would require additional, unanticipated adjuvant therapy based on nodal status. The 13% of patients with occult ENE would theoretically require unanticipated chemoradiotherapy. Of 32 patients with radiographically N0 or N1 disease who would potentially have received surgery alone, 22% received pathologic upstaging because of multiple positive nodes and likely would require unanticipated adjuvant radiotherapy.
Because of the uncertainty of preoperative imaging when assessing pathologic nodal disease and ENE, alternative methods for staging and treatment selection have been explored. Spellman et al22 recently advocated for a staging neck dissection upfront for cT1-2cN0 oropharyngeal cancers. They first performed the neck dissection, then allocated patients found to have pN2-3 disease or ENE on final results of pathologic analysis to chemoradiotherapy instead of completing TORS for management of the primary site.22 Of 19 patients examined, 5 (26%) were triaged postoperatively to radiotherapy or chemoradiotherapy for at least pN2 disease or pENE. Five of the 14 (36%) surgically triaged patients were upstaged from cN0 to pN1 without a change in management. Spellman et al22 reported that this methodology accurately categorized patients and appropriately selected those ideal for primary surgical therapy.
Because ENE plays an important role in the eighth edition of the Cancer Staging Manual of HPV-associated OPSCC, it is unclear whether ENE is associated with outcomes in this patient population. Some authors23,24 have found that ENE does not significantly affect most oncologic outcomes, whereas others have found it to be a significant indicator of outcomes, in particular of distant disease failure.25,26 Specifically regarding radiographic ENE, some studies27,28 have found radiographic ENE to correlate with outcomes in HPV-associated OPSCC, while others have not. These studies are mostly limited by their retrospective design. The National Cancer Center Network Guideline for the treatment of OPSCC indicates the addition of chemotherapy postoperatively for ENE in accordance with the results of the European Organization for Research Therapy Oncology Group Trial (EORTC trial 22931)7 and the Radiation Therapy Oncology Group 9501 trial.8 Grading of ENE, and specifically higher-grade ENE, may correlate better with outcomes in the HPV-associated OPSCC population compared with simply a binary system.29 Our study did not extend to the determination of oncologic outcomes based on pathologic findings.
Limitations
This study had a number of limitations, including those associated with its retrospective, multi-institutional nature. Unfortunately, 3 patients did not have the presence or absence of ENE mentioned specifically in the pathology reports. Images at each site were reviewed separately, and interinstitutional variability was not measured. In contrast to the criteria for suspicious adenopathy used in our study, some authors30-32 used different measurements, such as 3 or more borderline nodes, central radiolucency, and nonfat low-density areas within the node. Variations in criteria for suspicious adenopathy would affect the risk of occult nodal disease. In addition, the images were reviewed retrospectively, and results may have varied from the original reports at the time of treatment.
This study excluded locally advanced primary tumors on final pathology findings, but clinical decision making does not have this information available preoperatively and can only be estimated from imaging and physical examination findings. The scope of this study was limited to radiographic assessment and did not extend into adjuvant therapy and prediction of outcomes. Future directions of this work may include the implications of these findings on treatment regimens and outcomes.
Conclusions
In this multicenter study, 26% of patients had a postoperative change in nodal category, although only 13% had unanticipated ENE, potentially indicating a need for adjuvant chemotherapy. Our study’s results suggest that radiographically positive nodes and a more advanced nodal category may be associated with ENE, whereas the T category, size of the largest node, and tumor location may not. The occult nodal disease rate was 28%, which is comparable to historically reported rates in oropharyngeal cancers. Combining imaging modalities may slightly improve the sensitivity and specificity of preoperative imaging in assessing association with nodal disease. This study highlights the continued challenges when using radiographic criteria to assess which patients would benefit from either primary surgical or nonsurgical treatment of OPSCC.
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Article Information
Accepted for Publication: April 11, 2019.
Corresponding Author: John R. de Almeida, MD, MSc, Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Princess Margaret Cancer Center, 610 University Ave, Office 3-955, Toronto, ON M5G 2M9, Canada (john.dealmeida@uhn.ca).
Published Online: June 20, 2019. doi:10.1001/jamaoto.2019.1186
Author Contributions: Drs McMullen and de Almeida 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: McMullen, Garneau, Yu, Xu, Miles, de Almeida.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: McMullen, Su, de Almeida.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: McMullen, Su, Xu.
Administrative, technical, or material support: Garneau, Farinhas, Sarta, Smith, Miles.
