Ann Surg Oncol (2015) 22:1353–1359 DOI 10.1245/s10434-014-4106-7
ORIGINAL ARTICLE – HEAD AND NECK ONCOLOGY
Elective Neck Dissection in Patients With Head and Neck Adenoid Cystic Carcinoma: An International Collaborative Study Moran Amit, MD1,8, Shorook Na’ara, MD1,8, Kanika Sharma, MD2,8, Naomi Ramer, DMD3,8, Ilana Ramer, MD3,8, Abib Agbetoba, MD4,8, Joelle Glick, MD4,8, Xinjie Yang, MD, PhD5,8, Delin Lei, MD5,8, Kristine Bjoerndal, MD, PhD6,8, Christian Godballe, MD, PhD6,8, Thomas Mu¨cke, MD, DDS7,8, Wolff Klaus-Dietrich, MD, DDS, PhD7,8, Andre´ M. Eckardt, MD, DDS, PhD8,9, Chiara Copelli, MD8,10, Enrico Sesenna, MD8,10, Frank Palmer8,11, Ian Ganly, MD8,11, and Ziv Gil, MD, PhD8,1 1
Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel; 2Department of Radiotherapy and Oncology, Max Cancer Center, New Delhi, India; 3Departments of Pathology Mount Sinai Medical Center, The Mount Sinai School of Medicine, New York, NY; 4Otolaryngology, Mount Sinai Medical Center, The Mount Sinai School of Medicine, New York, NY; 5Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi0 an, People’s Republic of China; 6Department of Otolaryngology Head and Neck Surgery, Odense University Hospital, Odense, Denmark; 7Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany; 8Department of Otolaryngology Head and Neck Surgery, Tel Aviv Medical Center, Tel Aviv, Israel; 9Department of Cranio-Maxillofacial Surgery, Hannover Medical School, Hannover, Germany; 10 Maxillo-Facial Surgery, University-Hospital of Parma, Parma, Italy; 11Head and Neck Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY
ABSTRACT Background. Adenoid cystic carcinoma (ACC) accounts for 3–5 % of all head and neck malignancies. Investigations of outcomes from elective neck dissection (END) for patients with ACC are sparse. This study aimed to assess the impact of END on the survival of patients with ACC. Methods. This retrospective multicentered study investigated 270 patients who underwent neck dissection. A multivariate analysis assessed associations of clinical and histopathologic characteristics with survival outcomes. Results. The primary tumor sites included the oral cavity in 250 patients (55 %), the major salivary glands in 133 patients (29 %), the sinonasal mucosa in 68 patients (15 %), and the larynx in six patients (1 %). The overall
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4106-7) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 18 June 2014; Published Online: 24 September 2014 Z. Gil, MD, PhD e-mail: [email protected]
rate of occult nodal metastases among the patients who underwent END was 17 % (38/226). The highest incidence of occult nodal metastases was with the oral cavity (66 %). The 5-year overall survival (72 and 79 % for patients with or without END, respectively) and disease-specific survival (74 and 81 % for patients with or without END, respectively) were similar in the two groups. The subgroup analysis of patients according to the primary site showed no significant impact of END on outcome. In the multivariate analysis, primary site, T classification, and N classification were the only variables associated with outcome. Conclusions. The incidence of occult neck metastases among patients with ACC is 17 %. The highest incidence of occult metastases is with the oral cavity. Statistical analysis showed no survival advantage for patients who underwent END compared with those who did not. Adenoid cystic carcinoma (ACC) accounts for 3–5 % of all head and neck malignancies. Findings show that ACC is characterized by an intermediate growth rate, a low probability of lymphatic spread, and frequent lung metastases.1 The presence of cervical lymph node metastases is one of the most significant prognostic factors for patients with
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carcinomas of the head and neck. Because the survival rate for patients with neck metastases decreases according to the number and level of the nodes involved, treatment of the neck is crucial in the management of these patients.2–4 Clinical evidence of nodal metastases requires therapeutic neck dissection, whereas in the absence of clinical or radiologic evidence of nodal metastases, surgery may include an elective neck dissection (END). The decision regarding END should be based on the incidence of occult lymph node metastases and on the expected impact of treatment on survival. Considering that the management of primary head and neck ACC is largely surgical, the surgeon should weigh the benefits of surgical treatment of a clinically negative neck against the associated morbidity.5,6 However, due to the insufficiency of data regarding the incidence of neck metastasis and its association with outcomes for patients with ACC, the association between the presence of lymph node metastases and the overall survival rate for ACC remains inconclusive. The main objective of the study was to assess the impact of END on the survival of patients with ACC. METHODS Patients The International Study Group of the ACC cohort comprised 501 patients treated for ACC of the head and neck between 1985 and 2011 at nine cancer centers worldwide. Data were recorded retrospectively using uniform database templates to ensure consistent collection. Eligible patients had undergone primary surgery for head and neck ACC with or without adjuvant chemoradiotherapy. The current study comprised 457 patients of the cohort who had no preoperative clinical evidence for nodal metastasis (cN0), as indicated by physical examination or imaging studies including computed tomography (CT) and magnetic resonance imaging (MRI). END was performed for 226 of the patients (49 %) and involved levels I–III (n = 159, 70 %), I–IV (n = 10, 4 %), and I–V (n = 39, 17 %), or modified radical neck dissection (n = 3, 1 %), as described by the American Head and Neck Society.7 Bilateral END was performed for 18 patients (8 %). All the dissections involved levels I–V in the ipsilateral neck and I–III in the contralateral neck. Of the 457 patients, 231 (51 %) had primary tumor resection without END. The decision to perform END was based on the institutional protocol of treatment. The follow-up period ranged from 3 to 288 months (median, 64 months). The patients with a follow-up period shorter than 6 months were included when disease-specific death or early recurrence was within 6 months after surgery. The
