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Patterns of level II node metastasis in nasopharyngeal carcinoma
Radiotherapy and Oncology 89 (2008) 28–32 www.thegreenjournal.com
Node metastasis in NPC
Patterns of level II node metastasis in nasopharyngeal carcinoma XiaoShen Wanga, LongGen Lia, ChaoSu Hua,*, ZhengRong Zhoub, HongMei Yinga, JianHui Dingb, Yan Fenga a
Department of Radiation Oncology, and bDepartment of Diagnostic Radiology, Fudan University, Shanghai, People’s Republic of China
Abstract Purpose: To explore the pattern of metastasis to level II nodes and its relationship with tumor range in nasopharyngeal carcinoma (NPC) patients by using magnetic resonance imaging. Methods and materials: Magnetic resonance images of 618 NPC patients were reviewed. Nodes were classified as metastatic based on size criteria, the presence of nodal necrosis, and extracapsular spread. Results: Patients (87.9%, 543) had lymphadenopathy, 470 (86.5%) in level IIb and 326 (60.0%) in level IIa, respectively. Incidence of RLN involvement was less than that of level IIb node involvement (72.2% vs. 86.5%) in 543 patients with lymphadenopathy. Cranial boundaries (71.1%) of level IIb nodes was below the caudal border of C1, and 5.1% was below the skull base, while all the cranial boundaries of level IIa nodes were below the caudal edge of C1. Incidence of level IIb and/or level IIa node metastasis had no correlation with primary tumor extension. Incidence of level IIb metastasis did not differ significantly among T1, 2, 3, and 4 disease, nor did that of level IIa node. Conclusions: Cervical level IIb nodes were the most commonly involved nodes in NPC. Metastasis to level IIb and level IIa nodes had no correlation with primary tumor extension, or with T stage. Setting the cranial border of level IIb node at the skull base should be considered when delineating nodal target volume. c 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 89 (2008) 28–32.
Keywords: Nasopharyngeal carcinoma; Level II lymph node; Magnetic resonance imaging; Radiotherapy
Nasopharyngeal carcinoma (NPC) is common among Asians, especially in southern China. The nasopharynx has a well-developed network of lymphatics and cervical lymphadenopathy is common in NPC. Most patients with NPC (60–90%) have nodal metastases at presentation on computed tomography (CT) or magnetic resonance (MR) imaging [1–7]. Because radiation therapy is the standard treatment of both the primary tumor and nodal metastases in NPC, the pattern of nodal spread has an important bearing on radiotherapy treatment planning. The retropharyngeal lymph nodes (RLNs) and cervical level II nodes have been reported to be the most commonly involved nodal regions [3–5,7]. Patterns of RLN metastasis from NPC have been thoroughly investigated [7–10]. Yet there is little published information concerning the locations of level II node metastasis and their relationship with tumor extensions in NPC. The cranial border of level II lymph nodes in published literature varied from boundaries of the transverse process of the atlas (C1), the top of corpus C1, or the bottom of the corpus C1 [11–13]. As there remained a call for standardization of target volume delineation, in 2003 a consensus guideline for delineation of the node levels in the node-negative neck was discussed and agreed with representatives of the major cooperative groups in Europe (DAHANCA, EORTC,
GORTEC) and in North America (NCIC, RTOG) [14]. According to the consensus guideline, the cranial border of the level II lymph nodes is set at the caudal edge of lateral process of C1. Caudally, level II is limited by the body of the hyoid bone. Anteriorly by the posterior edge of the submandibular gland, posteriorly by the posterior edge of the sternocleidomastoid (SCM) muscle, medially by the medial edge of the carotid artery and the paraspinal muscles (levator scapulae and splenius capitis), and laterally by the medial edge of the SCM and the platysma. Level II is further subdivided into two compartments, IIa and IIb, separated by the posterior edge of the internal jugular vein (IJV). The question remains whether these boundaries are related to clinical microscopic spread of the malignant cells. Investigating the pattern of macroscopic lymph node spread can reveal possible pathways of microscopic spread. Since level II node was regarded as the first-echelon node in NPC [10,15], and the majority of nodal recurrence developed at level II [16], we designed this study to analyze the incidence and distribution of level II node metastasis in a cohort of patients with NPC, and to examine via MR imaging the relationship of these metastases with primary tumor extension and T stage to document patterns of level II node spread.
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.07.014
X. Wang et al. / Radiotherapy and Oncology 89 (2008) 28–32
Table 1 Clinical characteristics of the 618 patients with NPC Characteristics
Number of patients (%)
Age (years) <35 35–60 P60
75 (12.1) 412 (66.7) 131 (21.2)
Gender Male Female
474 (76.7) 144 (23.3)
Pathologic feature WHO Type II WHO Type III
70 (11.3) 548 (88.7)
Treatment Radiotherapy alone Combined chemoradiotherapy
205 (33.2) 413 (66.8)
29
Nodes were considered to be metastatic in the presence of necrosis or extracapsular spread [3,9,15,17]. Any lateral RLN with a shortest axial diameter P5 mm was considered metastatic, and any visible node in the median retropharyngeal group was considered malignant [3]. Cervical nodes were considered metastatic if their shortest axial diameter was P10 mm, or if there was a group of three or more nodes that were borderline in size [17].
Statistical analysis All statistical analyses were performed using the SPSS software (version 10.0). The chi-square test was used to analyze the relationship between level II node metastasis and the extent of primary tumor. A two-tailed p value of <0.05 was considered statistically significant in all cases.
