Adenoid cystic carcinoma of the head and neck

British Journal of Plastic Surgery (2001), 54, 476--480 9 2001 The British Association of Plastic Surgeons doi: 10.1054/bjps.2001.3636 PLASTC SURGERY Adenoid cystic carcinoma of the head and neck S. Chummun, N. R. McLean*, C. G. Kellyt, E J. D. K. Dawest, D. Meikle:~, Sheila Fellows1" and J. V. Soamesw The Medical School, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne; *Department of Plastic and Reconstructive Surgery, Royal Victoria nfirmary, Newcastle-upon-Tyne; +.Newcastle General Hospital, Newcastle-upon-Tyne; SFreeman Hospital, High Heaton, Newcastle-upon-Tyne; and w of Oral Pathology, The Dental School, Newcastle-upon-Tyne, UK SUMMARY. Adenoid cystic carcinoma (ACC) is a rare malignant tumour believed to arise from the epithelial cells of mucous-secreting glands. t is a slow-growing but aggressive tumour with a propensity for perineural invasion. A 10 year review of 45 patients (19 males and 26 females with a median age of 56 years) treated for ACC at a single institution between 1989 and 1999 was performed to analyse factors involved in treatment failure, local control, treatmentrelated morbidity and mortality. The data collected were treated for survival curves according to the Kaplan-Meier method and the log-rank test was used to assess the statistical significance of the various groups. The overall survivals at 3 years and 5 years were 71% and 65%, respectively, while the disease-free survivals at 3 years and 5 years were 73% and 63% respectively. Out of the 45 patients, only six had local recurrences, yielding an 87% locoregional freedom from relapse; 16 patients (35.6%) developed distant metastases, with the lung (8/16) being the commonest site. Patients treated for tumours of the nose and paranasal sinuses experienced more morbidity than those with tumours at other sites. Positive margins, perineural invasion and solid histology of ACC were associated with increased morbidity and treatment failure. Patients treated with combined therapy did better than those who underwent a single treatment modality. 9 2001 The British Association of Plastic Surgeons Keywords: adenoid cystic carcinoma, head and neck neoplasm, perineural invasion, disease-free survival. Adenoid cystic carcinoma (ACC) is a rare malignant tumour that accounts for less than 1% of all head and neck malignancies and approximately 10% of all salivarygland neoplasms. 1 ACC is known for its prolonged clinical course, multiple recurrence and the delayed onset of distant metastases. ACC was described by Conley and Dingman as 'one of the most biologically destructive and unpredictable tumours of the head and neck', 2 however, long-term survival is not uncommon, even with recurrent disease. 3 Many authors have studied the different histological patterns of ACC and have correlated the different histomorphological features with survival and local disease control. For example, in 1972, Eby et al reported that the solid subtype of ACC has a worse prognosis than the cribriform subtype, 4 and this was confirmed by subsequent authors. 5 The tubular type has been shown to have a better prognosis than the other types. 6 However, there are still many controversies regarding the clinical behaviour of this tumour. Spiro and Huvos considered that staging of the disease at the time of primary treatment played a far more important role than histological grading in determining the clinical outcome. 7 Garden et al reported a positive relationship between microscopic evidence of perineural invasion and poor prognosis. 8 This study reviews 45 patients with ACC in the head and neck region treated at a single institution and analyses the factors involved in local control, treatment-related morbidity, treatment failure and mortality. Materials and methods The medical notes of 45 patients diagnosed as having ACC of the head and neck, and treated at the Northern Centre for Cancer Treatment between 1989 and 1999, were reviewed. The cohort included 19 males and 26 females, ranging in age from 13 to 98 years (median: 56 years). The anatomical distribution of the ACCs is shown in Table 1: the commonest sites were the nose and paranasal sinuses and the parotid gland. The staging of all cases was determined according to the TNM classification of the American Joint Committee on Cancer (AJCC). nitially, the histological typing of the specimens was determined according to the World Health Organisation classification of tumours. 9 However, in nine cases, the tumours were described as mixed tumours of Table 1 Site Anatomical distribution of adenoid cystic carcinomata Number of cases nose and paranasal sinuses 10 parotid gland 10 submandibular gland 9 snblingual gland 5 palate 4 trachea 1 tongue 1 ear 2 pharyngeal wall 2 lacrimal gland 1 476

