ORIGINAL ARTICLE

Adenoid cystic carcinoma of thesalivary giands: A 20-year reviewwith iong-term foiiow-upAvi Khafif. MD; Yakir Anavi. DMD; Jacob Haviv, MD, MPH; Rafael Fienmesser, MD;Shlomo Calderon, DMD; Gideon Marshak, MD

AbstractThe behavior of adenoid cystic carcinoma (ACC) of lhesalivary glands has been shown to be ttnpredictable in lennsof local and distant spread and mortality. We retrospec-tively studied 35 operations in 34 patients who had had apathologic diaf^nosis of A CC of the salivary glands and whohad been treated over a 20-year period and followed for aminimum of 10 years. We analyzed the effect that differentfactors had on otttcomes. The site of origin appeared tobe an important factor in survival rates: survivitl amongpatients with tumors that had originated in the parotidgland was fairly good, while survival among those withtumors tlutt originated in the minor salivary glands wassignificantly worse. TNM staging was another significantfactor in suirival. Other poor prognostic indicators werelocal spread, nodal positivity, distant metastasis, and lo-cal and regional recurrence. Radiation and chemotherapydid not appear to be beneficial for patients with advanceddisease. We recommend radical surgery with completeresection for all patients with ACC ofthe salivary glandsand a careful assessment of the neck in patients with minorsalivary gland tumors.

IntroductionAdenoid cystic carcinoma (ACC) is a malignant neoplasmofthe salivary glands. It accounts for most cases of minorsalivary gland malignancie,s and a substantial proportionof parotid and submandibular gland malignancies.' Thebehavior of ACC has been shown to be unpredictable. Thetumorhas a significantpropensityforperineural spread and

From lhe Department of Otolaryngology-Head and Neck Surgery. TelAviv Sourasky Medical Center (Dr, Khalif): the Department ofOral and Maxillolacial Surgery (Dr. Anavi and Dr, Calderon).the Department of Otolaryngology-Head and Neck Surgery (Dr,Fienmesser), and the Institute of Oncology (Dr, Marshak). RabinMedical Center. Beilinson Campus, Petah-Tikva, Israel; and lheIsrael Defense Forces Medical Corps (Dr, Haviv).

Reprint requests.: Avi Khafif". MD. 66 Hashol'tim Si,, Ramat-Hasharon47210, Israel. Phone; 972-3-S40-0526; fax; 972-3-.*i40-n526:e-mail;khatif@tasmc,health.gov.il or avironit@be/eqinl,net

distant metastasis. ACC is associated with a high mortalityrate, and it often recurs after prolonged periods of time. Onthe other hand, some patients survive for a considerablelength of time even in the face of distant metastasis.-

Several factors have been considered indicative of a poorprognosis in patients with ACC. including an advancedtumor stage,'•' a solid histologic type.^^ the presence ofnodal metastasis.'' and the presence of positive margins andperineura! spread. Many studies have lacked a satisfactoryfollow-up period, a fact that may account for the differencesin prognosis among them. In an attempt to clarify someofthe inconsistencies regarding the behavior of ACC, westudied a series of patients who had been followed for 10to 30 years.

Patients and methodsFrom January 1970 through December 1989, 40 patientswith ACC ofthe salivary glands were treated at the Beilin-son Campus ofthe Rabin Medical Center in Petah-Tikva,Israel. Patients who had been treated within the previous10 years were excluded from the study to allow for at least10 years of follow-up.

Sufficient data for inclusion in this study were avail-able for 34 patients—17 men and 17 women, aged 22 to80 years (mean: 57.7). The 34 patients underwent a totalof 35 operations. Most of these patients had superficialparotid lesions and they had undergone a superhcial pa-rotidectomy; those who had tumors that involved the deeplobe underwent a total parotidectomy. Preservation of thefacial nerve was attempted in all cases unless the nerve wasclearly involved in the cancerous process. Submandibularand minor salivary gland tumors were resected with thegoal of achieving adequate margins of resection. Lymphnode dissection was performed only on patients who werelymphadenopathy-positive at presentation. Follow-upranged from 10 to 30 years (mean: 15).