Results Methods and materials Patients From January 2005 to December 2006, 618 patients with pathologically confirmed NPC were treated at our hospital. All patients underwent pre-treatment evaluation that consisted of a complete history, physical examination, hematology and biochemistry profiles, MR scan of the nasopharynx and neck, chest radiography, and abdominal sonography, patients with T3 or T4 disease, low cervical metastasis, or a lymph node >4 cm in size also underwent whole-body bone scan. Disease was staged according to the 2002 American Joint Committee on Cancer (AJCC) staging system. Selected patient clinical characteristics are shown in Table 1.
Imaging protocol All MR images were acquired with a GE 1.5 T unit using a head and neck coil. The examined area extended from the suprasellar cistern to the inferior margin of the sternal end of the clavicle. T1-weighted fast spin-echo images in the axial and sagittal planes (repetition time [TR] 400– 500 ms and echo time [TE] 10–15 ms), and T2-weighted fast spin-echo images in the axial plane (TR 4000–5000 ms and TE 80–100 ms) were obtained before injection of contrast material. After intravenous injection of gadolinium-complexed diethylene triamine pentaacetic acid at a dose of 0.1 mmol/kg of body weight, T1-weighted fast spoiled gradient echo (FSPGR) fat-suppressed axial and coronal sequences were acquired (TR 150–250 ms and TE 2–10 ms). Section thickness was 6 mm with a 1-mm interslice gap for the axial plane, and 4 mm without interslice gap for the coronal and sagittal planes.
Image assessment All MR images were evaluated by all members of the NPC research group together, which included five radiation oncologists and two diagnostic radiologists. The location of the cranial border of all metastatic level II nodes was recorded along with the corresponding cervical vertebral level.
Incidence and distribution of metastatic nodes Of the 618 patients, 543 (87.8%) had nodal involvement. Of these 543 patients, 35 (6.5%) had RLN metastasis only, 150 (27.6%) had level II lymph nodes metastasis only, and 356 (65.6%) exhibited an involvement of both the RLNs and level II lymph nodes. The incidence of RLN metastasis was lower than that of level II lymphadenopathy (72.2% vs. 93.2%). The distribution of metastatic nodes in these 543 patients is shown in Table 2.
The cranial border of metastatic level II nodes The cranial borders of metastatic level II node are shown in Table 3. All lymphadenopathy at level IIa were below the caudal edge of C1. But out of the 470 patients with level IIb nodal metastasis, 112 (23.8%) patients’ cranial boundary extended beyond the caudal edge of C1, reaching half of C1, and 24 (5.1%) reached the skull base (Fig. 1).
Relationship between level IIb node metastasis and tumor involvement The relationship between level IIb node metastasis and extensions of primary tumor is shown in Table 4. Incidence of level IIb node involvement was not significantly higher in
Table 2 Distribution of metastatic nodes in 543 patients with NPC Nodes
Unilateral (%)
Bilateral (%)
Total (%)
Level I Level II Level IIa Level IIb Level III Level IV Level V Level VI Retropharyngeal Parotid
20 239 195 237 173 57 168
1 (0.2) 267 (49.2) 131 (24.1) 233 (42.9) 64 (11.8) 15 (2.8) 32 (5.9) 0 176 (32.4) 0
21 506 326 470 237 72 200
(3.7) (44.0) (35.9) (43.6) (31.9) (10.5) (30.9) 0 216 (39.8) 7 (1.3)
Note: Numbers in parentheses are percentages.
(3.9) (93.2) (60.0) (86.5) (43.7) (13.3) (36.8) 0 392 (72.2) 7 (1.3)
30
Level II node metastasis in NPC
Table 3 The cranial borders of metastatic level II node on MR imaging Location on MR
Skull base 1/2 of C1 Caudal edge of C1
Cranial border Level IIb
Level IIa
24 (5.1%) 112 (23.8%) 334 (71.1%)
0 0 326 (100%)
Abbreviations: C1 refers to the first cervical vertebrae.
cases of extension of the primary tumor to the parapharyngeal space, the nasal cavity, oropharynx, muscles of velum palatini, prevertebral muscle, pterygoid muscle, skull base, pterygopalatine fossa, paranasal sinuses, orbit, or intracranial area.
Relationship between level IIa node metastasis and tumor involvement The relationship between level IIa node metastasis and extensions of primary tumor is shown in Table 5. Incidence of level IIa node involvement was not significantly higher in cases of extension of the primary tumor to the parapharyngeal space, the nasal cavity, oropharynx, muscles of velum palatini, prevertebral muscle, pterygoid muscle, skull base, pterygopalatine fossa, paranasal sinuses, orbit, or intracranial area.
Relationship between level II node metastasis and T stage Incidence of level IIb and level IIa node metastasis in different T stage is shown in Table 6. The incidence of level IIb node involvement did not differ significantly among cases of T1, T2, T3, and T4 disease (p = 0.47, v2 = 2.49), nor did that of level IIa node involvement (p = 0.39, v2 = 2.85).
Discussion
Fig. 1. Coronal T1-weighted fast spoiled gradient echo contrast enhanced MR image obtained with fat suppression shows bilateral level IIb node metastasis. The cranial border of level IIb node reached the skull base in the right neck, and reached half of C1 in the left neck.
