Abstract
Most studies of the clinicopathological characteristics and prognosis of patients with distant metastasis of salivary adenoid cystic carcinoma (SACC) have used small patient samples. To further explore this issue, a descriptive and prognostic study of 467 patients with SACC who were treated from 1963 to 2009 was conducted at a single institution. One hundred and forty-five patients (31.0%) had distant metastases. At least 20% of patients who presented with the early-stage disease and no recurrence developed distant metastasis. The overall 5-, 10-, and 20-year survival rates were 85.6%, 67.4%, and 50.4%, respectively, for patients without distant metastasis, and 69.1%, 45.7%, and 14.3%, respectively, for patients with distant metastasis. The median survival time after distant metastasis was 36 months (range 1–112 months). The prognosis was similar between patients who received treatment for metastasis and those who did not. Patients who were diagnosed with early-stage disease and without local recurrence of the primary tumours could also develop distant metastases. The biological characteristics of adenoid cystic carcinoma were different from those of squamous cell carcinoma. At present, the effectiveness of treatment for distant metastases is not ideal and further research is needed.
Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumours. It is characterized by invasive local growth and a high incidence of distant metastasis. Whereas ACC primarily metastasizes to the lung, it can also metastasize to bone, liver, the cerebrum, and to multiple organs. Most previous studies on distant metastasis of ACC have been clinicopathological analyses of small patient samples, and more comprehensive research on the clinical and pathological characteristics of distant metastasis of salivary adenoid cystic carcinoma (SACC) is needed. The aim of this study was to investigate the clinical and pathological characteristics of distant metastases of SACC by reviewing clinicopathological data from a large patient series at a single institution.
Materials and methods
From 1963 to December 2009, 613 patients with SACC were admitted to the study institution. Among them, 467 patients (76.2%) were given follow-up. The follow-up period, defined as the period from the time of diagnosis of SACC to the time of last data collection or of the patient’s death, ranged from 6 months to 32 years (median 12 years). The diagnosis of distant metastasis was confirmed by the histopathological examination of samples obtained by metastasectomy or by detection of metastasis by computerized tomography (CT), chest X-ray film, B ultrasound, or bone scans. The distant metastasis interval was defined as the period from the time of diagnosis of SACC to the time of diagnosis of distant metastasis.
The 2010 criteria of the International Union against Cancer (UICC) were used for the clinical staging of the major salivary gland tumours, whereas the criteria for squamous cell carcinoma (SCC) were used for the clinical staging of the minor salivary gland tumours. All histopathological specimens were reviewed by two experienced pathologists who independently allocated each tumour to one of three groups: tubular, cribriform, or solid. Each pathologist’s assessment was blinded to the other’s. Both pathologists agreed to classify a specimen as the solid subtype if the solid area comprised more than 30% of the tumour.
Of the 467 patients with SACC, 430 received surgery for the primary tumour. One hundred and seventy-one of the 430 patients received preoperative or postoperative radiotherapy (average radiation dose 60 Gy, range 40–76 Gy). The other 37 patients underwent radiotherapy or chemotherapy to treat the primary tumour without surgery because of their general physical condition.
The statistical analysis was performed using the SPSS software package (version 13.0; SPSS Inc., Chicago, IL, USA). Kaplan–Meier survival curves were constructed to plot the percent survival as a function of time. The log-rank test was applied to assess the statistical significance of clinicopathological differences among the SACC groups and of differences in survival rates.
Results
General clinical data
Of the 467 patients with SACC who had available clinicopathological and follow-up information, 210 (45.0%) were male and 257 (55.0%) were female. Their ages ranged from 16 to 80 years, with a median age of 47 years. Two hundred and thirty-two patients (49.7%) had SACC of the minor salivary glands and 235 patients (50.3%) had SACC of the major salivary glands.
Distant metastasis rate and sites
One hundred and forty-five patients (31.0%) had distant metastasis among the 467 SACC patients with follow-up. The lung was the predominant organ of distant metastasis (108 patients; 74.5%), followed by bone (10 patients; 6.9%), liver (five patients; 3.4%), cerebrum (three patients; 2.1%), and multiple sites (19 patients; 13.1%).
Distant metastasis period
The distant metastasis interval ranged from 0 to 252 months. Seventeen patients had distant metastasis at the time they were diagnosed with SACC, and 128 patients developed distant metastasis during follow-up. The median distant metastasis interval was 48 months. Eighty percent of the patients in our series developed distant metastasis within 8 years after the diagnosis of SACC. However, 20% of patients developed distant metastasis from 8 to 20 years after the diagnosis of SACC.
