Abstract

INTRODUCTION

Adenoid cystic carcinoma (ACC) accounts for 1% of all head and neck (HN) cancers and about 10-22% of all malignant tumors of the major and minor salivary glands.[1] Minor salivary glands (65%) are more frequently involved than major salivary glands (submandibular - 19%, parotid - 16%).[1] Occasionally, they arise from sites other than salivary glands, such as the lacrimal glands, the ceruminal glands of external auditory canal, nose, paranasal sinus, palate, nasophaynx, and larynx. ACC was initially described by Bilroth in 1856 and named as cylindroma for its classic histologic appearance.[2] Although these tumors are usually low-grade malignancies as per histologic differentiation, management of these tumors is a distinct therapeutic challenge because of the propensity for local invasion, perineural involvement, distant metastasis and ability to recur over a prolonged period.[3] Surgery is the cornerstone of management of ACC. Studies have demonstrated the utility of adjuvant radiation in terms of superior disease control over either modality alone.[4] However, the improvement in loco-regional control with combined modality treatment did not translate into a significant improvement in overall survival rate.[5] The role of chemotherapy is investigational and is often confined to recurrent, metastatic or advanced unresectable tumors. The response rate ranges from 10% to 25% depending on the choice of drugs.[6] Targeted therapy with biological agents has a response rate of < 10% and has failed to improve treatment outcome.[6] Hence, no consensus exists on the appropriate modality for the management of these malignancies. Most studies concur that overall survival rate for ACC is favorable, with 5-year survival ranging between 64% and 89% and 10-year survival between 37% and 77%.[3,7,8] The current study aimed at reviewing the clinical experience of management of HN ACC and analyzing the prognostic factors in this malignancy at a tertiary care institute in North India.

MATERIALS AND METHODS

Medical records were reviewed and data collected on all HN ACC over a 16-year period (1995-2011) from the institutional archives. A total of 90 patients of HN ACC cases were identified. Fourteen cases of ACC of the lacrimal gland and 10 cases with missing data were excluded from analysis. This study thus reports on 66 patients of HN ACC. Collected data were analyzed for a demographic profile, clinical presentation, disease site, stage, treatment modalities, and survival outcome. Patients were retrospectively staged as per American Joint Committee on Cancer (2010) TNM classification. The philosophy of treatment over the study period has been to assess all the patients in a multi-disciplinary HN cancer clinic comprising of an otolaryngologist, radiation oncologist, and medical oncologist.

Baseline staging work-up consisted of contrast enhanced computed tomography or magnetic resonance imaging of HN and X-ray of the chest. Complete blood count, liver function test, and kidney function tests were carried out in all patients.

Surgery was done primarily for all medically operable patients. The type of procedure was dependent on the primary site, the extent of disease, cosmetic considerations, and discretion of the surgeon. In general, an attempt was made to maximize local control with preservation of cosmetic and functional outcomes. Unresectable tumors were treated with radiation alone, the intent being curative or palliative, depending on the performance status of patients and the loco-regional extent of disease.

Postoperative radiotherapy was offered to almost all of these patients. Target volume included the postoperative bed along with any residual disease. Elective nodal irradiation was not done. The base of the skull was routinely included in the radiation portal for all tumors with named cranial nerve, invasion of the base of the skull or intra-cranial extension (ICE).

The dose of adjuvant radiation and addition of concurrent chemotherapy were decided based on the presence of high-risk factors in the postoperative histopathology report e.g., presence of positive or close margin, perinodal spread or more than one lymph node involvement. The dose of postoperative radiation (PORT) was 60-64 gray at 2 gray per fraction over 6-6.5 weeks depending on the presence of the aforementioned high-risk features. Patients treated with reirradiation on recurrence received radiation dose of 45 gray at 1.8 gray per fraction over 5 weeks and for metastatic bone disease, either 8 gray in single fraction or 20 gray in 5 fractions over 5 days were used. Extrapolating from the data of use of postoperative concurrent chemoradiation in high-risk squamous cell carcinoma of HN, cisplatin (40 mg/m2 body surface area intravenous weekly) was added to PORT in patients with positive margin and extracapsular extension in patients considered eligible for this intensified approach, else a higher dose of radiation was used in these cases.