We compiled data on factors that might influence survival,includingTNM stage, local spread(includingperineural andbone invasion), regional and distant spread, type of treat-

662 ENT-Ear, Nose & Throat Journal • October 2005

KHAFIF, ANAVI, HAVIV, FIENMESSER. CALDERON, MARSHAK

Table 1. Site of origin of ACC of the head and neck inthe 34 patients

Site

Parotid gland

Hard palate

Maxillary sinus

Base of tbe tongue

Floor of the mouth

Buccal mucosa

Submandibular gland

Oral tongue

Lower lip

Ethmoid sinus

n (%)

12 (35.3)

6(17.6)

3 (8.8)

3 (8.8)

3 (8.8)

2 (5.9)

2(5.9)

1 (2.9)

1 (2.9)

1 (2.9)

ment, local and regional recurrence, and distant metastasis.The impact of" these factors on outcome was evaluated bymultiple logistic regression, and the different categorieswere compared by a chi-square test performed with Sigma-Stat Statistical Software (SPSS: Chicago). Linear variableswere analyzed by linear correlation. Kaplan-Meier curveswere generated for disease-free survival.

ResultsThe most common sites of tumor origin were the parotidgland I35.y/r) and the minor salivary glands ofthe hardpalate (17.6%) (table 1). Prior to surgery, the mo.st commoncomplaint at presentation {b5.7^/c) and the most commonsign on physical examination (77.1%) was a lump in theinvolved gland. Other clinical complaints and physicalsigns were seen much less often; the most common ofthese were local pain and oral ulcer (8.69f each).

Ofthe 34 patients, 22 (64.7%) presented with early can-cers (Tl orT2). and the remaining 12 (35.3%) had localor regional advanced disease (T3 or T4) (table 2).

Only 4 patients (11.8%) had regional lymph node me-tastasis at the time of surgery (table 3). and their treatmentincluded neckdissection.Threepatients (8.8%) had distantmetastasis. In light ofthe small numbers of patients withregional and distant metastases al presentation, the effectof metastasis on survival could not be evaluated.

Histology. Histologic subtyping was available for 21patients, 4 of whom had predominantly solid tumors. Thissmall number precluded us from making any histologiccorrelations with any ofthe study parameters.

Treatment. All patients underwent surgical resectionof their primary tumor, with the exception of 1 patientwho had a distant metastasis at presentation; this patientwas treated with combined radio- and chemotherapy. Twopatients underwent 2 operations each. Nineteen patients(55.9%) received adjuvant radiotherapy in addition tosurgical excision; 6 of the 19 also received concomitantchemotherapy.

Table 2. Relationship of tumor stage to survival inthe 34 patients

Stage Patients Disease-free survivaln n (%)

Tl 10 6(60.0)T2 12 6 (50.0)

T3 3 1 (33.3)

T4 9 1(11.1)p - 0.0.^ (ihi-sqimre imalysi\ for linear uswcicilioti).

Recurrence and metastasis. Regional recurrence oc-curred in 12 of the 34 patients (35.3%); 8 of these recur-rences developed during follow-up. Distant metastasisdeveloped in 15 patients (44.1%); 3 tnetastases weredetected at presentation, and 12 developed during follow-up. All but 1 of the patients with regional recurrence andall patients with distant metastasis died of disease within3 years of diagnosis (survival: 8.3 and 0%, respectively).All patients who presented with regional metastasis died ofdisease during follow-up. The mean length of time to thedevelopment of regional recurrence (lO.Oyr) was simitarto the mean length of time to the development ol' distantmetastasis (9.7 yr); in both cases, the range was 1 to 30years. Only 9 ofthe 20 patients (45.0%) who developed aregional recurrence or distant metastasis during follow-updid so during the first 10 years of follow-up; the remaining11 patienls(55.0%)developedtheirrecurrenceormetastasisbetween 10 and 20 years of follow-up.

Survival. Duringfollow-up, 19ofthe34patients(55.9%)died of their disease and 1 patient {2.97c) remained alivewith disease. Ofthe remaining 14 patients. 10 (29.4%)were alive with no evidence of disease and 4 (11.8%) haddied of other causes with no evidence of disease; of thelatter 4 patients, 2 died 8 years following treatment and2 died 2 years after treatment. Disease-free survival wassimilar to overall survival—41.2 and 32.3%, respectively(table 4).

Risk factors. Analysis of different risk factors revealedthat the site and size ofthe tumor had a significant effecton survival, as did surgical margins:

Tumor site. Patients whose tumors originated in the pa-rotid gland (n = 12) had a significantly better survival thanthose whose primary tumors arose in the minor salivaryglands (n = 15) (table 5). The tumors in the remaining 7patients had originated in the maxillary sinus, base ofthetongue, or ethmoid sinus.

