The Importance of Clinical Staging of Minor Salivary Gland Carcinoma Ronald H. Spiro, MD, Howard T. Thaler, Phn, Wesley F. Hicks, MD, Uma A. Kher, MS, Andrew H. HUVOS,MD, Elliot W. Strong, MD, New York, New York

We reviewed a 45year experience with 459 patients who had previously untreated minor salivary gland neoplasms, 378 (82%) of which were malignant. Data were adequate for retrospective clinical staging in 353 of the 378 patients with malignant tumors using criteria identical to those for squamous carcinoma in the same sites. Five-, lo-, and 15-year survival rates for the patients with malignant tumors treated after 1966 were 75%, 62%, and 56%, respectively, a significant improvement compared with results reported previously. Multivariate analysis confirms that survival was significantly influenced by the clinical stage and the histologic grade, hut the applicability of grading was limited to patients with mucoepidermoid carcinoma or adenocarcinoma. Ten-year overall survival was 83%, 53%, 35%, and 24% for patients with stage I through stage IV, respectively. Results in these patients are similar to those we have recently reported in patients with major salivary gland carcinomas, hut we are unable to demonstrate that postoperative radiotherapy improved survival.

umors arising in the predominantly mucus-secreting, T submucosal so-called minor salivary glands of the upper aerodigestive tract show enormous variation in their morphology and presentation. Moreover, their infrequent occurrence leaves most oncologists with little personal experience on which to base clinical decisions. In a previous report, we emphasized that histologic findings, anatomic site, and tumor extent were the most significant factors influencing survival [Z]. Since then, a staging system for major salivary gland tumors has been proposed and accepted [2,3], and most clinicians now appreciate the overriding importance of clinical stage as a prognostic factor. Currently, no staging system exists for tumors of minor salivary gland origin. In this study, we have reassessed and updated our previously reported experience in order to confirm that the staging criteria used for head and neck squamous carcinomas are equally useful in patients with minor salivary gland carcinomas. PATIENTS

AND METHODS

From the more than 800 patients with minor salivary gland tumors seen at our hospital between 1939 and 1983, we have selected 459 patients for this retrospective analysis. Criteria for inclusion included the following: (1) the tumor was previously untreated; (2) curative treatment was given in our hospital; and (3) adequate clinical information was available. Pathology slides were re-reviewed in selected patients, particularly those with nasal cavity carcinomas or sinus adenocarcinomas, in order to exclude tumors that are now considered mucosal rather than salivary gland in origin [4]. Many of the patients in this study have been included in previous reports [ I,51 The tumors were malignant in 378 patients (82%) and benign in 8 1. There were 22 1 males and 238 females who ranged in age from 11 to 91 years. The median age of those with malignant tumors was 56 years, compared with 48 years in those whose tumors were benign. The palate was the site most often involved (172 patients; 37%), followed by the tongue (64 patients; 14%), the cheek (47 patients; lo%), and the antrum (43 patients; 9%). The sites of origin are listed in Table I in order of decreasing incidence. The histologic classification used was a modification of that proposed by Foote and Frazell [a. Adenoidcystic and mucoepidermoid carcinomas were encountered with greatest frequency (130 and 127 patients, respectively). Other malignant diagnoses included adenocarcinoma (79 patients), malignant mixed tumor (26 patients), anaplastic or oat cell carcinoma (10 patients), and acinic cell carcinoma (6 patients). The distribution of tumor types according to the site of origin is shown in Table II.

.

From the Head and Neck Service, Department of Surgery (RHS, WFH, EWS), the Department of Pathology (AHH), and the Division of Biostatistics (HTT, UAK), Memorial Sloan Kettering Cancer Center, New York, New York. Requests for reprints should be addressed to Ronald H. Spiro, MD, 425 East 67th Street, New York, New York 10021. Presented at the 37th Annual Meeting of the Society of Head and Neck Surgeons, Maui, Hawaii, May l-4, 1991.