M. Amit et al.
median follow-up period for the END group was 55 months (range, 7–258 months), compared with 88 months (range, 3–288 months) for the patients who did not undergo neck dissection (p = 0.01). All the patients had a preoperative workup including neck imaging with either CT or positron emission tomography (PET)-CT. Histopathologic Analysis After neck dissection, specimens were subjected to pathologic analysis by a certified head and neck pathologist at each center. Specimen dissection and tissue sampling of the primary tumor were performed according to the guidelines for the histopathologic assessment of head and neck carcinoma.8 Statistical Analysis Using the Kaplan-Meier method, 5-year overall survival (OS), disease-specific survival (DSS), regional control, and distant metastasis rates were calculated. Differences in survival rates were assessed by the log-rank test.9 The OS was measured from the date of surgery to the date of death or the last follow-up visit. The DSS was calculated from the time of diagnosis to death resulting from ACC. Associations between individual clinical features and survival were determined with the log-rank test.10 A multivariate analysis using the Cox proportional hazards regression model was performed to compare the factors with prognostic potential, as indicated by univariate analyses.11,12 The seventh edition of the tumor-nodemetastasis (TNM) staging system for head and neck cancer was used for TNM staging. The limit of significance for all analyses was defined as a p value lower than 0.05. Twosided statistical tests were used in all calculations. Statistical analysis of the distribution of the lymph node metastases was performed, and a correlation between distribution and primary sites was established. Calculations were performed using JMP Version 10 (JMP, SAS Institute Inc., Cary, NC, USA). Fisher’s exact test (StatCalc 2.0; University of Louisiana, Lafayette, LA, USA) was used when the number of events was less than ten. The study was approved by the local institutional review board committees of the participating centers. RESULTS The 457 patients in this study included 190 males (42 %) and 267 females (58 %). The median age was 56 years (range, 20–88 years). The primary tumor sites were the minor salivary glands of the oral cavity in 250 patients (55 %, including 23 cases [5 %] of oropharyngeal
Elective Neck Treatment for ACC of Head and Neck
Variable
Elective neck dissection n (%)
n
226 (49)
231 (51)
Mean age (years)
56 ± 14
57 ± 15
0.47
Male
105 (46)
83 (36)
0.04
Female
121 (54)
148 (64)
Oral cavity
116 (51)
132 (58)
Major salivary glands
85 (38)
51 (23)
Paranasal sinuses Larynx
24 (10) 1 (\ 1)
43 (17) 5 (2)
Sex Primary site
pT classification
p Value
0.02
1
62 (28)
58 (25)
89 (39)
79 (34)
3
41 (18)
23 (10)
4
34 (15)
71 (31)
N0
179 (79)
225 (98)
N1
35 (16)
6 (2)
N2a
5 (2)
0
N2b
2 (\ 1)
0
N2c
4 (2)
0
N3
1 (\ 1)
0
Yes
150 (66)
126 (55)
No
76 (34)
107 (45)
Adjuvant chemotherapy
Yes
57 (25)
30 (13)
0.02
Margin status
No Positive
169 (75) 37 (16)
201 (87) 35 (15)
0.07
Close (\ 5 mm)
61 (28)
80 (35)
Negative
127 (56)
116 (50)
pN classification
Lateral neck irradiation (dose [ 60 Gy)
A
B
Overall survival
0.8
0.08
0.09
Disease specific survival
0.6 END 5y-72%
0.4
No ND 5y-81%
0.8
No ND 5y-79%
Surviving
Surviving
0.1
1.0
1.0
0.6 END 5y-74%
0.4 0.2
0.2
p=0.06
p=0.08
0.0
0.0 0
20
40
60
80
100
120
0
20
Time (months) 1.0
40
60
80
D
p=0.22
0.8 No ND 5y-64%
0.4 0.2
120
Distant metastasis
1.0
0.8 0.6
100
Time (months)
Regional control rate
C
Surviving
FIG. 1 Kaplan-Meier analysis. 5-Year a overall survival, b disease-specific survival, c disease-free survival, and d distant metastases rates calculated by the Kaplan-Meier method according to neck management status (p \ 0.05). END, elective neck dissection
No neck dissection N (%)
2
Failing
TABLE 1 Patient demographic and clinical characteristics
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0.6 END 5y-36%
0.4 0.2
END 5y-64% p=0.69
No ND 5y-27%
0.0
0.0 0
20
40
60
80
Time (months)
100
120
0
20
40
60
80
Time (months)
100
120
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A
Major salivary glands
1.0
No ND 5y-87%
Surviving
0.8 0.6
END 5y-81% 0.4 0.2
p=0.14 0.0 0
20
40
80
60
100
120
Time (months)
B
Minor oral cavity salivary glands 1.0
No ND 5y-82%
Surviving
0.8 0.6
END 5y-81%
0.4 0.2
p=0.33 0.0 0
20
40
80
60
100
120
Time (months)
C
Minor sinonasal salivary glands
1.0 0.8
Surviving
involvement), the major salivary glands in 133 patients (29 %), the minor sinonasal salivary glands in 68 patients (15 %), and the larynx in six patients (1 %). Table 1 summarizes the patients’ demographic and clinical characteristics according to elective and therapeutic neck dissection. Advanced disease (T3–T4) was present in 94 patients (41 %) without neck dissection compared with 75 patients (33 %) in the END group (p = 0.1). Adjuvant therapeutic lateral neck irradiation was administered to 146 patients (66 %) who underwent END compared with 118 patients (55 %) without neck dissection (p = 0.09). The patients were treated with total doses ranging from 60 to 74 Gy. The mean doses were 61 ± 0.0.71 Gy in the END group and 61 ± 0.89 Gy in the no neck dissection group (p = 0.94). The overall rate of occult nodal metastases among the patients who underwent elective neck dissection was 17 % (38/226). Subgroup analysis showed that the highest incidences of occult nodal metastases were among the patients with oral cavity tumors (66 %, 25/38) and those with tumors of the major salivary gland (24 %, 9/38). The lowest incidence of occult neck metastases was among the patients with ACC of the paranasal sinuses (10 %, 4/38). Analysis for correlation between occult metastasis and pathologic adverse features, specifically high-grade histology or perineural invasion, showed no correlation between these variables (Pearson’s r correlation coefficients of 0.23 and 0.38, respectively). Figure 1 shows the Kaplan-Meier curves of patient outcomes after primary tumor resection according to neck management. The 5-year OS was 72 % for the patients who underwent END, compared with 79 % for the patients who did not (not statistically different). The 5-year DSS was 74 % for the patients who underwent END, compared with 81 % for the patients who did not (no statistically significant difference). Also, the 5-year regional control and distant metastasis rates did not differ significantly between the patients who underwent elective neck dissection and those who did not (Fig. 1). Subgroup analysis for survival outcome according to nodal status for the patients undergoing END showed a significantly better OS and DSS for the patients without occult metastases (Supplemental Fig. 1). The latter showed lower rates of regional and distant recurrence, whereas the local recurrence rate did not differ significantly between the groups (Supplemental Fig. 2). Next, we compared the impact of END on outcome according to the primary tumor site. The Kaplan-Meier graphs for the patients with primary tumors in the oral cavity, major salivary glands, or sinonasal salivary glands showed survival rates similar to those for the patients with and without END (Fig. 2). When the patients with T1–T2 and T3–T4 classifications were analyzed separately, END
