© 2007 Foundation for Promotion of Cancer Research
Prognostic Factors Affecting the Clinical Outcome of Adenoid Cystic Carcinoma of the Head and Neck
1 Division of Oncology, Department of Internal Medicine, Head and Neck and Cancer Multidisciplinary Team, Kangnam St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
2 Department of Hospital Pathology, Head and Neck and Cancer Multidisciplinary Team, Kangnam St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
3 Department of Radiation Oncology, Head and Neck and Cancer Multidisciplinary Team, Kangnam St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
4 Department of Otolaryngology-Head and Neck and Cancer Multidisciplinary Team, Kangnam St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
5 Department of Diagnostic Radiology, Head and Neck and Cancer Multidisciplinary Team, Kangnam St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
For reprints and all correspondence: Jin Hyoung Kang, Division of Oncology, Department of Internal Medicine, Kangnam St Mary's hospital, Catholic University, Banpo-dong 505, Seocho-gu, 137-701, Seoul, Korea, E-mail: jinkang{at}catholic.ac.kr
Received April 29, 2007; accepted August 4, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Adenoid cystic carcinoma (ACC) is an uncommon tumor, constituting approximately 10% of all head and neck tumors. Classically, ACC has been described as a tumor with indolent, but persistent and recurrent, growth and late onset of metastases, leading eventually to death. This study assessed the prognostic factors affecting the clinical outcome in patients with ACC in the head and neck region.
Methods: We performed a retrospective study of 42 patients who underwent primary tumor resection or radiotherapy with curative intent and evaluated the clinical parameters, treatment and clinical outcomes.
Results: Forty-two patients (18 males and 24 females with a median age of 65 years) received curative treatment. The overall 3- and 5-year survival was 87.4% and 55.3%, respectively, whereas the 3- and 5-year disease-free survival was 64.3% and 36.1%, respectively. Of the 32 patients in whom recurrence could be evaluated, 18 (56.3%) developed distant metastases, with the lung (72.2%) being the most common site. Perivascular invasion influenced metastasis to the lung with borderline significance (P = 0.053). The recurrence rate was higher (P = 0.045) in patients with high-grade tumor. The status of lymph node metastasis was significantly associated with overall survival (P = 0.030).
Conclusions: High tumor grade and lymph node involvement were predictive of recurrence and overall survival, respectively. Despite aggressive treatment, it seems to be impossible to prevent the development of distant metastasis. Therefore, more research is needed to identify molecular biomarkers that predict the clinical outcome and to develop effective treatment for patients with ACC.
Key Words: adenoid cystic carcinoma • head and neck neoplasm • perivascular invasion • prognosis
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Adenoid cystic carcinoma (ACC) is an uncommon epithelial tumor, constituting approximately 10% of all head and neck tumors (1). ACC occurring in the minor salivary glands of the head and neck tends to spread along nerves (2). Classically, ACC has been described as a tumor with indolent, but persistent and recurrent, growth and late onset of metastases, which eventually leads to death (3). It commonly presents with delayed metastases to the lungs, bone and liver (4). Histologically, ACC can be categorized into three histological subtypes based on the growth pattern: tubular, cribriform and solid (5).
Several studies have found that clinicopathological factors with an unfavorable effect on survival in ACC include old age, tumor location, advanced stage, solid histological subtype, high grade, major nerve involvement and the presence of perineural invasion or a positive surgical margin (2,6–9). Despite much research, however, no standard treatment for ACC has been established. Currently, surgery is the most effective treatment modality, which is usually followed by adjuvant radiotherapy. Some reports have indicated that patients who undergo post-operative radiotherapy had an improved survival compared with surgery alone (8,10). However, in unresectable cases or those with local recurrence after surgery, no efficient treatment strategy has been developed.
We performed this study to investigate the impact of various clinicopathological parameters on local recurrence and distant metastasis after primary treatment and disease-free and overall survival in patients with ACC in the head and neck region.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We performed a retrospective study of the patients with ACC in the head and neck region who had histologically confirmed diagnoses at Kangnam St. Mary's Hospital, the Catholic University of Korea. The study population consisted of 42 patients who underwent primary tumor resection or radiotherapy with curative intent between 1990 and 2004. This study was approved by our hospital institutional review board. Medical records were reviewed to evaluate clinical parameters, treatment and clinical outcomes. All of the patients were assigned a pathological TNM stage according to the criteria of the American Joint Committee on Cancer (AJCC) staging system, 6th ed. An experienced pathologist reviewed tumor tissue slides thoroughly for tumor growth pattern, histological grade, surgical resection margin and the presence of peritumoral lymphatic, vascular and neural invasion. ACC was classified according to its morphological growth pattern into the three types: cribriform, tubular and solid. The surgical resection was considered incomplete when residual tumor cells were discovered at the margin of the surgical specimens. The pathological tumor size (in centimeters) and the involvement of pathologically positive regional nodes were also recorded.
