Accepted 19 February 2010 Published online 19 May 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed.21436

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1 ORIGINAL ARTICLE FREQUENCY OF BILATERAL CERVICAL METASTASES IN OROPHARYNGEAL SQUAMOUS CELL CARCINOMA: A RETROSPECTIVE ANALYSIS OF 352 CASES AFTER BILATERAL NECK DISSECTION Bernhard Olzowy, MD, 1 Yulia Tsalemchuk, 1 Klaus-Juergen Schotten, MD, 2 Oliver Reichel, MD, 1 Ulrich Harréus, MD, PhD 1 1 Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig Maximilians University of Munich Medical Center, Munich, Germany. bernhard.olzowy@med.uni-muenchen.de 2 Department of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University of Munich Medical Center, Munich, Germany Accepted 19 February 2010 Published online 19 May 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. The decision whether to perform an elective neck dissection in patients with head and neck squamous cell carcinoma (HNSCC) and clinically negative lymph nodes (cn0) is made based on the probability of micrometastases in the neck for the given subsite and size of the primary. To date there is limited information about contralateral and bilateral cervical lymph node metastases of oropharyngeal carcinoma. Methods. A retrospective chart review was performed of 352 patients with oropharyngeal SCC who received a bilateral neck dissection. The frequency of histologically unveiled bilateral neck metastases was determined. Results. Carcinomas of the tonsillar fossa starting with a T2 classification and carcinomas of the soft palate, base of tongue, and pharyngeal wall at any stage showed a high frequency of bilateral metastases. Conclusions. Bilateral neck dissection should be recommended for all but T1 and selected cases of T2 carcinomas of the tonsillar fossa. VC 2010 Wiley Periodicals, Inc. Head Neck 33: , 2011 Keywords: oropharynx; carcinoma; neck dissection; metastases; bilateral The management of the contralateral N0 neck (neck without clinical evidence for cervical lymph node metastases) in patients with oropharyngeal carcinoma is controversial. It is widely accepted among head and neck surgeons to perform an elective neck dissection of the N0 neck in patients with head and neck squamous cell carcinoma (HNSCC), when the cervical Correspondence to: B. Olzowy This work was previously presented as an oral presentation at the Chilean Congress and extraordinary Congress of the Spanish-German Society of Otorhinolaryngology, Head and Neck Surgery in Pucón, Chile, December 3, 2008 and at the annual Congress of the German Society of Otorhinolaryngology, Head and Neck Surgery in Rostock, Germany, May 22, VC 2010 Wiley Periodicals, Inc. metastatic risk exceeds 15% to 20%. 1 3 Tumors originate from different anatomic regions of the oropharynx with potential differences in metastatic risk: tonsillar fossa, soft palate, base of tongue, and lateral and posterior pharyngeal wall. The risk of cervical lymph node metastases in patients with oropharyngeal carcinoma depends on the size and the exact location of the primary. 4 6 Little information is available about the frequency of neck metastases of different subsites and T classifications of oropharyngeal carcinoma. However, with the knowledge of metastatic risk, neck dissections and ongoing morbidity might be limited. An early study clinically evaluating patients with HNSCC with respect to cervical lymph node metastases at presentation encompassed 181 patients with oropharyngeal carcinoma and revealed rates for bilateral neck metastases ranging from 11.4% for tonsillar carcinoma to 28.6% for carcinoma of the base of tongue without subdividing for different T classifications of the primary. 5 For later large pathologic studies of neck dissection specimens, the neck dissection was performed only unilaterally in the vast majority of patients. 6 9 The only study directed at the probability of contralateral neck metastases of oropharyngeal carcinoma by examining bilateral neck dissection specimens encompassed only 43 patients with tonsillar carcinoma. 10 The aim of this retrospective analysis was to determine the probability of bilateral cervical lymph node metastases for the different subsites and T classifications of oropharyngeal carcinoma from a larger number of bilateral neck dissection specimens. PATIENTS AND METHODS A retrospective analysis was performed of patients treated with oropharyngeal SCC between 1990 and Bilateral Cervical Metastases in Oropharyngeal SCC HEAD & NECK DOI /hed February