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Retrospective clinical staging was possible in all but 25 of the 378 patients with malignant tumors using criteria identical to those for squamous carcinomas in similar sites [ 73. Most of the patients whose tumors could not be staged had sinus primaries. Of the 353 patients with stageable malignant tumors, 96 (27%), 115 (33%), 110 (31%), and 32 (9%) had stage I through stage IV disease, respectively. The distribution of clinical stage, according to the site of origin, is shown in Table III. Lesions were usually stage I or stage II when they arose in the palate or other oral sites. Most of the patients with oropharyngeal, sinus, or laryngeal primaries had stage III or stage IV lesions when first seen. Surgery was the treatment of choice in almost all of our patients. Of 8 1 patients with benign lesions, 77 had a limited peroral excision, whereas 3 required a maxillectomy and 1 had a mandibulotomy. Radiotherapy alone was the definitive treatment in only 23 of 378 patients with malignant tumors (6%), 15 of whom were seen during the early years of the study. Half of the remaining eight patients irradiated since 1966 had nasopharynx primaries. Of 353 patients with carcinoma treated surgically, 146 (4 1%) had limited peroral or transnasal excisions. Of 273 patients with oral or oropharyngeal lesions, 64 patients (23%) required a maxillectomy, and 52 (19%) required a mandibulectomy. In a few instances, a mandibulotomy or transhyoid approach was used (13 and 2 patients, respectively). Most of the 66 patients with nasal cavity or antral tumors required a maxillectomy (57; 86%), including 30 who had an orbital exenteration. Since 1966, only five patients have required an exenteration of orbital contents. Two patients have had a craniofacial resection. Total laryngectomy was performed in 13 of 16 patients with larynx primaries, whereas one patient

TABLE

TABLE

I Sites of Origln Benign

Malignant

Total

Palate Tongue (BOT) Cheek Antrum Nasal cavity Gingiva Floor of mouth Lip Larynx Tonsil Retromolar Nasophatynx Ethmoid Pharynx

58 2 (2) 9

114 62 (36) 30 42 20 22 21 11 15 9 9 7 5 3

172 64 47 43 23 22 21 16 15 10 9 7 5 5

Total

81

378

459

1 3 0 0 5 0 1 0 0 0 2

BOT = base of tongue.

1

each had a cordectomy, supraglottic laryngectomy, or total pharyngolaryngectomy with gastric transposition. Considering all 378 patients with malignant tumors, 53 (14%) had cervical metastases initially and 26 (7%) developed nodal involvement later, for an overall incidence of nodal involvement of 21%. A total of 65 neck dissections were performed (18%), 37 for obvious adenopathy. Nodal metastasis was confiied in all but one patient, as well as in 9 of 28 patients who had an elective lymphadenectomy. Of 123 patients with malignant tumors treated since 1966,40 patients had adjun&e radiotherapy and 87 had only surgery. Our experience with preoperative radiation, which started in 1960 and terminated in 1969, involved 6

II

Histology According to Site of Origin Total

Palate

Oral

Orophatyngeal

Sinus

Larynx 5 4 0 9 0 0 0 18

Adenoidcyst Mucoepidermoid Benign Adenocarcinoma Malignant mixed Anaplastic (oat) Acinic cell

130 127 81 79 26 IO 6

44 30 56 22 17 0 1

32 50 14 29 4 0 4

16 14 5 12 2 0

33 21 4 7 4 8 1

Total

459

172

141

50

78

TABLE

1

III

Cllnicel Stage According to Site*

Stage I Stage II Stage III Stage IV ‘353 patients with malignant

Total

Palate

Oral

Orophatyngeal

Sinus

Larynx

96 115 110 32

40 49 17 3

50 45 23 8

2 17 19 7

2 2 42 10

2 2 9 4

tumors

(excludes

25 unstageable

patients).

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0.7 0.6 0.5 0.4 0 Dead from any cause (378 Rs.) (370 Rs.) o Dead from Disease

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patients. Since 1966, we have used adjunctive radiation only postoperatively. For analysis, the 34 patients who were irradiated postoperatively were matched as closely as possible with 34 patients who were not irradiated, according to site, histologic findings, grade, and stage. The match was less satisfactory than the one we previously reported in patients with major salivary gland carcino mas because there were fewer patients and greater site diversity [8]. The radiation dose was at least 6,000 rads in 17 patients, between 4,500 and 6,000 rads in 9, and uncertain in the remaining 8. All patients in this study were eligible for a minimum of 7 years of observation. Follow-up was considered incomplete in 37 patients who were lost within 5 years without evidence of recurrence. In all, 414 patients (90%) were eligible for lO-year follow-up, and the median follow-up exceeded 11 years. Using the product limit method of Kaplan-Meier, survival curves were computed both overall (treating all deaths as failures and patients alive or lost to follow-up as censored) and causespecific (treating deaths due to disease as failure and deaths from other causes as censored observations) [9]. Causespecific survival was used because it was a better measure of the impact of the prognostic factors. 332

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F@re 2. Causegpecific swvlval of patients with low& mucoepld6tmokl carcinoma, low& wbnocarcinoma, and aclnlc cell carcinoma .qzompared wlthswhdofpatieNltswnhallothw histologic types. MMT = malignant mixed twnor.