Statistical Methods
Statistical calculations were performed using the statistical software package SPSS (version 13.0; SPSS, Chicago, IL, USA). Survival was determined from the date of surgery to the time of an event (recurrence or death) using the Kaplan–Meier method. Following an intent-to-treat approach, non-cancer-related deaths and patients lost to follow-up were included in the survival analyses, but considered censored data. The relationship between the clinicopathological features and metastasis was evaluated using Spearman's correlation of rank coefficient or Fisher's exact probability test. Statistical significance of differences in the cumulative survival curves was evaluated using the log-rank test. Multivariate survival analysis was performed on all parameters that were found to be significant in the univariate analysis using the Cox proportional hazard model. Survival rates and odds ratios are presented with their 95% confidence intervals (CIs). Statistical tests were two-sided at the 5% level of significance.
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RESULTS |
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Patient Characteristics
Table 1 summarizes the clinicopathological characteristics. The median age of the patients was 53 years (range, 23–75), and the subjects comprised 18 male and 24 female patients, for a male-to-female ratio of 1:1.3. Pain (20.7%) and a palpable mass (17.2%) were the most common complaints at the time of diagnosis. The distribution of stage was as follows: 16.7% Stage I, 23.8% Stage II, 26.2% Stage III and 31.0% Stage IV. Lymph node involvement of the tumor was observed in 6 (20.7%) of the 29 patients. The histological subtype was cribriform, tubular and solid in 19 (65.5%), 5 (17.2%) and 5 (17.2%) cases, respectively. Microscopic examination of the primary tumor tissue revealed that perineural invasion (78.1%) was frequent, followed by lymphatic invasion (34.5%) and vascular invasion (15.2%). ACC with perineural invasion was significantly correlated with the status of the resection margins (P = 0.001), age 50 years or older (P = 0.027) and lymphatic invasion (P = 0.049). Excluding one patient who was lost to follow-up, 39 of 41 underwent surgical resection and the other two received radiotherapy with curative intent as the primary treatment. Of the 39 patients who underwent primary surgical resection, 26 patients had post-operative adjuvant radiotherapy, two had concurrent chemoradiotherapy and two had chemotherapy. The radiation field included the entire pre-operative area involved by the tumor and the post-operative tumor bed sites. Only patients with pathologically proven nodal metastasis received post-operative irradiation to the neck in addition to the primary site. We used generous radiation fields to include regional nerve roots, especially for patients who had perineural invasions. Post-operative irradiation was given with a conventional fractionation schedule of 1.8 Gy per day five times a week. The total dose varied between 54.0 and 66.0 Gy with a mean of 60.3 Gy. In the concurrent chemoradiotherapy treatment, cisplatin (100 mg/m2) was administered intravenously every 3 weeks during radiation therapy. Although residual tumor cells were found at the surgical resection margins in 28 (80.0%) of 35 patients, additional radiotherapy or concurrent chemoradiotherapy was allowed in all patients with a positive surgical margin.
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Tumor Location
ACCs arising in the minor salivary glands (73.8%) were more common than those arising in the major salivary glands (26.2%, Table 2). In the minor salivary glands, 11 (35.5%) tumors were located in the maxilla sinus, five (16.1%) in the base of the tongue and five (16.1%) in the nasal cavity. In the major glands, seven (63.6%) tumors were located in the submandibular gland and four (36.4%) in the parotid gland.
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Recurrence after Primary Treatment
With a median follow-up of 49.2 months (range, 0.1–176.3), all 32 patients were evaluated for recurrence. Twenty-five (78.1%) patients experienced disease recurrence with a median time to relapse of 46.7 months (95% CI, 25.1–68.3), 11 (34.4%) cases experienced locoregional recurrence and distant metastasis occurred in 18 (56.3%) cases (Table 3). The median time to locoregional recurrence was 26.4 months (95% CI, 15.2–37.6), and the median time to distant metastasis was 36.7 months (95% CI, 17.6–55.8). The 3- and 5-year disease-free survival rates were 64.3% and 36.1%, respectively. Of the distant metastases, 13 (72.2%) cases were in the lung, six (33.3%) in bone and three (16.7%) in brain.
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Clinical Parameters Affecting Recurrence
In the univariate analysis, the factors significantly associated with the cumulative incidence of disease recurrence included histological grade (P = 0.030), pathological stage (P = 0.026) and tumor size (P = 0.041; Table 4). Histological growth subtype (solid type) and tumor location (minor salivary gland) tended to predict disease recurrence. In addition, the tumor growth pattern and histological grade were significantly correlated with local recurrence (P = 0.026 and 0.042, respectively). In contrast, pathologic stage and tumor size were significantly related to distant metastasis (P = 0.016 and 0.005, respectively). However, in the multivariate analysis, a poorly differentiated histological grade (hazard ratio 3.680; P = 0.045) was the only independent predictor of disease-free survival (Table 5, Fig. 1).
