Background
Adenoid cystic carcinoma of the head and neck (ACC) is a rare epithelial malignant tumor arising from exocrine glands such as the major and minor salivary glands of paranasal sinuses or the external auditory canal., and accounts for only 1% of head and neck cancers [
1]. In general, while ACC takes a relatively slow clinical course, the long-term prognosis is poor because of its high frequency of local recurrence and distant metastasis [
2]. The genomic hallmark of ACC is a recurrent t (6;9)(q23;p23) translocation [
3] that results in a fusion between the MYB and NFIB genes [
4]. The treatment consensus in ACC is resection to negative surgical margins followed by post-operative radiation (PORT) [
5‐
7]. Whereas, patients with metastatic disease are generally incurable due to the lack of effective systemic therapies, there are a few reports of molecular pathology associated with chemoresistance such as the SWI / SNF chromatin remodeling complex [
8]. Although multiple retrospective clinical studies of ACC have been reported to date [
9‐
12], most of the data were obtained from follow-up periods of 20 years or less, and survival curves were still decreasing at the end of observation. Furthermore, it is difficult to design and conduct large prospective clinical trials because of the rareness and long course of the disease. As yet, no robust prospective clinical trial has been reported. Given this background, clinically unknown points and questions remain. Therefore, it is meaningful to conduct a retrospective clinical study with long follow-up observation, more than 20 years, in a single institution with a relatively uniform therapeutic policy. Thus, a retrospective clinical study was performed to further understand and improve management of ACC in clinical practice, by clarifying multiple clinical questions, such as 1) long-term prognosis beyond 20 years, 2) usefulness and suitability for treatment of therapeutic interventions, 3) therapeutic goal to aim for, and 4) prognosis by recurrence sites.
Discussion
Although ACC is recognized to have a poor long-term prognosis, there are few reports showing long-term survival rates exceeding 20 years, and there still exist many uncertain clinical questions because of its rarity and its extraordinarily long clinical course. The present study found 25-year OS, DSS, and DFS rates of 20.0, 38.4, and 9.4%, respectively. Of the cases observed for more than 12.0 years when the difference between OS and DSS appeared, 60% of cases were finally in an ACC-cancer-bearing state regardless of whether they were alive or dead, and 30% were alive with ACC-cancer-bearing at the end of the observation period, which indicates the possibility of further decline of DSS after 25 years. Spiro et al. [
2] reported that 25-year OS and DSS of ACC were 15 and 27%, respectively, and the survival curves presented in the article can be seen to show further decline of both survival rates even at 25 years when the observation period ended. While the maximum disease-free interval from initial treatment in this study was 14.2 years at the longest, longer ones of 19 years were reported in the past [
2,
9]. Moreover, Jones et al. [
12] reported that the local recurrence rate at 30 years was 100% in the retrospective study including the longest follow-up of 39.2 years. Considering these facts comprehensively, it is practically difficult to cure ACC, or at least impossible to judge that ACC has been cured. Coca-Pelaz et al. [
6] stated the same in a systematic review article of ACC. Therefore, realistically, the major goal of treatment for ACC may be long-term survival, including cancer-bearing survival resulting in either natural death or intercurrent-disease death, rather than aiming to judge disease cure. Regarding recommended follow-up-observation period, although cost-effectiveness is a factor to be considered, unlimited follow-up may be desirable almost throughout life, because ACC takes an extraordinarily long-term course, and the long-term course beyond 30 years is not yet known. Moreover, long-term observation will result in further understanding of the disease in the future.
On multivariate analysis of prognostic factors, surgery for locoregional lesions and C-T type of histology were independent predictors of DSS. Surgical treatment has been recognized as the first-choice treatment for ACC to date [
6], and the present results supported this. The effect of postoperative radiotherapy on prognosis remains controversial [
11,
16‐
18], and in the present study, there was no significant difference between the surgery-alone group and the surgery with adjuvant therapy group. However, these results do not deny the usefulness of postoperative radiation, considering the possibility of bias that the more obvious positive surgical-margin cases might be included in the surgery with adjuvant therapy group. Regarding histological type, Perzin et al. suggested three basic patterns related to prognosis, namely tubular, cribriform, and solid [
19]. They reported that the solid pattern was associated with the poorest prognosis, followed by the cribriform and tubular patterns. Our results also support this finding.
In fact, comparing the prognosis of cM1 cases (Fig.
2) and all cases showing distant metastases throughout the observation period (Supplemental Figure
2), the latter 5-year DSS was 65.1%, whereas the former was 0% (the longest survival time was 3.3 years). This large difference indicates the poor prognosis of pre-therapy distant metastatic cases.
Salvage surgery for distant metastases as well as local ones also contributed to the improvement of DSS in this study. Girelli et al. [
20] examined the usefulness of lung metastasectomy for 109 cases in multiple institutions, and they reported that a DFI greater than 36 months after primary-tumor treatment and completeness of resection were the best prognostic variables of lung metastasectomy. The fact of a prognostic difference after lung metastasectomy according to the timing of the metastasis occurring might also be associated with the prognostic difference between cM1 and rM1 cases in the present study. Early distant metastasis could be attributed to solid type and/or other clinicopathological features, and they are difficult to control by treatment interventions. Because ligometastasis has also been reported to be associated with a favorable prognosis in head and neck cancer, a small number of lung metastases with long DFI may benefit from aggressive intervention even in ACC [
21].
Van der Wal et al. [
22] reported mean survival times after lung metastasis and after other metastases were 32.3 months and 20.6 months, respectively, and the present results also support this. Ho et al. reported that recurrent or metastatic ACC were enriched for alterations in key Notch and chromatin-remodeling genes and associated with poor prognosis [
23]. Differences in these gene mutations by metastatic site may also alter prognosis.
The limitation of the present study is the small number of cases (58 cases). There was no significant difference in survival rates according to several clinicopathological factors such as primary site, perineural invasion, surgical margin, and so on, which had been reported as possible prognostic predictors in the past [
1,
9,
10,
24]. In these analyses, the result was clearly affected by the weak statistical power. Although this study had one of the longest observation periods among previous reports, the observation period might not have been sufficient because the survival curves continued to decrease, and several patients were cancer bearing at final observation. Designing prospective clinical trials with longer-term follow-up is desired for further understanding of the extremely specific characteristics and course of ACC, but this may be practically difficult due to its low morbidity rate and long clinical course. Therefore, a multicenter, retrospective study with unified therapeutic strategies, sufficient case accumulation, and long-term follow-up of more than 30 years is realistic and desired.
Conclusions
A retrospective clinical statistical analysis of 58 head and neck ACC cases with long-term follow-up was performed. While surgical intervention for locoregional lesions as initial treatment and the C-T type of histology were independent prognostic factors for DSS, the recurrence rate was extremely high, and there was a large difference between 25-year DSS and DFS. This difference was mainly attributed to salvage surgery for either locoregional recurrence or lung metastases that were resectable, indicating that not only the initial treatment but also repetitive surgical resection of resectable recurrent lesions may lead to long-term survival in ACC cases. Distant metastases seen at the first visit may be different from delayed-onset distant metastases and related to aggressive characteristics such as solid type of histology. Realistically, the major goal of treatment for ACC can be long-term survival including cancer-bearing survival resulting in either natural death or intercurrent-disease death, since it is almost impossible to judge cure of ACC.
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