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Original Article |

Significant Invasion of the Pharyngeal Constrictor Muscle in Early Squamous Cell Carcinoma of the Tonsil:  Prediction of Multiple Regional Metastasis FREE

Jun-Ook Park, MD; Youn-Soo Lee, MD, PhD; Young-Hoon Joo, MD; Inn-Chul Nam, MD; Kwang-Jae Cho, MD, PhD; Jung-Hae Cho, MD; Min-Sik Kim, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Otolaryngology–Head and Neck Surgery (Drs Park, Joo, Nam, K.-J. Cho, J.-H. Cho, and Kim) and Pathology (Dr Lee), College of Medicine, The Catholic University of Korea, Seoul.


Arch Otolaryngol Head Neck Surg. 2012;138(11):1034-1039. doi:10.1001/2013.jamaoto.467.
Text Size: A A A
Published online

Objective To determine whether invasion of the pharyngeal constrictor muscle in early squamous cell carcinoma of the tonsil is correlated with lymph node metastasis.

Design Retrospective analysis of medical records and pathology specimens.

Setting Tertiary care referral center.

Patients Forty-eight patients who were diagnosed as having T2 squamous cell carcinoma of the tonsil and who underwent surgery. They were divided into 2 groups: an invasive group with invasion of the pharyngeal constrictor muscle and a noninvasive group without invasion of the pharyngeal constrictor muscle.

Main Outcome Measures Comparison of regional metastasis, 5-year locoregional recurrence, and 5-year disease-specific survival between the 2 groups.

Results Invasion of the pharyngeal constrictor muscle was found in 36 patients (75%) with T2 squamous cell carcinoma of the tonsil. The rate of lymph node metastasis, the mean (SD) number of positive nodes, and the mean (SD) lymph node density were 81%, 5.47 (9.27), and 0.15 (0.22) in the invasive group, respectively, and 50%, 1.33 (1.72), and 0.04 (0.04) in the noninvasive group, respectively (P = .04, P = .02, and P = .01, respectively). Five-year locoregional recurrence was significantly correlated with invasion of the pharyngeal constrictor muscle (P = .05) and with multiple lymph node metastasis (≥5 nodes) (P = .04) in the univariate analyses. No factor was correlated with 5-year locoregional recurrence in the multivariate analysis. Five-year disease-specific survival was significantly correlated with multiple lymph node metastasis (≥5 nodes) in the univariate analyses (P = .009). Five-year disease-specific survival was not significantly correlated with any clinicopathological factor in the multivariate analysis.

Conclusion Higher risk for multiple lymph node metastasis and 5-year locoregional recurrence seems to be predicted in patients with extratonsillar invasion of the pharyngeal constrictor muscle, even in early squamous cell carcinoma of the tonsil.

Figures in this Article

Squamous cell carcinoma of the tonsil is a common head and neck cancer, and the prognosis is variable according to the tumor size and lymph node status.13 Recently, human papillomavirus (HPV) infection has been regarded as a new prognostic factor.46 The American Joint Committee on Cancer staging system for squamous cell carcinoma of the tonsil bases the T category on the size and extent of local spread to the cervical lymph nodes. The T category is based on the diameter of the primary tumor, without regard to the presence or absence of extratonsillar invasion. The palatine tonsil is encapsulated by a thick fibrous barrier, which is composed of a tonsillar capsule and pharyngobasilar fascia laterally. The lateral side of this barrier is covered by the superior pharyngeal constrictor muscle, and it separates the tonsil from the parapharyngeal space.7,8 Therefore, extratonsillar invasion refers to penetration of the fibrous barrier to cancer spread, and the tumor may have a higher probability to spread locally. We hypothesized that the presence or absence of extratonsillar invasion of the pharyngeal constrictor muscle, as well as the size of the primary tumor, is significantly related to lymph node metastasis and to 5-year locoregional recurrence. We reviewed the English literature on this topic but found no such evaluation. Therefore, this study was designed to verify whether extratonsillar invasion of the pharyngeal constrictor muscle in early squamous cell carcinoma of the tonsil is correlated with lymph node metastasis and with 5-year locoregional recurrence.