Ttwtor .stage. Patients with larger tumors had a highermortality rate (p = 0.03) (table 2). Of 9 patients whopresented with T4 lesions. 8 (88.9%) died ofthe diseasedespite surgery and radiotherapy. Large tumors had agreatertendency to spread locally. Local spread (includingpcrineural and bone invasion) was found in II patients.

664 ENT-Ear, Nose & Throat Journal - October 2005

ADENOID CYSTIC CARCINOMA OF THE SALIVARY GLANDS:A 20-YEAR REVIEW WITH LONGTERM FOLLOW-UP

Table 3. TNM staging of ACC of the head and neckprior to 35 operations

NON1N2MOM1

Tx*1

0

0

0

1

T l

9

0

1

10

0

* Unknown primary litniot:

T2

12

0

0

11

1

T3

1

1

1

2

1

T38

1

0

9

0

and it had a detrimental effect on survival regardless oftumor stage. All 3 patients with parotid tumors who haddied of their disease had local spread.

5(/r^/a)/mflrgm.v. At leastone positive margin remainedin 10 patients postoperative I y, and 7 of these patients diedof disease. Ofthe 24 patients who had negative margins.there were only 11 deaths (45.8%).

DiscussionIn a study of a large series of patients with ACC. Fordlceet al reported that neither tumor site nor tumor stage hada significant effect on survival.^ However, consideringthe limited length of follow-up in that study (as little as 2yr in some cases) and the tendency of ACC to recur late,their conclusions should not be considered definitive. TheTNM stage of ACC at presentation appears to be relevantto survival. We demonstrated a linear increase in survivalwith decreasing tumor stage. We could not show a correla-tion between nodal staging and distant metastasis becauseofthe small number of patients, but we did find a 100%mortality in cases of lymphadenopathy at presentation.Fordice et al claimed that it was nodal positivity ratherthan nodal stage that is the important factor, and we tendto agree.**

Local spread developed in 12 of our patients—3 ofthe 12 {25.(y7v} who had a parotid tumor and 9 of tbe 22(40.9%) who had aminorsalivary gland tumor.Thegreaterpropensity of minor salivary gland tumors to spread infascial planes and nerves makes complete surgical excisionmuch more difficult. The main determinant of survival isprobably not the tumor site per se but the propensity forlocal spread, whicb is highly influenced by the site andwhich may result in apositive surgical margin. This isevenmore apparent in ca.ses of maxillary sinus carcinoma; inour study. 100% of these tumors spread locally, and allaftected patients died of the disease. Spiro et al have alsosuggested that local spread is a major factor in decreasingthe cure rate of patients with ACC.' Aggressive primaryresection might be the only way to lower the mortalityof patients with ACC in sites of prevalent local spread.Radiation may improve the prognosis in patients withadvanced disease. We did not find this to be meaningful in

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KHAFIF, ANAVI, HAVIV, FIENMESSER, CALDERON, MARSHAK

Table 4. Survival and mortality accordingstatus among the 34 patients

With ACC

Without ACC

Total

Aliven(%)

1 {2.9}

10(29.4)

11 (32.3)

Diedn (%)

19 (55.9)

4(11.8)

23 (67.7)

to disease

Totaln(%)

20 (58.8)

14 (41.2)

34(100)

our patients, but we cannot draw any conclusions becauseofthe selection bias—that is. patients with more advanceddisease were also treated with radiotherapy. In anotherstudy. Spiro et al' reported that postoperative radiotherapyconferred no advantage, but others^'' have shown that ACCis radiosensitive, although not necessarily radiocurable."Radiation, therefore, might still be of value both in treating(postoperutively) locally advanced disease and in treatingpatients who refuse surgical resection.

As expected, both regional recurrence and distant me-tastasis were predictors of poor survival, and aggressivetreatment of recurrences did not have an effect on outcome.Treatment delivered to the neck should be tailored to thespecific site of origin, as has been proposed by Garden etal.'" In our series, there was not even I case of regionalrecun-ence among the 12 patients with parotid ACC. asopposed to 11 regional recurrences in the remaining 22patients (50.0%). We suggest careful evaluation and foilow-upexaminations ofthe neck, including ultrasonography. incases of ACC that originate in the minor salivary glands.Surgery shouldentall lymph node dissection, which can belimited to the area of maximal drainage; one such optionis supraomohyoid neck dissection for oral cavity tumors.Again, we emphasize the poor prognosis of our patientswith regional recurrences (survival: 8.3'7 )̂. indicating theimportance of prevention of regional recurrence.

