Ann Surg Oncol (2012) 19:1995–2002 DOI 10.1245/s10434-011-2182-5
ORIGINAL ARTICLE – HEAD AND NECK ONCOLOGY
Treatment for T1-2 Oral Squamous Cell Carcinoma with or Without Perineural Invasion: Neck Dissection and Postoperative Adjuvant Therapy Shyh-Kuan Tai, MD1,2,3, Wing-Yin Li, MD4, Muh-Hwa Yang, MD2,5, Shyue-Yih Chang, MD1,2, Pen-Yuan Chu, MD2, Tung-Lung Tsai, MD2, Yi-Fen Wang, MD2, and Peter Mu-Hsin Chang, MD2,5 Department of Otolaryngology, National Yang-Ming University, Taipei, Taiwan; 2Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan; 3Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 4Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan; 5Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 1
ABSTRACT Background. Although perineural invasion (PNI) has been a poor prognostic factor for head and neck cancers, few studies have focused on oral squamous cell carcinoma (OSCC). The independent significance of PNI in early T1-2 OSCC and the benefit of treatment modification based on PNI status have not been assessed. This study investigated the role of PNI in T1-2 OSCC patients, with focus on the controversial issues of neck management and postoperative adjuvant therapy. Methods. PNI status was re-reviewed under hematoxylin and eosin staining in tumors of 307 consecutive T1-2 OSCC patients. Oncologic and survival outcomes were analyzed by univariate and multivariate analyses. Results. PNI was identified in 84 (27.4%) patients, correlating with several established poor prognostic factors. In multivariate analysis, PNI remained an independent predictor for neck metastasis, neck recurrence, and a worse 5-year disease-specific survival. Elective neck dissection contributed to a significantly better 5-year disease-specific survival only in cN0 patients with PNI-positive tumors (P = 0.0071) but not in those with PNI-negative tumors (P = 0.3566). In low-risk patients who were treated by surgery alone, including neck dissection, the 5-year disease-specific survival rates were almost the same in those
Ó Society of Surgical Oncology 2011 First Received: 1 September 2011; Published Online: 28 December 2011 S.-K. Tai, MD e-mail:
[email protected];
[email protected]
with PNI-positive tumors and those with PNI-negative tumors (92.0 vs. 92.9%; P = 0.9104). Conclusions. Elective neck dissection is indicated for cN0 patients with PNI-positive tumors for the efficacy of improving disease-specific survival as well as neck control. However, low-risk PNI-positive patients who undergo neck dissection do not need postoperative adjuvant therapy, because the residual risk from PNI is minimal.
INTRODUCTION Surgery is the mainstay of treatment for T1-2 oral squamous cell carcinoma (OSCC). Two common controversial issues for early OSCC are the management of clinical N0 (cN0) neck and the necessity of postoperative adjuvant therapy. Because neck metastasis and neck recurrence both indicate poor prognosis and occult neck metastasis rates can be as much as 15–40 percent, elective neck dissection (END) is widely performed for T1-2 OSCC with cN0 neck.1–3 However, most reported series demonstrate no survival benefit from END.4–7 Postoperative adjuvant therapy is the standard of care for patients at high risk for recurrence, such as those who have positive margin, advanced neck disease (N2–3), or extracapsular spread (ECS).8,9 In addition, worrisome pathologic features, such as perineural invasion (PNI), also have served as the bases for selecting patients for postoperative adjuvant therapy.10,11 PNI is a distinct pathologic feature characterized by the presence of tumor cells in the perineural space.12 It has gained recognition as a marker of poor prognosis not only in head and neck cancers (HNCs),13,14 but also in pancreatic, prostatic, and colorectal cancers.15–18 In HNCs,
1996