Adenoid cystic carcinoma of the head and neck 477 0.9 }i 1 08 o.t- L!------~...' Overall Survival... Disease-fTee Survival 0 6 [ Figure 1--Cribriform pattern of adenoid cystic carcinoma (x 50). 0.5,, 0 25 50 two different histological subtypes, namely cribriform/ tubular (7/9) and cribriform/solid (2/9). The slides of these tumours were reviewed but it was not possible to separate the tumours into single histological subtypes. t was consequently decided to group the tumours as follows: type : predominantly cribriform ACC (Fig. 1); type : mixed ACC, consisting of cribriform/tubular or cribriform/solid; and type : predominantly solid ACC. The follow-up period was defined as the time from the first curative intervention to data collection or the death of the patient. The disease-free period was defined as the time from the last intervention to data collection or the death of the patient. Statistical analysis was performed using PRSM 3.0. The data collected were treated for survival curves according to the Kaplan-Meier method and the log-rank test was used to assess the statistical significance of the various groups. Results The patients underwent a variety of treatment modalities. Out of the 45 patients, 30 received a combination of surgery and postoperative radiotherapy, five received surgery alone, six received radiotherapy alone and three received no treatment. One patient received a combination of radiotherapy and chemotherapy, Carboplatin (635 mg) and 5-fluorouracil (6920mg) over 4 days. The radiotherapy doses applied varied between 7 and 91 Gy (median: 50.5 Gy). Three patients developed local recurrence at the primary site, while four others developed local recurrence with distant metastases; 25 patients developed distant metastases alone, with the lung being the commonest site. Five patients died of distant metastases, two patients died of unrelated causes, one patient died of a secondary primary tumour and one patient died of a recurrence at the primary site. n all, 35 patients underwent surgery as the only treatment or as part of their treatment. Out of these, there were 13 complete resections of the ACC and 20 partial resections; no details were recorded about the excision margins in two cases. Overall and disease-free survival rates The sex and age of the patient had no statistically significant effect on prognosis. The follow-up period ranged Figure 2---Overall and disease-free survival rates of patients with adenoid cystic carcinoma of the head and neck. 0 i; "-4 2'5 s'o ~'5 1~o 1;,5 1~o 1~5 -- Parotid... Nose & Paranasal sinuses ---- Sublingual --- Submandibular Figure 3--Survival rates of patients with adenoid cystic carcinoma of the head and neck according to site. from 6 to 165, while the disease-free period ranged from 0 (when the patient presented with metastatic disease) to 121. The overall survival rates were 71% at 3 years and 65% at 5 years. The disease-free survival rate was 73% at 3 years and 63% at 5 years (Fig. 2). The survival rates after 3 years and 5 years for ACC of the nose and paranasal sinuses were the worst, being 50.5% at both intervals (Fig. 3). The prognosis for tumours of the nose and paranasal sinuses tended to be worse than for other sites, but the differences were not statistically significant (P > 5). Based on the AJCC staging, eight patients had stage T1 tumours, 10 patients had stage T2 tumours, nine patients had stage T3 tumours and 18 patients had stage T4 tumours. Patients with T4 tumours had the worst prognosis, with survival rates of 48.5% and 42.5% at 3 years and 5 years, respectively (P > 5) (Fig. 4). Tumour location n total, 24 (53%) tumours were located in the major salivary glands: 10 in the parotid gland, nine in the submandibular gland and five in the sublingual gland. n the minor salivary glands, 10 ACC occurred in the nose and paranasal sinuses, five in the oral cavity (including the palate and tongue), two in the pharyngeal wall, one in the trachea, one in the lacrimal gland and two in the external auditory meatus (Fig. 5).