M. Amit et al.
0.6
No ND 5y-50% 0.4
END 5y-42%
0.2
p=0.42 0.0 0
20
40
60
80
100
120
Time (months) FIG. 2 Kaplan-Meier analysis. 5-Year overall survival rates for patients with tumor of the a major salivary glands, b minor oral cavity salivary glands, and c minor sinonasal salivary glands. Adenoid cystic carcinoma (ACC) rates were calculated by the Kaplan-Meier method according to neck management status (p \ 0.05). END, elective neck dissection
was not shown to be associated with improved survival (Fig. 3). The variables introduced into a multivariate model were age, gender, primary site, margin status, T classification, N classification, extracapsular spread, perineural invasion, treatment group (surgery, surgery with radiotheraphy, surgery with chemoradiation), and neck management (END vs no neck dissection). The variables independently associated with both OS and DSS were primary site, T classification, and N classification
Elective Neck Treatment for ACC of Head and Neck
B
Early disease (T1-2) 1.0 No ND 5y-86%
0.8 0.6
END 5y-78% 0.4 0.2
Advanced disease (T3-4) 1.0 0.8
Surviving
A
Surviving
FIG. 3 Kaplan-Meier analysis. 5-Year overall survival rates for patients with a early (T1–T2) and b advanced (T3–T4) adenoid cystic carcinoma (ACC) calculated by the Kaplan-Meier method according to neck management status (p \ 0.05). END, elective neck dissection
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No ND 5y-69%
0.6 END 5y-60%
0.4 0.2
p=0.13
0.0
p=0.27
0.0 0
20
40
60
80
Time (months)
(Table 2). This analysis confirmed that performance of END was not associated with a better outcome. DISCUSSION Adenoid cystic carcinoma of the head and neck is an uncommon tumor. Its treatment includes surgery with or without adjuvant radiotherapy. Due to its rarity, data on the incidence of ACC nodal metastases and their impact on outcome are insufficient to determine the overall benefit of elective neck dissection in the management of ACC patients. Findings have shown nodal metastasis to be a common cause of treatment failure in this population.13 On the other hand, the reported incidence of neck metastasis in ACC is 6–10 %, considerably lower than for patients with squamous cell carcinoma of the head and neck.14,15 To achieve a large sample population, considering the low incidence of ACC, we performed an international collaborative study involving nine cancer centers. We collected detailed data on 457 patients with clinically negative neck nodal metastasis. The incidence of occult nodal metastases was 17 %. The rate was higher among patients with ACC of the oral cavity (22 %), lower among those with sinonasal ACC (17 %), and the lowest among patients with major salivary gland tumor (11 %). Whereas therapeutic neck dissection is performed as a matter of course for all patients with clinical evidence of nodal metastases, the decision to perform an elective neck dissection is complicated by the limited ability of imaging techniques to assess cervical metastases.16 For cases of head and neck squamous cell carcinoma, an elective neck dissection is indicated if the probability of occult cervical metastases is higher than 15–20 %.17 Up front, our finding of a 17 % rate for occult neck metastases among patients with ACC supports the performance of END for patients with ACC, as practiced for those with squamous cell carcinoma. However, to evaluate thoroughly whether END is associated with better patient outcomes, we compared the
100
120
0
20
40
60
80
100
120
Time (months)
survival of patients undergoing END with the survival of those not undergoing END. We found no statistically significant difference between the two groups in any survival measures. Furthermore, analysis of subgroups according to tumor site and disease stage suggested that even for patients at high risk of neck metastases (oral cavity) and with advanced T classification (T3–T4), END was not found to be associated with patient outcomes. We suggest a number of possible explanations for our findings. First, the established survival advantages of END for head and neck squamous cell carcinoma may be less prominent in ACC due to the relatively indolent course of the disease. Second, it is possible that elective radiation to the neck reaches results equal to those for END. However, our multivariate analysis identified T classification, N classification, and primary site as independent predictors of patient outcomes, whereas adjuvant radiotherapy was not significantly associated with improved patient outcomes. This is consistent with previous data showing that ACC is resistant to adjuvant therapy.18–21 Due to the retrospective design of this study, data on the patterns of recurrence and on specific levels of the neck metastases were missing for about half of the patients. Nevertheless, our data show occult nodal metastases only in levels I–III. Furthermore, none of the patients who underwent contralateral END had nodal metastases in the contralateral neck. This suggests that if performed, END should be limited to levels I–III on the ipsilateral side. Another limitation of the retrospective design was that despite the use of uniform data extraction sheets, the heterogeneity of the professionals involved in data collection (e.g., pathologists, radiologists, and radiation oncologists) may have led to inconsistency in reporting. Our data support the performance of a prospective trial to assess the role of END in ACC. Until such data are available, the tailoring of treatment for ACC should be based on risk stratification of each patient and on decisions of the multidisciplinary teams that manage the treatment of these patients.