aggressive treatment has been advocated at the presence of PNI, including neck dissection, postoperative adjuvant radiotherapy, or even chemoradiotherapy.11,19,20 In the National Comprehensive Cancer Network (NCCN) guidelines for HNCs, PNI is regarded as an adverse feature to recommend postoperative adjuvant therapy.21 Reporting PNI has been a standard in pathology reports for OSCC.22 However, many guideline recommendations continue to be debated because of lack of scientific evidence despite good consensus.23 The impacts of PNI on oncologic outcomes and survival have not been clarified for different subsites and stages of HNCs.24–28 Few previous studies have focused specifically on PNI in OSCC, and most did not evaluate the independent significance. It has never been assessed in detail whether the risk of PNI can be effectively rescued by any treatment modification for OSCC.17 This study was designed to determine the impact of PNI in guiding neck management and postoperative adjuvant therapy for T1-2 OSCC to better understand and properly apply this widely used pathologic parameter. PATIENTS AND METHODS Patient Population From June 2001 to Jan 2009, 332 consecutive patients with newly diagnosed T1-2 OSCC underwent surgery at the Department of Otolaryngology, Taipei Veterans General Hospital. Fifteen patients were excluded for synchronous primary cancers or previous cancer history within 2 years. Another ten patients were excluded because pathologic slides were not available for review. The demographic data of the remaining 307 patients were recruited from a comprehensive database. Data from medical records also were reviewed in detail and updated by a surgical oncologist. If patients were lost to follow-up for more than 1 year, they or their families were contacted. The hospital’s institutional review board approved the study protocol. Assessment of Tumor Stage and Risk of Recurrence Elective neck dissection, level I to III, at the time of tumor resection has been a general policy for cN0 neck management at our institute, and therapeutic neck dissection has been routinely performed for clinically positive neck (cN?). Tumor stage was determined by the multidisciplinary head and neck cancer tumor board according to the 2002 sixth edition of the American Joint Commission on Cancer TNM system. Tumor thickness was measured from the tumor surface or ulcer base to the deepest point of invasion.29 Resection margin were classified as ‘‘free,’’ ‘‘close or dysplasia,’’ and ‘‘positive.’’
S.-K. Tai et al.
Tumor cells within 2 mm of microscopic margins were classified as ‘‘close.’’ The presence of tumor cells at the microscopic margins was classified as positive, whereas ‘‘free’’ and ‘‘close or dysplasia’’ margins were classified as negative. Postoperative adjuvant therapy was given mainly for high-risk patients, defined in this study as those who had any of the following features: positive margin, N2-3 disease, or ECS. Low-risk patients were those who had negative margin, N0-1 disease, and no ECS. Histopathologic Analysis Because PNI status was not routinely reported at our institute before 2003, we collected the original hematoxylin and eosin (H&E)-stained slides of tumor resections of each patient from the pathology department. A senior pathologist with expertise to PNI who was blinded to clinical data re-reviewed all of the slides. PNI and lymphovascular invasion (LVI) were identified throughout the whole area of tumor sections, serially under 940 or 9100 magnification, and confirmed under 9200 magnification. PNI was defined as positive when tumor cell infiltration was identified in any layer of the nerve sheath, or tumor in close proximity involving more than one third of the nerve circumference.17 LVI was defined as the detection of tumor cell infiltration in endothelial-lined vessels or tumor nests within or attached to the endothelial cell lining of the lymphovascular space. Statistical Analysis The endpoints of interest were the association between PNI and neck metastasis, local/regional recurrence, and survival. The association of PNI with clinicopathologic characteristics was assessed using Pearson chi-square or Fisher’s exact tests. The independent effect was analyzed by binary logistic regression models. In survival analysis, follow-up time was defined as the interval between the date of surgery and events or last contact. Disease-specific death was defined as death from the index tumor or treatmentrelated events. The influence of PNI on survival was estimated by using the Kaplan-Meier method and was compared by using the log-rank test. The Cox’s proportional hazards model was applied to test the independent significance. Only significant variables in univariate analyses were selected for multivariate regression models. All analyses were performed using the Statistical Package of Social Sciences software version 17.0 (SPSS, Inc., Chicago, IL). All tests were two-sided, and results were considered significant at P \ 0.05.
