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Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients
Journal of Cranio-Maxillo-Facial Surgery xxx (2017) 1e4
Contents lists available at ScienceDirect
Journal of Cranio-Maxillo-Facial Surgery journal homepage: www.jcmfs.com
Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients €ltzsch a, Robert Cordesmeyer a, *, Henning Schliephake a, Philipp Kauffmann a, Markus Tro € bel c, Felix Bremmer c Rainer Laskawi b, Philipp Stro a €tsmedizin Go €ttingen, Robert-Koch-Str. 40, 37075 Department of Oral and Maxillofacial Surgery (Head: Prof. Dr. Dr. Henning Schliephake), Universita €ttingen, Germany Go b €tsmedizin Go €ttingen, Robert-Koch-Str. 40, 37075 Department of Otolaryngology-Head and Neck Surgery (Head: Prof. Dr. Martin Canis), Universita €ttingen, Germany Go c €tsmedizin Go €bel), Universita €ttingen, Robert-Koch-Str. 40, 37075 Go €ttingen, Germany Department of Pathology (Head: Prof. Dr. Philipp Stro
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 1 November 2016 Accepted 2 August 2017 Available online xxx
Purpose: Adenoid cystic carcinomas are rare malignant tumors of the salivary glands. They are characterized by a high rate of local recurrence, late distant metastasis and a poor disease-free survival. In this € ttingen over a study, we analyzed a series of 61 patients who were all treated at the University of Go period of 21.0 years. Materials and methods: In all 61 patients with salivary adenoid cystic carcinoma, clinical data, demographic data, risk factors, tumor location, tumor stage, status of surgical margin, surgical treatment, postoperative radiotherapy and follow-up interval were assessed. Results: The overall survival (OS) and the disease-free survival (DFS) of patients who underwent surgery and those who underwent combined surgery with radiotherapy showed no significant differences. Neither did the T-stage (T1/T2 vs. T3/T4) show significant differences in OS and DFS. Only the status of the surgical margin was significantly associated with a longer OS and a longer DFS. Conclusion: The present results confirm that the radical surgical resection with clear tumor-free margins is the most important predictor for a longer survival. Adjuvant radiotherapy should be discussed from case to case, but should not be seen as an absolute prognostic factor for OS. © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Adenoid cystic carcinoma Surgery Salivary gland Radiotherapy
1. Introduction Adenoid cystic carcinomas (ACCs) of the head and neck are rare malignant tumors and account for about 10% of all malignant tumors of the salivary glands (Bradley, 2004). They are located both in the major salivary glands (parotid, submandibular and sublingual salivary gland) and in the small salivary glands all over the upper aerodigestive tract (Bjørndal et al., 2011). They are clinically characterized by slow progressive growth, followed by pain due to the propensity for perineural invasion. Moreover, ACCs tend to be associated with multiple local recurrences as well as late distance metastasis, especially to lung, bone and liver (Kokemueller et al., 2004).
ACCs occur in all age groups, with a higher frequency in middleaged and older patients (Nascimento et al., 1986). The common established therapy is radical surgery and, depending on the status of the surgical margin and the histopathology results, adjuvant postoperative radiotherapy (Coca-Pelaz et al., 2015). Due to the perineural invasion and the anatomical variability, it is surgically challenging to achieve tumor-free margins. Because of the occurrence of late recurrences and distant metastasis, the long-term prognosis for ACC is rather poor (Lloyd et al., 2011). In the literature, various survival rates have been reported, mainly due to the relative rarity of ACC patients and the follow-up over many years. The objective of this study was to analyze the survival and prognostic factors in a group of 61 patients €ttingen, Germany, between treated with ACC at the University of Go 1995 and 2016.
