The Laryngoscope C 2015 The American Laryngological, V
Rhinological and Otological Society, Inc.
Polymorphous Low-Grade Adenocarcinoma of the Head and Neck: A Population-Based Study of 460 Cases Tapan D. Patel, BS; Alejandro Vazquez, MD; Emily Marchiano, BA; Richard Chan Park, MD; Soly Baredes, MD, FACS; Jean Anderson Eloy, MD, FACS Objectives/Hypothesis: Polymorphous low-grade adenocarcinoma (PLGA) is a rare malignant neoplasm of the minor salivary glands. This study analyzes the demographic, clinicopathologic, incidence, and survival characteristics of head and neck PLGA (HN-PLGA). Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for HN-PLGA cases from 2001 to 2011 (460 cases). Data analyzed included patient demographics, incidence trends, and survival outcomes. Results: Head and neck PLGA occurred most frequently in the sixth and seventh decades of life. Mean age at diagnosis was 61.3 (6 15.0) years. There was a female predilection with a female-to-male ratio of 2.15:1. There was a predilection toward blacks among the US population, with black-to-white incidence rate ratio of 2.33:1. The most common site of HNPLGA was the palate (57.2%), followed by the lip (7.0%). Average tumor size was 2.1 (6 1.3) cm at presentation. The majority of cases were localized at the time of presentation (70.5%), with rare distant metastasis (4.3%). The most common treatment modality was surgery alone (77.9%), followed by surgery with radiotherapy (19.5%). Elective neck dissection was performed in 5.3% of the cases. Survival analysis showed excellent 10-year disease-specific (96.4%) and relative (94.7%) survival rates. Ten-year disease-specific survival was better among those treated with surgery alone (98.0%) or surgery with adjuvant radiotherapy (90.9%) than those treated with radiotherapy alone (75.0%) (P < 0.0001). Conclusion: This study represents the largest cohort of HN-PLGA cases. Head and neck PLGA shows a predilection for women and blacks in the US population. It has an excellent survival outcome with surgery being the treatment of choice. Key Words: Polymorphous low-grade adenocarcinoma, malignancy, SEER, demographic, incidence, disease-specific survival, relative survival, palate, minor salivary glands. Level of Evidence: 4. Laryngoscope, 125:1644–1649, 2015
INTRODUCTION Polymorphous low-grade adenocarcinoma (PLGA) is a salivary gland tumor first described by Evans and Batsakis in 1984.1 PLGAs usually arise from the minor salivary glands; however, there have been reports of these tumors within the major salivary glands.2 They most commonly occur in the palate, but also can occur at extrapalatal sites including the tongue base, buccal mucosa, and inner upper lip.3,4 They are slow-growing unencapsulated tumors that have characteristic nuclear
Additional Supporting Information may be found in the online version of this article. From the Department of Otolaryngology–Head and Neck Surgery (T.D.P., A.V., E.M., R.C.P., S.B., J.A.E.); the Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey (S.B., J.A.E.); and the Department of Neurological Surgery (J.A.E.), Rutgers New Jersey Medical School, Newark, New Jersey, U.S.A. Editor’s Note: This Manuscript was accepted for publication February 23, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jean Anderson Eloy, MD, FACS, Professor and Vice Chairman, Director, Rhinology and Sinus Surgery; Director, Otolaryngology Research; Co-Director, Endoscopic Skull Base Surgery Program, Department of Otolaryngology–Head and Neck Surgery, Neurological Institute of New Jersey, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ 07103. E-mail: [email protected] DOI: 10.1002/lary.25266
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homogeneity and histologic heterogeneity with multiple growth patterns, including solid, ductotubular, cribriform, trabecular, and single file growth.3–6 Although they are locally invasive, distant metastasis is rare.1,7–10 Treatment for PLGA is surgical resection with or without radiotherapy.11 Recurrence rates are as high as 33%, and recurrent disease tends to show a more aggressive histology with a higher number of mitoses, increased papillary component, and greater likelihood of classification as an intermediate-grade adenocarcinoma.11 Interestingly, recurrence has not been associated with the presence of perineural invasion.12 To date, scholarship on PLGA is limited to small, single-institutional series and case reports.1–4,9,11,13–18 Most of these studies have focused on histopathologic characterization of this tumor. The largest study to date by Castle et al.3 analyzed 164 cases of PLGA using files from the tumor registries of the Armed Forces Institute of Pathology. However, no large study thus far has analyzed incidence trends and survival outcomes of this tumor. Here, we present an epidemiologic analysis of PLGA using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Database. We analyzed 460 cases of head and neck PLGA (HNPLGA) from 18 SEER registries, representing the largest cohort of HN-PLGA patients studied so far. Our analysis includes demographic and clinicopathologic features Patel et al.: SEER Head and Neck PLGA
of this rare neoplasm, along with its incidence trends and survival outcomes.