2 Table 1. Frequency of bilateral cervical lymph node metastases for the different localizations of the primaries ( subsites ) and T classifications of the patients who received a bilateral neck dissection. Classification Subsite T1 T2 T3 T4 All T classifications Tonsillar fossa 6.3% (3/48) 17.5% (14/80) 21.4% (9/42) 11.1% (3/27) 14.7% (29/197) Base of tongue 20.0% (4/20) 31.5% (17/54) 32.3% (10/31) 23.1% (3/13) 28.8% (34/118) Soft palate 14.3% (1/7) 33.3% (3/9) 12.5% (1/8) 66.7% (2/3) 25.9% (7/27) Pharyngeal wall 100.0% (1/1) 50.0% (2/4) 50.0% (2/4) 0.0% (0/1) 50.0% (5/10) All subsites 11.8% (9/76) 24.5% (36/147) 25.9% (22/85) 18.1% (8/44) 20.8% (75/352) Note: Values are given in % (no. of patients with bilateral metastases/total no. of patients) at the Department of Otorhinolaryngology, Head and Neck Surgery of the Ludwig-Maximilians- University of Munich, Germany. A total of 1099 patients were identified from the Munich cancer registry database and history files were obtained from the clinics archive. No history file was available for 128 patients. Patients were excluded from final data analysis if history files did not contain reports precisely determining primary location or tumor classification (n ¼ 24). No data were obtained in the event that patients were only diagnosed but not treated (n ¼ 30) and if they received primary treatment in another clinic (n ¼ 10). Also included in the exclusionary criteria was a tumor histology other than squamous cell cancer (n ¼ 17). Data were not evaluated if patients had other malignant diseases previously or synchronously (n ¼ 62) and in case of (chemo-)radiation as a final treatment (n ¼ 313). In all, 352 patients received a bilateral neck dissection as primary treatment and were included into the main data analysis. Only unilateral neck dissection was performed in 163 patients. To assess the bias that is inflicted by the surgeon s decision to perform either unilateral or bilateral neck dissection, a second data analysis was performed of all 515 patients who had received either unilateral or bilateral neck dissections under the assumption that none of the unilaterally operated patients had contralateral cervical metastases. For both groups, the frequency of bilateral and contralateral cervical lymph node metastases was determined depending on the T classification of the tumor subsites tonsillar fossa, base of tongue (including vallecula), soft palate (including uvula), and pharyngeal wall. SigmaStat v.3.5 (Systat Software, San Jose, CA) was used to analyze the results. The relationship between variables and bilateral neck metastases was analyzed by chi-square test. A value of p <.05 was considered significant. Statistics were calculated only for the patients after bilateral neck dissection. RESULTS Of the 352 patients who received a bilateral neck dissection, 78 were women and 274 were men. Mean age at the time of treatment was 56.8 years (range, years). Of the 704 neck dissections, 55 were radical, 50 were modified radical, and 539 were functional neck dissection. In 60 cases the type of the neck dissection was not specified, which is explained by the lack of specific chart data in this retrospective analysis. The frequency of bilateral cervical lymph node metastases for the different subsites and T classifications of the patients who received a bilateral neck dissection is given in Table 1. The frequency of bilateral cervical lymph node metastases for the different subsites and T classifications of all patients who received either bilateral or unilateral neck dissection, which assumed that none of the unilaterally operated patients had contralateral cervical metastases, is given in Table 2. The proportion of bilateral neck metastases was significantly higher for carcinomas of the base of tongue compared with carcinomas of the palatine tonsil (p ¼.004). Significantly fewer bilateral metastases were seen for T1 tumors compared with more advanced primaries (p <.001). Patients with 2 or Table 2. Frequency of bilateral cervical lymph node metastases for the different localizations of the primaries ( subsites ) and T classifications of all patients who received either bilateral or unilateral neck dissection. Classification Subsite T1 T2 T3 T4 All T classifications Tonsillar fossa 3.3% (3/92) 10.7% (14/131) 17.6% (9/51) 8.6% (3/35) 9.4% (29/309) Base of tongue 14.3% (4/28) 23.9% (17/71) 27.0% (10/37) 15.8% (3/19) 21.9% (34/155) Soft palate 10.0% (1/10) 25.0% (3/12) 11.1% (1/9) 50.0% (2/4) 20.0% (7/35) Pharyngeal wall 50.0% (1/2) 33.3% (2/6) 50.0% (2/4) 0.0% (0/4) 31.3% (5/16) All subsites 6.8% (9/132) 16.4% (36/220) 21.8% (22/101) 12.9% (8/62) 14.6% (75/515) Note: Values are given in % (no. of patients with bilateral metastases/total no. of patients). 240 Bilateral Cervical Metastases in Oropharyngeal SCC HEAD & NECK DOI /hed February 2011

3 more ipsilateral neck metastases showed significantly more bilateral metastases compared with patients with fewer than 2 positive ipsilateral lymph nodes (p <.001). DISCUSSION The presented study is based on routine clinical documentation. There was no particular processing of the pathologic specimens focusing on the detection of micrometastases. This may result in a certain unreliability of the data, which is an inherent problem of every retrospective analysis. However, this study design allowed the analysis of a larger number of patients, offering the largest dataset on metastatic behavior of different oropharyngeal cancer subsites. The only prospective study addressing the frequency of bilateral neck metastases of oropharyngeal carcinoma, in this case tonsillar carcinoma, encompassed 43 patients. 