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Regional Recurrence of Squamous Cell Carcinoma of the Nasal CavityA Systematic Review and Meta-analysis
W. Cooper Scurry Jr, MD;
David Goldenberg, MD;
Michael Y. Chee, BS;
Eugene J. Lengerich, VMD, MS;
Yihai Liu, PhD, MS;
Fred G. Fedok, MD
Arch Otolaryngol Head Neck Surg. 2007;133(8):796-800.
ABSTRACT
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Objective To demonstrate whether the regional recurrence (RR) of squamous cell carcinoma (SCC) of the nasal cavity is higher than previously suspected.
Data Sources Original articles, including a previously published series from our institution, were identified from systematic searches of the MEDLINE database.
Study Selection Studies that analyzed tumors other than SCC or tumors from sites other than the nasal cavity were excluded. Studies that did not report an RR were also excluded.
Data Extraction Studies identified by the literature search were reviewed by a single reviewer (W.C.S.), and studies not excluded were reviewed for data extraction by 2 reviewers (W.C.S. and M.Y.C.).
Data Synthesis From the 23 studies reviewed, the average weighted percentage RR for SCC of the nasal cavity was 18.1% (95% confidence interval, 13.4%-22.8%).
Conclusions Currently, few authors advocate elective treatment of the neck in patients with high-risk SCC of the nasal cavity. The results of this systematic review and meta-analysis demonstrate that the RR of this entity may be higher than previously suspected. Because many studies included other histopathologies or analyzed recurrence data from tumors of multiple subsites, a true RR for SCC of the nasal cavity has not been firmly established. Now that a uniform staging system exists for nasal cavity cancers, better prospective analysis of these tumors will be available. The authors suggest that the risk of RR of certain high-risk SCCs of the nasal cavity to the lymph nodes, including the perifacial and upper cervical lymphatics, may approach the frequently cited 20% risk suggestive of consideration for elective regional therapy.
INTRODUCTION
Cancer of the nasal cavity is difficult to study because of its low occurrence rate, its presentation in various subsites of the nose, and the existence of multiple tumor histopathologies. These cancers represent 0.5% of all malignant neoplasms, 3% of head and neck cancers, and 30% of all malignant neoplasms of the nose and paranasal sinuses.1 Bhattacharyya2 reviewed the Surveillance, Epidemiology, and End Results database and demonstrated that approximately 50% of all cancers of the nasal cavity are squamous cell carcinoma (SCC). This figure is consistent with other reports of the pathologic examination of this tumor.1, 3-6 Tumors such as adenocarcinoma, melanoma, and adenoid cystic carcinoma constitute the remaining 50% and, in many reviews of nasal cancer, all histopathologies are analyzed together. Treatment options for nasal cavity cancer include surgery, radiation therapy, or a combination of the two, and a recent large analysis1 reported 5-year survival and local control rates of 40% and 59%, respectively.
A historical lack of a unified staging system has hindered efforts to compare and contrast disease progression and treatment protocols for malignant neoplasms of the nasal cavity. Recently, cancer of the nasal cavity has been added to the American Joint Committee on Cancer staging system (released for use in January 20037 [Table 1]). Under the section for tumors of the paranasal sinuses, nasal cavity and ethmoid sinus tumors are classified separately. The nasal cavity is further divided into 4 subsites: septum, floor, lateral walls, and vestibule. The ethmoid sinus is divided into 2 subsites: right and left. To date, no reports have been published that use this new staging system.
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Table 1. Staging System for Tumors of the Nasal Cavity and Paranasal Sinuses According to AJCC a
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In 2000, Fornelli et al8 published a review of 32 patients with SCC of the nasal cavity and reported a 5-year disease-free survival of 42% and a 5-year overall survival of 50%. Primary treatment among their 32 patients included surgery (n = 15), external beam radiation (n = 9), and a combination of surgery with postoperative irradiation (n = 8). In that study, despite the fact that all patients presented without neck disease (stage N0), 13 of the 32 patients (41%) developed regional recurrence (RR) and most of the patients with RR (11 [85%]) died of disease. Six patients in that study elected to undergo prophylactic irradiation (PI) of the cervical lymph nodes and never developed RR. In contrast, 50% of those who did not undergo elective treatment of the neck (13 patients) developed RR of their cancer.8
This 50% RR described by Fornelli et al is higher than the typical 10% to 20% reported in the literature. Because of this discrepancy in rates of RR, the authors of this article set out to conduct a systematic review of the literature that would identify primary SCC of the nasal cavity and the reported RR of these tumors. This report presents the findings from a meta-analysis of the RR and survival for SCC of the nasal cavity.