MATERIALS AND METHODS Frequency, incidence, and survival data were obtained from the SEER 18 dataset for the years 2001 to 2011. We decided to restrict our search to this time period because the morphological code for PLGA was introduced in the year 2000 as part of the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3).19 The previous version of this classification scheme (ICD-O-2) did not have a code specifically for PLGA. For our study, institutional review board approval was not required because SEER does not report sensitive patient information. The SEER database was queried for patients diagnosed with HN-PLGA based on the ICD-O-3 code for PLGA (8525/3). Anatomic locations within the head and neck region were selected using the SEER “site and morphology/primary site-labeled” variable. We used the following ICD-O-3 topographical codes in our analysis: C00-C14, C30-C32, C41.0, C41.1, C44.0-C44.4, C47.0, C49.0, C69, C73.9, C75.0, C76.0, and C77.0. Frequency data were stratified and analyzed by age, gender, race, primary site, histologic grade, American Joint Committee on Cancer (AJCC) stage, tumor-node-metastasis classification, SEER LRD (local, regional, distant) stage, and treatment modality. Incidence data were age adjusted to the standard U.S. 2000 population and reported per 100,000 people at risk for cases diagnosed between 2001 and 2011. Five-year and 10-year survival rates were calculated using Kaplan-Meier analysis, yielding overall survival (OS) and disease-specific survival (DSS) rates. Relative survival (RS) for these time intervals were represented using the ratio between the observed survival rate and the expected age-adjusted survival rate for a similar segment of the population. SEER data were extracted using SEER*Stat 8.1.5 (National Cancer Institute, Bethesda, MD) software. Incidence data were analyzed via weighted least squares for annual percent change (APC) using 1-year end-points in SEER*Stat 8.1.5 software. Joinpoint Regression Program 4.1.1.1 (National Cancer Institute, Bethesda, MD) was used to calculate APC in incidence and assess the statistical significance of the trends observed. Survival data from SEER*Stat 8.1.5 were reorganized and reclassified in Microsoft Excel 2013 (Microsoft, Redmond, WA) and then imported into JMP Statistical Discovery 11 (SAS Institute, Cary, NC) for log-rank analysis to generate KaplanMeier curves and DSS rates. SEER*Stat 8.1.5 was also used to extract RS data. Probability values (P value) < 0.05 were considered statistically significant.
RESULTS Analysis of Demographic and Clinicopathologic Factors A total of 460 cases of HN-PLGA were reported in the SEER database between 2001 and 2011. Table I describes the demographic and clinicopathologic factors of HN-PLGA cases extracted from the SEER database. The mean age at diagnosis was 61.3 years with a standard deviation of 15.0 years. Females accounted for 68.3% of the HN-PLGA cases. The female-to-male ratio was 2.15:1. Whites accounted for 76.6% of the cases and blacks accounted for 21.2%. The most common primary site for the tumor was the palate, specifically the hard palate (26.1%) followed by the soft palate (15.9%). A Laryngoscope 125: July 2015
total of 9.6% of the cases were recorded as overlapping lesion of the palate and 5.7% of the cases were recorded as palate, not otherwise specified (NOS). This ambiguity of the classification system led us to consider the “palate” as one combined entity (including soft palate; hard palate; overlapping lesion of palate; and palate, NOS). Grouping the palatal cases in this way, we found 57.2% of the cases involving the palatal region. Lip (7.0%) and buccal mucosa (6.1%) were the next common sites of involvement. As the name implies, histologically PLGA is a low-grade tumor. Out of the cases for which histologic grade information was available in the SEER database (422 cases), 37.2% were of well-differentiated type (histologic grade I), and the remaining 62.8% cases were of moderately differentiated type (histologic grade II). AJCC staging information was available for 319 cases (i.e., those diagnosed after 2004 only): stage I (46.7%), stage II (17.6%), stage III (5.6%), and stage IV (11.9%). The majority of the cases had localized disease (70.5%) at diagnosis based on the SEER LRD stage. Only 4.3% of the cases were diagnosed with distant metastasis. Table II shows the cases categorized by treatment modality and neck dissection information. Treatments were categorized as single-modality radiotherapy, combined surgery and radiotherapy, or surgery alone. Treatment data were available for 416 cases. The majority of the patients underwent surgical therapy alone (77.9%), followed by surgery and radiotherapy (19.5%). Only 2.6% of the patients received radiotherapy alone. Information on neck dissection was queried based on nodal involvement. In patients with N0 neck disease, neck dissection was performed in 5.3% of the cases; whereas, in patients with N1 or N2 neck disease, neck dissection was performed in 62.5% of the cases.
