Acta Oto-Laryngologica. 2014; 134: 952–958
ORIGINAL ARTICLE
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Management of cervical lymph nodes for cN0 advanced glottic laryngeal carcinoma and its long-term results
HONGZHI MA1, MENG LIAN1, LING FENG1, PINGDONG LI1, LIZHEN HOU1, HONGCHUAN LIU3, XIAOHONG CHEN1, ZHIGANG HUANG1,2 & JUGAO FANG1,2 1
Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, Key Laboratory of Otorhinolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otorhinolaryngology, Beijing and 3School of Foreign Languages, Shanxi University, Xian, China
2
Abstract Conclusions: Cervical lymph node metastatic rates tend to increase by T stage in cN0 glottic laryngeal carcinoma (GLC). Moreover, cervical lymph node metastasis (LNM) shows a sequential pattern according to the regions involved and LNM affects the prognosis. Objectives: To investigate factors that contribute to LNM of N0 (cN0) T2–T4 GLC and their effect on prognosis. Methods: A total of 212 GLC patients who had been admitted between December 2002 and January 2013 were retrospectively analyzed. They included 202 men and 10 women, median age 58.6 years (range 29–85 years), whose identified tumor stages included T2 (n = 81), T3 (n = 67), and T4 (n = 64). Relevant factors of cervical LNM were analyzed; multivariate analyses and receiver operating characteristic (ROC) curve were carried out to predict the metastasis and prognosis. Results: The overall metastatic rate of N0 GLC was 14.6%. T staging and pathological classification were the risk factors for LNM. Metastatic rates for levels II, III, and IV were 10.2%, 14.6%, and 2.5%, respectively. Approximate 4.2% of patients experienced LNM with no recurrence of laryngeal cancer. Overall 3- and 5-year survival rates were 85% and 80%, respectively, compared with 66% and 57%, respectively, among patients with LNM. The inter-group survival curve comparison was statistically significant (p = 0.012).
Keywords: Larynx, tumor, lymph node, metastasis
Introduction Complete resection of primary lesions and cervical dissection are the main interventions in comprehensive treatment of laryngeal cancer (LC) and critically affect its prognosis. Although the advantage of dissection for patients with cervical lymph node metastasis (LNM) is well established, the necessity of cervical dissection for cN0 (no clinical LNM) in patients with LC remains controversial [1,2]. In this study, 212 patients who suffered from cN0 glottic laryngeal carcinoma (GLC) and had been admitted to our hospital from December 2002 to January 2013
were analyzed to investigate the importance of cervical dissection for different stages of LC. Material and methods General data A total of 212 patients with cN0 LC who underwent surgical intervention in our hospital from December 2002 to January 2013 were enrolled in this study. They were 202 men and 10 women, median age 58.6 years (range 29–85 years). Their identified tumor stages were T2 (n = 81), T3 (n = 67), and
Correspondence: Jugao Fang, Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. E-mail: [email protected]
(Received 28 February 2014; accepted 24 April 2014) ISSN 0001-6489 print/ISSN 1651-2251 online 2014 Informa Healthcare DOI: 10.3109/00016489.2014.920109
Treatment of glottic laryngeal carcinoma cN0 T4 (n = 64). All patients met the diagnosis criteria and none of them underwent preoperative radio/ chemotherapies (Table I).
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Diagnostic criteria Laryngeal carcinoma was diagnosed based on the TNM staging classification system (UICC, 2002). The cN0 LCs were diagnosed by the evaluation criteria proposed by Kowalski et al. [3]: (a) clinical examination found no swollen lymph nodes or swollen lymph nodes were 0.1079, the metastatic risk existed. Postoperative LNM A total of 189 patients were followed up for more than 1 year after the initial surgery, and 9 (4.2%) cases experienced LNM. Of the 137 patients who were followed up after surgery for more than 1 year and underwent cervical dissection, 8 (5.8%) had cervical LNM with no concomitant recurrence of LC. Of the 52 patients who were followed up after surgery for more than 1 year without cervical dissection, 1 (1.9%) who had been confirmed to have no LNM had cervical LNM with no concomitant recurrence of LC (Table V).