Perineural Invasion in T1-2 OSCC
1997
RESULTS
TABLE 1 Disease-specific survival and overall survival of 307 T1-2 OSCC patients
Clinicopathologic Characteristics
Characteristic
The clinicopathologic characteristics are listed in Table 1; 264 patients (86%) were cN0 at initial diagnosis, 170 (64.4%) of them underwent END, and 94 (35.6%) underwent observation. After pathologic re-review, PNI was identified in 84 patients (27.4%), and LVI was identified in 64 patients (20.8%). ECS was observed in 30 (39.0%) of the 77 patients with histologic neck metastasis after neck dissection. According our criteria, 68 patients (22.1%) were grouped as high-risk, whereas the remaining 239 patients (77.9%) were grouped as low-risk. Adjuvant RT or CRT was performed in 62 patients (20.2%), 50 (80.6%) of them belonged to the high-risk group. The RT dose (1.8–2 Gy per day) delivered to the primary and/or positive neck was 62.8 ± 3.55 Gy (mean ± SD) and 62 ± 2.83 Gy for patients with and without PNI, respectively. Platinum-based chemotherapy was added commonly after 2004 in 40 patients, generally based on tumor staging and the presence of adverse clinicopathologic features. Median follow-up time for surviving patients was 49.1 (range, 16–116) months. Patients who underwent observation for cN0 neck but developed neck recurrence within 2 years were considered positive for neck metastasis. Ultimately, 206 patients (67.1%) were assigned as negative for neck metastasis in this study. Local recurrence occurred in 46 patients (15%), and neck recurrence occurred in 45 patients (14.7%). Distant metastasis developed in 20 patients (6.5%), but 19 (95%) of them were associated with locoregional recurrence. Second primary cancers developed in 45 patients (14.7%), and 41 (93.2%) of them occurred in the head and neck. PNI Independently Predicted Neck Metastasis
5-year DSS %
All patients
307 100
B54 [54
172 135
56 44
Female
83.1 84
87
83.3
40
13
82.9
Subsites Floor of mouth
0.3819 78.8 79
0.9746 267
0.5865 78.7 78.3
0.3425
0.3369
15
4.9 82.5
75.7
Tongue
164
53.4 85.5
82.3
Buccal
93
30.3 83.1
74.7
Retromolar
18
5.9 80.2
74.5
Hard palate
12
3.9 60.6
60.6
1.7 75
75
Others
5
T classification
0.0063
T1
146
47.6 89.5
T2
161
52.4 78.0
cN classification cN0
0.0002 87.6 71.1
\0.0001 264
86
\0.0001
88.3
83.9
cN1
21
6.8 54.8
46.5
cN2
22
7.2 49.5
47.1
Neck management Neck dissection Observation
0.7587 213 94
69.4 84
0.6692 79.7
30.6 81.4
75.4 \0.0001
pN classification
\ 0.0001
pN0
136
44.3 96.6
91.8
pN1
30
9.8 69.4
66.7
pN2
47
15.3 53.6
50.6
pNxa
94
30.6 82.4
Resection margin
76.4 0.013
0.0053
230
74.9 85.6
81.2
Close/dysplasia
55
17.9 82.9
79.2
Positive
22
7.2 58.8
Tumor thickness (mm) B2
52.3 0.1194
0.0123
20
6.5 75
2–5
115
37.5 88.2
86.1
5–7
48
15.6 85.7
82.4
7–10
61
19.9 82
71.1
[10
63
20.5 75.4
Well
70
71.3 \0.0001
Differentiation 204
0.0032
66.4 87
80.6
Moderate
72
23.5 83.5
82.1
Poor
31
10.1 57.8
59.6
No
223
72.6 88.1
82.9
Yes
84
27.4 70.4
68
\0.0001
Perineural invasion
P value
78.5 0.8589
Sex Male
5-year OS
P value %
83.3
Age (mean 54 year)
Free
The presence of PNI correlated with several poor prognostic factors, as shown in Table 2. PNI was associated with a larger tumor size determined by T2 tumors or increased tumor thickness (P \ 0.001), but it was not associated with positive margins (P = 0.453). PNI also correlated with several adverse pathologic features, including less differentiation (P = 0.013), the presence of LVI (P \ 0.001), and ECS (P = 0.001). Thus, PNI-positive rates were nearly threefold higher among high-risk patients versus low-risk patients (55.9 vs. 19.2%; P \ 0.001). Of note, the presence of PNI correlated with neck metastasis. Patients with neck metastasis were three times more likely to have PNI-positive tumors than patients without neck metastasis (49.5 vs. 16.5%; P \ 0.001). In multivariate analysis, PNI remained an independent predictor for neck metastasis after controlling for LVI, tumor thickness, T classification, and differentiation (Table 3).