Incidence and Survival Analysis The incidence analysis was performed for the years 2001 to 2011 (Supp Table SI; online version only). Overall age-adjusted mean incidence rate of HN-PGLA was 0.051 cases per 100,000 of population at risk (95% confidence interval (CI), 0.046–0.056). The average incidence in males was 0.035 cases per 100,000 of male population (95% CI, 0.030–0.042), and the average incidence in females was 0.065 cases per 100,000 of female population (95% CI, 0.056–0.072), with a female-to-male incidence rate ratio of 1.82:1. The incidence analysis by race showed an overall age-adjusted mean incidence rate for blacks of 0.110 cases per 100,000 (95% CI, 0.088–0.135) and 0.047 cases per 100,000 for whites (95% CI, 0.042– 0.0524). The black-to-white incidence rate ratio was 2.33:1. In addition, the incidence trend analysis by race also showed decreasing trends for whites (APC of 22.33%) and blacks (APC of 21.42%) from 2001 to 2011, but these trends were not statistically significant. Overall, HN-PLGA rate in 2011 was 0.053 cases per 100,000 population at risk and decreased from 0.061 cases per 100,000 population in 2001 (Supp. Fig. S1; online version only). Joinpoint regression model revealed a decreasing incidence of HN-PLGA with the APC of Patel et al.: SEER Head and Neck PLGA
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TABLE I. Demographic and Clinicopathologic Characteristics of Head and Neck Polymorphous Low-Grade Adenocarcinoma (2001–2011). n
%
460
100
TABLE I. (Continued) n
%
282 11
88.4% 3.4%
N Classification* Total Mean Age at Diagnosis, Years (6 SD) Age Groups
61.3 (6 15.0)
N2
0–19 years
2
0.4%
20–29 years 30–39 years
6 28
1.3% 6.1%
40–49 years
69
15.0%
50–59 years 60–69 years
100 100
21.7% 21.7%
70–79 years
93
20.2%
53
11.5%
Male
146
31.7%
Female Race
314
68.3%
White
344
76.6%
Black Asian or Pacific Islander
95 8
21.2% 1.8%
801 years Gender
American Indian or Alaska Native
2
0.4%
11
–
Hard palate
120
26.1%
Soft palate Overlapping lesion of palate
73 44
15.9% 9.6%
Palate, NOS
26
5.7%
Lip Mouth, NOS
32 31
7.0% 6.7%
Buccal mucosa
28
6.1%
Parotid gland Other major salivary glands
24 19
5.2% 4.1%
Unknown Location
Nasal cavity and paranasal sinuses
22
4.8%
Tongue Other head and neck sites
10 31
2.2% 6.7%
Average Tumor Size, cm (6 SD)
2.1 (6 1.3)
Histologic Grade Well differentiated, grade I
157
37.2% 62.8%
38
–
I
149
46.7%
II III
56 18
17.6% 5.6%
IV
38
11.9%
58
18.2%
T1
153
48.0%
T2 T3
64 14
20.1% 4.4%
T4
32
10.0%
Tx
56
17.6%
Unknown/not recorded AJCC Stage†
Unknown T Classification†
5
1.6%
21
6.6%
M0
297
93.1%
M1 Mx
5 17
1.6% 5.3%
Localized Regional
309 110
70.5% 25.1%
Distant
19
4.3%
Unknown
22
–
Nx M Classification†
SEER LRD Stage
*Percentages are out of n 5 319 (cases diagnosed 2004 and onward). AJCC 5 American Joint Committee on Cancer; LRD 5 local, regional, distant; NOS 5 not otherwise specified; SD 5 standard deviation; SEER 5 Surveillance, Epidemiology, and End Results; TNM 5 tumor, node, metastasis.