* Corresponding author. Fax: þ49 0 551 3912653. E-mail address: [email protected] (R. Cordesmeyer). http://dx.doi.org/10.1016/j.jcms.2017.08.004 1010-5182/© 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
2
R. Cordesmeyer et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2017) 1e4
2. Materials and methods In this study, we analyzed 68 patients with an ACC, covering the years 1995e2016. Medical charts were reviewed and the following data were collected: gender, age, type of salivary gland, tumor stage, risk factors, operation modalities, surgical margin, postoperative radiotherapy, local and distant recurrence, and follow-up time. Seven patients were excluded because of missing follow-up data, and the remaining 61 patients were included in the retrospective analysis. The type of surgical procedure was dependent on the preoperative staging and the extent of the local disease. In the included 61 patients, surgery was done in 59 cases, and two patients were treated with radiotherapy alone. A total of 23 patients (37.7%) were treated with a combination of surgery and radiotherapy, and 36 patients (59.0%) only had surgery. Clearly negative margins were defined as a pathological tumorfree margin between 3 and 5 mm, whereas a margin was considered as positive in cases of 3 mm or less. Since 21 years is a very long follow-up period, the treatment protocols have changed with time. The decision to treat a patient with an additional radiotherapy was in the majority a T-stage of 3 and 4 or a positive margin. In the majority of cases, radiotherapy was generally given to a total dose of 60e70 Gy. Different modalities of postoperative radiotherapy for ACCs were used. Some patients received neutron irradiation, photons or a mixed photon/ neutron beam. Radiotherapy in these patients was carried out at other radiotherapy cancer centers, so it was not reasonable to compare the various radiation doses. Patients were seen monthly during the first year, every 2e3 months in the second year, 3e4 months in the third year, and 4e6 months in the fourth and fifth years after treatment, respectively. After 5 years, the controls were continued yearly. Overall survival (OS) was defined as the interval between the date of diagnosis and the date of death or last follow-up control. Disease-free survival (DFS) was defined as the interval between the date of diagnosis and the date of recurrence, death or last follow-up. Disease-free survival and overall survival of the therapy, the Tstage and the surgical margin were compared by the Mann Whitney U Test. A value of P 0.05 was considered to be statistically significant for all analyses. 3. Results The median age of the study population was 56.4 years (range 28e84 years). Of the patients, 34 were female (55.7%) and 27 were male (44.3%). A total of 46 cases (75.4%) involved the minor salivary glands, with the most common occurrence in the oral cavity and the nasopharynx. Eighteen patients (29.5%) were regular smokers (mean of 21.7 pack-years) and two patients had chronical alcohol abuse. Table 1 provides the demographic, tumor and treatment data. The most affected major salivary gland was the submandibular gland. The exact distributions of the primary tumor are reported in Table 2. Recurrence data are provided in Table 3. During the follow-up period, 21 patients (34.4%) experienced recurrence. Of these, five patients (8.2%) had locoregional relapse, 12 (19.7%) developed both local and distant metastasis, and four patients (6.6%) had distant metastasis. The predominant sites for distant metastasis were the lung (60.8%), brain (17.4%), liver (13.0%), bone (8.7%) and combinations of these. The follow-up ranged from 4 to 235 months (mean 71.2 months). The mean interval between time of diagnosis and the appearance of local recurrence was 67.6 months (range 15e150 months). The median interval from the time of diagnosis to the appearance of distant metastases was 92.2 months (range 12e214 months).