478 British Journal of Plastic Surgery t.00-0.75-0.50-0.25- L:il i... i "1 L... ~T1 ---72 ----T3... T4 0 0 2'5 ~ r 1~0 1~5 1;0 65 Figure 4--Survival rates of patients with adenoid cystic carcinoma of the head and neck according to staging. 1.0" 0.8 0~4- "T..., 14 _.................... --Type... Type --- Type fll 25 5b 7~ ~o &5 1~o c~ Figure 6--Survival rates of patients with adenoid cystic carcinoma of the head and neck according to the histological grading. Histological type The histological type of 23 (51.1%) tumours was Type, seven were Type and 15 were Type ll The survival rates at 3 years and 5 years for patients with Type tumours were 75.2% and 73.1%, respectively, while the survival rates for patients with Type tumours at 3 years and 5 years were 62.0% and 48.5%, respectively (P > 5) (Fig. 6). Figure 5---CT scan of adenoid cystic carcinoma invading the right external auditory meatus. Five of the patients with ACC of the nose and paranasal sinuses had distant metastases. Four (16.7%) out of 24 patients with ACC in the major salivary glands had distant metastases. The mean follow-up of patients with ACC in the nose and paranasal sinuses was 29.6, compared to 47.3 for patients with ACC in the major salivary glands. Statistical analysis, however, revealed no significant differences. Recurrence after surgical treatment Out of the 35 (77.8%) patients who underwent primary surgical treatment, seven developed recurrences. Of these, three patients had local recurrences alone, while the remaining four had local recurrences associated with distant metastases. Five of the seven patients who had local recurrences had primaries in the nose and paranasal sinuses. Of these, two had complete excision of the tumour, one had incomplete excision and two received radiotherapy alone. The remaining cases were in the parotid gland and the submandibular gland, respectively. Distant metastases There were 16 cases of distant metastases, of which eight were in the lungs (50%), five in bone, two in the liver and one in the brain. Distant metastases developed most often in patients with the solid subtype of the tumour. However, there were no statistically significant differences in the metastatic rate between the solid subtype (Type ) and the other two subtypes (Types and ). The highest metastatic rate was from ACC of the nose and paranasal sinuses (10 out of 16 cases), followed by the parotid gland (five out of 16 cases) and the lacrimal gland (one out of 16 cases). Distant metastases to bone were associated with a more fulminant disease, with the mean survival time being only 11.6. Regional lymph node metastases were found in four patients; all were of N2 nodal status. Perineural invasion The overall rate of perineural invasion was 51.1% (23 cases); this rate was highest in the parotid gland, with eight out of 10 cases. The survival rate for patients without perineural invasion at both 3 years and 5 years was 93.5%, while the 3 year and 5 year survival rates for patients with perineural invasion were 72.5% and 68.0%, respectively (P < 5). The prognosis of patients with nerve involvement was worse than for those without nerve involvement (Fig. 7). Treatment modalities The overall survival rates for patients who were treated by a combination of surgery and radiotherapy were 86.0% and 78.4% at 3 years and 5 years, respectively,

Adenoid cystic carcinoma of the head and neck 479 while the survival rate of those treated by surgery alone was 6% at both 3 years and 5 years. Patients given radiotherapy alone had survival rates of 56.5% and 28.5% at 3 years and 5 years, respectively. There were no statistically significant differences between the three treatment moralities (P= 0.19) (Fig. 8). The survival rate of patients who had complete excision was 89.5% at both 3 years and 5 years, while the survival rates of those with incomplete excision were 74.5% and 69.5% at 3 years and 5 years, respectively (Fig. 9). The prognosis of patients with complete excision was significantly better than those with incomplete excision (P < 01). \ --with 18 sb r'5 lbo 1~8 1;0 68... without Figure 7--Survival rates of patients with adenoid cystic carcinoma of the head and neck with and without perineural invasion. 