21.55%. However, this trend was not statistically significant (P 5 0.3838). The incidence trend analysis by gender showed a decreasing trend in incidence for females initially from 2001 to 2004 (APC of 218.52%), followed by an increasing trend from 2004 to 2011 (APC of 5.41%). These trends were found to be statistically significant (P < 0.05). Supporting Figure S2 (online version only) shows the incidence trend curve for females. For males, the incidence trend analysis showed a decreasing trend (APC of 22.63%) from 2001 (0.033 per 100,000) to 2011 (0.030 per 100,000); however, this trend was not found to be statistically significant.
TABLE II. Treatment of Head and Neck Polymorphous Low-Grade Adenocarcinoma (2001–2011).
265
Moderately differentiated, grade II
N0 N1
n
%
Surgery Radiotherapy
324 11
77.9% 2.6%
Surgery and radiotherapy
81
19.5%
44
–
15 266
5.3% 94.7%
1
–
10
62.5%
6
37.5%
Treatment
None/unknown Neck Dissection No nodal involvement ND No ND Unknown Nodal involvement (N1) ND No ND ND 5 neck dissection.
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Patel et al.: SEER Head and Neck PLGA
TABLE III. Five-Year Survival Analysis for Head and Neck Polymorphous Low-Grade Adenocarcinoma. 5 Years n
All Cases Location
378
Hard palate
OS
P Value
–
98.6%
–
0.0266*
100.0%
1.0000
100
91.5%
61
100.0%
< 2 cm
161
94.8%
2 cm AJCC Stage
144
90.6%
168
93.6%
42
85.4%
Advanced (stages III and IV) Treatment Modality
DSS
91.1%
Soft palate Tumor Size
Early (stages I and II)
P Value
Surgery
273
92.0%
Radiotherapy Surgery and radiotherapy
6 65
75.0% 94.5%
100.0% 0.2802
100.0%
0.2750
98.6% 0.0475*
100.0%
0.0039*
94.4% 0.2964
99.3%
< 0.0001*
75.0% 100.0%
RS
95% CI
98.8%
84.8%–99.9%
96.6%
78.6%–99.5%
100.0%
–
99.5%
83.9%–100.0%
99.1%
86.3%–99.9%
99.7%
84.9%–100.0%
88.8%
67.5%–96.5%
98.9%
94.3%–99.8%
– 98.4%
– 39.3%–100.0%
*Statistical significance AJCC 5 American Joint Committee on Cancer; CI 5 confidence interval; DSS 5 disease-specific survival; OS 5 overall survival; RS 5 relative survival.
Tables III and IV show 5- and 10-year survival analyses for 378 HN-PLGA cases, respectively, for which survival data was available in SEER. Overall survival, DSS, and RS were calculated. Overall survival takes into account two causes of deaths: deaths due to disease of interest and deaths due to all other causes. Diseasespecific survival takes into account only deaths attributable to the cancer of interest.20 Relative survival is obtained by dividing the OS by the expected survival of a comparative segment of the population. Relative sur-
vival is the standard measure of net survival in population-based cancer studies.20,21 Overall survival for all cases was 91.1% at 5 years and 72.7% at 10 years. The 5- and 10-year DSS were found to be 98.6% and 96.4%, respectively. The 5- and 10-year RS were 98.8% (95% CI, 84.8%–99.9%) and 94.7% (95% CI, 60.9%–99.4%), respectively. Survival analysis was also carried out comparing the two most common HN-PLGA tumor sites, namely the hard and the soft palate. The 5-year OS was 91.5% for the hard
TABLE IV. Ten-Year Survival Analysis for Head and Neck Polymorphous Low-Grade Adenocarcinoma.