PATIENTS AND TREATMENT MODALITY

We retrospectively reviewed the clinicopathological data of 72 patients who had been diagnosed as having T2 squamous cell carcinoma of the tonsil and had undergone surgery at the Department of Otolaryngology–Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, between March 1, 1992, and December 31, 2010. The institutional review board of Seoul St Mary's Hospital, Seoul, Korea, approved this retrospective review of medical records and the use of archived pathology specimens. We included only T2 squamous cell carcinoma of the tonsil to minimize the bias of tumor size. Forty-eight patients who met the following criteria were included: (1) no previous treatment for the same diagnosis (cancer of the head and neck) before hospitalization and (2) initial surgical treatment with curative intent and a minimum follow-up period of 12 months. The study patients were divided into 2 groups: an invasive group with invasion or penetration of the pharyngeal constrictor muscle and a noninvasive group without invasion or penetration of the pharyngeal constrictor muscle. Primary tumors were removed via a combined transoral and lateral pharyngotomy approach en bloc for all patients. The communicating defect between the oropharynx and the neck after the primary resection was reconstructed with a free flap. Patients who underwent transoral surgery only (transoral laser or robotic surgery) were excluded from this study because they were unsuitable for investigating invasion of the pharyngeal constrictor muscle. Prophylactic selective neck dissection was performed in clinically negative necks, and modified radical neck dissection was performed in clinically positive necks. Adjuvant treatment was considered when the cancer-free margin was insufficient (<5 mm) or extracapsular invasion was found or if multiple lymph node metastases were found. Most patients were followed up every 6 months for the first 2 years and then every 12 months. The follow-up assessment tools included computed tomography, magnetic resonance imaging, liver and bone imaging, and positron emission tomography. The patients' disease was categorized according to the 2002 American Joint Committee on Cancer staging system.

HISTOPATHOLOGICAL REVIEW

The resected tissue was fixed in 10% formaldehyde and embedded in paraffin. The surgical specimens had been sectioned serially, 2 mm apart, in a direction perpendicular to the mucosal tumor surface. The relationship between the tumor and the pharyngeal constrictor muscle was evaluated by a pathologist (Y.-S. Lee) who specialized in head and neck pathology. The association was graded according to the following 4-point scale: (1) no invasion (normal tissue remained between the tumor and the pharyngeal constrictor muscle); (2) attachment (no normal tissue remained between the tumor and the medial surface of the pharyngeal constrictor muscle, but no cancer cells were seen in the pharyngeal constrictor muscle tissue); (3) invasion (cancer cells were seen in the pharyngeal constrictor muscle tissue but not in the lateral surface of the pharyngeal constrictor muscle); and (4) penetration (cancer cells were seen in the lateral surface of the pharyngeal constrictor muscle) (Figure 1). Those patients with grade 1 or 2 were allocated to the noninvasive group, and those with grade 3 or 4 were allocated to the invasive group.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Relationship between squamous cell carcinoma of the tonsil and the pharyngeal constrictor muscle. A, No invasion (normal tissue remained between the tumor and the pharyngeal constrictor muscle). B, Attachment (no normal tissue remained between the tumor and the medial surface of the pharyngeal constrictor muscle, but no cancer cells were seen in the pharyngeal constrictor muscle tissue). C, Invasion (cancer cells were seen in the pharyngeal constrictor muscle tissue but not in the lateral surface of the pharyngeal constrictor muscle). D, Penetration (cancer cells were seen in the lateral surface of the pharyngeal constrictor muscle).

IN SITU HYBRIDIZATION OF HPV

In situ hybridization of HPV was performed with an automated system (Benchmark; Ventana Medical Systems) using a probe for a cocktail of HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 66 (INFORM HPV III Family 16 Probe; Ventana Medical Systems) according to the manufacturer's recommendations. The nuclear hybridization signal was assessed by a pathologist (Y.-S. Lee) who specialized in head and neck pathology.

STATISTICAL ANALYSIS

The χ2 test, Fisher exact test, t test, and correlation analysis were used as appropriate to identify significant differences in the clinicopathological parameters according to invasion of the pharyngeal constrictor muscle. To determine the statistical significance of relationships between prognosis (5-year locoregional recurrence and 5-year disease-specific survival) and the variables studied, we used the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. P < .05 indicated statistical significance. All analyses were performed using commercially available software (SPSS, version 13.0; SPSS Inc).