Table 1 Patients, risk factors, tumor location and postoperative treatment. Sex Male Female Age Postoperative radiotherapy Yes No No surgery, only radiotherapy Type of salivary gland Major Minor Risk factors Tobacco smoking Chronic alcohol abuse
27 (44.3%) 34 (55.7%) 28e84 years (mean 56.4 years) 23 (37.7%) 36 (59.0%) 2 (3.3%) 15 (24.6%) 46 (75.4%) 18 (29.5%, mean 21.7 pack years) 2 (3.3%)
In all, 23 patients underwent surgery with postoperative radiotherapy. The median OS of this group was 67.2 months, the median DFS was 53.8 months. A total of 36 patients underwent surgery alone, with a median OS of 76.3 months and a median DFS of 61.4 months. Fig. 1 shows that there were no significant differences between these treatment modalities. In addition, two patients received radiotherapy to the primary because of nonresectable tumor, with a median OS of 26 months. Fig. 2 compares the OS of the T-stage T1/T2 and T3/T4. Although we can see a trend toward improved OS for earlier T-stage, the two groups did not differ statistically. Of the patients who received surgery, 83.3% had clear negative margins. The median OS of the patients with clear margins was 78.6 months, and the median DFS was 64.8 months. The 16.7% with positive margins had a median OS of 44.1 months and a median DFS of 28.1 months. Fig. 3 shows a significant difference of the OS (P ¼ 0.03) and the DFS (P ¼ 0.005) between negative and positive margins. 4. Discussion There was a female predominance within our group (F:M ratio 1.26:1), which was in agreement with previous studies in European countries (Ciccolallo et al., 2009). In our group, the mean age of occurrence was 56.4 years, ranging from 28 to 84 years. This was consistent with other reports (Spiro et al., 1974; Bjørndal et al., 2011). Regarding the primary tumor site, there were all anatomical locations represented. Most cases were located in the minor salivary glands (75.4%), especially in the oral cavity. Of the major salivary glands, 53.3% of the tumors involved the submandibular gland and 46.7% the parotid gland. These findings are in line with the literature (Zhang et al., 2013). In accordance with previous literature, we found, in this singlecenter cohort study, that the margin status was the strongest prognostic factor. The OS time is significantly correlated with a negative, free margin (Garden et al., 1995; Gomez et al., 2008; Oplatek et al., 2010; Coca-Pelaz et al., 2015). Due to the infiltrative growth and perineural invasion, a free margin is often not Table 2 Distribution of primary tumor site. Major salivary glands Parotid Submandibular Sublingual
Minor salivary glands 7 8 0
Infratemporal fossa Larynx/trachea Nasopharynx Oral cavity/lip Oropharynx Tongue External auditory canal
1 6 9 23 1 5 1
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
R. Cordesmeyer et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2017) 1e4
3
Table 3 Development of recurrence. Total number of recurrences Local recurrence Distant metastasis Local and distant recurrence
21 (34.4%) 5 (8.2%) 4 (6.6%) 12 (19.7 %)
achievable. In particular, the free margin is a problem in difficult anatomical regions. A radical surgical resection should be the main goal of any therapy. In close or positive surgical margins, a reexcision should be implemented. A surgical therapy concept should take this into account and a functional reconstruction can secondarily be done after the final pathology. Comparing the patients who received only surgery with patients who received surgery and radiotherapy, we saw no significant difference of the OS and the DFS (Fig. 1). The value of adjuvant radiotherapy and especially the modalities of radiotherapy have been intensively discussed in the literature. However, indications for adjuvant radiotherapy should also be considered. In this study, the indication for radiotherapy was, in the majority of cases, a Tstage of 3 and 4 or a positive margin. Silverman et al. (2004) also discussed that the indication for radiotherapy for patients with early T stage and negative surgical margins may not be necessary. Meyers et al. (2016) also reported that adjuvant radiotherapy did not emerge as a prognostic factor. Other authors such as Mendenhall et al. (2004) compared radiotherapy alone to a combined therapy and concluded that a combination treatment is, in general, preferable. If clear surgical margins cannot be achieved, there should be very close follow-up. The decision regarding adjuvant radiotherapy should be individually discussed, but should not be seen as an absolute therapeutic measure. It is to be discussed whether radiotherapy should be reserved to treat local recurrence. In various studies, tumor sizes were associated with a poorer outcome (Khan et al., 2001; Silverman et al., 2004; Oplatek et al., 2010). Looking on the present study, there are no significant differences of the OS between the T-stages T1/T2 and T3/T4. The mean OS of stage T1/T2 patients shows only a trend toward improved OS for earlier T-stage. The OS from the appearance of local recurrence to death or last follow-up examination was 43.2 months (range 3e137 months). The survival period from the appearance of distant metastasis to death or last follow-up examination was 15.6 months (range 1e99
Fig. 2. Overall survival depending on T-stage.