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Overall Survival after Primary Treatment
With a median follow-up of 49.2 months (range, 0.1–176.3), the median overall survival was 87.8 months (95% CI, 42.5–133.1) and the overall survival rate was 87.4% at 3 years and 55.3% at 5 years, with 20 deaths during the follow-up period.
In the univariate analysis, histological grade, pathologic stage and lymph node metastasis were significantly associated with the overall survival (Table 4). In contrast, in the multivariate analysis, lymph node metastasis (hazard ratio 14.226; P = 0.030) was the only independent predictor of overall survival (Table 5, Fig. 2).
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Clinicopathological Variables that Affect Lung Metastasis
The lung (72.2%) was the most common site of distant metastases from ACC in the head and neck region. The median time to recurrence in the lung was 28.7 months (95% CI, 1.6–146.1). Of the clinicopathological variables, perivascular invasion was significantly correlated with pulmonary metastases (P = 0.053; Table 6). The overall median survival after the diagnosis of lung metastasis was 21.2 months.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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ACC, which accounts for approximately 10% of head and neck cancers, is rare among all malignancies of the salivary glands (1,11). Clinically, it is characterized by slow progression, multiple recurrences and late distant metastasis (1,3). The 5-year survival rate is relatively high, however, the 10- to 20-year survival rates are dismally low (1). Therefore, further understanding of the characteristic biological behavior and molecular genetics of ACC may provide new insights into the novel treatment of the disease.
Our data concur with previous reports that ACC is predominantly a tumor of adulthood, with a definite peak incidence in the fourth to sixth decades and female predominance (2,12). The median age of our patients was 53 years and the male-to-female ratio was 1:1.3. ACCs occur mainly in the minor salivary glands, particularly in the oral cavity (palate) (2,11,13). Similarly, in our series, ACCs arose predominantly in the minor salivary glands (73.8%) and maxillary sinus (21.4%), including the palate, which were the most frequent sites. The stage of disease was relatively evenly distributed in all patients. ACCs arising in the minor salivary glands are often advanced at the time of diagnosis due to later presentation (2,11). Indeed, of 31 patients with ACCs arising in the minor salivary glands, 12 (38.7%) patients had Stage IV disease, whereas only 1 (9.1%) of 11 patients with ACCs arising in the major salivary glands had Stage IV disease. Histopathologically, perineural invasion is common in ACC. In our series, 25 (78.1%) of 32 patients had perineural invasion, even with early stage tumors, as reported in other studies (11). Perineural invasion is likely associated with clinical parameters such as tumor cells at the surgical margin, major salivary gland tumors and advanced stage (2).
Currently, ACC remains an extremely difficult disease to treat. Regarding the general treatment strategies for ACC in the head and neck, surgery and radiotherapy are considered effective treatment modalities. Nevertheless, with unresectable locoregional recurrence after surgery, no efficient treatment strategy for local control has been confirmed. In our series, the 28 patients with positive surgical margins had adjunctive radiation therapy with a median 58.1 Gy as adjuvant treatment. ACC is relatively radiosensitive and may have a dose–response relationship with radiation (6,10), but positive surgical margins may represent resistant disease (14). Indeed, Kreitner et al. (11) reported that radiotherapy with a total dose of 70–80 Gy achieved good local control in all patients with ACC (15). However, it generally considered difficult to deliver 70 Gy or more with conventional radiotherapy. Avery et al. (16) reported that post-operative radiotherapy with a maximum dose of 65 Gy successfully achieved local control.
Despite aggressive therapy, locoregional recurrence occurs at a rate of 20–50% and may present as early as 2 years after primary treatment (12,17). The incidence of distant metastases in ACC, most often in the lungs, ranges from 35–50% (18). The overall 5- and 10-year survival rates are 56–72% and 32–44%, respectively (2,12,17). In our series, 34.4% of the patients experienced local recurrence at a median time of 26.4 months after surgery and 56.3% of the patients had distant metastases at a median time 36.7 months. The median overall survival was 87.8 months and the overall survival rates were 87.4% at 3 years and 55.3% at 5 years.
Several clinicopathological factors have been proposed as prognostic factors in ACC, including age, tumor location, disease stage, histological subtype, tumor grade, perineural invasion and the presence of a positive surgical margin (2,6–9). In the multivariate analysis, we found that histological grade was associated with disease-free survival, whereas lymph node metastasis had a significant relationship with an unfavorable overall survival.