No. %
0.0005
1998
S.-K. Tai et al.
TABLE 1 continued Characteristic
No. %
5-year DSS %
Lymphovascular invasion
5-year OS
P value % 0.0112
79.2 85.8
80.7
Yes
64
20.8 74.6
73.4
47
61
69.1
30
39
43.8
0.0945
0.0562
\0.0001
239
77.9 91.2
87.13
High
68
22.1 55.5
50.17 \0.0001
245
RT
22
CRT
40
79.8 88.5 7.2 81.3 13
53.9
Floor of mouth Tongue Buccal
40.7
Low Adjuvant therapy
according
No. of patients
to
clinicopathologic
PNI positive N
%
307
84
27.4
15 164
5 49
33.3 29.9
93
13
14
Subsites
66.9 \0.0001
Risk group
None
Characteristic
All patients 243
Yes
invasion
P valuea
0.0517
No Extracapsular spreadb No
P value
TABLE 2 Perineural characteristics
0.49
Retromolar
18
3
16.7
Hard palate
12
2
16.7
5
2
40
T1
146
25
17.1
T2
161
59
36.6
cN0
264
62
23.5
cN?
43
22
51.2
No
206
34
16.5
Yes
101
50
49.5
20
0
0
Other
\0.001
T classification \0.0001
83.8 71.3 52.5
DSS disease-specific survival, OS overall survival, OSCC oral squamous cell carcinoma, RT radiotherapy, CRT chemoradiotherapy a
cN0 patients undergoing neck observation
b
Evaluated in the 77 patients who were pN? after neck dissection
\0.001
cN classification
\0.001
Neck metastasis
Tumor thickness (mm) B2
\0.001
PNI Independently Predicted Neck Recurrence and Worse Survival Outcomes
2–5
115
11
5–7
48
12
25
9.6
7–10
61
21
34.4
T2 tumors, increased tumor thickness, and positive margin predicted local recurrence in this study. PNI was not associated with local recurrence (P = 0.221) but was strongly associated with neck recurrence. Patients who developed neck recurrence were twice more likely to have PNI-positive tumors than those under neck control (48.9 vs. 23.7%; P \ 0.001; Table 2). Neck observation and T2 tumors also predicted neck recurrence in univariate analysis. In multivariate analysis, PNI remained an independent predictor for neck recurrence. The likelihood of developing neck recurrence was fourfold greater in patients with PNIpositive tumors than in those with PNI-negative tumors (Table 3). The prognostic significance of PNI was further confirmed by its association with worse disease-specific survival (DSS) and overall survival (OS; Table 1). The 5-year DSS was significantly lower in patients with PNIpositive tumors than in those with PNI-negative tumors (70.4 vs. 88.1%; P \ 0.0001). Similar results were also observed for 5-year OS (68 vs. 82.9%; P = 0.0005). In the multivariate Cox regression model, the presence of PNI remained an independent predictor for a worse DSS after controlling for neck metastasis, resection margin, T classification, differentiation, and LVI (Table 3).