months). These results confirm the common opinion that asymptomatic patients with incurable disease may be observed for years without systemic therapy (Coca-Pelaz et al., 2015). Systemic chemotherapy should be generally reserved for palliative treatment. Yet the long-term survival rate is low, and depends on the presence and management of distant metastasis. In the future, systemic targeted therapies may affect the incidence and progress of local and distant metastasis. 5. Conclusion The present results confirm that radical surgical resection with clear negative margins is the most important predictor for survival. Adjuvant radiotherapy should be discussed from case to case, but should not be taken as an absolute therapeutic measure. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. All procedures performed in studies involving human participants were in
Fig. 1. Disease-free survival (DFS) and overall survival (OS), depending on surgery or surgery combined with radiotherapy.
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
4
R. Cordesmeyer et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2017) 1e4
Fig. 3. Disease-free survival (DFS) and overall survival (OS) depending on the surgical margin.
accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Funding This work was supported by the Department of Oral & Maxillofacial Surgery, the Department of Otolaryngology-Head and Neck € ttingen, Surgery and the Department of Pathology, University of Go Germany. Conflict of interest All authors declare that they have no conflict of interest. Informed consent For this type of study, formal consent was not required. References Bradley PJ: Adenoid cystic carcinoma of the head and neck: a review. Curr Opin Otolaryngol Head Neck Surg 12: 127e132, 2004 Bjørndal K, Krogdahl A, Therkildsen MH, Kristensen CA, Charabi B, Andersen E, et al: Salivary gland carcinoma in Denmark 1990e2005: a national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA). Oral Oncol 47: 677e682, 2011 Ciccolallo L, Licitra L, Cantú G, Gatta G, EUROCARE Working Group: Survival from salivary glands adenoid cystic carcinoma in European populations. Oral Oncol 45: 669e674, 2009 Coca-Pelaz A, Rodrigo JP, Bradley PJ, Vander Poorten V, Triantafyllou A, Hunt JL, et al: Adenoid cystic carcinoma of the head and neckean update. Oral Oncol 51: 652e661, 2015
Garden AS, Weber RS, Morrison WH, Ang K, Peters LJ: The influence of positive margins and nerve invasion in adenoid cystic carcinoma of head and neck treated with surgery and radiation. Int J Radiat Oncol Biol Phys 32: 619e626, 1995 Gomez DR, Hoppe BS, Wolden SL, Zhung JE, Patel SG, Kraus DH, et al: Outcomes and variables in adenoid cystic carcinoma of the head and neck: a recent experience. Int J Radiat Oncol Biol Phys 70: 1365e1372, 2008 Khan AJ, DiGiovanna MP, Ross DA, Sasaki CT, Carter D, Son YH, et al: Adenoid cystic carcinoma: a retrospective clinical review. Int J Cancer J Int Cancer 96: 149e158, 2001 Kokemueller H, Eckardt A, Brachvogel P, Hausamen JE: Adenoid cystic carcinoma of the head and neckea 20 years experience. Int J Oral Maxillofac Surg 33: 25e31, 2004 Lloyd S, Yu JB, Wilson LD, Decker RH: Determinants and patterns of survival in adenoid cystic carcinoma of the head and neck, including an analysis of adjuvant radiation therapy. Am J Clin Oncol 34: 76e81, 2011 Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Hinerman RW, Villaret DB: Radiotherapy alone or combined with surgery for adenoid cystic carcinoma of the head and neck. Head Neck 26: 154e162, 2004 Meyers M, Granger B, Herman P, Janot F, Garrel R, Fakhry N, et al, REFCOR members: Head and neck adenoid cystic carcinoma: a prospective multicenter REFCOR study of 95 cases. Eur Ann Otorhinolaryngol Head Neck Dis 133: 13e17, 2016 Nascimento AG, Amaral AL, Prado LA, Klingerman J, Silveira TR: Adenoid cystic carcinoma of salivary glands. A study