CLINICOPATHOLOGICAL CHARACTERISTICS ACCORDING TO INVASION OF THE PHARYNGEAL CONSTRICTOR MUSCLE

The histopathological results revealed no invasion of the pharyngeal constrictor muscle in 6 patients (12%), attachment in 6 patients (12%), invasion in 24 patients (50%), and penetration in 12 patients (25%). Therefore, the invasive group consisted of 36 patients (75%), and the noninvasive group consisted of 12 patients (25%). The ratio of women to men was not significantly different between the groups (P = .13). Nineteen patients (40%) were positive for HPV, including 6 patients (50%) in the noninvasive group and 13 patients (36%) in the invasive group; the difference between groups was not significant (P = .50). Age, sex, pack-years of smoking, histopathological differentiation, and treatment modality were not significantly different between the 2 groups (Table 1). The mean (SD) follow-up periods were 37.63 (36.11) months in the invasive group and 51.31 (30.13) months in the noninvasive group (P = .24).

Table Graphic Jump LocationTable 1. Clinicopathological Characteristics of 48 Patients According to Invasion of the Pharyngeal Constrictor Muscle
LYMPH NODE METASTASIS ACCORDING TO INVASION OF THE PHARYNGEAL CONSTRICTOR MUSCLE

Lymph node metastasis was found in 35 patients (73%) with T2 squamous cell carcinoma of the tonsil. The mean (SD) number of positive nodes and lymph node density (LND [the number of positive nodes divided by the number of dissected nodes]) were 4.44 (8.25) and 0.12 (0.20), respectively. The rate of lymph node metastasis, the mean (SD) number of positive nodes, and the mean (SD) LND were 81%, 5.47 (9.27), and 0.15 (0.22) in the invasive group, respectively, and 50%, 1.33 (1.72), and 0.04 (0.04) in the noninvasive group, respectively (P = .04, P = .02, and P = .01, respectively) (Table 1).

FIVE-YEAR LOCOREGIONAL RECURRENCE AND DISEASE-SPECIFIC SURVIVAL

The final outcomes among 48 patients were as follows: 7 patients died of disease, 7 patients died of other causes, 32 patients survived with no further evidence of disease, and 2 patients survived with 5-year locoregional recurrence. The 5-year overall survival and disease-specific survival rates were 70% and 81%, respectively. In the univariate analyses, a significant positive correlation with 5-year locoregional recurrence was found for invasion of the pharyngeal constrictor muscle (P = .05) and for multiple lymph node metastasis (≥5 nodes) (P = .04) (Table 2). The multivariate analysis confirmed that no factor was significantly correlated with 5-year locoregional recurrence. In the univariate analyses, a significant positive correlation with 5-year disease-specific survival was found for multiple lymph node metastasis (≥5 nodes) (P = .009). The 5-year disease-specific survival rate in the invasive group was lower than that in the noninvasive group (73% vs 100%); this difference was not statistically significant (P = .09). The multivariate analysis confirmed that no factor was significantly correlated with 5-year disease-specific survival.

Table Graphic Jump LocationTable 2. Correlation Between Clinicopathological Characteristics of 48 Patients and Prognosis