0 L 1---1 ~/... -- Surgery alone... Radiotherapy alone --- Surgery and radiotherapy 2'~ 5'0 18 1~0 1~6 lho 1-~s Figure 8---Survival rates of patients with adenoid cystic carcinoma of the head and neck according to treatment modality. 0.4. 0.2. ----t 2'5 s'o r'5 1~o 1~5 lho l~s -- Complete... neomplete Figure 9--Survival rates of patients with adenoid cystic carcinoma of the head and neck with complete or incomplete excision margins. Discussion ACC is a tumour that usually occurs in the fifth decade of life 10'11 and rarely before the second decade, as noted in our study. Although there are divergent reports concerning the incidence of ACC in males and females, 1't~ we did not find any significant differences. ACC is characterised by its propensity for perineural invasion and its insidious diffuse local spread. 2,1t n our series, patients with ACC of the solid histological subtype had a greater incidence of distant metastasis and local recurrence, as reported by other investigators. 6't~ The location of the tumour influenced the prognosis. ACC of the nose and paranasal sinuses, in particular tumours of the maxillary antrum, had the worst prognosis. This could be due to the extensive invasion of bones and tissues, such that surgery could rarely achieve a complete cure. Moreover, patients with ACC of the maxillary antrum tended to present with advanced disease, an observation that has also been reported by other investigators, t4 The clinical staging of the ACC was another critical factor determining outcome. n our study, patients with T4 disease did worse than those with T1 disease, but there were no statistically significant differences between the groups, which could be due to the uneven distribution of the cases and the small number of cases in some groups. Spiro and Huvos identified clinical staging as the most important factor in determining outcome and argued that, because of the mixed cellularity of any given tumour (as noted in our series), histological typing is a subjective process and consequently cannot be used as a determining factor. 7 However, Greiner et al questioned whether using the criteria of the AJCC was the best method of classifying the tumours. 15 They found that the criteria tended to segregate the tumours into stages T1 and T3. We were unable to use the criteria set out by Szanto et a113 because of the mixed cellularity of some tumours, and so we grouped the lesions according to the predominant cellularity. ACC with intraneural and/or perineural invasion is associated with a reduced survival rate and has also been reported to be associated with an increased incidence of distant metastasis. 16 However, the occurrence of distant metastases was not correlated with tumour site or local recurrence. n our study, we failed to detect any statistically significant differences, despite the fact that patients with perineural invasion had worse survival rates at both 3 years and 5 years than those without perineural invasion. The effect of surgical margins on the prognosis has been discussed by several investigators, 6'8'11 and, in our study, tumours with positive margins had a significantly worse prognosis than those with negative margins (P<01). Haddad et al suggested that positive surgical margins might represent resistant and aggressive disease rather than an inadequate surgical resection of the specimen. 16 Wide resection of the tumour, with negative margins, appears to offer the best prognosis. However, there is evidence that radical resection may not improve the survival rate or reduce the recurrence rate when compared with conservative surgery and radiotherapy. ACC is radiosensitive but not radiocurable: tumours that initially respond to radiotherapy tend to recur later. TM These observations