Relationship between the primary tumour and distant metastases
Table 1 shows distant metastasis rates by primary cancer site, T stage, and histological subtype. SACC that originated from the submandibular gland, tongue, or maxillary sinus had a higher distant metastasis rate than SACC that originated from other sites. Larger tumours had higher distant metastasis rates than smaller tumours. Of note, the distant metastasis rate was 23.9% among patients who were diagnosed with T1, early-stage SACC, compared with 38.6% among patients who were diagnosed with the most advanced disease. The distant metastasis rates were 27.3%, 29.9%, and 47.7% for the tubular, cribriform, and solid subtypes, respectively. There was a statistically significant difference among the three groups. Patients with the solid subtype of SACC were most likely to develop distant metastasis.
| Patients with SACC, n | Median follow-up, months (95% CI) | Patients with distant metastases, n | Distant metastasis rate (%) | P -value * | |
|---|---|---|---|---|---|
| Primary site | 0.575 | ||||
| Parotid gland | 87 | 64 (49–79) | 25 | 28.7 | |
| Submandibular gland | 72 | 48 (36–60) | 27 | 37.5 | |
| Sublingual gland | 72 | 48 (37–59) | 22 | 30.6 | |
| Palate | 125 | 60 (51–69) | 32 | 25.6 | |
| Tongue | 41 | 48 (31–63) | 15 | 36.6 | |
| Buccal | 24 | 69 (44–94) | 7 | 29.2 | |
| Postmolar triangle | 22 | 69 (49–89) | 6 | 27.3 | |
| Maxillary sinus | 18 | 60 (26–94) | 8 | 44.4 | |
| Lip | 6 | 108 (61–155) | 3 | 50.0 | |
| Tumour stage classification | 0.042 | ||||
| T1 | 117 | 60 (49–71) | 28 | 23.9 | |
| T2 | 174 | 72 (63–81) | 49 | 28.2 | |
| T3 | 49 | 49 (33–65) | 19 | 38.8 | |
| T4 | 127 | 36 (29–43) | 49 | 38.6 | |
| Histological subtypes | 0.038 | ||||
| Tubular | 99 | 86 (73–99) | 27 | 27.3 | |
| Cribriform | 324 | 54 (48–60) | 97 | 29.9 | |
| Solid | 44 | 36 (20–52) | 21 | 47.7 | |
| Primary site recurrence | 0.030 | ||||
| Recurrence | 242 | 72 (64–79) | 86 | 35.5 | |
| No recurrence | 225 | 48 (41–55) | 59 | 26.2 | |
| Total | 467 | 144 (110–177) | 145 | 31.0 | |
During the follow-up period, 242 of the 467 (51.8%) SACC patients presented with recurrence. Table 1 also shows the relationship between primary tumour recurrence and distant metastasis: 35.5% of patients with recurrent tumours developed distant metastasis, whereas 26.3% of patients without recurrent tumours developed distant metastasis. The difference between these two groups was statistically significant.
Survival rates in patients with and without distant metastasis
The 5-, 10-, 15-, and 20-year cumulative survival rates were 79.5%, 58.3%, 43.8%, and 32.1%, respectively, for the 467 patients with SACC. The 5-, 10-, 15-, and 20-year cumulative survival rates were 69.1%, 45.7%, 26.5%, and 14.3%, respectively, for the 145 patients with distant metastasis, compared with 85.6%, 67.4%, 57.6%, and 50.4%, respectively, for the patients without distant metastasis, as illustrated in Fig. 1 . Thus, the survival rate was much lower for patients with distant metastasis ( P < 0.001).
Post-distant metastasis survival times according to the distant metastasis sites
Among the 145 patients with distant metastasis, there were 108 patients (74.5%) with pulmonary metastasis alone, who were referred to as the ‘pulmonary metastasis group’. Thirty-seven patients (25.5%) had metastases to bone, liver, cerebrum, or multiple sites, and this group was referred to as the ‘other distant metastasis group’. The median survival time after distant metastasis was 36 months (range 1–112 months). The survival rates of the pulmonary metastasis group and the other distant metastasis group are illustrated in Fig. 2 . Patients in the other distant metastasis group had significantly lower survival rates than those in the pulmonary metastasis group ( P = 0.005).
For the 145 patients with distant metastasis, the 1-, 3-, and 5-year survival rates after distant metastasis were 75.3%, 47.1%, and 26.5%, respectively. The median survival time was 36 months. The post-distant metastasis survival analysis according to the different sites of distant metastasis is shown in Table 2 . The median survival time after distant metastasis in patients with isolated lung metastasis was 44 months and the 1-, 3-, and 5-year survival rates were 90.0%, 55.1%, and 28.2%, respectively. In contrast, the median survival time after distant metastasis to bone, liver, and cerebrum was 8 months and the 1-, 3-, and 5-year survival rates in this group were 36.7%, 28.5%, and 28.5%, respectively. The post-distant metastasis survival rates were significantly different between the pulmonary metastasis group and the other distant metastasis group ( P = 0.005).
| Patients, n | Survival rate (%) | Median survival time, months (95% CI) | P -value * | |||
|---|---|---|---|---|---|---|
| 1-year (95% CI) | 3-year (95% CI) | 5-year (95% CI) | ||||
| Distant metastasis sites | <0.005 | |||||
| Lung | 108 | 90.0 (83.7–96.3) | 55.1 (42.7–67.4) | 28.2 (15.3–41.1) | 44 (33–55) | |
| Other organs | 37 | 36.7 (20.4–52.9) | 28.5 (12.4–44.6) | 28.5 (12.4–44.6) | 8 (3–13) | |
| Distant metastasis treatment | 0.478 | |||||
| No | 120 | 72.9 (64.3–81.5) | 45.6 (34.0–57.2) | 29.9 (17.8–42.0) | 36 (27–45) | |
| Yes | 25 | 82.0 (67.9–96.1) | 54.7 (32.2–77.2) | 13.7 (0–35.6) | 44 (28–59) | |
| Total | 145 | 75.3 (67.7–82.9) | 47.1 (36.7–57.5) | 26.5 (15.7–37.3) | 36 (29–43) | |
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