In this study of 618 patients with NPC, we found that 87.8% had nodal involvement at presentation. Cervical level IIb node was the most commonly involved nodal regions, followed by RLN, and then level IIa node. About 30% of the cranial border of level IIb node was beyond the caudal border of C1; however, all level IIa node was below the caudal border of C1. Level IIb and/or level IIa node metastasis did not correlate with the extension of primary tumor, nor with T stage.
Table 4 Relationship between level IIb node metastasis and extent of primary tumor Extent of primary tumor
Parapharyngeal space Muscles of velum palatini Oropharynx Nasal cavity Longus colli muscle Pterygoid muscles Base of the sphenoid bone Foramen lacerum Clivus Foramen ovale Apex of the petrous temporal bone Pterygopalatine fossa Greater wing of the sphenoid bone Paranasal sinus Orbit Cavernous sinus Note: Numbers in parentheses are percentages.
No. of patients with level IIb node metastasis (%) Site not involved
Site involved
v2 value
p value
243/317 251/329 439/575 386/502 307/407 419/544 392/510 383/503 329/433 400/519 363/476 437/576 392/517 384/495 454/599 415/540
227/301 (75.4) 219/289 (75.8) 31/43 (72.1) 84/116 (72.4) 163/211 (77.3) 51/74 (68.9) 78/108 (72.2) 87/115 (75.7) 141/185 (76.2) 70/99 (70.7) 107/142 (75.4) 33/42 (78.6) 78/101 (77.2) 86/123 (69.9) 16/19 (84.2) 55/78 (70.5)
0.131 0.022 0.131 1.038 0.253 2.348 1.054 0.012 0.004 1.849 0.050 0.157 0.092 3.171 0.716 1.504
0.718 0.881 0.718 0.308 0.615 0.125 0.305 0.911 0.950 0.174 0.824 0.892 0.762 0.075 0.397 0.220
(76.6) (76.3) (76.3) (76.9) (75.4) (77.0) (76.9) (76.1) (76.0) (77.1) (76.3) (75.9) (75.8) (77.6) (75.8) (76.8)
X. Wang et al. / Radiotherapy and Oncology 89 (2008) 28–32
31
Table 5 Relationship between level IIa node metastasis and extent of primary tumor Extent of primary tumor
No. of patients with level IIa node metastasis (%)
Parapharyngeal space Muscles of velum palatini Oropharynx Nasal cavity Longus colli muscle Pterygoid muscles Base of the sphenoid bone Foramen lacerum Clivus Foramen ovale Apex of the petrous temporal bone Pterygopalatine fossa Greater wing of the sphenoid bone Paranasal sinus Orbit Cavernous sinus
Site not involved
Site involved
v2 value
p value
169/317 172/329 299/575 268/502 209/407 291/544 269/510 270/503 233/433 279/519 254/476 306/576 280/517 261/495 315/599 290/540
157/301 (52.2) 154/289 (53.3) 27/43 (62.8) 58/116 (50.0) 117/211 (55.4) 35/74 (47.3) 57/108 (52.8) 56/115 (48.7) 93/185 (50.3) 47/99 (47.5) 72/142 (50.7) 20/42 (47.6) 46/101 (45.5) 65/123 (52.8) 11/19 (57.9) 36/78 (46.2)
0.082 0.063 1.869 0.434 0.937 1.003 0.001 0.932 0.698 1.012 0.310 0.476 2.515 0.001 0.208 1.5559
0.774 0.802 0.172 0.510 0.333 0.317 0.995 0.334 0.403 0.303 0.578 0.490 0.113 0.981 0.648 0.212
(53.3) (52.3) (51.9) (53.4) (51.4) (53.5) (52.7) (53.7) (53.8) (53.7) (53.4) (53.1) (54.2) (52.7) (52.6) (53.7)
Note: Numbers in parentheses are percentages.
Table 6 Relationship between level II node metastasis and T stage No. of patients (%)
IIb negative IIb positive IIa negative IIa positive
T1
T2
T3
T4
29/130 (22.3) 101/130 (77.7) 59/130 (45.4) 71/130 (54.6)
55/237 (23.2) 182/237 (76.8) 118/237 (49.8) 119/237 (50.2)
29/132 (22.0) 103/132 (78.0) 57/132 (43.2) 75/132 (56.8)
35/119 84/119 58/119 61/119
(29.4) (70.6) (48.7) (51.3)
Note: Numbers in parentheses are percentages.