Rather than assuming a proportional hazards model, we used the maximum likelihood method. Survival comparisons were made using SAS PRGC LIPFREG to tit log-normal distributions [IO]. Prognostic factors tested included site, stage, histologic diagnosis, and grade, as well as age, gender, and year of diagnosis (pm-1966 versus post- 1966) RESULTS

In 436 patients treated surgically, there were six postoperative deaths (1.3%), all of which occurred prior to 1967. Local recurrence was documented in 5 of 8 1 patients who had benign tumors (6%). Cumulative 5, lO-, 15-, and 20-year overall survival rates for patients with malignant tumors were 73% 56%, 46%, and 35%, respectively (corresponding causespecific survival was 75%, 62%, 57%, and 51%) (Fcgure 1). There were no significant differences in survival rates when compared with 470 previously untreated patients with major salivary gland carcinoma who received therapy during the same time period [II]. Patients with sinus primaries had a significantly lower overall survival rate than did those with tumors arising in the palate or other oral sites (32% versus 57% at 10

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I

10 Time in Years

coramgto ainmi stage.

J

I

years). Results were significantly better in patients who had low-grade mucoepidermoid carcinoma, low-grade adenocarcinoma, or acinic cell carcinoma (93% at 10 years). Similar but lower survival rates were observed in those with malignant mixed tumor, high-grade mucoepidermoid carcinoma, high-grade adenocarcinoma, or adenoidcystic carcinoma (42% to 58% at 10 years), except that diseaserelated deaths occurred in patients with adenoidcystic carcinoma for as long as they were followed. The cause-specific survival according to the histo logic diagnosis is shown in F@rre 2. Ten-year overall survival, according to the clinical stage, was 8396, 52% 2596, and 23% for patients with stages I through IV disease, respectively (corresponding cause-specific survival was 931, 68%, 3296, and 27%) (Figure 3). Multivariate analysis confii that the clinical stage of the tumor and its histologic grade at the time of treatment were sign&ant predictors of survival. In patients with mucoepidermoid carcinoma or adenocarcinoma, cause-specific survival after resection of high-grade, lowstage tumors was almost comparable to that observed after treatment of low-grade tumors. In those patients with adenoidcystic carcinoma, stage was a significant pmdictor of survival, but grade was not (FIgnre 4). When adjusted for stage, the site of origin was not a significant predictor of survival. The year of diagnosis was another significant variable. Survival rates were 75% 62% and 56% at 5,10, and 15 years after surgery in patients treated since 1966, compared to 65%,45%, and 36% for similar follow-up intervals in patients treated before 1966. This significant difference is at least partly explained by the higher proportion of low-grade and non-adenoidcystic tumors treated in recent years. The distribution of patients according to stage has remained constant, with perhaps a slight increase in the proportion of patients with stage III or stage IV tumors treated since 1966. With the exception that fewer radical procedures have been performed in recent years, the surgical approach to these tumors has not changed appreciably. We were unable to demonstrate any significant impact by adjunctive, postoperative radiation therapy on survival even when the patients so treated THE AMERICAN

were compared to historic controls matched as closely as possible according to site, stage, and histologic fmdings. Information was adequate for analysis of failure in 168 unsuccessfully treated patients. Local recurrence was documented in 122 patients (73%), 58 of whom also had distant metastases or uncontrolled disc in the neck. Uncontrolled disease was noted in 45 patients (27%), 30 of whom had local recurrence or distant spread as well. A total of 72 patients (43%) had distant metastases. Distant metastasis was the only indication of treatment failure in 23 patients (14%). The actual incidence of distant metastasis remains uncertain. When calculated as a proportion of the 378 who had carcinomas, at least 19% of the patients developed distant spread. The likelihood of tumor dissemination was significantly related to the initial status of the neck: 17% when the neck was clinically negative and 3 1% when enlarged nodes were evident (p = 0.04). Published reports about minor salivary gland tumors show some significant discrepancies, undoubtedly related to their rather uncommon occurrence. The incidence varies from less than 10% to more than 30% of all salivary gland tumors (22% in our experience) [12-IS]. Minor salivary gland tumors are more likely to be malignant than their counterparts arising in the parotid or submandibular gland. Our proportion of malignant tumors (more than 80%) is much higher than others report (45% to 50%), but this is not surprising considering the referral bias in any study based on patients treated in a major cancer center. We limited our review to previously untreated patients in order to permit retrospective clinical staging. This fact, and the decision to match time frames (1939 to 1965; 1966 to 1983) with our recent report on major salivary gland tumors [I I], has facilitated comparisom and highlighted some interesting trends. First, there was no significant difference in survivorship when patients treated for major or minor salivary gland carcinomas were compared. Second, as was noted in those with major salivary gland cancers, survival in the more recently treated patients with minor salivary gland carcinomas has improved significantly.