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M. Amit et al.
TABLE 2 Multivariate analysis of prognostic factors for overall and disease-specific survival Variable
Overall survival p Value
HR
95 % CI
Disease-specific survival
Regional recurrence-free survival
p Value
p Value
HR
95 % CI
HR
95 % CI
Age
Years
0.05
6.1
3.4–12.5
0.07
NA
NA
0.004
9.3
4.1–15.8
Gender
Male
0.42
NA
NA
0.22
NA
NA
0.45
NA
NA
0.002
1
1.05–2.1
0.004
1
1.1–1.9
0.001
Female Primary site
Major glands
1.47 Oral cavity
1.28
Sinonasal
1.46–2.9
1
1.3–2.4
1.87
2.4–3.9
3.13
2.08
1.8–2.5
2.12
Margins
Negative Close (\ 5 mm) Positive
0.09
NA
NA
0.44
NA
NA
0.24
Pathologic T classification
T1
0.001
1
1.2–3.1
0.0003
1
1.5–3.7
0.04
1.74
2.1–4.46
T2
3.08
T3
4.34
1.2–7.3
1
2.1–4.3
NA
NA
1
1.1–3.4
2.1
2.11–7.5 2.5–11.8
1.96
2.1–4.5
4.14
3.12
2.96–6.7
6.1
4.71
T4 Pathologic N classification
N0
0.008
0.01
N1
1
1.02–1.5
1.19
1.1–2.23
N2
3.13
3.4–6.5
1.48
N3
5.17
4.8–10.5
2.14
1.4–3.6
0.23
NA
NA
7.66 Extracapsular spread
No
0.3
NA
NA
0.38
NA
NA
NA*
NA
NA
0.7
NA
NA
0.64
NA
NA
0.11
NA
NA
0.21
NA
NA
0.22
NA
NA
0.39
NA
NA
0.91
NA
NA
0.84
NA
NA
0.63
NA
NA
Yes Perineural invasion
No Yes
Treatment
Surgery Surgery ? RT Surgery ? CRT
Neck management
END No ND
HR hazard ratio; CI confidence interval; NA not available; RT radiation therapy; CRT chemoradiation; END elective neck dissection; ND neck dissection
CONCLUSIONS In a multisite cohort, the incidence of occult neck metastases among the patients with ACC was 17 %. Occult nodal metastasis was found only in the ipsilateral upper neck (levels I–III). In a multivariate analysis, T classification, N classification, and primary site were significant predictors of outcome. Although the high rate of occult nodal metastasis in oral cavity and major salivary gland ACC suggests performing END in cases involving these sites, we found no survival advantage for the patients who underwent END compared with those who did not regardless of site. The relatively high rate of occult nodal metastases among patients with ACC suggests that routine
imaging methods such as PET-CT and neck ultrasonography may be considered for routine follow-up evaluation in this population. CONFLICT OF INTEREST
There are no conflicts of interest.
REFERENCES 1. Bhayani MK, Yener M, El-Naggar A, et al. Prognosis and risk factors for early-stage adenoid cystic carcinoma of the major salivary glands. Cancer 2012;118(11):2872-8. 2. Spiro RH, Alfonso AE, Farr HW, Strong EW. Cervical node metastasis from epidermoid carcinoma of the oral cavity and oropharynx. A critical assessment of current staging. American Journal of Surgery 1974;128(4):562-7.
Elective Neck Treatment for ACC of Head and Neck 3. Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. American Journal of Surgery 1990;160(4):405-9. 4. Snow GB, van den Brekel MW, Leemans CR, Patel P. Surgical management of cervical lymph nodes in patients with oral and oropharyngeal cancer. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer 1994;134:43-55. 5. 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(19):1945-52. 6. 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(19):1937-44. 7. Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Archives of otolaryngolog 2008;134(5):536-8. 8. Pn g. Guidelines for the examination and reporting of head and neck cancer specimens. Ed.LEEDS: Yorkshire Cancer Network 2007 1-12. 9. Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457-481. 10. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemotherapy Reports Part 1 1966;50(3):163-70. 11. Cox DR. Regression models and life-tables. J R Stat Soc 1972;34:187-220. 12. Gil Z, Patel SG, Singh B, et al. Analysis of prognostic factors in 146 patients with anterior skull base sarcoma: an international collaborative study. Cancer 2007;110(5):1033-41. 13. Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional
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control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head & Neck 2004;26(8):681-92. Balamucki CJ, Amdur RJ, Werning JW, et al. Adenoid cystic carcinoma of the head and neck. American Journal of Otolaryngology 2012;33(5):510-8. Min R, Siyi L, Wenjun Y, et al. Salivary gland adenoid cystic carcinoma with cervical lymph node metastasis: a preliminary study of 62 cases. International Journal of Oral and Maxillofacial Surgery 2012;41(8):952-7. Wei WI, Ferlito A, Rinaldo A, et al. Management of the N0 neck–reference or preference. Oral Oncology 2006;42(2):115-22. Pitman KT. Rationale for elective neck dissection. American Journal of Otolaryngology 2000;21(1):31-7. Adachi M, Mitsudo K, Yamamoto N, et al. Chemoradiotherapy for maxillary sinus adenoid cystic carcinoma using superselective intra-arterial infusion via a superficial temporal artery. Head & Neck 2013;35(3):E89-93. Verweij J, de Mulder PH, de Graeff A, et al. Phase II study on mitoxantrone in adenoid cystic carcinomas of the head and neck. EORTC Head and Neck Cancer Cooperative Group. Annals of Oncology : Official Journal of the European Society for Medical Oncology 1996;7(8):867-9. Budd GT, Groppe CW. Adenoid cystic carcinoma of the salivary gland. Sustained complete response to chemotherapy. Cancer 1983;51(4):589-90. Amit M, Binenbaum Y, Sharma K, et al. Analysis of failure in patients with adenoid cystic carcinoma of the head and neck an international collaborative study.2013 Head Neck 36(7):9981004.