Supervision: Farinhas, Yu, Som, Miles, de Almeida.
Conflict of Interest Disclosures: Dr Smith reported receiving a stipend as education coordinator from the American Academy of Otolaryngology–Head and Neck Surgery and reported receiving editor and author royalties from UpToDate not associated with this topic.
References
1.
Chen AM, Daly ME, Luu Q, Donald PJ, Farwell DG. Comparison of functional outcomes and quality of life between transoral surgery and definitive chemoradiotherapy for oropharyngeal cancer. Head Neck. 2015;37(3):381-385. doi:10.1002/hed.23610PubMedGoogle ScholarCrossref
2.
Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck. 2011;33(12):1683-1694. doi:10.1002/hed.21669PubMedGoogle ScholarCrossref
3.
Weinstein GS, Quon H, Newman HJ, et al. Transoral robotic surgery alone for oropharyngeal cancer: an analysis of local control. Arch Otolaryngol Head Neck Surg. 2012;138(7):628-634. doi:10.1001/archoto.2012.1166
ArticlePubMedGoogle ScholarCrossref
4.
de Almeida JR, Byrd JK, Wu R, et al. A systematic review of transoral robotic surgery and radiotherapy for early oropharynx cancer: a systematic review. Laryngoscope. 2014;124(9):2096-2102. doi:10.1002/lary.24712PubMedGoogle ScholarCrossref
5.
Pitman KT, Johnson JT, Myers EN. Effectiveness of selective neck dissection for management of the clinically negative neck. Arch Otolaryngol Head Neck Surg. 1997;123(9):917-922. doi:10.1001/archotol.1997.01900090023004
ArticlePubMedGoogle ScholarCrossref
6.
Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990;160(4):405-409. doi:10.1016/S0002-9610(05)80554-9PubMedGoogle ScholarCrossref
7.
Bernier J, Domenge C, Ozsahin M, et al; European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945-1952. doi:10.1056/NEJMoa032641PubMedGoogle ScholarCrossref
8.
Cooper JS, Pajak TF, Forastiere AA, et al; Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937-1944. doi:10.1056/NEJMoa032646PubMedGoogle ScholarCrossref
9.
Candela FC, Kothari K, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck. 1990;12(3):197-203.PubMedGoogle ScholarCrossref
10.
Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137. doi:10.3322/caac.21389PubMedGoogle ScholarCrossref
11.
Smith RV, Schiff BA, Garg M, Haigentz M. The impact of transoral robotic surgery on the overall treatment of oropharyngeal cancer patients. Laryngoscope. 2015;125(suppl 10):S1-S15. doi:10.1002/lary.25534PubMedGoogle ScholarCrossref
12.
Chai RL, Rath TJ, Johnson JT, et al. Accuracy of computed tomography in the prediction of extracapsular spread of lymph node metastases in squamous cell carcinoma of the head and neck. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1187-1194. doi:10.1001/jamaoto.2013.4491
ArticlePubMedGoogle ScholarCrossref
13.
Souter MA, Allison RS, Clarkson JH, Cowan IA, Coates MH, Wells JE. Sensitivity and specificity of computed tomography for detection of extranodal spread from metastatic head and neck squamous cell carcinoma. J Laryngol Otol. 2009;123(7):778-782. doi:10.1017/S0022215109004332PubMedGoogle ScholarCrossref
14.
Prabhu RS, Magliocca KR, Hanasoge S, et al. Accuracy of computed tomography for predicting pathologic nodal extracapsular extension in patients with head-and-neck cancer undergoing initial surgical resection. Int J Radiat Oncol Biol Phys. 2014;88(1):122-129. doi:10.1016/j.ijrobp.2013.10.002PubMedGoogle ScholarCrossref
15.
Coatesworth AP, MacLennan K. Squamous cell carcinoma of the upper aerodigestive tract: the prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck. Head Neck. 2002;24(3):258-261. doi:10.1002/hed.10020PubMedGoogle ScholarCrossref
16.
Geltzeiler M, Clayburgh D, Gleysteen J, et al. Predictors of extracapsular extension in HPV-associated oropharyngeal cancer treated surgically. Oral Oncol. 2017;65:89-93. doi:10.1016/j.oraloncology.2016.12.025PubMedGoogle ScholarCrossref
17.
Adams S, Baum RP, Stuckensen T, Bitter K, Hör G. Prospective comparison of 18F-FDG PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head and neck cancer. Eur J Nucl Med. 1998;25(9):1255-1260. doi:10.1007/s002590050293PubMedGoogle ScholarCrossref
18.