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The better results since 1966 are partly explained by changing tumor factors. Although the distribution of patients according to the clinical stage has not changed over the years, proportionately fewer patients with adenoidcystic carcinoma have been treated recently (24% of malignant tumors compared to 40% previously). Most of the difference was made up by patients with mucoepidermoid carcinoma, including a higher proportion with low-grade tumors (15% of recently diagnosed malignant tumors compared with 10% previously). It is uncertain whether 334

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wlul

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w

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to cllnkal vlfk suvlval In stasesM-9 patbnts wlth lowgrade adeMCWcln+ macomparedwtthsuvhrallnthosewlth hl&rade leskns of slmllar hbMoglc type classlfled according to cllnkal caWMpeclfk suWal scege.In patbnts with bwgade adenoleystk carcinoma compared wlth survh/al In thoWwlth~tumorsclas$med accordingto cllnkal stage. tmors

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according

this reflects a true change in the incidence of these subtypes. With respect to factors influencing survival, histologic diagnosis alone was of limited value. There was no significant difference in survival whether the patient had a malignant mixed tumor, an intermediate or high-grade mucoepidermoid carcinoma, a high-grade adenocarcinoma, or an adenoidcystic carcinoma. Results were clearly better in those patients with low-grade lesions and worse in the few with anaplastic tumors. Although grading was

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important in two subgroups of patients (mucoepidermoid carcinoma and adenocarcinoma), the value of staging was obvious in all patients, regardless of the histologic diagnosis. Consistent with our previous report, tumor grading was of no value in predicting survival rates in patients with adenoidcystic carcinoma [16’J. Multivariate analysis confirms that the staging criteria employed for squamous carcinoma were useful for predicting treatment results in patients with minor salivary gland carcinomas. It is interesting to note that the clinical stage was less predictive of survival in patients with adenoidcystic carcinoma than in patients with mucoepidermoid carcinoma or adenocarcinoma. The lower survival rate noted in patients with sinus tumors was not substantiated on multivariate analysis and, obviously, relates to staging bias. Other parallels with squamous carcinoma can be drawn. In inaccessible sites, such as the sinuses, minor salivary gland tumors tend to be extensive by the time of diagnosis and treatment. The surgical approach for minor salivary lesions is usually identical to that used for squamous carcinomas in similar sites, except for the obvious concerns that arise when treating an adenoidcystic carcinoma, a tumor that is often more extensive than can be appreciated clinically or radiologically. Finally, as in patients with squamous carcinomas, there is a trend towards less radical surgery. In recent years, few patients have required radical maxillectomy with orbital exe&ration or segmental mandibulectomy. It is diflicult to ascribe this to a lower incidence of advanced tumors when our data indicate that the proportion with stage IV disease has not changed since 1966. What seems more likely is that our recent preference for preservation of vital structures is a result of a growing confidence that adjunctive radiotherapy will control any microscopic residual when resection margins are close to the tumor. Several studies have described significantly reduced local failure rates and improved survival when patients who received only surgery were compared retrospectively with those who received surgery and radiotherapy [16-211. Certain caveats apply to these data: (1) the reported experience with combination therapy for minor salivary gland carcinomas remains minimal; (2) the indications for combined therapy have not been clearly de fm&, and (3) the follow-up has often been inadequate. We found that the disease-free interval was 5 years or more in 24 of our patients in whom treatment failed (15%) and exceeded 10 years in 6 (4%), only some of whom had low-grade tumors. Recognizing that the impact of different treatment modalities is always difficult to assess retrospectively, we attempted to assess the impact of adjunctive radiotherapy by a matched-pair analysis. The methodology was identical to that which we recently used in a study limited to major salivary gland carcinomas, which showed improved survival only in patients who had stage III or stage IV disease [8]. In our patients with malignant minor salivary gland tumors, we were unable to demonstrate a survival benefit in those who received combination therapy. However, certain contraints were apparent. The

match was less satisfactory due to smaller numbers and greater diversity in tumor site in the minor salivary gland group, and some of the patients that were irradiated received doses that were probably suboptimal. Notwithstanding these limitations, there was a trend towards better control of the primary tumor in the irradiated patients. Our experience suggests that patients with minor salivary gland carcinoma require an adequate surgical resection that encompasses all gross and microscopic tumor. Postoperative radiotherapy seems appropriate in any patients who have high-stage tumors (especially if also high grade) or when there is concern about the adequacy of surgical margins. There are as yet no data to support the conclusion that radiotherapy is routinely indicated in all patients with malignant tumors. What seems clear is the desirability of multicenter, prospective studies to better target those patients who will benefit from such adjunctive treatment. The significant incidence of distant metastasis, especially in those who present with nodal involve ment, highlights the need for an effective chemotherapy regimen.