ORIGINAL ARTICLE – HEAD AND NECK ONCOLOGY
Elective Neck Dissection in Patients With Head and Neck Adenoid Cystic Carcinoma: An International Collaborative Study Moran Amit, MD1,8, Shorook Na’ara, MD1,8, Kanika Sharma, MD2,8, Naomi Ramer, DMD3,8, Ilana Ramer, MD3,8, Abib Agbetoba, MD4,8, Joelle Glick, MD4,8, Xinjie Yang, MD, PhD5,8, Delin Lei, MD5,8, Kristine Bjoerndal, MD, PhD6,8, Christian Godballe, MD, PhD6,8, Thomas Mu¨cke, MD, DDS7,8, Wolff Klaus-Dietrich, MD, DDS, PhD7,8, Andre´ M. Eckardt, MD, DDS, PhD8,9, Chiara Copelli, MD8,10, Enrico Sesenna, MD8,10, Frank Palmer8,11, Ian Ganly, MD8,11, and Ziv Gil, MD, PhD8,1 1
Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, The Technion, Israel Institute of Technology, Haifa, Israel; 2Department of Radiotherapy and Oncology, Max Cancer Center, New Delhi, India; 3Departments of Pathology Mount Sinai Medical Center, The Mount Sinai School of Medicine, New York, NY; 4Otolaryngology, Mount Sinai Medical Center, The Mount Sinai School of Medicine, New York, NY; 5Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi0 an, People’s Republic of China; 6Department of Otolaryngology Head and Neck Surgery, Odense University Hospital, Odense, Denmark; 7Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany; 8Department of Otolaryngology Head and Neck Surgery, Tel Aviv Medical Center, Tel Aviv, Israel; 9Department of Cranio-Maxillofacial Surgery, Hannover Medical School, Hannover, Germany; 10 Maxillo-Facial Surgery, University-Hospital of Parma, Parma, Italy; 11Head and Neck Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY
ABSTRACT Background. Adenoid cystic carcinoma (ACC) accounts for 3–5 % of all head and neck malignancies. Investigations of outcomes from elective neck dissection (END) for patients with ACC are sparse. This study aimed to assess the impact of END on the survival of patients with ACC. Methods. This retrospective multicentered study investigated 270 patients who underwent neck dissection. A multivariate analysis assessed associations of clinical and histopathologic characteristics with survival outcomes. Results. The primary tumor sites included the oral cavity in 250 patients (55 %), the major salivary glands in 133 patients (29 %), the sinonasal mucosa in 68 patients (15 %), and the larynx in six patients (1 %). The overall
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4106-7) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 18 June 2014; Published Online: 24 September 2014 Z. Gil, MD, PhD e-mail: [email protected]
rate of occult nodal metastases among the patients who underwent END was 17 % (38/226). The highest incidence of occult nodal metastases was with the oral cavity (66 %). The 5-year overall survival (72 and 79 % for patients with or without END, respectively) and disease-specific survival (74 and 81 % for patients with or without END, respectively) were similar in the two groups. The subgroup analysis of patients according to the primary site showed no significant impact of END on outcome. In the multivariate analysis, primary site, T classification, and N classification were the only variables associated with outcome. Conclusions. The incidence of occult neck metastases among patients with ACC is 17 %. The highest incidence of occult metastases is with the oral cavity. Statistical analysis showed no survival advantage for patients who underwent END compared with those who did not. Adenoid cystic carcinoma (ACC) accounts for 3–5 % of all head and neck malignancies. Findings show that ACC is characterized by an intermediate growth rate, a low probability of lymphatic spread, and frequent lung metastases.1 The presence of cervical lymph node metastases is one of the most significant prognostic factors for patients with
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carcinomas of the head and neck. Because the survival rate for patients with neck metastases decreases according to the number and level of the nodes involved, treatment of the neck is crucial in the management of these patients.2–4 Clinical evidence of nodal metastases requires therapeutic neck dissection, whereas in the absence of clinical or radiologic evidence of nodal metastases, surgery may include an elective neck dissection (END). The decision regarding END should be based on the incidence of occult lymph node metastases and on the expected impact of treatment on survival. Considering that the management of primary head and neck ACC is largely surgical, the surgeon should weigh the benefits of surgical treatment of a clinically negative neck against the associated morbidity.5,6 However, due to the insufficiency of data regarding the incidence of neck metastasis and its association with outcomes for patients with ACC, the association between the presence of lymph node metastases and the overall survival rate for ACC remains inconclusive. The main objective of the study was to assess the impact of END on the survival of patients with ACC. METHODS Patients The International Study Group of the ACC cohort comprised 501 patients treated for ACC of the head and neck between 1985 and 2011 at nine cancer centers worldwide. Data were recorded retrospectively using uniform database templates to ensure consistent collection. Eligible patients had undergone primary surgery for head and neck ACC with or without adjuvant chemoradiotherapy. The current study comprised 457 patients of the cohort who had no preoperative clinical evidence for nodal metastasis (cN0), as indicated by physical examination or imaging studies including computed tomography (CT) and magnetic resonance imaging (MRI). END was performed for 226 of the patients (49 %) and involved levels I–III (n = 159, 70 %), I–IV (n = 10, 4 %), and I–V (n = 39, 17 %), or modified radical neck dissection (n = 3, 1 %), as described by the American Head and Neck Society.7 Bilateral END was performed for 18 patients (8 %). All the dissections involved levels I–V in the ipsilateral neck and I–III in the contralateral neck. Of the 457 patients, 231 (51 %) had primary tumor resection without END. The decision to perform END was based on the institutional protocol of treatment. The follow-up period ranged from 3 to 288 months (median, 64 months). The patients with a follow-up period shorter than 6 months were included when disease-specific death or early recurrence was within 6 months after surgery. The