Early-stage squamous cell carcinoma of the tonsil can be treated using radiation therapy or surgical modalities, with comparable locoregional control and survival results. The 5-year disease-free survival rates are 75% to 85% for patients with T1 disease and 55% to 80% for patients with T2 disease.1,2 However, squamous cell carcinoma of the tonsil readily metastasizes to the cervical lymph nodes, even in an early T category and often bilaterally, a feature that is related to its invasiveness and one that is suggestive of a poorer prognosis.3 The rate of cervical lymph node metastasis in patients with invasion of the pharyngeal constrictor muscle was significantly higher than that in patients without invasion in our study. The number of positive nodes and the LND were also higher in patients with invasion of the pharyngeal constrictor muscle. The increased risk for lymph node metastasis may be explained by the anatomical structure and lymph node drainage system around the tonsil. The palatine tonsil is a lymphoid tissue in the oropharynx and is encapsulated by thick fibrous barriers of the tonsillar capsule and pharyngobasilar fascia laterally. The lateral side of these barriers is covered by the superior pharyngeal constrictor muscle. The fibrous barriers and this muscle separate the tonsillar fossa from the parapharyngeal space. These fibrous barriers between the tonsil and the superior pharyngeal constrictor muscle are pierced by the tonsillar arteries and veins.7,8 Most of the subepithelial lymph node tissue in the palatine tonsils is in the lateral areas near the capsule, where septal, interfollicular, and subreticular vessels penetrate. In the region of blood vessel passages, channels of lymph vessels can be observed in the capsule, and tonsillar lymph nodes communicate with the cervical lymph node system through these lymph vessels.9 The fibrous barrier may function as a barrier to cancer invasion, and a tumor confined to the tonsil can spread only through the perforating lymph vessels to the cervical lymph nodes. However, once the tumor penetrates the barrier, it seems easier for the cancer to spread into the parapharyngeal space because the pharyngeal constrictor muscle is a poor barrier to tumor spread. Therefore, cancer seems to spread directly to the cervical lymph node networks, and it spreads more easily to the cervical lymph nodes multifocally (Figure 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Possible patterns of lymph node spread according to the presence or absence of extratonsillar invasion of the pharyngeal constrictor muscle. A, Tumor confined to the tonsil can spread only via the lymph vessels perforating to the cervical lymph nodes. B, Tumor with extratonsillar invasion can spread to the cervical lymph node network directly and then spread more easily to the cervical lymph nodes.

In our study, only 2 of 10 patients with 5-year locoregional recurrence had a positive surgical margin, and all recurrences in the area occurred around level 2. We verified that the presence of invasion of the pharyngeal constrictor muscle and multiple lymph node metastasis increased the risk for 5-year locoregional recurrence in the univariate analyses. However, we consequently failed to demonstrate a correlation between invasion of the pharyngeal constrictor muscle and 5-year locoregional recurrence in the multivariate analysis. Because the study group comprised patients with early T2 disease, recurrence and disease-specific death were infrequent. Therefore, unless we conduct a very large multicenter study, it would be difficult to show a significant correlation in the multivariate analysis. All lymph nodes harvested from neck dissection were examined, with the LND calculated as the number of positive nodes divided by the number of dissected nodes. The LND is superior to lymph node metastasis status in predicting survival after surgery for bladder cancer.10 Some authors have demonstrated that the LND may be useful in predicting the prognosis in patients with oral squamous cell carcinoma.11,12 In our study, the increased risk for 5-year locoregional recurrence may be attributable to the higher LND in patients with invasion of the parapharyngeal constrictor muscle. In addition, penetration of the superior pharyngeal constrictor muscle and invasion of the parapharyngeal fat pad are thought to be analogous to the presence of extracapsular spread in cervical metastasis. Other authors have suggested that a carcinoma infiltrating and spreading beyond the capsule of the lymph node represents more aggressive disease, further decreases survival rates, and is associated with increased rates of regional and distant metastases.13,14 Consequently, the increased risk for 5-year locoregional recurrence may be explained by the concept of extracapsular spread.

In conclusion, higher risk for multiple lymph node metastasis and 5-year locoregional recurrence seems to be predicted in patients with extratonsillar invasion of the pharyngeal constrictor muscle, even in early squamous cell carcinoma of the tonsil. Therefore, we cautiously recommend more aggressive postoperative adjuvant treatment in patients having tonsillar carcinoma with extratonsillar invasion.

Correspondence: Min-Sik Kim, MD, PhD, Department of Otolaryngology–Head and Neck Surgery, College of Medicine, The Catholic University of Korea, 505 Banpodong Seochogu, Seoul 137-040, Korea (entkms@catholic.ac.kr).

Submitted for Publication: May 11, 2012; final revision received July 11, 2012; accepted August 3, 2012.