The nasopharynx has a well-developed network of lymphatics and the primary drainage is the lateral pathway, which drains the lateral nasopharynx, and flows into the lateral half of the upper internal jugular chain or into the lateral RLN [18]. This indicates that both RLN and cervical level II nodes might be the first-echelon nodes in NPC [7]. King et al. regarded only RLN as first-echelon nodes in NPC [3]. Ng et al. reported that cervical level II nodes were the firstechelon nodes in NPC [15]. In this study, incidence of level IIb node metastasis was higher than that of RLN metastasis (93.2% vs. 72.2%). Previous studies have detailed the patterns of RLN metastasis and locations of metastatic RLN relative to the vertebral bodies [1,3,7,10]. Yet there is little published information concerning the locations of level II node metastasis and their relationship with tumor extensions in NPC. Because radiation therapy is the standard treatment of both the primary tumor and nodal metastases in NPC, the pattern of nodal spread has an important bearing on radiotherapy treatment planning. Adequate irradiation of the lymph nodes at risk is crucial for loco-regional control and survival. In recent years much attention has been paid to the development of target delineation guidelines. The cranial border of the level II lymph nodes mentioned in these
guidelines varied from boundaries of the transverse process of C1, the top of corpus C1, or the bottom of the corpus C1 [11–13]. In 2003, a consensus guideline for delineation of the node levels in the node-negative neck was reached by representatives of the major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG) [14]. According to the consensus guideline, the cranial border of the level II lymph nodes is set at the caudal edge of lateral process of C1, and were proposed for target volume delineation in the clinically negative neck for all head and neck primary sites. However, one may expect that different primary sites may be associated with different patterns of nodal spread. Whether these boundaries fully cover the lymphatic pathway of NPC need to be explored. Investigating the pattern of macroscopic lymph node spread can reveal possible pathways of microscopic spread. Braam et al. have described the cranial location of level II node in patients with head and neck cancer other than NPC [19,20]. In NPC patients included in this study, 23.8% of cranial boundary of level IIb node reached half of C1, and 5.1% reached the skull base among the 470 patients with level IIb nodal metastasis. But all level IIa nodes were below the caudal border of C1. So we infer that there are lymphatic pathways connecting nasopharynx and level IIb nodal
32
Level II node metastasis in NPC
region at C1 level, and that setting the caudal edge of lateral process of C1 as the cranial border of the level II lymph nodes cannot fully cover all the lymphatic pathways in the neck for NPC. Lymphatic drainage of carcinomas of the head and neck has been reported to associate with primary tumor location and adjacent subsites to which the tumor spread [21]. When the primary tumor invades beyond the confinement of the pharyngobasilar fascia, the risk of RLN metastasis increases [7,8]. In our previous study, we also found that the incidence of RLN metastasis was associated with tumor extension to the parapharyngeal space [10]. However, in this study, incidence of level IIb and/or level IIa node involvement was not significantly higher in cases of extension of the primary tumor to the parapharyngeal space, the nasal cavity, oropharynx, muscles of velum palatini, prevertebral muscle, pterygoid muscle, skull base, pterygopalatine fossa, paranasal sinuses, orbit, or intracranial area. Furthermore,we found no statistical difference between incidence of level IIb and/or level IIa node metastasis among patients with T1, T2, T3 and T4 disease. This pattern of nodal spread agreed with the routine practice that level IIb and level IIa lymph nodes were irradiated regardless of the primary tumor extension and stage [22–24]. In conclusion, cervical level II nodes are the most commonly involved nodal regions in NPC. Incidence of level IIb and level IIa node metastasis does not associate with primary tumor extension, nor with T stage. Based on our observation that about 30% of the cranial border of level IIb node was beyond the caudal border of C1, we infer that there may exist lymphatic pathway between the nasopharynx and the neck at C1 level, and setting the cranial border of level IIb node at the skull base should be considered when delineating nodal target volume for NPC. * Corresponding author. ChaoSu Hu, Department of Radiation Oncology, Cancer Hospital, Fudan University, 270 Dong’an Road, Shanghai 200032, People’s Republic of China E-mail address: [email protected] Received 3 May 2008; received in revised form 27 June 2008; accepted 16 July 2008; Available online 1 September 2008
References [1] Chong VF, Fan YF, Khoo JB. Retropharyngeal lymphadenopathy in nasopharyngeal carcinoma. Eur J Radiol 1995;21:100–5. [2] Ng SH, Chang TC, Ko SF, et al. Nasopharyngeal carcinoma: MRI and CT assessment. Neuroradiology 1997;39:741–6. [3] King AD, Ahuja AT, Leung SF, et al. Neck node metastases from nasopharyngeal carcinoma: MRI of patterns of disease. Head Neck 2000;22:275–81. [4] Wang XS, Hu CS, Wu YR, et al. Analysis of computed tomography-based distribution of metastatic cervical nodes in 218 cases of nasopharyngeal carcinoma. Ai Zheng 2004;23:1056–9. [5] Sham JST, Cheung YK, Choy D, et al. Computed tomography evaluation of neck node metastases from nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1993;26:787–92. [6] Kao CH, Hsieh JF, Tsai SC, et al. Comparison of 18F-2-fluoro-2deoxyglucose positron emission tomography and computed tomography in detection of cervical lymph node metastases of nasopharyngeal carcinoma. Ann Otol Rhinol Laryngol 2000;109:1130–4.