ROC curve 1.0
Survival rates The 1-year, 3-year, and 5-year survival rates were 98%, 85%, 80%, respectively, for all patients, compared with 92%, 66%, and 57%, respectively, for patients with LNM. The inter-group comparison of survival curves (Figure 2) between patients with LNM and with no LNM was statistically significant (p = 0.012 < 0.05). At the end of follow-up, 52 deaths were reported. Among these 52 patients, 18 deaths were related to
0.8
Sensitivity
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Biopsy (2)
0.6
0.4
0.2 Table IV. Area of ROC curve.
0.0 0.0
0.2
0.4 0.6 1-Specificity
0.8
Asymptotic 95% confidence interval
1.0
Figure 1. ROC curve of the metastatic predicted probability in GLC cN0. Diagonal segments are produced by ties.
Area
SE
Asymptotic sig. b
Lower
Upper
0.709
0.047
0.000
0.617
0.801
Treatment of glottic laryngeal carcinoma cN0
955
Table V. Lymph node metastasis (LNM) data for metastatic regions for T2–T4 cN0 patients with glottic laryngeal carcinoma during follow-up. Neck dissection
Without neck dissection
Status
1
2
3
4
5
6
7
8
9
T stage
T4
T4
T4
T4
T3
T3
T2
T2
T4
P
P
PN1, 2
P
II III IV
P
P P
P
P
Widely metastatic
P
P
P
topical recurrence, 10 to lung metastasis, 5 to lymph node recurrence, and 4 to pulmonary infection. Other causes of death included metastasis to other sites such as liver, brain, and kidney; depression; eating difficulties; and systemic failure. Discussion Laryngeal carcinoma accounts for 13.9% of head and neck cancers, with an incidence of 1.5–3.4 per 100 000 and its incidence tends to increase year by year. The prognosis is generally good for LC, with 5-year survival rates of 70–80% for T2 lesions and 40–60% for T3–T4 lesions in the absence of distant metastasis [4]. Therefore, minimization of surgery and restoration of function are major trends in the treatment of LC, based on the supposition that they will not increase relapse risk. The importance of neck dissection has been established as a surgical intervention for LC, especially for
advanced cases, and it has evolved from radical neck dissection, to modified neck dissection, to the present more acceptable selective neck dissection. Currently, most patients free of clinical LNM of LC (‘cN0 LC’) choose selective neck dissection as the first-line surgical intervention. However, no LNM was found in many patients with cN0 LC following selective neck dissection, as well as in many patients who do not receive selective neck dissection during long-term follow-up. Moreover, some patients who were intraoperatively confirmed to have no LNM experienced cervical LNM with no concomitant LC recurrence. Despite its limited impairment effects, selective neck dissection produces postoperative injuries with diverse intensity in almost all patients, such as hematomas, accessory nerve damage, lymphatic fistulas, compromised appearance, scar discomfort, facial swelling, and local sensorimotor dysfunction, all of which diminish patients’ quality of life [5]. Although injuries induced by radical neck dissection are
Survival functions Groups
1.0
Without metastasis Occult metastasis Without metastasis censored
0.8 Cum survival
Acta Otolaryngol Downloaded from informahealthcare.com by Northeastern University on 01/14/15 For personal use only.
VI
Occult metastasis censored
0.6
0.4
0.2
0.0 0
20
40
60
80
100
120
Survival (months) Figure 2. Comparison of inter-group survival curves.