10 This number is too small to reliably interpret a subdivision into different T classifications. Moreover, data on all other oropharyngeal cancers are missing. In other studies retrospectively addressing the question of bilateral neck metastases of oropharyngeal cancers on the basis of neck dissection specimens, bilateral neck dissection was performed in only a small minority of the analyzed patients. Candela et al 7 focused on the distribution of nodal metastases in different neck levels and analyzed 204 patients with oropharyngeal carcinoma who received a radical neck dissection. Only 9 patients received a bilateral neck dissection. It is mentioned that many patients presented with bilateral cervical metastases and were treated with radiotherapy or chemotherapy prior to operation. These patients were excluded from data analysis. 7 Therefore, the frequency of bilateral metastases cannot be assessed. In a 1999 publication, Woolgar 6 reported a series of 326 neck dissections in 253 patients with intraoral and oropharyngeal carcinoma; 40 patients had an oropharyngeal carcinoma, 4 of whom had bilateral metastases. In a second publication in 2007, Woolgar 8 reported another series of 526 neck dissections in 439 patients with intraoral and oropharyngeal carcinoma; 80 patients had an oropharyngeal carcinoma, 8 of whom had bilateral metastases. The patients with bilateral metastases had at least T2 disease or greater. 8 In both studies, it is not mentioned how many of the 40, respectively 80, patients received a bilateral neck dissection. Patients with oropharyngeal carcinoma were not further divided into different subsites. The presented study allows for assessment of different T classifications of the main subsites of oropharyngeal carcinoma. These data are the best currently available for risk assessment of bilateral neck metastases in the individual patient with oropharyngeal carcinoma. In interpretation of the data, some bias has to be considered: the patients who received bilateral neck dissection represent a selected group of patients with oropharyngeal carcinoma. By trend, patients with smaller tumors and a lower risk of bilateral metastases are more likely to be treated with unilateral neck dissection. Patients with advanced primaries and extensive cervical metastases will have preferably received (chemo-)radiation. Therefore, performing an analysis of the group of patients who received bilateral neck dissection, the risk of bilateral metastases for small tumors (especially T1 and T2 tonsillar carcinoma) is likely to be overestimated, but underestimated for advanced tumors. Although 352 patients received a bilateral neck dissection, 163 patients had neck surgery only unilaterally. The decision of the surgeons to perform the neck dissection bilaterally suggests an initially higher risk for bilateral neck metastases. To address this bias, a second calculation was performed under the unlikely assumption that none of the unilaterally operated patients had metastases of the contralateral neck. However, these numbers consequently represent a definite underestimation of the risk of bilateral neck metastases. In all, 313 patients received (chemo-)radiation as initial therapy. During the whole study period until the present, surgery used to be the first-line therapy for oropharyngeal carcinoma at our institution. (Chemo-)radiation was chosen as initial therapy if surgery could not be performed because of the extent of tumor growth and/or an inoperable condition of the patient or because the patient refused to have surgery. A frequent limitation for surgery might be an infiltration of neck metastases and the primary respectively into the carotid artery and/or the prevertebral fascia. By trend, the group of patients who received primary (chemo-)radiation is likely to contain a higher proportion of patients with widespread neck metastases in general and, therefore, also more patients with bilateral metastases. A detailed analysis of these patients, as performed for the patients after unilateral neck dissection, was not performed because of the high degree of uncertainty of clinical tumor staging. Our data show, expectedly, that T1 tumors have a lower risk of contralateral metastases than that of more advanced primaries. This is well in accord with the literature reporting a strong correlation of the size of the primary and the risk of contralateral neck metastases. 5,10 14 Obviously, not only the size of a tumor, but also its proximity to the midline will be of importance for the risk of bilateral neck metastases. On this note, our data show that tumors of the base of tongue have a higher risk of contralateral metastases than that of tumors of the tonsillar fossa. Although not statistically significant, tumors of the soft palate and the pharyngeal walls also seem to have a higher risk of contralateral metastases. Appropriately, O Sullivan et al 15 showed that involvement of the soft palate or the base of tongue is associated with an increased risk Bilateral Cervical Metastases in Oropharyngeal SCC HEAD & NECK DOI /hed February