10 Years P Value
RS
95% CI
96.4%
–
94.7%
60.9%–99.4%
0.2527
96.3% 100.0%
0.5050
96.6% 99.2%
78.6%–99.5% 0.0–100.0%
80.3% 62.2%
0.0210*
98.0% 94.2%
0.3691
99.5% 83.0%
83.9%–100.0% 49.7%–95.1%
168 42
86.7% 85.4%
0.1316
100.0% 94.4%
0.0039*
– –
– –
Surgery Radiotherapy
273 6
74.1% 75.0%
0.3215
98.0% 75.0%
< 0.0001*
96.7% –
12.4%–99.9% –
Surgery and radiotherapy
65
70.5%
85.3%
38.1%–97.4%
All Cases
n
OS
P Value
378
72.7%
–
100 61
81.2% 83.0%
161 144
DSS
Location Hard palate Soft palate Tumor Size < 2 cm 2 cm AJCC Stage Early (stages I and II) Advanced (stages III and IV) Treatment Modality
90.9%
*Statistical significance. AJCC 5 American Joint Committee on Cancer; CI 5 confidence interval; DSS 5 disease-specific survival, OS 5 overall survival; RS 5 relative survival.
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Fig. 1. Kaplan-Meier analysis of 10-year disease-specific survival (DSS) for HN-PLGA by treatment modality. Note: A small sample size of six cases was found for the radiotherapy (RT) alone group. The maximum follow-up period of this group was 56 months.
palate and 100.0% for the soft palate (P 5 0.0266). The 5-year DSS was 100.0% for both locations (P < 0.0001). Five-year RS was 96.6% for hard palate and 100.0% for the soft palate. Better survival outcomes were observed for tumors with size smaller than 2 cm compared to the tumors with size 2 cm. The 10-year OS for tumors less than 2 cm was 80.3%, whereas the OS for tumors 2 cm was 62.2% (P 5 0.0210). Similarly, the 10-year RS for tumors smaller than 2 cm (99.5%) was found to be better than that for tumors 2 cm (83.0%). When stratified by AJCC stage, patients with advanced stage disease (i.e., AJCC stage III or IV) had poorer overall survival outcomes at 5 and 10 years compared to patients with early-stage disease (i.e., AJCC stage I or II). At 5 years, the OS was 93.6% for patients with early stage disease and 85.4% for patients with advanced stage disease (P 5 0.0475). The 5- and 10-year DSS also showed worse survival for patients with advanced-stage disease compared to patients with early-stage disease (P 5 0.0039). Figures 1 and 2 show 10-year OS and DSS KaplanMeier survival curves grouped by treatment modality. The 10-year OS was 74.1% for surgery alone, 70.5% for surgery with radiotherapy, and 75.0% for radiotherapy alone (P 5 0.3215). The 10-year DSS was 98.0% for surgery alone, 90.9% for surgery and radiotherapy, and 75.0% for radiotherapy alone (P < 0.0001). The treatment modality did show some impact on survival outcomes; a trend toward poor DSS outcome was seen for patients receiving radiotherapy alone. However, in our analysis it should be noted that survival information was available only for six patients out of the 11 patients who received radiotherapy alone. The 10-year DSS for these patients was 75.0%. Of these 6 patients, two patients were older than 75 years, and the remaining four had an advanced stage disease (AJCC stage III or IV).