M. Amit et al.
median follow-up period for the END group was 55 months (range, 7–258 months), compared with 88 months (range, 3–288 months) for the patients who did not undergo neck dissection (p = 0.01). All the patients had a preoperative workup including neck imaging with either CT or positron emission tomography (PET)-CT. Histopathologic Analysis After neck dissection, specimens were subjected to pathologic analysis by a certified head and neck pathologist at each center. Specimen dissection and tissue sampling of the primary tumor were performed according to the guidelines for the histopathologic assessment of head and neck carcinoma.8 Statistical Analysis Using the Kaplan-Meier method, 5-year overall survival (OS), disease-specific survival (DSS), regional control, and distant metastasis rates were calculated. Differences in survival rates were assessed by the log-rank test.9 The OS was measured from the date of surgery to the date of death or the last follow-up visit. The DSS was calculated from the time of diagnosis to death resulting from ACC. Associations between individual clinical features and survival were determined with the log-rank test.10 A multivariate analysis using the Cox proportional hazards regression model was performed to compare the factors with prognostic potential, as indicated by univariate analyses.11,12 The seventh edition of the tumor-nodemetastasis (TNM) staging system for head and neck cancer was used for TNM staging. The limit of significance for all analyses was defined as a p value lower than 0.05. Twosided statistical tests were used in all calculations. Statistical analysis of the distribution of the lymph node metastases was performed, and a correlation between distribution and primary sites was established. Calculations were performed using JMP Version 10 (JMP, SAS Institute Inc., Cary, NC, USA). Fisher’s exact test (StatCalc 2.0; University of Louisiana, Lafayette, LA, USA) was used when the number of events was less than ten. The study was approved by the local institutional review board committees of the participating centers. RESULTS The 457 patients in this study included 190 males (42 %) and 267 females (58 %). The median age was 56 years (range, 20–88 years). The primary tumor sites were the minor salivary glands of the oral cavity in 250 patients (55 %, including 23 cases [5 %] of oropharyngeal
Elective Neck Treatment for ACC of Head and Neck
Variable
Elective neck dissection n (%)
n
226 (49)
231 (51)
Mean age (years)
56 ± 14
57 ± 15
0.47
Male
105 (46)
83 (36)
0.04
Female
121 (54)
148 (64)
Oral cavity
116 (51)
132 (58)
Major salivary glands
85 (38)
51 (23)
Paranasal sinuses Larynx
24 (10) 1 (\ 1)
43 (17) 5 (2)
Sex Primary site
pT classification
p Value
0.02
1
62 (28)
58 (25)
89 (39)
79 (34)
3
41 (18)
23 (10)
4
34 (15)
71 (31)
N0
179 (79)
225 (98)
N1
35 (16)
6 (2)
N2a
5 (2)
0
N2b
2 (\ 1)
0
N2c
4 (2)
0
N3
1 (\ 1)
0
Yes
150 (66)
126 (55)
No
76 (34)
107 (45)
Adjuvant chemotherapy
Yes
57 (25)
30 (13)
0.02
Margin status
No Positive
169 (75) 37 (16)
201 (87) 35 (15)
0.07
Close (\ 5 mm)
61 (28)
80 (35)
Negative
127 (56)
116 (50)
pN classification
Lateral neck irradiation (dose [ 60 Gy)
A
B
Overall survival
0.8
0.08
0.09
Disease specific survival
0.6 END 5y-72%
0.4
No ND 5y-81%
0.8
No ND 5y-79%
Surviving
Surviving
0.1
1.0
1.0
0.6 END 5y-74%
0.4 0.2
0.2
p=0.06
p=0.08
0.0
0.0 0
20
40
60
80
100
120
0
20
Time (months) 1.0
40
60
80
D
p=0.22
0.8 No ND 5y-64%
0.4 0.2
120
Distant metastasis
1.0
0.8 0.6
100
Time (months)
Regional control rate
C
Surviving
FIG. 1 Kaplan-Meier analysis. 5-Year a overall survival, b disease-specific survival, c disease-free survival, and d distant metastases rates calculated by the Kaplan-Meier method according to neck management status (p \ 0.05). END, elective neck dissection
No neck dissection N (%)
2
Failing
TABLE 1 Patient demographic and clinical characteristics
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0.6 END 5y-36%
0.4 0.2
END 5y-64% p=0.69
No ND 5y-27%
0.0
0.0 0
20
40
60
80
Time (months)
100
120
0
20
40
60
80
Time (months)
100
120
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A
Major salivary glands
1.0
No ND 5y-87%
Surviving
0.8 0.6
END 5y-81% 0.4 0.2
p=0.14 0.0 0
20
40
80
60
100
120
Time (months)
B
Minor oral cavity salivary glands 1.0
No ND 5y-82%
Surviving
0.8 0.6
END 5y-81%
0.4 0.2
p=0.33 0.0 0
20
40
80
60
100
120
Time (months)
C
Minor sinonasal salivary glands
1.0 0.8
Surviving
involvement), the major salivary glands in 133 patients (29 %), the minor sinonasal salivary glands in 68 patients (15 %), and the larynx in six patients (1 %). Table 1 summarizes the patients’ demographic and clinical characteristics according to elective and therapeutic neck dissection. Advanced disease (T3–T4) was present in 94 patients (41 %) without neck dissection compared with 75 patients (33 %) in the END group (p = 0.1). Adjuvant therapeutic lateral neck irradiation was administered to 146 patients (66 %) who underwent END compared with 118 patients (55 %) without neck dissection (p = 0.09). The patients were treated with total doses ranging from 60 to 74 Gy. The mean doses were 61 ± 0.0.71 Gy in the END group and 61 ± 0.89 Gy in the no neck dissection group (p = 0.94). The overall rate of occult nodal metastases among the patients who underwent elective neck dissection was 17 % (38/226). Subgroup analysis showed that the highest incidences of occult nodal metastases were among the patients with oral cavity tumors (66 %, 25/38) and those