Some studies have identified advanced clinical stage as the most important prognostic factor for an unfavorable clinical outcome, including poor survival and lower local and distant control (2,6–8). However, it remains disputed whether the criteria of the AJCC are the best way to classify ACC because of the tendency to set apart the tumors into Stages I and III (9,12). We found that the median survival time was not reached in patients with Stage I disease, whereas it was 92.2 months in Stage II disease, 67.1 months in Stage III disease and 41.5 months in Stage IV disease. Our observation supports the AJCC criteria as a simple, useful guide for evaluating the tumor burden and predicting the potential outcome. Lymph node metastasis in ACC is rare at the time of diagnosis (4,8) and occurred in only 20.7% of the patients in our series. In our study, regional lymph node metastasis and tumor size (
3 cm) had a significant effect on distant metastasis, but not on local recurrence. Moreover, nodal involvement was a strong independent predictor of overall survival. In a series of 54 ACC patients, Le et al. (8) found that the presence of involved lymph nodes on admission was associated with an increased risk of distant metastasis and reduced survival. This observation is supported by our result that 75% of the patients with initial nodal involvement eventually developed distant metastases. Spiro et al. (19) reported that tumor size in excess of 3 cm and cervical node involvement were highly predictive of distant metastases in 196 ACC patients.
Grade may also play a role as a prognostic factor in ACC (9). However, its significance as a marker of outcome remains unresolved, with both proponents (5) and opponents (20). High-grade tumors in our series were more likely to predict unfavorable clinical outcomes, such as poor survival, frequent recurrence and local relapse.
In addition, some studies have emphasized the importance of histological subtype. Most have reported that ACC patients with solid type are more likely to have a worse prognosis, resulting from the development of distant metastasis (2,5). In this study, the growth pattern did not have a significant effect on the overall survival, but tended to affect recurrence (P = 0.086). Furthermore, patients with the solid subtype had a greater correlation with local recurrence (P = 0.026) compared with distant metastasis (P = 0.518), in contrast to previous reports (2,5). Since our data on the growth pattern were limited to 29 of 42 cases, we were unable to address the lack of a significant relationship between the solid growth pattern and distant metastasis.
Several reports have also found a strong correlation between the site of origin and prognosis. Nevertheless, it is still unclear whether the major or minor salivary glands have a poorer clinical outcome (2,12,21,22). The univariate analysis showed that tumors of the minor salivary glands, including the sinonasal cavity, tended to recur. This finding supports the fact that patients with ACC arising from a site near the cranial base (nasal cavity and maxilla sinus) have an increased risk of recurrence (7).
Some studies have reported that perineural invasion was an indicator of a poor prognosis because of the high risks of local recurrence and distant metastasis (14,23), whereas others did not find a positive correlation between perineural invasion and a poor prognosis (17). In our study, 78% of the patients with perineural invasion had a positive resection margin, likely due to the proximity to major nerves, as demonstrated by Khan et al. (2). We found that perineural invasion tended to be related to local recurrence, although this was not significant. However, it was not correlated with distant metastasis or overall survival. The presence of a positive surgical margin seems be an important prognostic factor, although some studies have been unable to confirm this observation (23,24). We also failed to find a significant correlation between a positive surgical margin and clinical outcome. As noted above, we postulated that this is due to the effect of active adjuvant radiotherapy for local control, as stated by Avery et al. (16,23).
The natural history of ACC is characterized by a relatively low probability of regional lymph node metastases and a high likelihood of hematogenous dissemination (4). The lung was the most common site (72.2%) of distant metastasis in our series, as reported in other studies (22,25). In addition, aggressive resection of resectable metastatic nodules may be worthwhile when the primary tumor grade is low and the disease-free interval is long (11). We performed a statistical analysis of potential clinicopathological variables affecting pulmonary metastasis. With a median time to lung recurrence of 28.7 months, five patients with lung metastasis received regimens containing 5-fluorouracil as salvage chemotherapy. Even after detecting lung metastasis, seven patients are still alive at a median time of 21.2 months. We found that only perivascular invasion showed an association with lung metastasis (P = 0.053), albeit marginally. We postulate that factors related to angiogenesis, such as vascular endothelial growth factor (VEGF) and VEGF-receptor, are possible targets for inhibiting the progression and metastasis of human salivary ACC (26,27).
In summary, high tumor grade was predictive of recurrence, and lymph node involvement predicted overall survival. However, our series has several limitations: it was a retrospective analysis of a relatively small number of patients and the follow-up period was short in many patients. Moreover, we were missing medical data due to loss during follow-up. Nevertheless, we expect that our data on the clinicopathological characteristics of ACC will provide new insights into the management of ACC. Despite aggressive treatment, including surgery and radiation therapy, it seems to be impossible to prevent the development of distant metastasis. Therefore, much more research is needed to identify molecular biomarkers that will predict the clinical outcome and to develop an effective treatment for patients with ACC.
Conflict of interest statement
None declared.
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References |
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