METHODS
A systematic review of the literature was performed on November 18, 2005, in the following manner. First, the Ovid search engine was used to query the MEDLINE database. The terms nose.mp, squamous cell carcinoma.mp, and recurrence.mp were combined with AND searches, initially resulting in 79 articles. The titles and abstracts of the articles were carefully reviewed, and those that pertained to reconstruction, surgical technique, or general head and neck tumors were excluded. Case reports, reports on nonhuman studies, and non-English reports were also excluded.
Next, a similar search was performed using the PubMed search engine to query the MEDLINE database. The terms nasal cavity cancer and squamous cell carcinoma were applied, and the search initially produced 83 articles. The same exclusion criteria were applied.
The results from these 2 search strategies were combined to yield 44 unique papers that were then evaluated to identify studies that had measured the RR and the presence of lymph node metastases at presentation for patients with a diagnosis of SCC of the nasal cavity. References of the studies were reviewed for additional potentially relevant studies. Studies reporting data on nasal cancers other than SCC and studies reporting data on tumors outside the nasal cavity (eg, in the maxillary sinus) were also excluded, resulting in a total of 23 articles appropriate for this study.5, 8-29 Studies identified by the literature search were reviewed by a single reviewer (W.C.S.), and studies not excluded were reviewed for data extraction by 2 reviewers (W.C.S. and M.Y.C.).
The pooled RR was calculated as the weighted average of RR from the individual studies that met the inclusion criteria. In addition, the pooled 5-year survival rate was calculated as the weighted average of data from the studies that reported survival rates. The weight for each calculation was the number of patients in the original study.
For studies that reported separate RR for patients who did and did not receive PI, we calculated the odds ratio of RR with PI. The statistical significance of each odds ratio was tested with the Fisher exact procedure.30
To estimate the relative risk of RR with PI, individual odds ratios were used in a meta-analysis conducted with the non–model-based Cochran-Mantel-Haenszel (CMH) and the model-based logistic regression approaches. These 2 approaches are often used in meta-analyses that involve binary outcomes (eg, recurrence vs nonrecurrence) because the approaches estimate the pooled odds ratio and test the homogeneity of effect from the individual studies.31 The logistic regression approach also allows inclusion of covariates in the model and does not restrict the sample size. In the CMH approach, the analysis created a 3-way contingency table stratified by study. The homogeneity of effect for the CMH approach was determined with the Breslow-Day test, and that for the logistic regression approach was determined with the Wald test. The FREQ procedure in SAS statistical software32 was used to estimate the RR, odds ratios, 95% confidence intervals (CIs), Fisher exact procedure, and CMH procedure. The LOGISTIC procedure in SAS32 was used for logistic regression. All statistical tests were 2-sided, with P < .05.
RESULTS
Our literature search identified 23 original studies5, 8-29 published between 1974 and 2002 that reported on the treatment of SCC of the nasal cavity. The mean age of the 927 patients in these studies was 63.1 years and 73.4% were male. The mean patient follow-up period was 4.4 years (range, 2-11 years) (Table 2).
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Table 2. Studies Describing Squamous Cell Carcinoma of the Nasal Cavity, 1974-2002
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The weighted average RR for SCC of the nasal cavity from the 23 studies was 18.1% (95% CI, 13.4%-22.8%; range, 0% [Schaefer and Hill28] to 50% [Fornelli et al8]). The weighted 5-year disease-free survival for the 9 studies5, 8, 12-13,15-17,19-20 that reported this measure was 59.7% (95% CI, 58.2%-61.3%). The weighted 5-year overall survival for the 13 studies5, 8, 11-13,17, 19-21,24-26,29 that reported this outcome was 62.7% (95% CI, 61.9%-63.5%).