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minimized by use of selective neck dissection, local structures must be preserved, which requires more careful intraoperative procedures, increased anesthesia time, and precise technique. Because of the injuries of additional cervical dissection, the probability of laryngeal infection is expected to increase. All these factors might be associated with the increased difficulty of diagnosis and treatment [6]. Otherwise, postoperative LNMs occurred in some patients with pathological N0 LC who needed further neck dissection. An initial neck dissection could change the normal anatomy of local tissues and induce local adhesions, making important structures less discernible. All these factors greatly increase the difficulty and risk of another operation. Injuries to prevertebral fascia and carotid sheath can increase the risk of tumor spread and invasion to neck vessels and nerves, which can adversely affect prognosis. Furthermore, cervical dissection can produce scars that might adversely affect the efficacy of radiation, thus decreasing the effective dosage in the target region. All these factors affect the prognosis of patients with LC. Neck dissection should be necessary if the risk of cervical LNM is >15–20% [7]. Supraglottic and glottic LCs are common specimens of this malignancy, as shown by clinical data. Supraglottic structures are enriched with lymph ducts that are connected to each other, while there are less lymph ducts in the glottic region. The metastasis rate of cervical lymph node was reported to be 0.44–10% [8,9], and the invasion of anterior commissure has no relationship with the LNM of T2 cN0 GLC [10]. Therefore, lymph node dissection is not generally recommended for early-stage GLC. In the present study, patients with potentially metastatic cervical lymph nodes were selected to undergo selective cervical dissection among the 212 patients with cN0 GLC. As shown by postoperative pathology results, 14.6% of cervical lymph nodes were confirmed to be metastatic. The LNM rate of our study is higher than the data reported before. Perhaps this result is related to the fact that some early-stage cases of T2 whose clinical exams showed no possibility of LNM and who only underwent laser surgery were not enrolled in our study. Metastasis rates of T2, T3, and T4 lesions were 8.6%, 13.4%, and 23.4%, respectively. The metastasis rate of cN0 cervical lymph node appears to be closely related to T staging in patients with GLC, and tends to increase with the progress of T staging. As shown by multivariate analysis, T staging and pathology classification, but not age and sex, were correlated to LNM. The LNM rate for T3 was 167.1% higher than for T2; the T4 rate was 324.2% higher than for T2; and the T4 rate was 194.0% higher than for T3. The LNM rate increases
by3.349 in moderately differentiated cases compared with highly differentiated cases, by 1.642 in poorly differentiated cases compared with highly differentiated cases, and by 0.490 in poorly differentiated cases compared with moderately differentiated cases. These observations might reflect the higher malignancy of poorly differentiated lesions, which would metastasize in their early stages, leading to clear LNM. Most of the poorly differentiated cases presented as distinct (N +) or even severe LNM. Therefore, prophylactic cervical dissection is necessary for advanced GLC, especially when the Pn >0.1079. Currently, cervical lymph node dissections usually focus on levels II, III, and IV [11,12]. However, recent studies also showed instances of rare metastasis to level IIB and IV [13,14]. Statistical analyses of regional metastasis in this study identified levels II and III as the main regions of metastasis; metastasis rates of GLC were 10.2%, 14.6%, and 2.5% for levels II, III, and IV, respectively. There were no obvious rules to follow for the metastasis among levels II, III, and IV. However, three level IIB LNMs in our study were concomitant with ipsilateral level IIA LNM. Patients with no IIA metastasis also had no level IIB metastases. Only one T3 case which passed over the center line occurred contralateral lymph node metastases, so ipsilateral metastasis is predominant for lymph node metastases. GLC could metastasize simultaneously to levels II, III, and IV. Metastasis to level II might originate from level IIA, without jumping into level IIB directly. In the absence of ipsilateral region metastasis, contralateral metastasis is infrequent. In conclusion, the range of prophylactic neck dissection against cN0 GLC should be based on the intraoperative frozen section examination. For example, dissection of level IIB might be unnecessary in the absence of level IIA metastasis, and contralateral dissection might be unnecessary in the absence of ipsilateral metastasis. Levels II and III are the major regions that need to be examined in the prophylactic neck dissection. Clinical data show that recurrence of metastasis in cervical lymph nodes is common in the first 3 postoperative years, with highest incidence in the first year [15,16]. The survival rate of patients with LNM was significantly lower than for those without such metastasis. So the neck dissection was very necessary for the patients with LNM. In this study, 189 patients were followed for more than 1 year. Eight patients who underwent cervical dissection experienced cervical LNM without LC recurrence; the lesions were identified as advanced lesions, mainly in level VI and IV as the dominant metastasis sites. Therefore, for patients with advanced disease, especially those with subglottic involvement, assessment and dissection of