with tumors of the major salivary gland (24 %, 9/38). The lowest incidence of occult neck metastases was among the patients with ACC of the paranasal sinuses (10 %, 4/38). Analysis for correlation between occult metastasis and pathologic adverse features, specifically high-grade histology or perineural invasion, showed no correlation between these variables (Pearson’s r correlation coefficients of 0.23 and 0.38, respectively). Figure 1 shows the Kaplan-Meier curves of patient outcomes after primary tumor resection according to neck management. The 5-year OS was 72 % for the patients who underwent END, compared with 79 % for the patients who did not (not statistically different). The 5-year DSS was 74 % for the patients who underwent END, compared with 81 % for the patients who did not (no statistically significant difference). Also, the 5-year regional control and distant metastasis rates did not differ significantly between the patients who underwent elective neck dissection and those who did not (Fig. 1). Subgroup analysis for survival outcome according to nodal status for the patients undergoing END showed a significantly better OS and DSS for the patients without occult metastases (Supplemental Fig. 1). The latter showed lower rates of regional and distant recurrence, whereas the local recurrence rate did not differ significantly between the groups (Supplemental Fig. 2). Next, we compared the impact of END on outcome according to the primary tumor site. The Kaplan-Meier graphs for the patients with primary tumors in the oral cavity, major salivary glands, or sinonasal salivary glands showed survival rates similar to those for the patients with and without END (Fig. 2). When the patients with T1–T2 and T3–T4 classifications were analyzed separately, END
M. Amit et al.
0.6
No ND 5y-50% 0.4
END 5y-42%
0.2
p=0.42 0.0 0
20
40
60
80
100
120
Time (months) FIG. 2 Kaplan-Meier analysis. 5-Year overall survival rates for patients with tumor of the a major salivary glands, b minor oral cavity salivary glands, and c minor sinonasal salivary glands. Adenoid cystic carcinoma (ACC) rates were calculated by the Kaplan-Meier method according to neck management status (p \ 0.05). END, elective neck dissection
was not shown to be associated with improved survival (Fig. 3). The variables introduced into a multivariate model were age, gender, primary site, margin status, T classification, N classification, extracapsular spread, perineural invasion, treatment group (surgery, surgery with radiotheraphy, surgery with chemoradiation), and neck management (END vs no neck dissection). The variables independently associated with both OS and DSS were primary site, T classification, and N classification
Elective Neck Treatment for ACC of Head and Neck
B
Early disease (T1-2) 1.0 No ND 5y-86%
0.8 0.6
END 5y-78% 0.4 0.2
Advanced disease (T3-4) 1.0 0.8
Surviving
A
Surviving
FIG. 3 Kaplan-Meier analysis. 5-Year overall survival rates for patients with a early (T1–T2) and b advanced (T3–T4) adenoid cystic carcinoma (ACC) calculated by the Kaplan-Meier method according to neck management status (p \ 0.05). END, elective neck dissection
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No ND 5y-69%
0.6 END 5y-60%
0.4 0.2
p=0.13
0.0
p=0.27
0.0 0
20
40
60
80
Time (months)
(Table 2). This analysis confirmed that performance of END was not associated with a better outcome. DISCUSSION Adenoid cystic carcinoma of the head and neck is an uncommon tumor. Its treatment includes surgery with or without adjuvant radiotherapy. Due to its rarity, data on the incidence of ACC nodal metastases and their impact on outcome are insufficient to determine the overall benefit of elective neck dissection in the management of ACC patients. Findings have shown nodal metastasis to be a common cause of treatment failure in this population.13 On the other hand, the reported incidence of neck metastasis in ACC is 6–10 %, considerably lower than for patients with squamous cell carcinoma of the head and neck.14,15 To achieve a large sample population, considering the low incidence of ACC, we performed an international collaborative study involving nine cancer centers. We collected detailed data on 457 patients with clinically negative neck nodal metastasis. The incidence of occult nodal metastases was 17 %. The rate was higher among patients with ACC of the oral cavity (22 %), lower among those with sinonasal ACC (17 %), and the lowest among patients with major salivary gland tumor (11 %). Whereas therapeutic neck dissection is performed as a matter of course for all patients with clinical evidence of nodal metastases, the decision to perform an elective neck dissection is complicated by the limited ability of imaging techniques to assess cervical metastases.16 For cases of head and neck squamous cell carcinoma, an elective neck dissection is indicated if the probability of occult cervical metastases is higher than 15–20 %.17 Up front, our finding of a 17 % rate for occult neck metastases among patients with ACC supports the performance of END for patients with ACC, as practiced for those with squamous cell carcinoma. However, to evaluate thoroughly whether END is associated with better patient outcomes, we compared the
100
120
0
20
40
60
80
100
120
Time (months)