those reported in other published studies.3,4,9,11,17,22–24 Head and neck PLGA occurs over a wide age range; however, it tends to occur more frequently in the sixth and seventh decades of life.22–24 In our study, the mean age at diagnosis was 61.3 years, and 43.4% of the cases were found in the age range of 50 to 69 years. There appears to be a female preponderance in PLGA, with a female-tomale ratio of 2:1.3,4,22,23 We also found a similar female predilection in our cohort of 460 patients, with our female-to-male ratio of 2.15:1. Based on the results of our incidence analysis, we found a predilection toward blacks, with a black-to-white incidence rate ratio of 2.33:1. Consistent with prior studies,4,17,22–25 we found the palate to be the most common site for the tumor origin. It accounted for 57.2% of the cases in our study. The second most common site was the lip, followed by the buccal mucosa. Because there is a preponderance of minor salivary gland tissues in these sites, PLGA can be considered primarily a neoplasm of minor salivary gland tissue. Prior studies have reported an average tumor size at diagnosis between 2 cm and 2.5 cm.3,4,9 In our study, we found an average tumor size of 2.1 cm at presentation among 361 cases for whom size information was available in SEER. Although a malignant neoplasm, PLGA exhibits limited metastatic behavior, differentiating it from other malignant salivary gland tumors. Regional metastasis rates of 5% to 15% have been reported in prior studies.4,9,17 However, we found a regional spread in 25.1% cases at the time of presentation. Distant metastasis is rare. Earlier studies have reported distant metastasis rates between 0.6 to 7.5%.3,4,26,27 Consistent with these reports, our distant metastasis rate at diagnosis was 4.3%. Complete surgical resection of the tumor was the treatment of choice in this current analysis. A total of 77.9% of the patients received surgery alone for the management of the tumor. Surgery with radiotherapy was the second most common treatment. Pogodzinski et al.9 and Gonzalez-Garcia et al.28 have recommended against elective neck dissections unless major resection or reconstruction is planned. Consistent with this recommendation, neck dissections were not performed in the
DISCUSSION Polymorphous low-grade adenocarcinoma is a rare neoplasm of minor salivary glands that exhibits slow growth and indolent behavior. The demographic and clinicopathologic features in our study generally match Laryngoscope 125: July 2015
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Fig. 2. Kaplan-Meier analysis of 10-year overall survival (OS) for HN-PLGA by treatment modality. Note: A small sample size of six cases was found for the radiotherapy (RT) alone group. The maximum follow-up period of this group was 56 months.
Patel et al.: SEER Head and Neck PLGA
majority of patients with N0 disease (94.7%) in this analysis. Head and neck PLGA has an excellent prognosis. The 5- and 10-year RS were 98.8% and 94.7%, respectively. As expected, patients with tumors 2 cm in size had worse 5- and 10-year RS compared to patients with tumors less than 2 cm at presentation. In the study by Castle et al.,3 DSS of 97.6% was reported, without evidence of recurrence nearly a decade after surgical management. Similarly in our analysis, the 10-year DSS for patients receiving surgery alone was 98.0%, matching the DSS rate reported by Castle et al. Only 11 patients received radiotherapy alone, and the survival data was available for only six of these patients. The 10-year DSS for these patients was found to be significantly lower (75.0%) than that for surgery alone (98.0%) or surgery combined with radiotherapy (90.9%, P < 0.0001). The reasons for the poor survival outcomes for the radiotherapy alone group may be that these patients had an advanced stage disease (AJCC stage III or IV) or that surgery was not advised due to their mature age. Furthermore, given the small sample size for the radiotherapy group, a strong conclusion that radiotherapy alone leads to poor prognosis cannot be drawn. Because our study was a population-based analysis of HN-PLGA, there are certain limitations inherent to this type of study. We used ICD-O-3 morphological and topographical codes to select HN-PLGA cases from the SEER database. However, one limitation of using such a coding system is that it introduces the possibility of inaccuracy through the miscoding of cases. Retrospective population-based studies are dependent on accurate coding and consistent data collection among numerous sites. In addition, SEER does not contain complete information regarding the extent of therapeutic intervention, such as the number of cycles of radiotherapy applied or the specific surgical techniques utilized. Furthermore, SEER does not currently have information on tumor recurrence, which precludes us from reporting on the recurrence and disease-free survival rates on this tumor. Likewise, data about chemotherapy was unavailable for our analysis, even though some of the patients in our study might have received chemotherapy. Consequently, the results should be interpreted with these limitations in mind. Despite such limitations, a cohort of this magnitude has not been previously analyzed, and as such it provides important information on this tumor.
CONCLUSION Polymorphous low-grade adenocarcinoma is a slowgrowing malignant tumor that is predominantly found in the minor salivary glands of the oral cavity. It has a predilection for females and blacks in the US population. The palate is the most common site for this neoplasm. This tumor has an excellent survival outcome, with surgery being the treatment of choice. The role of radiotherapy currently remains unclear in the management of this tumor.