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Treatment of glottic laryngeal carcinoma cN0 level VI and IV should be seriously considered. Among the eight patients, six cases were intraoperatively confirmed to have no LNM. Also, two patients experienced soft tissue metastasis, which might be due to the inability of cervical dissection to completely remove micro-metastasis, the continuous growth of cancer cells surviving between the primary and metastatic lesions [17], and possibly to the destruction of a natural immune barrier against neck tumors as a result of unnecessary neck dissection. Intraoperative metastasis might also be involved in this process. Of those patients without cervical dissection, one of the T4 lesions had cervical LNM in level VI with no concomitant recurrence of LC. Moreover, conventional sectioning and hematoxylin and eosin (H&E) staining are commonly used in pathological diagnosis. These methods might not be helpful in identifying micro-metastases. As some studies demonstrated, most micro-metastases that are difficult to identify by conventional pathology are detected in T3 or T4 [18]. Therefore, in patients with advanced GLC surgeons still need to pay attention to level VI and IV during neck dissection. With medical developments and health expectations increasing, the proportion of patients with cN0 LC tends to increase on an annual basis, and to meet the need of postoperative health and quality of life, individualized intervention strategies should be suggested according to different cN0 LC conditions. Analyses of survival rates suggest a direct correlation between cervical LNM and prognosis. As patients with LNM have poor prognoses, they need more powerful and comprehensive therapies. Moreover, improvement of preoperative diagnostic accuracy for cervical LNM of LC has become a research highlight. Currently, commonly used approaches, such as CT, B-ultrasound, and cervical lymph node biopsy, have some limits. Recently, some biomarkers of tumor tissues, such as PTEN and thrombospondin 2 have been correlated with LNM [19] and are therefore worth investigating. In addition, local administration of radionuclides can help to locate metastatic lymph nodes and determine the range of dissection [20]. We need to investigate these results further. Conclusion Based on our data analysis, levels IIA and III are considered as the regions that need to be intervened in for cN0 GLC. Observation can be carried out instead of neck dissection for T2 lesions of cN0 GLC. Unilateral lymph node dissection might be considered as a treatment for T3 and T4 unilateral lesions. Results of cryosection examination of lesion-involved lymph
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nodes can indicate whether contralateral lymph node dissection should be considered for T3 and T4 cN0 GLC. Level IIB dissection is not advisable for patients with no level IIA LNM. Region IV lymph dissection might not be immediately advisable for T2 and T3 GLC with no intraoperative region metastasis. For patients with advanced disease, especially for lesions that involve the subglottic region, assessment or exploration of region VI lymph nodes should be considered. Moreover, when Pn >0.1079, a neck dissection is suggested.
Acknowledgments This work was supported by the Beijing Natural Science Foundation of China (grant no. 7112019) and the National Natural Science Foundation of China (NSFC) (grant no. 81272267). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Fiorella R, Di Nicola V, Fiorella ML, Russo C. ‘Conditional’ neck dissection in management of laryngeal carcinoma. Acta Otorhinolaryngol Ital 2006;26:356–9. [2] Goudakos JK, Markou K, Nikolaou A, Themelis C, Vital V. Management of the clinically negative neck (N0) of supraglottic laryngeal carcinoma: a systematic review. Eur J Surg Oncol 2009;35:223–9. [3] Kowalski LP, Bagietto R, Lara JR, Santos RL, Silva JF Jr, Magrin J. Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck 2000;22: 207–14. [4] Jia SS, Xiang C, Liu WS, He HJ. Supraglottic horizontal partial laryngectomies in 163 cases. Clin J Otorhinolaryngeal Head Neck Surg 2006;41:763–6. [5] Koybasioflu A, Uslu S, Yilmaz M, Inal E, Ileri F, Asal K. Lymphatic metastasis to the supraretrospinal recess in laryngeal squamous cell carcinoma. Ann Otol Rhinol Laryngol 2002;111:96–9. [6] Bohannon IA, Desmond RA, Clemons L, Magnuson JS, Carroll WR, Rosenthal EL. Management of the N0 neck in recurrent laryngeal squamous cell carcinoma. Laryngoscope 2010;120:58–61. [7] Pillsbury HC 3rd, Clark M. A rationale for therapy of the N0 neck. Laryngoscope 1997;107:1294–315. [8] Li W, Ji WY, Liu R. [Preliminary study on the correlation factors of cervical lymphatic metastasis of glottic carcinoma]. Zhonghua Er Bi Yan Hou Ke Za Zhi 2003;38:304–6; in Chinese. [9] Deganello A, Gitti G, Meccariello G, Parrinello G, Mannelli G, Gallo O. Effectiveness and pitfalls of elective neck issection in N0 laryngeal cancer. Acta Otorhinolaryngol Ital 2011;31:216–21. [10] Erdag TK, Guneri EA, Avincsal O, Sarioglu S, Ecevit MC, Guneri A, et al. Is elective neck dissection necessary for the
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[11]
[12]
[13]
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[14]
[15]
M. Hongzhi et al. surgical management of T2N0 glottic carcinoma? Auris Nasus Larynx 2013;40:85–8. Zhang B, Xu ZG, Tang PZ. Elective lateral neck dissection for laryngeal cancer in the clinically negative neck. J Surg Oncol 2006;93:464–7. Katilmis¸ H, Oztürkcan S, Ozdemir I, Tuna B, Güvenç IA, Ozkul Y. Is dissection of levels 4 and 5 justified for cN0 laryngeal and hypopharyngeal cancer? Acta Otolaryngol 2007;127:1202–6. Ferlito A, Silver CE, Rinaldo A. Selective neck dissection (IIA, III): a rational replacement for complete functional neck dissection in patients with N0 supraglottic and glottic squamous carcinoma. Laryngoscope 2008;118:676–9. Takahiro CC, Fontana KH, Rodrigo M. Levels II and III neck dissection for larynx cancer with N0 neck. Braz J Otorhinolaryngol 2012;78:59–63. Alpert TE, Morbidini-Gaffney S, Chung CT, Bogart JA, Hahn SS, Hsu J, et al. Radiotherapy for the clinically negative neck in supraglottic laryngeal cancer. Cancer J 2004;10:335–8.