of 61 cases with clinicopathologic correlation. Cancer 57: 312e319, 1986 Oplatek A, Ozer E, Agrawal A, Bapna S, Schuller DE: Patterns of recurrence and survival of head and neck adenoid cystic carcinoma after definitive resection. Laryngoscope 120: 65e70, 2010 Silverman DA, Carlson TP, Khuntia D, Bergstrom RT, Saxton J, Esclamado RM: Role for postoperative radiation therapy in adenoid cystic carcinoma of the head and neck. Laryngoscope 114: 1194e1199, 2004 Spiro RH, Huvos AG, Strong EW: Adenoid cystic carcinoma of salivary origin. A clinicopathologic study of 242 cases. Am J Surg 128: 512e520, 1974 Zhang CY, Xia RH, Han J, Wang BS, Tian WD, Zhong LP, et al: Adenoid cystic carcinoma of the head and neck: clinicopathologic analysis of 218 cases in a Chinese population. Oral Surg Oral Med Oral Pathol Oral Radiol 115: 368e375, 2013
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
Contents lists available at ScienceDirect
Journal of Cranio-Maxillo-Facial Surgery journal homepage: www.jcmfs.com
Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients €ltzsch a, Robert Cordesmeyer a, *, Henning Schliephake a, Philipp Kauffmann a, Markus Tro € bel c, Felix Bremmer c Rainer Laskawi b, Philipp Stro a €tsmedizin Go €ttingen, Robert-Koch-Str. 40, 37075 Department of Oral and Maxillofacial Surgery (Head: Prof. Dr. Dr. Henning Schliephake), Universita €ttingen, Germany Go b €tsmedizin Go €ttingen, Robert-Koch-Str. 40, 37075 Department of Otolaryngology-Head and Neck Surgery (Head: Prof. Dr. Martin Canis), Universita €ttingen, Germany Go c €tsmedizin Go €bel), Universita €ttingen, Robert-Koch-Str. 40, 37075 Go €ttingen, Germany Department of Pathology (Head: Prof. Dr. Philipp Stro
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 1 November 2016 Accepted 2 August 2017 Available online xxx
Purpose: Adenoid cystic carcinomas are rare malignant tumors of the salivary glands. They are characterized by a high rate of local recurrence, late distant metastasis and a poor disease-free survival. In this € ttingen over a study, we analyzed a series of 61 patients who were all treated at the University of Go period of 21.0 years. Materials and methods: In all 61 patients with salivary adenoid cystic carcinoma, clinical data, demographic data, risk factors, tumor location, tumor stage, status of surgical margin, surgical treatment, postoperative radiotherapy and follow-up interval were assessed. Results: The overall survival (OS) and the disease-free survival (DFS) of patients who underwent surgery and those who underwent combined surgery with radiotherapy showed no significant differences. Neither did the T-stage (T1/T2 vs. T3/T4) show significant differences in OS and DFS. Only the status of the surgical margin was significantly associated with a longer OS and a longer DFS. Conclusion: The present results confirm that the radical surgical resection with clear tumor-free margins is the most important predictor for a longer survival. Adjuvant radiotherapy should be discussed from case to case, but should not be seen as an absolute prognostic factor for OS. © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Adenoid cystic carcinoma Surgery Salivary gland Radiotherapy
1. Introduction Adenoid cystic carcinomas (ACCs) of the head and neck are rare malignant tumors and account for about 10% of all malignant tumors of the salivary glands (Bradley, 2004). They are located both in the major salivary glands (parotid, submandibular and sublingual salivary gland) and in the small salivary glands all over the upper aerodigestive tract (Bjørndal et al., 2011). They are clinically characterized by slow progressive growth, followed by pain due to the propensity for perineural invasion. Moreover, ACCs tend to be associated with multiple local recurrences as well as late distance metastasis, especially to lung, bone and liver (Kokemueller et al., 2004).