In the specific case of ACC of the submandibular gland,we recommend surgical excision of the submandibulartriangle as the biopsy procedure. We cannot recommendelective treatment to the neck for these patients because ofthe small number of patients in our study who had primarydisease at that site. Obviously, more studies are neededto determine the patterns of regional spread in ACC, aswell as the preferred treatment modality and the role ofpreventive neck dissections.

Of the 6 patients in our series who received chemo-therapy. I had early-stage disease and survived, and theother 5 had advanced disease and died of their diseasedespite aggressive treatment. Thus, in contrast to findingsreported by Spiroet al,̂ we observed no advantage to addingchemotherapy to tfie treatment protocol for patients withadvanced ACC. Asimilar observation was reported by Hillet al. who found that the combination of cispiatinum and5-fluorouracil resulted in no major improvement in survival

666 ENT-Ear, Nose & Throat Journal • October 2005

ADENOID CYSTIC CARCINOMA OF THE SALIVARY GLANDS:A 20 YEAR REVIEW WITH LONG-TERM FOLLOW-UP

Table 5. Outcome of the 27 patients withminor salivary gland tumors

Disease-free survival*n(<Vb)

Parotid 9 (33.3)

Minor salivary glands 3 (11.1)

parotid and

Disease^n (o/o)

3(11.1)

12 (44.4)

p - 0.0005 hy logistic regression with mtiltivuriiite (intilysi.s.Odds ratio: l5.0(95''/r confideme interval ICl]: 1.9 lo 74).Rate ratio - i.75 (95% Cl: 1.3 to 10.9).* Alive with no evidence of ACC or dead of another cause wilb noevidence of ACC.f Dead of ACC or alive with ACC in = I).

or symptom control in patients with ACC."

In conclusion, the prognosis of patients whose ACC

originates in the parotid gland is better than that of patients

whose ACC arises in the minor salivary glands; the better

outcome is attributable to the low rates of local spread

and regional recurrence. Regional recurrences, which are

most common in cases of ACC that arise in the minor

salivary glands, carry an ominous outcome. Surgery is

the preferred primary treatment, and complete resection

of the tumor with negative margins is indicated. In our

series, no advantage was achieved from adjuvant radiation

or chemotherapy.

References1. Spim RH. Thaler HT, Hicks WF. et al. The importance ofclinical

staging o!" minor salivary glanil carcinoma. Am J Surg IM9l:l(i2:330-6,

2. Spiro RH. Distant metastasis in adenoid cystic carcinoniaolsali varyorigin. Am J Surg 1997:174:495-8.

3. Spiro RH, Huvos AG. Strong EW. Adenoid cystic carcinoma ofsalivary origin. A clinicopathnlogic study of 242 cases. Am J Surg1974:128:512-20.

4. Spiro RH. Huvos AG. Strong EW. Adenoid cystic carcinoma:Factors influencing survival. Am J Surg 1979:138:579-83.

5. Mutsuba HM. Simpson JR. Mauney M. Thawley SE. Adenoidcystic salivary gland carcinoma: A clinicopathologic correlation.Head Neck Surg 1986;S:20()-4.

6. Goepfert H. t.una MA, Lindberg RD. White AK. Malignant sali-vary gland tumors ofthe paranasal sinuses and nasal cavity. ArchOtolaryngol l983:in«):662-8,

7. Perzin KH. Gullane P. Clairmont AC. Adenoid cystic carcinomasarising in salivary glands; A correlation of histologic features andclinical course. Cancer 1978:42:265-82.

S. Fordice J. Kershaw C. el-Naggar A. Goepfert H. Adenoid cysticcarcinoma of ihe head and neck: Predictors of morbidity andmortality. Arch Otolaryngol Head Neck Surg 1999; 125:149-52.

9. Vikram B. Strong EW, Shah JP. Spiro RH. Radiation therapy inadenoid-cystic carcinoma, hit J Radiat Oncol Biol Phys 1984:10:221-3,

10. Garden AS. Weber RS. Aiig KK. et al. Postoperative radiationtherapy for malignant lumors of minor salivary glands. Outcomeand patterns of failure. Cancer 1994:73:2563-9.

11. Hill ME. Constenla DO. A'Hcm RP et al, Cisplatin and 5-fluo-rouracil for symptom control in advanced salivary adenoid cysticcarcinoma. Oral Oncol 1997:33:275-8.

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