Patients in 7 of the 23 studies were treated with PI of the regional lymphatics,5, 8, 11, 15, 17-18,25 but only 5 studies5, 8, 15, 17-18 reported data separately for patients who did and did not receive PI. The odds ratios from 4 of these 5 studies was less than 1.0, which suggests that PI reduced the risk of RR; none of the odds ratios in these individual studies, however, was statistically significant at the P < .05 level (Table 3). The range of the odds ratios for these 5 studies was 0.08 (Fornelli et al8) to 1.57 (Levendag and Pomp17). In 4 of the 5 studies analyzed, however, no patient who received PI developed RR.5, 8, 15, 18
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Table 3. Odds Ratios of RR for Patients Receiving PI of the Neck for SCC of the Nasal Cavity a
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In the meta-analysis, both the CMH test and the logistic regression test were used to calculate a pooled odds ratio (Table 3). The CMH approach produced a pooled odds ratio of 0.18 (95% CI, 0.04-0.77; P = .009). The Breslow-Day test for homogeneity of effect was not statistically significant (P = .08), suggesting that the results of the individual studies were homogeneous. Using the logistic regression approach, the pooled odds ratio was 0.16 (95% CI, 0.03-0.72; P = .02). The Wald test for homogeneity was statistically significant (P = .005), suggesting that the results of the individual studies were not homogeneous.
COMMENT
The management and natural history of SCC of the nasal cavity have been difficult to study. Its low incidence and the historic lack of a unified staging system have made it difficult to design studies to delineate its natural history, response to therapy, and risk of regional metastasis. To date, to our knowledge, no single study on SCC of the nasal cavity has analyzed a sufficient number of patients with tumors of like location and pathologic characteristics to definitively state a rate of RR. In this meta-analysis of SCC of the nasal cavity, the herein-described statistical methods have determined an RR of 18.1%. In addition, from a subset of studies in which the RR of patients receiving PI was analyzed separately from the RR of patients not receiving PI, a pooled odds ratio was calculated that demonstrates that the use of PI reduces the risk of RR for SCC of the nasal cavity (Table 3).
Over the years, several studies have focused on tumors of specific sites such as the nasal vestibule, nasal septum, and maxillary sinus.5, 9-10,12-13,15-18,22, 24-27,29, 33-35 The statistical analysis of these smaller studies has been limited because of the small population size. In contrast, few studies have focused on the nasal cavity in its entirety. Combining the intranasal sites (and excluding the paranasal sinus sites) allows the combination of a large pool of data for statistical analysis. The authors of this report argue that combining the analysis of tumors labeled as nasal vestibule and nasal cavity is valid because of the common lymphatic drainage of tumors in these 2 overlapping regions. The lymphatic drainage of the nasal cavity has been well documented. Drainage from the anterior subsites, including the nasal vestibule, occurs by way of lymphatic channels traveling to the facial, anterior parotid, or submandibular nodes. More posterior regions of the nasal cavity typically drain anteriorly to a plexus in front of the torus tubarius, posteriorly to the retropharyngeal nodes, and inferiorly to the posterior and superior deep cervical nodes.36-37
In addition to establishing a weighted RR of 18.1% from 23 studies, this meta-analysis demonstrated that PI may reduce the risk of RR in SCC of the nasal cavity. According to the results of the 5 studies that reported RR by PI status,5, 8, 15, 17-18 PI of the regional lymphatics significantly reduced RR. The statistical methods associated with pooling data from individual studies increase the precision of estimates of individual studies by effectively increasing the sample size. All of the studies were considered to be of equal value, including those yielding estimates that were outliers. Estimates of the effect (ie, odds ratios) of PI of the neck on RR using the 2 analytic approaches were similar: 0.18 from the CMH approach and 0.16 from the logistic regression approach. This finding strengthens support for the contention that PI of the neck is an effective method for reducing RR of SCC of the nasal cavity.Again, in 4 of the 5 studies analyzed in this manner, no patient who received PI developed RR.5, 8, 15, 18 The results from these 5 studies may have been somewhat different because the homogeneity tests of the 2 approaches produced slightly different results. Indeed, the study by Levendag and Pomp17 had an odds ratio that was greater than 1.0, whereas the odds ratios from the other 4 studies were less than 1.0. However, the 95% CI for the odds ratio from the study by Levendag and Pomp was quite wide and the lower confidence limit was 0.21, close to the estimate of effect from the other 4 studies.
Management of the clinically negative neck (N0) in SCC of the head and neck remains a controversial topic. Tumors in regions such as the supraglottis are accepted to have a high rate of regional metastasis, and N0 necks in patients with these tumors are treated prophylactically with either neck dissection or irradiation.38 In general, most of the literature concerning head and neck cancer supports elective treatment of the N0 neck when the probability of occult lymph node metastasis is greater than 20%.38-39 In the present meta-analysis of SCC of the nasal cavity excluding the paranasal sinuses, the risk of RR was 18.1%. Although this finding falls short of the 20% threshold suggested for the prophylactic (or elective) treatment of the regional lymphatics, it is the authors' contention that the decision to treat the neck is dependent on several factors. Certain tumor characteristics such as perineural spread, lymphovascular invasion, T-stage, and size may make certain tumors "high-risk."