[16] Yu ZK, Han DM, Huang ZG. The distribution of metastatic cervical lymph nodes in laryngeal carcinoma. J Clin Otorhinolaryngol 2002;16:471–3. [17] Ma WC, Kan J. Cervical lymph node metastasis in patients with N0 supraglottic laryngeal carcinoma and its treatment. J Clin Otorhinolaryngol Head Neck Surg 2008;22:430–2. [18] Negm H, Mosleh M, Fathy H, Hareedy A, Elbattawy A. Cytokeratin immunohistochemically detected nodal micrometastases in N0 laryngeal cancer: impact on the overall occult metastases. Eur Arch Otorhinolaryngol 2013;270: 1085–92. [19] Bai W, Wang L, Ji W, Gao H. Expression profiling of supraglottic carcinoma: PTEN and thrombospondin 2 are associated with inhibition of lymphatic metastasis. Acta Otolaryngol 2009;129:569–74. [20] Hu G, Zhong S, Xiao Q, Li Z, Hong S. Radiolocalization of sentinel lymph nodes in clinically N0 laryngeal and hypopharyngeal cancers. Ann Otol Rhinol Laryngol 2011; 120:345–50.
ORIGINAL ARTICLE
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Management of cervical lymph nodes for cN0 advanced glottic laryngeal carcinoma and its long-term results
HONGZHI MA1, MENG LIAN1, LING FENG1, PINGDONG LI1, LIZHEN HOU1, HONGCHUAN LIU3, XIAOHONG CHEN1, ZHIGANG HUANG1,2 & JUGAO FANG1,2 1
Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, Key Laboratory of Otorhinolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otorhinolaryngology, Beijing and 3School of Foreign Languages, Shanxi University, Xian, China
2
Abstract Conclusions: Cervical lymph node metastatic rates tend to increase by T stage in cN0 glottic laryngeal carcinoma (GLC). Moreover, cervical lymph node metastasis (LNM) shows a sequential pattern according to the regions involved and LNM affects the prognosis. Objectives: To investigate factors that contribute to LNM of N0 (cN0) T2–T4 GLC and their effect on prognosis. Methods: A total of 212 GLC patients who had been admitted between December 2002 and January 2013 were retrospectively analyzed. They included 202 men and 10 women, median age 58.6 years (range 29–85 years), whose identified tumor stages included T2 (n = 81), T3 (n = 67), and T4 (n = 64). Relevant factors of cervical LNM were analyzed; multivariate analyses and receiver operating characteristic (ROC) curve were carried out to predict the metastasis and prognosis. Results: The overall metastatic rate of N0 GLC was 14.6%. T staging and pathological classification were the risk factors for LNM. Metastatic rates for levels II, III, and IV were 10.2%, 14.6%, and 2.5%, respectively. Approximate 4.2% of patients experienced LNM with no recurrence of laryngeal cancer. Overall 3- and 5-year survival rates were 85% and 80%, respectively, compared with 66% and 57%, respectively, among patients with LNM. The inter-group survival curve comparison was statistically significant (p = 0.012).