ACCs occur in all age groups, with a higher frequency in middleaged and older patients (Nascimento et al., 1986). The common established therapy is radical surgery and, depending on the status of the surgical margin and the histopathology results, adjuvant postoperative radiotherapy (Coca-Pelaz et al., 2015). Due to the perineural invasion and the anatomical variability, it is surgically challenging to achieve tumor-free margins. Because of the occurrence of late recurrences and distant metastasis, the long-term prognosis for ACC is rather poor (Lloyd et al., 2011). In the literature, various survival rates have been reported, mainly due to the relative rarity of ACC patients and the follow-up over many years. The objective of this study was to analyze the survival and prognostic factors in a group of 61 patients €ttingen, Germany, between treated with ACC at the University of Go 1995 and 2016.
* Corresponding author. Fax: þ49 0 551 3912653. E-mail address: [email protected] (R. Cordesmeyer). http://dx.doi.org/10.1016/j.jcms.2017.08.004 1010-5182/© 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
2
R. Cordesmeyer et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2017) 1e4
2. Materials and methods In this study, we analyzed 68 patients with an ACC, covering the years 1995e2016. Medical charts were reviewed and the following data were collected: gender, age, type of salivary gland, tumor stage, risk factors, operation modalities, surgical margin, postoperative radiotherapy, local and distant recurrence, and follow-up time. Seven patients were excluded because of missing follow-up data, and the remaining 61 patients were included in the retrospective analysis. The type of surgical procedure was dependent on the preoperative staging and the extent of the local disease. In the included 61 patients, surgery was done in 59 cases, and two patients were treated with radiotherapy alone. A total of 23 patients (37.7%) were treated with a combination of surgery and radiotherapy, and 36 patients (59.0%) only had surgery. Clearly negative margins were defined as a pathological tumorfree margin between 3 and 5 mm, whereas a margin was considered as positive in cases of 3 mm or less. Since 21 years is a very long follow-up period, the treatment protocols have changed with time. The decision to treat a patient with an additional radiotherapy was in the majority a T-stage of 3 and 4 or a positive margin. In the majority of cases, radiotherapy was generally given to a total dose of 60e70 Gy. Different modalities of postoperative radiotherapy for ACCs were used. Some patients received neutron irradiation, photons or a mixed photon/ neutron beam. Radiotherapy in these patients was carried out at other radiotherapy cancer centers, so it was not reasonable to compare the various radiation doses. Patients were seen monthly during the first year, every 2e3 months in the second year, 3e4 months in the third year, and 4e6 months in the fourth and fifth years after treatment, respectively. After 5 years, the controls were continued yearly. Overall survival (OS) was defined as the interval between the date of diagnosis and the date of death or last follow-up control. Disease-free survival (DFS) was defined as the interval between the date of diagnosis and the date of recurrence, death or last follow-up. Disease-free survival and overall survival of the therapy, the Tstage and the surgical margin were compared by the Mann Whitney U Test. A value of P 0.05 was considered to be statistically significant for all analyses. 3. Results The median age of the study population was 56.4 years (range 28e84 years). Of the patients, 34 were female (55.7%) and 27 were male (44.3%). A total of 46 cases (75.4%) involved the minor salivary glands, with the most common occurrence in the oral cavity and the nasopharynx. Eighteen patients (29.5%) were regular smokers (mean of 21.7 pack-years) and two patients had chronical alcohol abuse. Table 1 provides the demographic, tumor and treatment data. The most affected major salivary gland was the submandibular gland. The exact distributions of the primary tumor are reported in Table 2. Recurrence data are provided in Table 3. During the follow-up period, 21 patients (34.4%) experienced recurrence. Of these, five patients (8.2%) had locoregional relapse, 12 (19.7%) developed both local and distant metastasis, and four patients (6.6%) had distant metastasis. The predominant sites for distant metastasis were the lung (60.8%), brain (17.4%), liver (13.0%), bone (8.7%) and combinations of these. The follow-up ranged from 4 to 235 months (mean 71.2 months). The mean interval between time of diagnosis and the appearance of local recurrence was 67.6 months (range 15e150 months). The median interval from the time of diagnosis to the appearance of distant metastases was 92.2 months (range 12e214 months).