survival of patients undergoing END with the survival of those not undergoing END. We found no statistically significant difference between the two groups in any survival measures. Furthermore, analysis of subgroups according to tumor site and disease stage suggested that even for patients at high risk of neck metastases (oral cavity) and with advanced T classification (T3–T4), END was not found to be associated with patient outcomes. We suggest a number of possible explanations for our findings. First, the established survival advantages of END for head and neck squamous cell carcinoma may be less prominent in ACC due to the relatively indolent course of the disease. Second, it is possible that elective radiation to the neck reaches results equal to those for END. However, our multivariate analysis identified T classification, N classification, and primary site as independent predictors of patient outcomes, whereas adjuvant radiotherapy was not significantly associated with improved patient outcomes. This is consistent with previous data showing that ACC is resistant to adjuvant therapy.18–21 Due to the retrospective design of this study, data on the patterns of recurrence and on specific levels of the neck metastases were missing for about half of the patients. Nevertheless, our data show occult nodal metastases only in levels I–III. Furthermore, none of the patients who underwent contralateral END had nodal metastases in the contralateral neck. This suggests that if performed, END should be limited to levels I–III on the ipsilateral side. Another limitation of the retrospective design was that despite the use of uniform data extraction sheets, the heterogeneity of the professionals involved in data collection (e.g., pathologists, radiologists, and radiation oncologists) may have led to inconsistency in reporting. Our data support the performance of a prospective trial to assess the role of END in ACC. Until such data are available, the tailoring of treatment for ACC should be based on risk stratification of each patient and on decisions of the multidisciplinary teams that manage the treatment of these patients.
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M. Amit et al.
TABLE 2 Multivariate analysis of prognostic factors for overall and disease-specific survival Variable
Overall survival p Value
HR
95 % CI
Disease-specific survival
Regional recurrence-free survival
p Value
p Value
HR
95 % CI
HR
95 % CI
Age
Years
0.05
6.1
3.4–12.5
0.07
NA
NA
0.004
9.3
4.1–15.8
Gender
Male
0.42
NA
NA
0.22
NA
NA
0.45
NA
NA
0.002
1
1.05–2.1
0.004
1
1.1–1.9
0.001
Female Primary site
Major glands
1.47 Oral cavity
1.28
Sinonasal
1.46–2.9
1
1.3–2.4
1.87
2.4–3.9
3.13
2.08
1.8–2.5
2.12
Margins
Negative Close (\ 5 mm) Positive
0.09
NA
NA
0.44
NA
NA
0.24
Pathologic T classification
T1
0.001
1
1.2–3.1
0.0003
1
1.5–3.7
0.04
1.74
2.1–4.46
T2
3.08
T3
4.34
1.2–7.3
1
2.1–4.3
NA
NA
1
1.1–3.4
2.1
2.11–7.5 2.5–11.8
1.96
2.1–4.5
4.14
3.12
2.96–6.7
6.1
4.71
T4 Pathologic N classification
N0
0.008
0.01
N1
1
1.02–1.5
1.19
1.1–2.23
N2
3.13
3.4–6.5
1.48
N3
5.17
4.8–10.5
2.14
1.4–3.6
0.23
NA
NA
7.66 Extracapsular spread
No
0.3
NA
NA
0.38
NA
NA
NA*
NA
NA
0.7
NA
NA
0.64
NA
NA
0.11
NA
NA
0.21
NA
NA
0.22
NA
NA
0.39
NA
NA
0.91
NA
NA
0.84
NA
NA
0.63
NA
NA
Yes Perineural invasion
No Yes
Treatment
Surgery Surgery ? RT Surgery ? CRT
Neck management
END No ND
HR hazard ratio; CI confidence interval; NA not available; RT radiation therapy; CRT chemoradiation; END elective neck dissection; ND neck dissection
CONCLUSIONS In a multisite cohort, the incidence of occult neck metastases among the patients with ACC was 17 %. Occult nodal metastasis was found only in the ipsilateral upper neck (levels I–III). In a multivariate analysis, T classification, N classification, and primary site were significant predictors of outcome. Although the high rate of occult nodal metastasis in oral cavity and major salivary gland ACC suggests performing END in cases involving these sites, we found no survival advantage for the patients who underwent END compared with those who did not regardless of site. The relatively high rate of occult nodal metastases among patients with ACC suggests that routine
imaging methods such as PET-CT and neck ultrasonography may be considered for routine follow-up evaluation in this population. CONFLICT OF INTEREST
There are no conflicts of interest.
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Elective Neck Treatment for ACC of Head and Neck 3. Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. American Journal of Surgery 1990;160(4):405-9. 4. Snow GB, van den Brekel MW, Leemans CR, Patel P. Surgical management of cervical lymph nodes in patients with oral and oropharyngeal cancer. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer 1994;134:43-55. 5. 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(19):1945-52. 6. 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(19):1937-44. 7. Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Archives of otolaryngolog 2008;134(5):536-8. 8. Pn g. Guidelines for the examination and reporting of head and neck cancer specimens. Ed.LEEDS: Yorkshire Cancer Network 2007 1-12. 9. Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457-481. 10. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemotherapy Reports Part 1 1966;50(3):163-70. 11. Cox DR. Regression models and life-tables. J R Stat Soc 1972;34:187-220. 12. Gil Z, Patel SG, Singh B, et al. Analysis of prognostic factors in 146 patients with anterior skull base sarcoma: an international collaborative study. Cancer 2007;110(5):1033-41. 13. Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional
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