[10
63
40
63.5
230
59
25.7
Close/dysplasia
55
17
30.9
Positive
22
8
36.4
204
46
22.5
Resection margin Free
0.453
Differentiation Well
0.013
Moderate
72
24
33.3
Poor
31
14
45.2 \0.001
Lymphovascular invasion No
243
50
20.6
64
34
53.1
No
47
16
34
Yes
30
22
73.3
Low
239
46
19.2
high
68
38
55.9
No
261
68
26.1
Yes
46
16
34.8
262
62
23.7
Yes Extracapsular spreadb
0.001
\0.001
Risk group
Local recurrence
0.221
\0.001
Neck recurrence No
Perineural Invasion in T1-2 OSCC
1999
TABLE 2 continued Characteristic
No. of patients
Yes
45
PNI positive N
%
22
48.9
P value
a
PNI perineural invasion a
Pearson’s chi-square test
b
Evaluated in the 77 patients who were pN? after neck dissection
Elective Neck Dissection Improved Survival only in cN0 Patients with PNI-Positive Tumors In all 307 patients, neck dissection contributed to a lower neck recurrence rate compared with neck observation (10.8 vs. 23.2%, P = 0.005), but not a better 5-year DSS (84 vs. 81.4%, P = 0.7587; Table 1). Similarly, in the 264 cN0 patients, END contributed to a lower neck recurrence rate (9.4 vs. 22.3%; P = 0.004), but not a better 5-year DSS (90.9 vs. 82.4%; P = 0.158; Fig. 1a). To investigate the role of PNI in guiding neck management, stratification by PNI status was done. In the 62 cN0 patients with PNI-positive tumors, END contributed to a significantly better 5-year DSS (82.1 vs. 36%; P = 0.0071; Fig. 1b) as well as a lower neck recurrence rate (18 vs. 83.3%; P \ 0.001; Table 4). On the contrary, in the 202 cN0 patients with PNI-negative tumors, END contributed to neither a significantly lower neck recurrence rate (5.8 vs. 13.4%; P = 0.063; Table 4), nor a better 5-year DSS (94.5 vs. 88.7%; P = 0.3566; Fig. 1c). TABLE 3 Multivariate analysis of independent predictors for neck metastasis, neck recurrence, and diseasespecific survival
No Survival Impact of PNI in Low-Risk Patients who Underwent Neck Dissection Because high-risk patients already required postoperative adjuvant therapy, the role of PNI in guiding postoperative adjuvant therapy was evaluated in low-risk patients who were treated by surgery alone. In these 227 low-risk patients, the presence of PNI was predictive of a higher neck recurrence rate (31.7 vs. 9.1%; P \ 0.001), but not a worse 5-year DSS (84.5 vs. 92.6%; P = 0.1057; Fig. 2a). However, in the 84 patients who underwent observation for cN0 neck, PNI was associated with both a higher neck recurrence rate (88.9 vs. 13.3%; P \ 0.001) and a worse 5-year DSS (53.6 vs. 90.7%; P = 0.0014; Fig. 2b). In contrast, in the 143 patients whose surgery included neck dissection (cN? in ten patients), the presence of PNI did not correlate with a significantly higher neck recurrence rate (15.6 vs. 6.3%; P = 0.14), and the 5-year DSS rates were almost the same in those with PNIpositive tumors and those with PNI-negative tumors (92 vs. 92.9%; P = 0.9104; Fig. 2c). DISCUSSION To the best of our knowledge, this study contains the largest number of T1-2 OSCC patients reported to date, analyzing treatment decisions in relation to PNI status. Our study demonstrates that PNI correlates with several established poor prognostic factors. In fact, PNI-positive rates are twofold and threefold higher in cN? and high-risk patients, respectively, who already require neck dissection and postoperative adjuvant therapy under current treatment
Variable
P value
HR
95% CI
1.85–6.1
Neck metastasis \0.001
3.36
Lymphovascular invasion (positive vs. negative)
0.003
2.61
1.38–4.94
Tumor thickness ([5 mm vs. B5 mm)
0.491
1.25
0.67–2.33
T classification (T2 vs. T1)
0.33
1.34
0.75–2.4
Differentiation (moderate to poor vs. well)
0.233
1.4
0.81–2.41
Perineural invasion (positive vs. negative)
Neck recurrence Perineural invasion (positive vs. negative)
\0.001
4.25
2.01–8.98
Neck management (observation vs. neck dissection)
\0.001
5.45
2.45–12.11
0.013
2.65
1.23–5.71
T classification (T2 vs. T1) Disease-specific survival Perineural invasion (positive vs. negative)
0.027
2.08
1.09–3.99
\0.001
4.15
2.16–8
Resection margin (positive vs. negative) T classification (T2 vs. T1)
0.018 0.193
2.75 1.32
1.19–6.38 0.78–3.34
Only variables with significant impact (P \ 0.05) in univariate analyses were selected for each multivariate regression model
Neck metastasis (positive vs. negative)
Differentiation (moderate to poor vs. well)
0.347
1.36
0.72–2.59
HR hazard ratio, CI confidence interval
Lymphovascular invasion (positive vs. negative)
0.891
1.05
0.53–2.08
2000
S.-K. Tai et al.