Weekly toxicity assessment was done during the course of radiotherapy according to Radiation Therapy and Oncology Group acute radiation morbidity scoring criteria.[9] Radiation was withheld in the emergence of Grade 3/4 toxicity.

Disease-free survival (DFS) was defined as the interval between the date of diagnosis and the date of recurrence and was estimated by Kaplan-Meier product-limit method. Log-rank test was used for univariate analysis of factors impacting DFS. Cox proportional hazard regression model was used for multivariate analysis. SPSS version 12.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. P ≤ 0.05 was considered to be statistically significant for all analysis.

RESULTS

A total of 66 patients met the study criteria. The male:female ratio was 34:32. Median age at presentation was 40 years (range: 17-73 years). Ten patients had clinical node-positive disease and of 11 necks sampled, 8 patients had pathological node positivity. The rest of the patient and tumor characteristics have been summarized in Table 1.

Table 1

The difference in the results regarding the impact of PORT and the variation in survival rates across the studies may be attributed to patient selection criteria and different therapeutic approach like the extent of surgery and radiotherapy target volume. Existing literature has heterogeneity regarding elective nodal irradiation of neck[3,17,18] due to individualization of treatment decisions. The coverage of skull base has also differed from series to series. We have routinely included the base of the skull in the postoperative treatment volume in case of perineural invasion of any major named nerve, the base of skull invasion or ICE. The discrepancies can also be partially due to the difference in the demographic and clinicopathologic factors across these studies done from different parts of the world. Results of our series are in concordance with other reported studies in the literature [Table 3].

Lymph node involvement and base of skull invasion or ICE were noted to be risk factors for poor DFS on univariate analysis in our series. Study from Memorial Sloan-Kettering Cancer Centre showed that T4 stage and gross or clinical nerve involvement (P = 0.002) were associated with decreased progression-free survival, whereas T4 stage and lymph node involvement were associated with decreased overall survival.[19] The association of lymph node involvement with poorer outcome has also been demonstrated by Fordice et al.[16] Multiple studies have pointed out the adverse impact of perineural invasion or nerve involvement on local control and survival. However in our study, perineural involvement did not have any significant impact on DFS. This might be because of our cautious approach in the inclusion of base of the skull in the radiation target volume in all such patients, which nullified the risk of recurrence.

In our series, local failure was observed to be the predominant pattern of failure that is in accordance with the results obtained by Khan et al.,[13] Kokenmueller et al.[14] and other studies.[20,21] However, in the UCSF series reported by Chen et al.,[3] distant metastasis was the most common pattern of failure. Sites of distant failure in this study were as follows: 25 lung (71%), 5 bone (14%), 3 liver (9%), and 2 brain (6%) metastasis. A longer follow-up in our study might unveil further distant metastasis.

The current study, in accordance with literature from different parts of the world, shows excellent tolerance to PORT with favorable acute toxicity profile. However, lack of attention to late toxicity, which might be significant in long-term survivors, is a limitation of our study.

Although subject to inherent limitations of any retrospective study, the current study highlights the superiority of surgery, followed by adjuvant radiation in managing patients of HN ACC. Invasion of skull base or ICE was found to be an independent prognostic factor in our study. However, the adverse prognostic impact of positive margin was negated by the routine use of high dose PORT. The median follow-up duration in the present study is comparatively shorter than other contemporary series, which is essentially due to poor compliance to long-term follow-up policy, mandatory for HN ACC. Last but not the least; more attention needs to be focused on late toxicity, functional outcome, and quality of life in long-term survivors.

CONCLUSION

The current single institutional analysis clearly demonstrates the superiority of multi-modality management in the form of surgery and adjuvant radiation in the management of HN ACC. Invasion of skull base or ICE confers poor prognosis. However, the prognostic impact of positive margin on local control and survival can be nullified by the routine use of high dose radiation therapy in such cases. Special attention needs to be given to late morbidities and quality of life issues in long-term survivors.