Although few patients with nasal cancer present with regional disease (approximately 5%), patients who present with lymph node metastasis have poor survival.2, 12 One study has demonstrated that this metastatic progression can occur in a delayed fashion.40 Salvage after RR, however, is variably reported. While some argue that such disease is predictably salvageable,9, 15-16,41 others suggest that these patients have significantly diminished survival.1, 14, 28, 42-44
The 18.1% RR suggested by the present study may be clinically significant. Therefore, we recommend that patients with intranasal SCCs with additional high-risk characteristics be considered for prophylactic treatment of the regional lymphatics via either irradiation or selective neck dissection. Because the perifacial lymph nodes can be a difficult and potentially morbid region to dissect, patients may require radiation therapy to treat the so-called moustache area in addition to the upper cervical lymphatics. With intensity-modulated radiation therapy, parotid sparing could minimize the morbidity of such elective treatment (Henry Wagner, MD, written communication, January 1, 2007).
This study is limited by several factors. First, it was restricted to the published literature, which may have caused a publication bias. Second, the studies had various lengths of posttreatment observation. This variation may be a source of bias in the estimates of RR and survival rates. Finally, our study is limited by an inability to compare tumors of similar stage owing to the previous lack of a unified staging system for nasal cavity cancers. Review of the 23 studies revealed multiple forms of detailing nasal cavity tumors. Some9, 12, 16-17,22, 24 used a staging system proposed by Wang,45 2 reported tumors according to size,8, 25 and 1 classified tumors as "early" vs "late."10 Despite the use of these different staging systems, the proportion of early to advanced tumors was compared qualitatively across all studies and appeared to be consistent. Although this study has weaknesses, the data obtained through this meta-analysis would be difficult to obtain in a prospective manner because of the rarity of nasal cancer.
In conclusion, our meta-analysis yielded an 18.1% RR in patients with intranasal SCC. In addition, PI may decrease the incidence of RR. Although further study is needed, we suggest that patients with intranasal SCCs that demonstrate high-risk characteristics be considered for prophylactic treatment of the neck with either surgery or radiation therapy.
AUTHOR INFORMATION
Correspondence: Fred G. Fedok, MD, Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, Penn State College of Medicine, PO Box 850, 500 University Dr, Mail Code H091, Hershey, PA 17033 (ffedok{at}psu.edu).
Submitted for Publication: August 14, 2006; final revision received February 9, 2007; accepted March 25, 2007.
Author Contributions: Drs Scurry, Goldenberg, and Fedok had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Scurry, Goldenberg, Chee, Lengerich, and Fedok. Acquisition of data: Scurry, Chee, and Fedok. Analysis and interpretation of data: Scurry, Goldenberg, Lengerich, Liu, and Fedok. Drafting of the manuscript: Scurry, Goldenberg, Chee, Lengerich, and Fedok. Critical revision of the manuscript for important intellectual content: Scurry, Lengerich, Liu, and Fedok. Statistical analysis: Scurry, Lengerich, and Liu. Administrative, technical, and material support: Fedok. Study supervision: Scurry, Goldenberg, and Fedok.
Financial Disclosure: None reported.
Previous Presentation: This work was presented as a poster at the 2006 annual meeting and research conference of the American Head and Neck Society; August 17-20, 2006; Chicago, Illinois.
Additional Information: Dr Liu completed his work on this project while at the Division of Epidemiology, Department of Health Evaluation Sciences, Penn State University.
Additional Contributions: Henry Wagner, MD, Department of Radiation Oncology, Penn State Milton S. Hershey Medical Center, contributed information regarding parotid-sparing intensity-modulated radiation therapy for SCC of the nasal cavity. Deb Lovett, BS, assisted with our literature searches and the preparation of this manuscript.
Author Affiliations: Division of Otolaryngology–Head and Neck Surgery, Department of Surgery (Drs Scurry, Goldenberg, and Fedok and Mr Chee), and Division of Epidemiology, Department of Health Evaluation Sciences (Dr Lengerich), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Liu).
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