a
b All CN0 patients
Cumulative survival 1.0
c
Cumulative survival 1.0
P = 0.1580
PNI positive
P = 0.0071
Cumulative survival 1.0
0.8
0.8
0.8
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
END Observation 0
20
40
60
80
100
120
END Observation 0
Time (months)
20
40
60
80
Time (months)
100
120
PNI negative
P = 0.3566
0.2
END Observation 0
20
40
60
80
100
120
Time (months)
FIG. 1 Kaplan–Meier curves of disease-specific survival according to neck management in 264 cN0 patients. a All 264 cN0 patients. b Subgroup of cN0 patients with PNI-positive tumors (n = 62).
c Subgroup of cN0 patients with PNI-negative tumors (n = 202). END elective neck dissection
TABLE 4 Impact of neck management on neck recurrence in 264 cN0 patients stratified by PNI
still recommend END for patients with PNI-negative tumors for better neck control and precise risk stratification by histologic evaluation of cervical lymph nodes. Postoperative adjuvant therapy is important for OSCC patients at high risk of recurrence, whereas it is not beneficial for those at low risk.10,30 PNI has been used as an adverse feature to recommend adjuvant RT, or even CRT for HNCs,20,21 based on its poor prognostic impact. Supporting this recommendation is the use of PNI for selecting poor risk advanced HNC patients in the European Organization for Research and Treatment of Cancer 22931 trial, which focused on postoperative adjuvant CRT, but not on PNI.19 We believe that whether to arrange postoperative adjuvant therapy at the presence of PNI in low-risk T1-2 OSCC should be based on the residual risk after neck dissection, which has never been clearly elucidated. In this study, subgroup analysis of the 227 low-risk patients who have negative margin, N0-1 disease, and no ECS clearly demonstrates that the residual risk of PNI is minimal after neck dissection. These findings clearly indicate the need to perform neck dissection but spare postoperative adjuvant therapy for low-risk T1-2 OSCC patients whose tumors exhibit PNI. Aggressive arrangement of RT or CRT can be an overtreatment for the negative impacts on quality of life resulting from late adverse effects, including xerostomia, dysphagia, softtissue fibrosis, or radionecrosis.19,31,32 In long-term followup, the possibility of radiation-induced malignancies should be taken into consideration. T1-2 OSCC patients generally are younger and are possible long-term survivors. Their leading long-term problem turns out to be second primary cancers mostly arising in the head and neck.33 Further surgery or irradiation for second primary cancers
Neck Management
Total
NR (?)
NR (-)
N
N
%
P value
%
PNI positive (n = 62) END
50
9
Observation 12 PNI negative (n = 202)
10
83.3
2
16.7
120
7
5.8
113
94.2
82
11
13.4
71
86.6
END Observation
18
41
82
\0.001a
0.063b
PNI perineural invasion, END elective neck dissection, NR neck recurrence a
Fisher’s exact test
b
Pearson’s chi-square test
policy. Therefore, the role of PNI in T1-2 OSCC can be most contributory in cN0 and low-risk subgroups, because these are the patients for whom PNI status may potentially change the decision of whether to perform aggressive neck dissection or postoperative adjuvant therapy. Given that PNI independently predicts neck metastasis and neck recurrence, but not local recurrence, our data support the concept that END should be performed for T1-2 OSCC cN0 patients who have PNI-positive tumors.6,11 These findings are consistent with the notion that PNI represents a distinct metastatic process but not simply tumor cell migration through a low-resistant plane.12,17 Furthermore, our results demonstrate that only in PNI-positive subgroup can survival benefit of END be observed (Fig. 1b). This provides a strong and direct support for performing END at the presence of PNI in T1-2 OSCC. Nevertheless, we
Perineural Invasion in T1-2 OSCC
2001
a
b
Cumulative survival 1.0
All low risk, op alone
P = 0.1057
c
Cumulative survival 1.0
Observation P = 0.0014
Cumulative survival 1.0