480 British Journal of Plastic Surgery have led to the formulation of a combined-therapy policy for most ACCs. However, Fordice et al considered that the use of appropriately aggressive surgery achieving negative margins was the linchpin of successful combined therapy.ll n our series, patients who had combined therapy had better local control and survival rates than those who underwent either surgery or radiotherapy alone. ACC remains a very difficult tumour to treat. From our relatively small series, we conclude that positive margins and perineural invasion were important factors influencing prognosis. The data collected from our series also indicate the value of combined therapy in the management of this tumour. References 1. Spirt RH, Huvos AG, Strong EW. Adenoid cystic carcinoma of salivary origin: a clinicopathologic study of 242 cases. Am J Surg 1974; 128: 512-20. 2. Conley J, Dingman DL. Adenoid cystic carcinoma in the head and neck (cylindroma). Arch Otolaryngol 1974; 100: 81-90. 3. Kim KH, Sung MW, Chung PS, Rhee CS, Park C, Kim WH. Adenoid cystic carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1994; 120: 721-6. 4. Eby LS, Johnson DS, Baker HW. Adenoid cystic carcinoma of the head and neck. Cancer 1972; 29: 1160-8. 5. Matsuba HM. Simpson JR, Mauney M, Thawley SE. Adenoid cystic salivary gland carcinoma: a clinicopathologic correlation. Head Neck Surg 1986; 8: 200-4. 6. Perzin KH, Gullane P, Clairmont AC. Adenoid cystic carcinomas arising in salivary glands: a correlation of histologic features and clinical course. Cancer 1978; 42: 265-82. 7. Spirt RH, Huvos AG. Stage means more than grade in adenoid cystic carcinoma. Am J Surg 1992; 164: 623-8. 8. Garden AS, Weber RS, Morrison WH, Ang KK, Peters LJ. The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation. nt J Radiat Oncol Biol Phys 1995; 32: 619-26. 9. Seifert G, Sobin LH. Histological Typing of Salivary Gland Tumours, 2nd ed. World Health Organisation nternational Classification of Tumours. Berlin: Springer-Verlag, 199 l. 10. Nascimento AG, Amaral ALP, Prado LAF, Kligerman J, Silveira TRP. Adenoid cystic carcinoma of salivary glands: a study of 61 cases with clinicopathologic correlation. Cancer 1986; 57: 312-19. 11. Fordice J, Kershaw C, E1-Naggar A, Goepfert H. Adenoid cystic carcinoma of the head and neck: predictors of morbidity and mortality. Arch Otolaryngol Head Neck Surg 1999; 125: 149-52. 12. Ampil FL, Misra RP. Factors influencing survival of patients with adenoid cystic carcinoma of the salivary glands. J Oral Maxillofac Surg 1987; 45: 1005-10. 13. Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984; 54: 1062-9. 14. Spirt RH, Huvos AG, Strong EW. Adenoid cystic carcinoma: factors influencing survival. Am J Surg 1979; 138: 579-83. 15. Greiner TC, Robinson RA, Maves MD. Adenoid cystic carcinoma: a clinicopathologic study with flow cytometric analysis. Am J Clin Pathol 1989; 92: 711-20. 16. Haddad A, Enepekides DJ, Manolidis S, Black M. Adenoid cystic carcinoma of the head and neck: a clinicopathologic study of 37 cases. J Otolaryngol 1995; 24: 201-5. The Authors Shaheel Chummun, Medical Student The Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK. N. R. McLean MD, FRCS, Consultant Head and Neck/Plastic and Reconstructive Surgeon Department of Plastic and Reconstructive Surgery, Royal Victoria nfirmary, Queen Victoria Road, Newcastle-upon-Tyne NE1 4LP, UK. C. G. Kelly FRCP, FRCR, DMRT, Consultant Oacologist P. J. D. K. Dawes FRCR, Consultant Oncologist Sheila Fellows, Research Nurse Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne NE4 6BE, UK. D. Meilde BMedSei, FRCS, Consultant Otolaryngologist Freeman Hospital, Freeman Road, High Heaton, Newcastle-upon-Tyne NE7 7DN, UK. J. V. Soames BDS, PD, FDSRCPS, FRCPath, Head of Department of Oral Pathology The Dental School, Framlington Place, Newcastle-upon-Tyne NE2 4BW, UK. Correspondence to Mr N. R. McLean. Paper received 8 January 2001. Accepted 23 March 2001.