Author Contributions: Drs Park and Kim 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: Park, Joo, K.-J. Cho, and Kim. Acquisition of data: Park, Lee, Nam, and J.-H. Cho. Analysis and interpretation of data: Park. Drafting of the manuscript: Park and Lee. Critical revision of the manuscript for important intellectual content: Park, Joo, Nam, K.-J. Cho, J.-H. Cho, and Kim. Statistical analysis: Park. Obtained funding: Nam. Administrative, technical, and material support: Lee, Joo, J.-H. Cho, and Kim. Study supervision: Joo, K.-J. Cho, and Kim.

Conflict of Interest Disclosures: None reported.

Previous Presentation: This study was presented at the Eighth International Conference on Head and Neck Cancer; July 22, 2012; Toronto, Ontario, Canada.

Mizono GS, Diaz RF, Fu KK, Boles R. Carcinoma of the tonsillar region.  Laryngoscope. 1986;96(3):240-244
PubMed   |  Link to Article
Spiro JD, Spiro RH. Carcinoma of the tonsillar fossa: an update.  Arch Otolaryngol Head Neck Surg. 1989;115(10):1186-1189
PubMed   |  Link to Article
Talamini R, La Vecchia C, Levi F, Conti E, Favero A, Franceschi S. Cancer of the oral cavity and pharynx in nonsmokers who drink alcohol and in nondrinkers who smoke tobacco.  J Natl Cancer Inst. 1998;90(24):1901-1903
PubMed   |  Link to Article
Osborne RF, Brown JJ. Carcinoma of the oral pharynx: an analysis of subsite treatment heterogeneity.  Surg Oncol Clin N Am. 2004;13(1):71-80
PubMed   |  Link to Article
Dahlstrand H, Näsman A, Romanitan M, Lindquist D, Ramqvist T, Dalianis T. Human papillomavirus accounts both for increased incidence and better prognosis in tonsillar cancer.  Anticancer Res. 2008;28(2B):1133-1138
PubMed
Lindquist D, Romanitan M, Hammarstedt L,  et al.  Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7.  Mol Oncol. 2007;1(3):350-355
PubMed   |  Link to Article
Goeringer GC, Vidić B. The embryogenesis and anatomy of Waldeyer's ring.  Otolaryngol Clin North Am. 1987;20(2):207-217
PubMed
Suarez FR. The clinical anatomy of the tonsillar (Waldeyer’s) ring.  Ear Nose Throat J. 1980;59(11):447-453
PubMed
Werner JA, Dünne AA, Myers JN. Functional anatomy of the lymphatic drainage system of the upper aerodigestive tract and its role in metastasis of squamous cell carcinoma.  Head Neck. 2003;25(4):322-332
PubMed   |  Link to Article
Kassouf W, Agarwal PK, Herr HW,  et al.  Lymph node density is superior to TNM nodal status in predicting disease-specific survival after radical cystectomy for bladder cancer: analysis of pooled data from MDACC and MSKCC.  J Clin Oncol. 2008;26(1):121-126
PubMed   |  Link to Article
Gil Z, Carlson DL, Boyle JO,  et al.  Lymph node density is a significant predictor of outcome in patients with oral cancer.  Cancer. 2009;115(24):5700-5710
PubMed   |  Link to Article
Kim SY, Nam SY, Choi SH, Cho KJ, Roh JL. Prognostic value of lymph node density in node-positive patients with oral squamous cell carcinoma.  Ann Surg Oncol. 2011;18(8):2310-2317
PubMed   |  Link to Article
Wenzel S, Sagowski C, Kehrl W, Metternich FU. The prognostic impact of metastatic pattern of lymph nodes in patients with oral and oropharyngeal squamous cell carcinomas.  Eur Arch Otorhinolaryngol. 2004;261(5):270-275
PubMed   |  Link to Article
Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx.  Head Neck. 1998;20(1):16-21
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Relationship between squamous cell carcinoma of the tonsil and the pharyngeal constrictor muscle. A, No invasion (normal tissue remained between the tumor and the pharyngeal constrictor muscle). B, Attachment (no normal tissue remained between the tumor and the medial surface of the pharyngeal constrictor muscle, but no cancer cells were seen in the pharyngeal constrictor muscle tissue). C, Invasion (cancer cells were seen in the pharyngeal constrictor muscle tissue but not in the lateral surface of the pharyngeal constrictor muscle). D, Penetration (cancer cells were seen in the lateral surface of the pharyngeal constrictor muscle).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Possible patterns of lymph node spread according to the presence or absence of extratonsillar invasion of the pharyngeal constrictor muscle. A, Tumor confined to the tonsil can spread only via the lymph vessels perforating to the cervical lymph nodes. B, Tumor with extratonsillar invasion can spread to the cervical lymph node network directly and then spread more easily to the cervical lymph nodes.