0.8
0.8
0.8
0.6
0.6
0.6
0.4
0.4
0.4
0.2
PNI negative PNI positive 0
20
40
60
80
Time (months)
100
120
0.2
PNI negative PNI positive 0
20
40
60
80
100
120
Neck dissection
P = 0.9104
0.2
PNI negative PNI positive 0
Time (months)
20
40
60
80
100
120
Time (months)
FIG. 2 Kaplan–Meier curves of disease-specific survival according to perineural invasion in 227 low-risk patients treated by surgery alone. a All 227 low-risk patients. b Subgroup of low-risk patients
undergoing neck observation (n = 84). c Subgroup of low-risk patients undergoing neck dissection (n = 143). PNI perineural invasion
will be difficult inside the area undergoing previous heavy chemoradiotherapy. The major limitation of this study is the retrospective design with small patient numbers in the subgroups of patients with PNI-positive tumors, patients undergoing neck observation, and patients receiving adjuvant therapy. Due to the established poor prognostic impact of PNI in HNCs, a prospective, randomized study, however, might raise ethical concerns. Although higher tumor stages can be observed in patients undergoing neck dissection and patients with PNIpositive tumors, these biases do not interfere with the judgment of the survival benefit of END, and the abrogation of PNI risk by neck dissection. Another limitation is the lower sensitivity in detecting PNI under H&E staining. Kurtz et al. reported a PNI rate of 82% in 40 OSCC patients (T1 to T4) by immunostaining of S100 protein.25 However, prognostic impact was not observed with such high PNI detection rate and they suggested less clinical significance of PNI on fine nerve fibers. Nevertheless, we believe that sensitive molecular detection of PNI is still important in mechanistic research for PNI-related metastasis, which remains largely in the infancy.12,17 In conclusion, PNI under H&E staining is a poor prognostic feature that independently predicts neck metastasis, neck recurrence, and decreased DSS for T1-2 OSCC. The presence of PNI indicates the need for END in cN0 patients for the efficacy of improving DSS as well as neck control. In low-risk patients who receive neck dissection, postoperative adjuvant therapy is not indicated because the postoperative residual risk from PNI is minimal. Our data also suggest important roles of nerve-tumor interaction leading to PNIrelated metastasis and may provide meaningful clues to
guide future research designed to identify novel treatment targets in PNI-related metastasis pathway. ACKNOWLEDGMENT We thank the Clinical Research Core Laboratory, Taipei Veterans General Hospital, for technical assistance. This work was supported in part by National Science Council of Taiwan (grant number NSC 98-2314-B-010-013-MY3), and Taipei Veterans General Hospital (grant numbers V98C1-169, V99C1-117, V100C-090). CONFLICT OF INTEREST interest.
The authors declare no conflict of
REFERENCES 1. Beenken SW, Krontiras H, Maddox WA, Peters GE, Soong S, Urist MM. T1 and T2 squamous cell carcinoma of the oral tongue: prognostic factors and the role of elective lymph node dissection. Head Neck. 1999;21:124–30. 2. Yuen AP, Lam KY, Chan AC, Wei WI, Lam LK, Ho WK, Ho CM. Clinicopathological analysis of elective neck dissection for N0 neck of early oral tongue carcinoma. Am J Surg. 1999; 177:90–2. 3. Yuen AP, Wei WI, Wong YM, Tang KC. Elective neck dissection versus observation in the treatment of early oral tongue carcinoma. Head Neck. 1997;19:583–8. 4. Vandenbrouck C, Sancho-Garnier H, Chassagne D, Saravane D, Cachin Y, Micheau C. Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity: results of a randomized clinical trial. Cancer. 1980;46:386–90. 5. Yuen AP, Ho CM, Chow TL, et al. Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma. Head Neck. 2009;31:765–72. 6. D’Cruz AK, Siddachari RC, Walvekar RR, et al. Elective neck dissection for the management of the N0 neck in early cancer of the oral tongue: need for a randomized controlled trial. Head Neck. 2009;31:618–24.