REFERENCES 1. Spiro RI-I, Koss LG, Hajdu SI, Strong EW. Tumors of minor salivary origin, a clinicopathologic study of 492 cases. Cancer 1973; 31: 117-29. 2. Spiro RI-I, Huvos AH, Strong EW. Carcinoma of the parotid gland, a clinicopathologic study of 286 primary cases. Am J Surg 1975; 130: 452-9. 3. American Joint Committee for Cancer Staging and End Results Reporting. Manual for staging of cancer. Chicago: American Joint committee, 1978. 4. Alessi DM, Trapp TK, Fu YS, Calcaterra T. Nonsalivary sinonasal adenocarcinoma. Arch Gtolaryngol Head Neck Surg 1988; 114: 996-9. 5. Spiro RI-I. Salivary neoplasm overview of a 35 year experience with 2,807 patients. Head Neck Surg 1986; 8: 177-84. 6. Foote FW, Fraxell EL. Tumors of the major salivary glands. Cancer 1953; 6: 1065-133. 7. American Joint Committee on Cancer. Manual for staging of cancer. 3rd ed. Philadelphia: American Joint Committee, 1988. 8. Armstrong JG, Harrison LB, Spiro RH, Fass DE, Strong EW. Malignant tumors of major salivary gland origin, a matched pair analysis of the role of combined surgery and postoperative radie therapy. Arch Gtolaryngol Head Neck Surg 1990,116: 290-3. 9. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. 10. SA!3 Institute, Inc. SAS/STAT user’s guide. Version 6,4th ed, vol 2. Cary, North Carolina: 1989; 997-1069. 11. Spiro RH, Armstrong JA, Harrison L, Geller NL, Shiow-Yun Lin, Strong EW. Carcinoma of major salivary glands. Arch Gtolaryngol Head Neck Surg 1989; 115: 316-21. 12. Eneroth CM. Salivary gland tumors in the parotid gland, submandibular gland, and the palate region. Cancer 1971; 27: 1415-8. 13. Chaudry AP, Labay GR, Yamane GM, Jacobs MS, Cutler IS, Watkins KV. Clinico-pathologic and histogenetic study of 189 intraoral minor salivary gland tumors. J Oral Med 1984,39: 58-78. 14. Eveson JW, Qwson RA. Tumours of minor (oropharyngeal) salivary glands, a demographic study of 336 cases. J Oral Path01 1985; 14: 500-9. 15. Ma Da-Quan, Yu Guang-Yan. Tumours of the minor salivary

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glands, a clinicopathologic study of 243 cases. Acta Otolaryngol (Stockh) 1987; 103: 325-31. 16. Spiro RH, Huvos AG, Strong EW. Adenoid cystic carcinoma, factors influencing survival. Am J Surg 1979; 138: 579-83. 17. Fu KK, Lcibel SA, Levine ML, Friedlander LM, Boles R, Phillips TL. Carcinoma of the major and minor salivary glands, analysis of treatment results and sites and causes of failure. Cancer 1977; 40: 2882-90. 18. Guillamondequi OM, Byers RM, Luna MA, Chiminaazo H, Jesse RH, Fletcher GH. Aggressive surgery in treatment for parot-

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id cancer, the role of adjunctive postoperative radiotherapy. AJR Am J Roentgen01 1975; 123: 49-54. 19. Tu G, Hu Y, Jiang P, Qin D. The superiority of combined therapy (surgery and postoperative irradiation) in parotid cancer. Arch Otolaryngol Head Neck Surg 1982; 108: 710-3. 20. Fitzpatrick PJ, Theriault C. Malignant salivary gland tumors. J Radiat Oncol Biol Phys 1986; 12: 1743-7. 21. Borthne A, Kjellevold K, Kaalhus 0, Vermund H. Salivary gland malignant neoplasma, treatment and prognosis. J Radiat Oncol Biol Phys 1986; 12: 747-54.

VOLUME 162 OCTOBER 1991

The importance of clinical staging of minor salivary gland carcinoma.

We reviewed a 45-year experience with 459 patients who had previously untreated minor salivary gland neoplasms, 378 (82%) of which were malignant. Dat...
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