Keywords: Larynx, tumor, lymph node, metastasis
Introduction Complete resection of primary lesions and cervical dissection are the main interventions in comprehensive treatment of laryngeal cancer (LC) and critically affect its prognosis. Although the advantage of dissection for patients with cervical lymph node metastasis (LNM) is well established, the necessity of cervical dissection for cN0 (no clinical LNM) in patients with LC remains controversial [1,2]. In this study, 212 patients who suffered from cN0 glottic laryngeal carcinoma (GLC) and had been admitted to our hospital from December 2002 to January 2013
were analyzed to investigate the importance of cervical dissection for different stages of LC. Material and methods General data A total of 212 patients with cN0 LC who underwent surgical intervention in our hospital from December 2002 to January 2013 were enrolled in this study. They were 202 men and 10 women, median age 58.6 years (range 29–85 years). Their identified tumor stages were T2 (n = 81), T3 (n = 67), and
Correspondence: Jugao Fang, Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. E-mail: [email protected]
(Received 28 February 2014; accepted 24 April 2014) ISSN 0001-6489 print/ISSN 1651-2251 online 2014 Informa Healthcare DOI: 10.3109/00016489.2014.920109
Treatment of glottic laryngeal carcinoma cN0 T4 (n = 64). All patients met the diagnosis criteria and none of them underwent preoperative radio/ chemotherapies (Table I).
Acta Otolaryngol Downloaded from informahealthcare.com by Northeastern University on 01/14/15 For personal use only.
Diagnostic criteria Laryngeal carcinoma was diagnosed based on the TNM staging classification system (UICC, 2002). The cN0 LCs were diagnosed by the evaluation criteria proposed by Kowalski et al. [3]: (a) clinical examination found no swollen lymph nodes or swollen lymph nodes were 0.1079, the metastatic risk existed. Postoperative LNM A total of 189 patients were followed up for more than 1 year after the initial surgery, and 9 (4.2%) cases experienced LNM. Of the 137 patients who were followed up after surgery for more than 1 year and underwent cervical dissection, 8 (5.8%) had cervical LNM with no concomitant recurrence of LC. Of the 52 patients who were followed up after surgery for more than 1 year without cervical dissection, 1 (1.9%) who had been confirmed to have no LNM had cervical LNM with no concomitant recurrence of LC (Table V).
ROC curve 1.0
Survival rates The 1-year, 3-year, and 5-year survival rates were 98%, 85%, 80%, respectively, for all patients, compared with 92%, 66%, and 57%, respectively, for patients with LNM. The inter-group comparison of survival curves (Figure 2) between patients with LNM and with no LNM was statistically significant (p = 0.012 < 0.05). At the end of follow-up, 52 deaths were reported. Among these 52 patients, 18 deaths were related to
0.8
Sensitivity
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Biopsy (2)
0.6
0.4
0.2 Table IV. Area of ROC curve.
0.0 0.0
0.2
0.4 0.6 1-Specificity
0.8
Asymptotic 95% confidence interval
1.0
Figure 1. ROC curve of the metastatic predicted probability in GLC cN0. Diagonal segments are produced by ties.
Area
SE
Asymptotic sig. b
Lower
Upper
0.709
0.047
0.000
0.617
0.801
Treatment of glottic laryngeal carcinoma cN0
955
Table V. Lymph node metastasis (LNM) data for metastatic regions for T2–T4 cN0 patients with glottic laryngeal carcinoma during follow-up. Neck dissection
Without neck dissection
Status
1
2
3
4
5
6
7
8
9
T stage
T4
T4
T4
T4
T3
T3
T2
T2
T4
P
P
PN1, 2
P
II III IV
P
P P
P
P
Widely metastatic
P
P
P
topical recurrence, 10 to lung metastasis, 5 to lymph node recurrence, and 4 to pulmonary infection. Other causes of death included metastasis to other sites such as liver, brain, and kidney; depression; eating difficulties; and systemic failure. Discussion Laryngeal carcinoma accounts for 13.9% of head and neck cancers, with an incidence of 1.5–3.4 per 100 000 and its incidence tends to increase year by year. The prognosis is generally good for LC, with 5-year survival rates of 70–80% for T2 lesions and 40–60% for T3–T4 lesions in the absence of distant metastasis [4]. Therefore, minimization of surgery and restoration of function are major trends in the treatment of LC, based on the supposition that they will not increase relapse risk. The importance of neck dissection has been established as a surgical intervention for LC, especially for
advanced cases, and it has evolved from radical neck dissection, to modified neck dissection, to the present more acceptable selective neck dissection. Currently, most patients free of clinical LNM of LC (‘cN0 LC’) choose selective neck dissection as the first-line surgical intervention. However, no LNM was found in many patients with cN0 LC following selective neck dissection, as well as in many patients who do not receive selective neck dissection during long-term follow-up. Moreover, some patients who were intraoperatively confirmed to have no LNM experienced cervical LNM with no concomitant LC recurrence. Despite its limited impairment effects, selective neck dissection produces postoperative injuries with diverse intensity in almost all patients, such as hematomas, accessory nerve damage, lymphatic fistulas, compromised appearance, scar discomfort, facial swelling, and local sensorimotor dysfunction, all of which diminish patients’ quality of life [5]. Although injuries induced by radical neck dissection are
Survival functions Groups
1.0
Without metastasis Occult metastasis Without metastasis censored
0.8 Cum survival
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VI
Occult metastasis censored
0.6
0.4
0.2
0.0 0
20
40
60
80
100
120
Survival (months) Figure 2. Comparison of inter-group survival curves.