2002 7. Fakih AR, Rao RS, Borges AM, Patel AR. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg. 1989;158:309–13. 8. Cooper JS, Pajak TF, Forastiere A, et al. Precisely defining highrisk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head Neck. 1998;20:588–94. 9. Langendijk JA, de Jong MA, Leemans CR, de Bree R, Smeele LE, Doornaert P, Slotman BJ. Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time. Int J Radiat Oncol Biol Phys. 2003;57: 693–700. 10. Bernier J, Vermorken JB, Koch WM. Adjuvant therapy in patients with resected poor-risk head and neck cancer. J Clin Oncol. 2006;24:2629–35. 11. O’Brien CJ, Lahr CJ, Soong SJ, Gandour MJ, Jones JM, Urist MM, Maddox WA. Surgical treatment of early-stage carcinoma of the oral tongue: would adjuvant treatment be beneficial? Head Neck Surg. 1986;8:401–8. 12. Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev. 2010; 21:77–82. 13. Fagan JJ, Collins B, Barnes L, D’Amico F, Myers EN, Johnson JT. Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124:637–40. 14. Rahima B, Shingaki S, Nagata M, Saito C. Prognostic significance of perineural invasion in oral and oropharyngeal carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:423–31. 15. Pour PM, Bell RH, Batra SK. Neural invasion in the staging of pancreatic cancer. Pancreas. 2003;26:322–5. 16. Beard CJ, Chen MH, Cote K, Loffredo M, Renshaw AA, Hurwitz M, D’Amico AV. Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer. Int J Radiat Oncol Biol Phys. 2004;58:19–24. 17. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer. 2009;115: 3379–91. 18. Liebig C, Ayala G, Wilks J, et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol. 2009;27:5131–7. 19. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–52. 20. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359:1143–54.
S.-K. Tai et al. 21. National Comprehensive Cancer Network. Head and Neck Cancers. Clinical practice guidelines in oncology-v2. 2011. http:// www,nccn.org/index.asp. 22. College of American Pathologists: Cancer Protocols and Checklists. Northfield, IL: College of American Pathologists, 2010. 23. Poonacha TK, Go RS. Level of scientific evidence underlying recommendations arising from the National Comprehensive Cancer Network clinical practice guidelines. J Clin Oncol. 2011; 29:186–91. 24. Byers RM, El-Naggar AK, Lee YY, et al. Can we detect or predict the presence of occult nodal metastases in patients with squamous carcinoma of the oral tongue? Head Neck. 1998;20: 138–44. 25. Kurtz KA, Hoffman HT, Zimmerman MB, Robinson RA. Perineural and vascular invasion in oral cavity squamous carcinoma: increased incidence on re-review of slides and by using immunohistochemical enhancement. Arch Pathol Lab Med. 2005;129: 354–9. 26. Liao CT, Chang JT, Wang HM, et al. Does adjuvant radiation therapy improve outcomes in pT1-3N0 oral cavity cancer with tumor-free margins and perineural invasion? Int J Radiat Oncol Biol Phys. 2008;71:371–6. 27. Soo KC, Carter RL, O’Brien CJ, Barr L, Bliss JM, Shaw HJ. Prognostic implications of perineural spread in squamous carcinomas of the head and neck. Laryngoscope. 1986;96:1145–8. 28. Carter RL, Tanner NS, Clifford P, Shaw HJ. Perineural spread in squamous cell carcinomas of the head and neck: a clinicopathological study. Clin Otolaryngol Allied Sci. 1979;4:271–81. 29. Breslow A. Prognostic factors in the treatment of cutaneous melanoma. J Cutan Pathol. 1979;6:208–12. 30. Laramore GE, Scott CB, al-Sarraf M, et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys. 1992;23:705–13. 31. Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol. 2008;26:3582–9. 32. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamouscell carcinoma of the head and neck. N Engl J Med. 2004; 350:1937–44. 33. Morris LG, Sikora AG, Patel SG, Hayes RB, Ganly I. Second primary cancers after an index head and neck cancer: subsitespecific trends in the era of human papillomavirus-associated oropharyngeal cancer. J Clin Oncol. 2011;29:739–46.