Tables

Table Graphic Jump LocationTable 1. Clinicopathological Characteristics of 48 Patients According to Invasion of the Pharyngeal Constrictor Muscle
Table Graphic Jump LocationTable 2. Correlation Between Clinicopathological Characteristics of 48 Patients and Prognosis

References

Mizono GS, Diaz RF, Fu KK, Boles R. Carcinoma of the tonsillar region.  Laryngoscope. 1986;96(3):240-244
PubMed   |  Link to Article
Spiro JD, Spiro RH. Carcinoma of the tonsillar fossa: an update.  Arch Otolaryngol Head Neck Surg. 1989;115(10):1186-1189
PubMed   |  Link to Article
Talamini R, La Vecchia C, Levi F, Conti E, Favero A, Franceschi S. Cancer of the oral cavity and pharynx in nonsmokers who drink alcohol and in nondrinkers who smoke tobacco.  J Natl Cancer Inst. 1998;90(24):1901-1903
PubMed   |  Link to Article
Osborne RF, Brown JJ. Carcinoma of the oral pharynx: an analysis of subsite treatment heterogeneity.  Surg Oncol Clin N Am. 2004;13(1):71-80
PubMed   |  Link to Article
Dahlstrand H, Näsman A, Romanitan M, Lindquist D, Ramqvist T, Dalianis T. Human papillomavirus accounts both for increased incidence and better prognosis in tonsillar cancer.  Anticancer Res. 2008;28(2B):1133-1138
PubMed
Lindquist D, Romanitan M, Hammarstedt L,  et al.  Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7.  Mol Oncol. 2007;1(3):350-355
PubMed   |  Link to Article
Goeringer GC, Vidić B. The embryogenesis and anatomy of Waldeyer's ring.  Otolaryngol Clin North Am. 1987;20(2):207-217
PubMed
Suarez FR. The clinical anatomy of the tonsillar (Waldeyer’s) ring.  Ear Nose Throat J. 1980;59(11):447-453
PubMed
Werner JA, Dünne AA, Myers JN. Functional anatomy of the lymphatic drainage system of the upper aerodigestive tract and its role in metastasis of squamous cell carcinoma.  Head Neck. 2003;25(4):322-332
PubMed   |  Link to Article
Kassouf W, Agarwal PK, Herr HW,  et al.  Lymph node density is superior to TNM nodal status in predicting disease-specific survival after radical cystectomy for bladder cancer: analysis of pooled data from MDACC and MSKCC.  J Clin Oncol. 2008;26(1):121-126
PubMed   |  Link to Article
Gil Z, Carlson DL, Boyle JO,  et al.  Lymph node density is a significant predictor of outcome in patients with oral cancer.  Cancer. 2009;115(24):5700-5710
PubMed   |  Link to Article
Kim SY, Nam SY, Choi SH, Cho KJ, Roh JL. Prognostic value of lymph node density in node-positive patients with oral squamous cell carcinoma.  Ann Surg Oncol. 2011;18(8):2310-2317
PubMed   |  Link to Article
Wenzel S, Sagowski C, Kehrl W, Metternich FU. The prognostic impact of metastatic pattern of lymph nodes in patients with oral and oropharyngeal squamous cell carcinomas.  Eur Arch Otorhinolaryngol. 2004;261(5):270-275
PubMed   |  Link to Article
Brasilino de Carvalho M. Quantitative analysis of the extent of extracapsular invasion and its prognostic significance: a prospective study of 170 cases of carcinoma of the larynx and hypopharynx.  Head Neck. 1998;20(1):16-21
PubMed   |  Link to Article

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