Branstetter BF IV, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT more accurate than PET or CT alone? Radiology. 2005;235(2):580-586. doi:10.1148/radiol.2352040134PubMedGoogle ScholarCrossref
19.
Stoeckli SJ, Steinert H, Pfaltz M, Schmid S. Is there a role for positron emission tomography with 18F-fluorodeoxyglucose in the initial staging of nodal negative oral and oropharyngeal squamous cell carcinoma. Head Neck. 2002;24(4):345-349. doi:10.1002/hed.10057PubMedGoogle ScholarCrossref
20.
Krabbe CA, Dijkstra PU, Pruim J, et al. FDG PET in oral and oropharyngeal cancer: value for confirmation of N0 neck and detection of occult metastases. Oral Oncol. 2008;44(1):31-36. doi:10.1016/j.oraloncology.2006.12.003PubMedGoogle ScholarCrossref
21.
Haerle SK, Strobel K, Ahmad N, Soltermann A, Schmid DT, Stoeckli SJ. Contrast-enhanced 18F-FDG-PET/CT for the assessment of necrotic lymph node metastases. Head Neck. 2011;33(3):324-329.PubMedGoogle Scholar
22.
Spellman J, Sload R, Kim P, Martin P, Calzada G. Staging neck dissection and transoral robotic surgery treatment algorithm in palatine tonsil cancer. Otolaryngol Head Neck Surg. 2018;158(3):479-483. doi:10.1177/0194599817742615PubMedGoogle ScholarCrossref
23.
Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer. 2013;119(18):3302-3308. doi:10.1002/cncr.28169PubMedGoogle ScholarCrossref
24.
Kharytaniuk N, Molony P, Boyle S, et al. Association of extracapsular spread with survival according to human papillomavirus status in oropharynx squamous cell carcinoma and carcinoma of unknown primary site. JAMA Otolaryngol Head Neck Surg. 2016;142(7):683-690. doi:10.1001/jamaoto.2016.0882
ArticlePubMedGoogle ScholarCrossref
25.
An Y, Park HS, Kelly JR, et al. The prognostic value of extranodal extension in human papillomavirus–associated oropharyngeal squamous cell carcinoma. Cancer. 2017;123(14):2762-2772. doi:10.1002/cncr.30598PubMedGoogle ScholarCrossref
26.
Shevach J, Bossert A, Bakst RL, et al. Extracapsular extension is associated with worse distant control and progression-free survival in patients with lymph node–positive human papillomavirus–related oropharyngeal carcinoma. Oral Oncol. 2017;74:56-61. doi:10.1016/j.oraloncology.2017.09.014PubMedGoogle ScholarCrossref
27.
Kann BH, Buckstein M, Carpenter TJ, et al. Radiographic extracapsular extension and treatment outcomes in locally advanced oropharyngeal carcinoma. Head Neck. 2014;36(12):1689-1694. doi:10.1002/hed.23512PubMedGoogle ScholarCrossref
28.
Liu JT, Kann BH, De B, et al. Prognostic value of radiographic extracapsular extension in locally advanced head and neck squamous cell cancers. Oral Oncol. 2016;52:52-57. doi:10.1016/j.oraloncology.2015.11.008PubMedGoogle ScholarCrossref
29.
Sinha P, Lewis JS Jr, Piccirillo JF, Kallogjeri D, Haughey BH. Extracapsular spread and adjuvant therapy in human papillomavirus–related, p16-positive oropharyngeal carcinoma. Cancer. 2012;118(14):3519-3530. doi:10.1002/cncr.26671PubMedGoogle ScholarCrossref
30.
Som PM. Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. AJR Am J Roentgenol. 1992;158(5):961-969. doi:10.2214/ajr.158.5.1566697PubMedGoogle ScholarCrossref
31.
Stoeckli SJ, Haerle SK, Strobel K, Haile SR, Hany TF, Schuknecht B. Initial staging of the neck in head and neck squamous cell carcinoma: a comparison of CT, PET/CT, and ultrasound-guided fine-needle aspiration cytology. Head Neck. 2012;34(4):469-476. doi:10.1002/hed.21764PubMedGoogle ScholarCrossref
32.
van den Brekel MW, Stel HV, Castelijns JA, et al. Cervical lymph node metastasis: assessment of radiologic criteria. Radiology. 1990;177(2):379-384. doi:10.1148/radiology.177.2.2217772PubMedGoogle ScholarCrossref
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