[7] Liu LZ, Zhang GY, Xie CM, Liu XW, Cui CY, Li L. Magnetic resonance imaging of retropharyngeal lymph node metastasis in nasopharyngeal carcinoma: patterns of spread. Int J Radiat Oncol Biol Phys 2006;66:721–30. [8] Chua DTT, Sham JST, Kwong DLW, et al. Retropharyngeal lymphadenopathy in patients with nasopharyngeal carcinoma. Cancer 1997;79:869–77. [9] Lam WW, Chan YL, Leung SF, et al. Retropharyngeal lymphadenopathy in nasopharyngeal carcinoma. Head Neck 1997;19:176–81. [10] Wang XS, Hu CS, Ying HM, Zhou ZR, Ding JH, Feng Y. Patterns of retro- pharyngeal node metastasis in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2008 Jun 4. [Epub ahead of print]. [11] Gregoire V, Coche E, Cosnard G, et al. Selection and delineation of lymph node target volumes in head and neck conformal radiotherapy. Proposal for standardizing terminology and procedure based on the surgical experience. Radiother Oncol 2000;56:135–50. [12] Nowak PJ, Wijers OB, Lagerwaard FJ, et al. A three-dimensional CT-based target definition for elective irradiation of the neck. Int J Radiat Oncol Biol Phys 1999;45:33–9. [13] Shah JP, Medina JE, Shaha AR, et al. Cervical lymph node metastasis. Curr Probl Surg 1993;30:1–335. [14] Gregoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol 2003;69:227–36. [15] Ng SH, Chang JT, Chan SC, et al. Nodal metastases of nasopharyngeal carcinoma: patterns of disease on MRI and FDG PET. Eur J Nucl Med Mol Imaging 2004;31: 1073–80. [16] Khoo ML, Soo KC, Lim DT, Fong KW, Goh CH, Sethi DS. The pattern of nodal recurrence following definitive radiotherapy for nasopharyngeal carcinoma. Aust N Z J Surg 1999;69:354–6. [17] Van den Brekel MWM, Stel HV, Castelijns JA, et al. Cervical lymph node metastasis: assessment of radiologic criteria. Radiology 1990;177:379–84. [18] Sobin LH, Wittekind CH. International Union Against Cancer (UICC): TNM classification of malignant tumours. 5th ed. New York: Wiley; 1997. [19] Prins-Braam PM, Raaijmakers CP, Terhaard CH. Location of cervical lymph node metastases in oropharyngeal and hypopharyngeal carcinoma: implications for cranial border of elective nodal target volumes. Int J Radiat Oncol Biol Phys 2004;58:132–8. [20] Braam PM, Raaijmakers CP, Terhaard CH. Cranial location of level II lymph nodes in laryngeal cancer: implications for elective nodal target volume delineation. Int J Radiat Oncol Biol Phys 2007;67:462–8. [21] Mukherji SK, Armao D, Joshi VM. Cervical nodal metastases in squamous cell carcinoma of the head and neck: what to expect. Head Neck 2001;23:995–1005. [22] Eisbruch A, Foote RL, O’Sullivan B, Beitler JJ, Vikram B. Intensity-modulated radiation therapy for head and neck cancer: emphasis on the selection and delineation of the targets. Semin Radiat Oncol 2002;12:238–49. [23] Kam MK, Teo PM, Chau RM, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. Int J Radiat Oncol Biol Phys 2004;60:1440–50. [24] Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function. Cancer 2004;101:1584–93.
Node metastasis in NPC
Patterns of level II node metastasis in nasopharyngeal carcinoma XiaoShen Wanga, LongGen Lia, ChaoSu Hua,*, ZhengRong Zhoub, HongMei Yinga, JianHui Dingb, Yan Fenga a
Department of Radiation Oncology, and bDepartment of Diagnostic Radiology, Fudan University, Shanghai, People’s Republic of China
Abstract Purpose: To explore the pattern of metastasis to level II nodes and its relationship with tumor range in nasopharyngeal carcinoma (NPC) patients by using magnetic resonance imaging. Methods and materials: Magnetic resonance images of 618 NPC patients were reviewed. Nodes were classified as metastatic based on size criteria, the presence of nodal necrosis, and extracapsular spread. Results: Patients (87.9%, 543) had lymphadenopathy, 470 (86.5%) in level IIb and 326 (60.0%) in level IIa, respectively. Incidence of RLN involvement was less than that of level IIb node involvement (72.2% vs. 86.5%) in 543 patients with lymphadenopathy. Cranial boundaries (71.1%) of level IIb nodes was below the caudal border of C1, and 5.1% was below the skull base, while all the cranial boundaries of level IIa nodes were below the caudal edge of C1. Incidence of level IIb and/or level IIa node metastasis had no correlation with primary tumor extension. Incidence of level IIb metastasis did not differ significantly among T1, 2, 3, and 4 disease, nor did that of level IIa node. Conclusions: Cervical level IIb nodes were the most commonly involved nodes in NPC. Metastasis to level IIb and level IIa nodes had no correlation with primary tumor extension, or with T stage. Setting the cranial border of level IIb node at the skull base should be considered when delineating nodal target volume. c 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 89 (2008) 28–32.
Keywords: Nasopharyngeal carcinoma; Level II lymph node; Magnetic resonance imaging; Radiotherapy
Nasopharyngeal carcinoma (NPC) is common among Asians, especially in southern China. The nasopharynx has a well-developed network of lymphatics and cervical lymphadenopathy is common in NPC. Most patients with NPC (60–90%) have nodal metastases at presentation on computed tomography (CT) or magnetic resonance (MR) imaging [1–7]. Because radiation therapy is the standard treatment of both the primary tumor and nodal metastases in NPC, the pattern of nodal spread has an important bearing on radiotherapy treatment planning. The retropharyngeal lymph nodes (RLNs) and cervical level II nodes have been reported to be the most commonly involved nodal regions [3–5,7]. Patterns of RLN metastasis from NPC have been thoroughly investigated [7–10]. Yet there is little published information concerning the locations of level II node metastasis and their relationship with tumor extensions in NPC. The cranial border of level II lymph nodes in published literature varied from boundaries of the transverse process of the atlas (C1), the top of corpus C1, or the bottom of the corpus C1 [11–13]. As there remained a call for standardization of target volume delineation, in 2003 a consensus guideline for delineation of the node levels in the node-negative neck was discussed and agreed with representatives of the major cooperative groups in Europe (DAHANCA, EORTC,
GORTEC) and in North America (NCIC, RTOG) [14]. According to the consensus guideline, the cranial border of the level II lymph nodes is set at the caudal edge of lateral process of C1. Caudally, level II is limited by the body of the hyoid bone. Anteriorly by the posterior edge of the submandibular gland, posteriorly by the posterior edge of the sternocleidomastoid (SCM) muscle, medially by the medial edge of the carotid artery and the paraspinal muscles (levator scapulae and splenius capitis), and laterally by the medial edge of the SCM and the platysma. Level II is further subdivided into two compartments, IIa and IIb, separated by the posterior edge of the internal jugular vein (IJV). The question remains whether these boundaries are related to clinical microscopic spread of the malignant cells. Investigating the pattern of macroscopic lymph node spread can reveal possible pathways of microscopic spread. Since level II node was regarded as the first-echelon node in NPC [10,15], and the majority of nodal recurrence developed at level II [16], we designed this study to analyze the incidence and distribution of level II node metastasis in a cohort of patients with NPC, and to examine via MR imaging the relationship of these metastases with primary tumor extension and T stage to document patterns of level II node spread.