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minimized by use of selective neck dissection, local structures must be preserved, which requires more careful intraoperative procedures, increased anesthesia time, and precise technique. Because of the injuries of additional cervical dissection, the probability of laryngeal infection is expected to increase. All these factors might be associated with the increased difficulty of diagnosis and treatment [6]. Otherwise, postoperative LNMs occurred in some patients with pathological N0 LC who needed further neck dissection. An initial neck dissection could change the normal anatomy of local tissues and induce local adhesions, making important structures less discernible. All these factors greatly increase the difficulty and risk of another operation. Injuries to prevertebral fascia and carotid sheath can increase the risk of tumor spread and invasion to neck vessels and nerves, which can adversely affect prognosis. Furthermore, cervical dissection can produce scars that might adversely affect the efficacy of radiation, thus decreasing the effective dosage in the target region. All these factors affect the prognosis of patients with LC. Neck dissection should be necessary if the risk of cervical LNM is >15–20% [7]. Supraglottic and glottic LCs are common specimens of this malignancy, as shown by clinical data. Supraglottic structures are enriched with lymph ducts that are connected to each other, while there are less lymph ducts in the glottic region. The metastasis rate of cervical lymph node was reported to be 0.44–10% [8,9], and the invasion of anterior commissure has no relationship with the LNM of T2 cN0 GLC [10]. Therefore, lymph node dissection is not generally recommended for early-stage GLC. In the present study, patients with potentially metastatic cervical lymph nodes were selected to undergo selective cervical dissection among the 212 patients with cN0 GLC. As shown by postoperative pathology results, 14.6% of cervical lymph nodes were confirmed to be metastatic. The LNM rate of our study is higher than the data reported before. Perhaps this result is related to the fact that some early-stage cases of T2 whose clinical exams showed no possibility of LNM and who only underwent laser surgery were not enrolled in our study. Metastasis rates of T2, T3, and T4 lesions were 8.6%, 13.4%, and 23.4%, respectively. The metastasis rate of cN0 cervical lymph node appears to be closely related to T staging in patients with GLC, and tends to increase with the progress of T staging. As shown by multivariate analysis, T staging and pathology classification, but not age and sex, were correlated to LNM. The LNM rate for T3 was 167.1% higher than for T2; the T4 rate was 324.2% higher than for T2; and the T4 rate was 194.0% higher than for T3. The LNM rate increases
by3.349 in moderately differentiated cases compared with highly differentiated cases, by 1.642 in poorly differentiated cases compared with highly differentiated cases, and by 0.490 in poorly differentiated cases compared with moderately differentiated cases. These observations might reflect the higher malignancy of poorly differentiated lesions, which would metastasize in their early stages, leading to clear LNM. Most of the poorly differentiated cases presented as distinct (N +) or even severe LNM. Therefore, prophylactic cervical dissection is necessary for advanced GLC, especially when the Pn >0.1079. Currently, cervical lymph node dissections usually focus on levels II, III, and IV [11,12]. However, recent studies also showed instances of rare metastasis to level IIB and IV [13,14]. Statistical analyses of regional metastasis in this study identified levels II and III as the main regions of metastasis; metastasis rates of GLC were 10.2%, 14.6%, and 2.5% for levels II, III, and IV, respectively. There were no obvious rules to follow for the metastasis among levels II, III, and IV. However, three level IIB LNMs in our study were concomitant with ipsilateral level IIA LNM. Patients with no IIA metastasis also had no level IIB metastases. Only one T3 case which passed over the center line occurred contralateral lymph node metastases, so ipsilateral metastasis is predominant for lymph node metastases. GLC could metastasize simultaneously to levels II, III, and IV. Metastasis to level II might originate from level IIA, without jumping into level IIB directly. In the absence of ipsilateral region metastasis, contralateral metastasis is infrequent. In conclusion, the range of prophylactic neck dissection against cN0 GLC should be based on the