Table 1 Patients, risk factors, tumor location and postoperative treatment. Sex Male Female Age Postoperative radiotherapy Yes No No surgery, only radiotherapy Type of salivary gland Major Minor Risk factors Tobacco smoking Chronic alcohol abuse
27 (44.3%) 34 (55.7%) 28e84 years (mean 56.4 years) 23 (37.7%) 36 (59.0%) 2 (3.3%) 15 (24.6%) 46 (75.4%) 18 (29.5%, mean 21.7 pack years) 2 (3.3%)
In all, 23 patients underwent surgery with postoperative radiotherapy. The median OS of this group was 67.2 months, the median DFS was 53.8 months. A total of 36 patients underwent surgery alone, with a median OS of 76.3 months and a median DFS of 61.4 months. Fig. 1 shows that there were no significant differences between these treatment modalities. In addition, two patients received radiotherapy to the primary because of nonresectable tumor, with a median OS of 26 months. Fig. 2 compares the OS of the T-stage T1/T2 and T3/T4. Although we can see a trend toward improved OS for earlier T-stage, the two groups did not differ statistically. Of the patients who received surgery, 83.3% had clear negative margins. The median OS of the patients with clear margins was 78.6 months, and the median DFS was 64.8 months. The 16.7% with positive margins had a median OS of 44.1 months and a median DFS of 28.1 months. Fig. 3 shows a significant difference of the OS (P ¼ 0.03) and the DFS (P ¼ 0.005) between negative and positive margins. 4. Discussion There was a female predominance within our group (F:M ratio 1.26:1), which was in agreement with previous studies in European countries (Ciccolallo et al., 2009). In our group, the mean age of occurrence was 56.4 years, ranging from 28 to 84 years. This was consistent with other reports (Spiro et al., 1974; Bjørndal et al., 2011). Regarding the primary tumor site, there were all anatomical locations represented. Most cases were located in the minor salivary glands (75.4%), especially in the oral cavity. Of the major salivary glands, 53.3% of the tumors involved the submandibular gland and 46.7% the parotid gland. These findings are in line with the literature (Zhang et al., 2013). In accordance with previous literature, we found, in this singlecenter cohort study, that the margin status was the strongest prognostic factor. The OS time is significantly correlated with a negative, free margin (Garden et al., 1995; Gomez et al., 2008; Oplatek et al., 2010; Coca-Pelaz et al., 2015). Due to the infiltrative growth and perineural invasion, a free margin is often not Table 2 Distribution of primary tumor site. Major salivary glands Parotid Submandibular Sublingual
Minor salivary glands 7 8 0
Infratemporal fossa Larynx/trachea Nasopharynx Oral cavity/lip Oropharynx Tongue External auditory canal
1 6 9 23 1 5 1
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
R. Cordesmeyer et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2017) 1e4
3
Table 3 Development of recurrence. Total number of recurrences Local recurrence Distant metastasis Local and distant recurrence
21 (34.4%) 5 (8.2%) 4 (6.6%) 12 (19.7 %)
achievable. In particular, the free margin is a problem in difficult anatomical regions. A radical surgical resection should be the main goal of any therapy. In close or positive surgical margins, a reexcision should be implemented. A surgical therapy concept should take this into account and a functional reconstruction can secondarily be done after the final pathology. Comparing the patients who received only surgery with patients who received surgery and radiotherapy, we saw no significant difference of the OS and the DFS (Fig. 1). The value of adjuvant radiotherapy and especially the modalities of radiotherapy have been intensively discussed in the literature. However, indications for adjuvant radiotherapy should also be considered. In this study, the indication for radiotherapy was, in the majority of cases, a Tstage of 3 and 4 or a positive margin. Silverman et al. (2004) also discussed that the