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.07.014
X. Wang et al. / Radiotherapy and Oncology 89 (2008) 28–32
Table 1 Clinical characteristics of the 618 patients with NPC Characteristics
Number of patients (%)
Age (years) <35 35–60 P60
75 (12.1) 412 (66.7) 131 (21.2)
Gender Male Female
474 (76.7) 144 (23.3)
Pathologic feature WHO Type II WHO Type III
70 (11.3) 548 (88.7)
Treatment Radiotherapy alone Combined chemoradiotherapy
205 (33.2) 413 (66.8)
29
Nodes were considered to be metastatic in the presence of necrosis or extracapsular spread [3,9,15,17]. Any lateral RLN with a shortest axial diameter P5 mm was considered metastatic, and any visible node in the median retropharyngeal group was considered malignant [3]. Cervical nodes were considered metastatic if their shortest axial diameter was P10 mm, or if there was a group of three or more nodes that were borderline in size [17].
Statistical analysis All statistical analyses were performed using the SPSS software (version 10.0). The chi-square test was used to analyze the relationship between level II node metastasis and the extent of primary tumor. A two-tailed p value of <0.05 was considered statistically significant in all cases.
Results Methods and materials Patients From January 2005 to December 2006, 618 patients with pathologically confirmed NPC were treated at our hospital. All patients underwent pre-treatment evaluation that consisted of a complete history, physical examination, hematology and biochemistry profiles, MR scan of the nasopharynx and neck, chest radiography, and abdominal sonography, patients with T3 or T4 disease, low cervical metastasis, or a lymph node >4 cm in size also underwent whole-body bone scan. Disease was staged according to the 2002 American Joint Committee on Cancer (AJCC) staging system. Selected patient clinical characteristics are shown in Table 1.
Imaging protocol All MR images were acquired with a GE 1.5 T unit using a head and neck coil. The examined area extended from the suprasellar cistern to the inferior margin of the sternal end of the clavicle. T1-weighted fast spin-echo images in the axial and sagittal planes (repetition time [TR] 400– 500 ms and echo time [TE] 10–15 ms), and T2-weighted fast spin-echo images in the axial plane (TR 4000–5000 ms and TE 80–100 ms) were obtained before injection of contrast material. After intravenous injection of gadolinium-complexed diethylene triamine pentaacetic acid at a dose of 0.1 mmol/kg of body weight, T1-weighted fast spoiled gradient echo (FSPGR) fat-suppressed axial and coronal sequences were acquired (TR 150–250 ms and TE 2–10 ms). Section thickness was 6 mm with a 1-mm interslice gap for the axial plane, and 4 mm without interslice gap for the coronal and sagittal planes.
Image assessment All MR images were evaluated by all members of the NPC research group together, which included five radiation oncologists and two diagnostic radiologists. The location of the cranial border of all metastatic level II nodes was recorded along with the corresponding cervical vertebral level.
Incidence and distribution of metastatic nodes Of the 618 patients, 543 (87.8%) had nodal involvement. Of these 543 patients, 35 (6.5%) had RLN metastasis only, 150 (27.6%) had level II lymph nodes metastasis only, and 356 (65.6%) exhibited an involvement of both the RLNs and level II lymph nodes. The incidence of RLN metastasis was lower than that of level II lymphadenopathy (72.2% vs. 93.2%). The distribution of metastatic nodes in these 543 patients is shown in Table 2.
The cranial border of metastatic level II nodes The cranial borders of metastatic level II node are shown in Table 3. All lymphadenopathy at level IIa were below the caudal edge of C1. But out of the 470 patients with level IIb nodal metastasis, 112 (23.8%) patients’ cranial boundary extended beyond the caudal edge of C1, reaching half of C1, and 24 (5.1%) reached the skull base (Fig. 1).
Relationship between level IIb node metastasis and tumor involvement The relationship between level IIb node metastasis and extensions of primary tumor is shown in Table 4. Incidence of level IIb node involvement was not significantly higher in
Table 2 Distribution of metastatic nodes in 543 patients with NPC Nodes
Unilateral (%)
Bilateral (%)
Total (%)
Level I Level II Level IIa Level IIb Level III Level IV Level V Level VI Retropharyngeal Parotid
20 239 195 237 173 57 168
1 (0.2) 267 (49.2) 131 (24.1) 233 (42.9) 64 (11.8) 15 (2.8) 32 (5.9) 0 176 (32.4) 0
21 506 326 470 237 72 200
(3.7) (44.0) (35.9) (43.6) (31.9) (10.5) (30.9) 0 216 (39.8) 7 (1.3)
Note: Numbers in parentheses are percentages.