intraoperative frozen section examination. For example, dissection of level IIB might be unnecessary in the absence of level IIA metastasis, and contralateral dissection might be unnecessary in the absence of ipsilateral metastasis. Levels II and III are the major regions that need to be examined in the prophylactic neck dissection. Clinical data show that recurrence of metastasis in cervical lymph nodes is common in the first 3 postoperative years, with highest incidence in the first year [15,16]. The survival rate of patients with LNM was significantly lower than for those without such metastasis. So the neck dissection was very necessary for the patients with LNM. In this study, 189 patients were followed for more than 1 year. Eight patients who underwent cervical dissection experienced cervical LNM without LC recurrence; the lesions were identified as advanced lesions, mainly in level VI and IV as the dominant metastasis sites. Therefore, for patients with advanced disease, especially those with subglottic involvement, assessment and dissection of
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Treatment of glottic laryngeal carcinoma cN0 level VI and IV should be seriously considered. Among the eight patients, six cases were intraoperatively confirmed to have no LNM. Also, two patients experienced soft tissue metastasis, which might be due to the inability of cervical dissection to completely remove micro-metastasis, the continuous growth of cancer cells surviving between the primary and metastatic lesions [17], and possibly to the destruction of a natural immune barrier against neck tumors as a result of unnecessary neck dissection. Intraoperative metastasis might also be involved in this process. Of those patients without cervical dissection, one of the T4 lesions had cervical LNM in level VI with no concomitant recurrence of LC. Moreover, conventional sectioning and hematoxylin and eosin (H&E) staining are commonly used in pathological diagnosis. These methods might not be helpful in identifying micro-metastases. As some studies demonstrated, most micro-metastases that are difficult to identify by conventional pathology are detected in T3 or T4 [18]. Therefore, in patients with advanced GLC surgeons still need to pay attention to level VI and IV during neck dissection. With medical developments and health expectations increasing, the proportion of patients with cN0 LC tends to increase on an annual basis, and to meet the need of postoperative health and quality of life, individualized intervention strategies should be suggested according to different cN0 LC conditions. Analyses of survival rates suggest a direct correlation between cervical LNM and prognosis. As patients with LNM have poor prognoses, they need more powerful and comprehensive therapies. Moreover, improvement of preoperative diagnostic accuracy for cervical LNM of LC has become a research highlight. Currently, commonly used approaches, such as CT, B-ultrasound, and cervical lymph node biopsy, have some limits. Recently, some biomarkers of tumor tissues, such as PTEN and thrombospondin 2 have been correlated with LNM [19] and are therefore worth investigating. In addition, local administration of radionuclides can help to locate metastatic lymph nodes and determine the range of dissection [20]. We need to investigate these results further. Conclusion Based on our data analysis, levels IIA and III are considered as the regions that need to be intervened in for cN0 GLC. Observation can be carried out instead of neck dissection for T2 lesions of cN0 GLC. Unilateral lymph node dissection might be considered as a treatment for T3 and T4 unilateral lesions. Results of cryosection examination of lesion-involved lymph
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nodes can indicate whether contralateral lymph node dissection should be considered for T3 and T4 cN0 GLC. Level IIB dissection is not advisable for patients with no level IIA LNM. Region IV lymph dissection might not be immediately advisable for T2 and T3 GLC with no intraoperative region metastasis. For patients with advanced disease, especially for lesions that involve the subglottic region, assessment or exploration of region VI lymph nodes should be considered. Moreover, when Pn >0.1079, a neck dissection is suggested.
Acknowledgments This work was supported by the Beijing Natural Science Foundation of China (grant no. 7112019) and the National Natural Science Foundation of China (NSFC) (grant no. 81272267). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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