4 of contralateral neck failure after unilateral radiotherapy of T2 tonsillar carcinoma. In addition to size and location of the primary, the N classification of the ipsilateral neck seems to be an important predictor of contralateral neck metastases In this study patients with 2 or more ipsilateral neck metastases showed significantly more bilateral metastases compared with patients with fewer than 2 positive ipsilateral lymph nodes. Detailed knowledge about the metastatic risk of oropharyngeal cancer is an important basis for whatever treatment modality is used. The alternative to the bilateral neck dissection is radiotherapy of the contralateral neck in the case of a relevant risk of bilateral metastases, particularly in patients receiving planned adjuvant radiotherapy postoperatively. In contrast to radiotherapy, the neck dissection is not only a therapeutic procedure, but also a diagnostic one. Metastases of the contralateral neck significantly reduce long-term survival, 4,9,10,16 and the neck dissection allows for the most reliable classification. 1,2 Elective neck dissection of the contralateral neck in oropharyngeal carcinoma can safely be performed as neck dissection of regions II, III, and IV. 4,17,18 As such a limited procedure, the neck dissection has few complications or long-lasting side effects, and offers the advantage of an accurate classification. 1,2 For patients with surgically treated oropharyngeal carcinoma with a relevant risk of contralateral metastases we, thus, recommend neck dissection instead of prophylactic radiation therapy of the neck in most cases. Based on the widely accepted practice to perform a neck dissection in the N0 neck when the individual metastatic risk exceeds 15% to 20%, the following recommendations might be made based on our data. In T1 tonsillar carcinoma, contralateral neck metastases rarely occur (3 of 48 patients [6.3%]), and a bilateral neck dissection should not generally be recommended. In T2 tonsillar carcinoma, the frequency of bilateral lymph node metastases among 14 of 80 of the bilaterally operated patients was thus 17.5%, including 14 of 131 of the unilaterally operated patients (10.7%). A bilateral neck dissection should not generally be recommended, but should be considered in patients with ipsilateral Nþ neck and with primaries involving the soft palate or the base of tongue. In patients with T3 or T4 tonsillar carcinoma neck dissection should be performed bilaterally. Lim et al 10 suggested the bilateral neck dissection in tonsillar carcinoma, classified T3 or greater, when ipsilateral cervical lymph node metastases are present. These suggestions are based on a series of 43 patients with tonsillar carcinoma and clinically negative contralateral neck, in whom the frequency of occult contralateral lymph node metastases was determined. 10 Our series discovered a relatively high frequency of contralateral metastases in T2 tonsillar carcinoma, and justifies the recommendation of a bilateral neck dissection in patients with clinically positive ipsilateral neck. The carcinoma of the base of tongue seems to have a high propensity to produce bilateral neck metastases. In the case of involvement of the base of tongue, the neck should be operated on bilaterally, independent of T classification of the primary. T1 carcinomas of the soft palate showed bilateral metastases in 1 of 7 patients (14.3%), when also considering the 1 of 10 unilaterally operated patients (10.0%). Given the uncertainty arising from the small number of cases, the bilateral neck dissection should be recommended in patients with tumors close to the midline and in clinical occurrence of ipsilateral neck metastases. In carcinomas of the soft palate greater than T1, bilateral neck dissection should generally be recommended because of a high frequency of bilateral metastases, which might be based on the natural proximity of soft palate cancers T2 or larger to the midline. Carcinomas originating from the pharyngeal wall seem to be a rare entity with a high risk of bilateral neck metastases. The overall number of 16 patients, 10 of whom were operated on bilaterally, is too small to be subdivided into T classifications. Moreover, midline proximity could not retrospectively be evaluated in all of these cases. Given the overall frequency of bilateral metastases of 5 of 10 and 5 of 16 patients (50.0% and 31.3%, respectively), bilateral neck dissection should be recommended for all T classifications. The retrospective data support our surgical planning. However, prospective data on the metastatic behavior of the different subsites of oropharyngeal cancers and cancers of other origin in the head and neck are warranted in the future. Based on such data, surgical intervention and accompanying morbidity could be significantly reduced, keeping up ideal cancer treatment and patient safety. REFERENCES 1. Wei WI, Ferlito A, Rinaldo A, et al. Management of the N0 neck reference or preference. Oral Oncol 2006; 42: Ferlito A, Rinaldo A, Silver CE, et al. Elective and therapeutic selective neck dissection. Oral Oncol 2006;42: Pitman KT. Rationale for elective neck dissection. Am J Otolaryngol 2000;21: Lim YC, Koo BS, Lee JS, Lim JY, Choi EC. 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