(3.9) (93.2) (60.0) (86.5) (43.7) (13.3) (36.8) 0 392 (72.2) 7 (1.3)
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Level II node metastasis in NPC
Table 3 The cranial borders of metastatic level II node on MR imaging Location on MR
Skull base 1/2 of C1 Caudal edge of C1
Cranial border Level IIb
Level IIa
24 (5.1%) 112 (23.8%) 334 (71.1%)
0 0 326 (100%)
Abbreviations: C1 refers to the first cervical vertebrae.
cases of extension of the primary tumor to the parapharyngeal space, the nasal cavity, oropharynx, muscles of velum palatini, prevertebral muscle, pterygoid muscle, skull base, pterygopalatine fossa, paranasal sinuses, orbit, or intracranial area.
Relationship between level IIa node metastasis and tumor involvement The relationship between level IIa node metastasis and extensions of primary tumor is shown in Table 5. Incidence of level IIa node involvement was not significantly higher in cases of extension of the primary tumor to the parapharyngeal space, the nasal cavity, oropharynx, muscles of velum palatini, prevertebral muscle, pterygoid muscle, skull base, pterygopalatine fossa, paranasal sinuses, orbit, or intracranial area.
Relationship between level II node metastasis and T stage Incidence of level IIb and level IIa node metastasis in different T stage is shown in Table 6. The incidence of level IIb node involvement did not differ significantly among cases of T1, T2, T3, and T4 disease (p = 0.47, v2 = 2.49), nor did that of level IIa node involvement (p = 0.39, v2 = 2.85).
Discussion
Fig. 1. Coronal T1-weighted fast spoiled gradient echo contrast enhanced MR image obtained with fat suppression shows bilateral level IIb node metastasis. The cranial border of level IIb node reached the skull base in the right neck, and reached half of C1 in the left neck.
In this study of 618 patients with NPC, we found that 87.8% had nodal involvement at presentation. Cervical level IIb node was the most commonly involved nodal regions, followed by RLN, and then level IIa node. About 30% of the cranial border of level IIb node was beyond the caudal border of C1; however, all level IIa node was below the caudal border of C1. Level IIb and/or level IIa node metastasis did not correlate with the extension of primary tumor, nor with T stage.
Table 4 Relationship between level IIb node metastasis and extent of primary tumor Extent of primary tumor
Parapharyngeal space Muscles of velum palatini Oropharynx Nasal cavity Longus colli muscle Pterygoid muscles Base of the sphenoid bone Foramen lacerum Clivus Foramen ovale Apex of the petrous temporal bone Pterygopalatine fossa Greater wing of the sphenoid bone Paranasal sinus Orbit Cavernous sinus Note: Numbers in parentheses are percentages.
No. of patients with level IIb node metastasis (%) Site not involved
Site involved
v2 value
p value
243/317 251/329 439/575 386/502 307/407 419/544 392/510 383/503 329/433 400/519 363/476 437/576 392/517 384/495 454/599 415/540
227/301 (75.4) 219/289 (75.8) 31/43 (72.1) 84/116 (72.4) 163/211 (77.3) 51/74 (68.9) 78/108 (72.2) 87/115 (75.7) 141/185 (76.2) 70/99 (70.7) 107/142 (75.4) 33/42 (78.6) 78/101 (77.2) 86/123 (69.9) 16/19 (84.2) 55/78 (70.5)
0.131 0.022 0.131 1.038 0.253 2.348 1.054 0.012 0.004 1.849 0.050 0.157 0.092 3.171 0.716 1.504
0.718 0.881 0.718 0.308 0.615 0.125 0.305 0.911 0.950 0.174 0.824 0.892 0.762 0.075 0.397 0.220
(76.6) (76.3) (76.3) (76.9) (75.4) (77.0) (76.9) (76.1) (76.0) (77.1) (76.3) (75.9) (75.8) (77.6) (75.8) (76.8)
X. Wang et al. / Radiotherapy and Oncology 89 (2008) 28–32
31
Table 5 Relationship between level IIa node metastasis and extent of primary tumor Extent of primary tumor
No. of patients with level IIa node metastasis (%)
Parapharyngeal space Muscles of velum palatini Oropharynx Nasal cavity Longus colli muscle Pterygoid muscles Base of the sphenoid bone Foramen lacerum Clivus Foramen ovale Apex of the petrous temporal bone Pterygopalatine fossa Greater wing of the sphenoid bone Paranasal sinus Orbit Cavernous sinus
Site not involved
Site involved
v2 value
p value
169/317 172/329 299/575 268/502 209/407 291/544 269/510 270/503 233/433 279/519 254/476 306/576 280/517 261/495 315/599 290/540
157/301 (52.2) 154/289 (53.3) 27/43 (62.8) 58/116 (50.0) 117/211 (55.4) 35/74 (47.3) 57/108 (52.8) 56/115 (48.7) 93/185 (50.3) 47/99 (47.5) 72/142 (50.7) 20/42 (47.6) 46/101 (45.5) 65/123 (52.8) 11/19 (57.9) 36/78 (46.2)
0.082 0.063 1.869 0.434 0.937 1.003 0.001 0.932 0.698 1.012 0.310 0.476 2.515 0.001 0.208 1.5559
0.774 0.802 0.172 0.510 0.333 0.317 0.995 0.334 0.403 0.303 0.578 0.490 0.113 0.981 0.648 0.212
(53.3) (52.3) (51.9) (53.4) (51.4) (53.5) (52.7) (53.7) (53.8) (53.7) (53.4) (53.1) (54.2) (52.7) (52.6) (53.7)
Note: Numbers in parentheses are percentages.