indication for radiotherapy for patients with early T stage and negative surgical margins may not be necessary. Meyers et al. (2016) also reported that adjuvant radiotherapy did not emerge as a prognostic factor. Other authors such as Mendenhall et al. (2004) compared radiotherapy alone to a combined therapy and concluded that a combination treatment is, in general, preferable. If clear surgical margins cannot be achieved, there should be very close follow-up. The decision regarding adjuvant radiotherapy should be individually discussed, but should not be seen as an absolute therapeutic measure. It is to be discussed whether radiotherapy should be reserved to treat local recurrence. In various studies, tumor sizes were associated with a poorer outcome (Khan et al., 2001; Silverman et al., 2004; Oplatek et al., 2010). Looking on the present study, there are no significant differences of the OS between the T-stages T1/T2 and T3/T4. The mean OS of stage T1/T2 patients shows only a trend toward improved OS for earlier T-stage. The OS from the appearance of local recurrence to death or last follow-up examination was 43.2 months (range 3e137 months). The survival period from the appearance of distant metastasis to death or last follow-up examination was 15.6 months (range 1e99
Fig. 2. Overall survival depending on T-stage.
months). These results confirm the common opinion that asymptomatic patients with incurable disease may be observed for years without systemic therapy (Coca-Pelaz et al., 2015). Systemic chemotherapy should be generally reserved for palliative treatment. Yet the long-term survival rate is low, and depends on the presence and management of distant metastasis. In the future, systemic targeted therapies may affect the incidence and progress of local and distant metastasis. 5. Conclusion The present results confirm that radical surgical resection with clear negative margins is the most important predictor for survival. Adjuvant radiotherapy should be discussed from case to case, but should not be taken as an absolute therapeutic measure. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. All procedures performed in studies involving human participants were in
Fig. 1. Disease-free survival (DFS) and overall survival (OS), depending on surgery or surgery combined with radiotherapy.
Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004
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Fig. 3. Disease-free survival (DFS) and overall survival (OS) depending on the surgical margin.
accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Funding This work was supported by the Department of Oral & Maxillofacial Surgery, the Department of Otolaryngology-Head and Neck € ttingen, Surgery and the Department of Pathology, University of Go Germany. Conflict of interest All authors declare that they have no conflict of interest. Informed consent For this type of study, formal consent was not required. References Bradley PJ: Adenoid cystic carcinoma of the head and neck: a review. Curr Opin Otolaryngol Head Neck Surg 12: 127e132, 2004 Bjørndal K, Krogdahl A, Therkildsen MH, Kristensen CA, Charabi B, Andersen E, et al: Salivary gland carcinoma in Denmark 1990e2005: a national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA). Oral Oncol 47: 677e682, 2011 Ciccolallo L, Licitra L, Cantú G, Gatta G, EUROCARE Working Group: Survival from salivary glands adenoid cystic carcinoma in European populations. Oral Oncol 45: 669e674, 2009 Coca-Pelaz A, Rodrigo JP, Bradley PJ, Vander Poorten V, Triantafyllou A, Hunt JL, et al: Adenoid cystic carcinoma of the head and neckean update. Oral Oncol 51: 652e661, 2015
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Please cite this article in press as: Cordesmeyer R, et al., Clinical prognostic factors of salivary adenoid cystic carcinoma: A single-center analysis of 61 patients, Journal of Cranio-Maxillo-Facial Surgery (2017), http://dx.doi.org/10.1016/j.jcms.2017.08.004