Table 6 Relationship between level II node metastasis and T stage No. of patients (%)
IIb negative IIb positive IIa negative IIa positive
T1
T2
T3
T4
29/130 (22.3) 101/130 (77.7) 59/130 (45.4) 71/130 (54.6)
55/237 (23.2) 182/237 (76.8) 118/237 (49.8) 119/237 (50.2)
29/132 (22.0) 103/132 (78.0) 57/132 (43.2) 75/132 (56.8)
35/119 84/119 58/119 61/119
(29.4) (70.6) (48.7) (51.3)
Note: Numbers in parentheses are percentages.
The nasopharynx has a well-developed network of lymphatics and the primary drainage is the lateral pathway, which drains the lateral nasopharynx, and flows into the lateral half of the upper internal jugular chain or into the lateral RLN [18]. This indicates that both RLN and cervical level II nodes might be the first-echelon nodes in NPC [7]. King et al. regarded only RLN as first-echelon nodes in NPC [3]. Ng et al. reported that cervical level II nodes were the firstechelon nodes in NPC [15]. In this study, incidence of level IIb node metastasis was higher than that of RLN metastasis (93.2% vs. 72.2%). Previous studies have detailed the patterns of RLN metastasis and locations of metastatic RLN relative to the vertebral bodies [1,3,7,10]. Yet there is little published information concerning the locations of level II node metastasis and their relationship with tumor extensions in NPC. Because radiation therapy is the standard treatment of both the primary tumor and nodal metastases in NPC, the pattern of nodal spread has an important bearing on radiotherapy treatment planning. Adequate irradiation of the lymph nodes at risk is crucial for loco-regional control and survival. In recent years much attention has been paid to the development of target delineation guidelines. The cranial border of the level II lymph nodes mentioned in these
guidelines varied from boundaries of the transverse process of C1, the top of corpus C1, or the bottom of the corpus C1 [11–13]. In 2003, a consensus guideline for delineation of the node levels in the node-negative neck was reached by representatives of the major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG) [14]. According to the consensus guideline, the cranial border of the level II lymph nodes is set at the caudal edge of lateral process of C1, and were proposed for target volume delineation in the clinically negative neck for all head and neck primary sites. However, one may expect that different primary sites may be associated with different patterns of nodal spread. Whether these boundaries fully cover the lymphatic pathway of NPC need to be explored. Investigating the pattern of macroscopic lymph node spread can reveal possible pathways of microscopic spread. Braam et al. have described the cranial location of level II node in patients with head and neck cancer other than NPC [19,20]. In NPC patients included in this study, 23.8% of cranial boundary of level IIb node reached half of C1, and 5.1% reached the skull base among the 470 patients with level IIb nodal metastasis. But all level IIa nodes were below the caudal border of C1. So we infer that there are lymphatic pathways connecting nasopharynx and level IIb nodal
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Level II node metastasis in NPC
region at C1 level, and that setting the caudal edge of lateral process of C1 as the cranial border of the level II lymph nodes cannot fully cover all the lymphatic pathways in the neck for NPC. Lymphatic drainage of carcinomas of the head and neck has been reported to associate with primary tumor location and adjacent subsites to which the tumor spread [21]. When the primary tumor invades beyond the confinement of the pharyngobasilar fascia, the risk of RLN metastasis increases [7,8]. In our previous study, we also found that the incidence of RLN metastasis was associated with tumor extension to the parapharyngeal space [10]. However, in this study, incidence of level IIb and/or level IIa node involvement was not significantly higher in cases of extension of the primary tumor to the parapharyngeal space, the nasal cavity, oropharynx, muscles of velum palatini, prevertebral muscle, pterygoid muscle, skull base, pterygopalatine fossa, paranasal sinuses, orbit, or intracranial area. Furthermore,we found no statistical difference between incidence of level IIb and/or level IIa node metastasis among patients with T1, T2, T3 and T4 disease. This pattern of nodal spread agreed with the routine practice that level IIb and level IIa lymph nodes were irradiated regardless of the primary tumor extension and stage [22–24]. In conclusion, cervical level II nodes are the most commonly involved nodal regions in NPC. Incidence of level IIb and level IIa node metastasis does not associate with primary tumor extension, nor with T stage. Based on our observation that about 30% of the cranial border of level IIb node was beyond the caudal border of C1, we infer that there may exist lymphatic pathway between the nasopharynx and the neck at C1 level, and setting the cranial border of level IIb node at the skull base should be considered when delineating nodal target volume for NPC. * Corresponding author. ChaoSu Hu, Department of Radiation Oncology, Cancer Hospital, Fudan University, 270 Dong’an Road, Shanghai 200032, People’s Republic of China E-mail address: [email protected] Received 3 May 2008; received in revised form 27 June 2008; accepted 16 July 2008; Available online 1 September 2008
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