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BIBLIOGRAPHY 1. Evans HL, Batsakis JG. Polymorphous low-grade adenocarcinoma of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Cancer 1984;53:935–942. 2. Nagao T, Gaffey TA, Kay PA, Minato H, Serizawa H, Lewis JE. Polymorphous low-grade adenocarcinoma of the major salivary glands: report of three cases in an unusual location. Histopathology 2004;44:164–171. 3. Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer 1999;86:207–219. 4. Evans HL, Luna MA. Polymorphous low-grade adenocarcinoma: a study of 40 cases with long-term follow up and an evaluation of the importance of papillary areas. Am J Surg Pathol 2000;24:1319–1328. 5. Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization classification of tumours: pathology and genetics of head and neck tumours. Lyon, France: IARC Press; 2005. 6. Thompson LD. Polymorphous low-grade adenocarcinoma. Ear Nose Throat J 2014;93:24–25. 7. Thennavan A, Rao L, Radhakrishnan R. Polymorphous low-grade adenocarcinoma of maxillary alveolus metastasising to the abdomen: the role of immunomarkers in diagnosis. BMJ Case Rep 2013;2013. pii: bcr2013009633. doi: 10.1136/bcr-2013–009633. 8. Thomas KM, Cumberworth VL, McEwan J. Orbital and skin metastases in a polymorphous low grade adenocarcinoma of the salivary gland. J Laryngol Otol 1995;109:1222–1225. 9. Pogodzinski MS, Sabri AN, Lewis JE, Olsen KD. Retrospective study and review of polymorphous low-grade adenocarcinoma. Laryngoscope 2006; 116:2145–2149. 10. Crean SJ, Bryant C, Bennett J, Harris M. Four cases of polymorphous low-grade adenocarcinoma. Int J Oral Maxillofac Surg 1996;25:40–44. 11. Seethala RR, Johnson JT, Barnes EL, Myers EN. Polymorphous low-grade adenocarcinoma: the University of Pittsburgh experience. Arch Otolaryngol Head Neck Surg 2010;136:385–392. 12. Verma V, Mendenhall WM, Werning JW. Polymorphous low-grade adenocarcinoma of the head and neck. Am J Clin Oncol 2013;37:624–626. doi: 10.1097/COC.0b013e31827e5537. 13. Batsakis JG, Pinkston GR, Luna MA, Byers RM, Sciubba JJ, Tillery GW. Adenocarcinomas of the oral cavity: a clinicopathologic study of terminal duct carcinomas. J Laryngol Otol 1983;97:825–835. 14. Freedman PD, Lumerman H. Lobular carcinoma of intraoral minor salivary gland origin. Report of twelve cases. Oral Surg Oral Med Oral Pathol 1983;56:157–166. 15. Tralongo V, Becchina G, Genovese F, Nagar C, Ottoveggio G, Pinto G. Polymorphous low-grade adenocarcinoma of the salivary glands: clinicopathological and immunohistochemical study of a case. Anticancer Res 2002;22:1347–1352. 16. Fife TA, Smith B, Sullivan CA, Browne JD, Waltonen JD. Polymorphous low-grade adenocarcinoma: a 17 patient case series. Am J Otolaryngol 2013;34:445–448. 17. Vincent SD, Hammond HL, Finkelstein MW. Clinical and therapeutic features of polymorphous low-grade adenocarcinoma. Oral Surg Oral Med Oral Pathol 1994;77:41–47. 18. Kimple AJ, Austin GK, Shah RN, et al. Polymorphous low-grade adenocarcinoma: a case series and determination of recurrence. Laryngoscope 2014;124:2714–2719. 19. WHO. International Classification of Diseases for Oncology, 3rd ed. Geneva, Switzerland: World Health Organization; 2012. 20. Sarfati D, Blakely T, Pearce N. Measuring cancer survival in populations: relative survival vs cancer-specific survival. Int J Epidemiol 2010;39:598–610. 21. Yu B, Tiwari RC, Cronin KA, McDonald C, Feuer EJ. CANSURV: a Windows program for population-based cancer survival analysis. Comput Methods Programs Biomed 2005;80:195–203. 22. Buchner A, Merrell PW, Carpenter WM. Relative frequency of intra-oral minor salivary gland tumors: a study of 380 cases from northern California and comparison to reports from other parts of the world. J Oral Pathol Med 2007;36:207–214. 23. Waldron CA, el-Mofty SK, Gnepp DR. Tumors of the intraoral minor salivary glands: a demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol 1988;66:323–333. 24. Yih WY, Kratochvil FJ, Stewart JC. Intraoral minor salivary gland neoplasms: review of 213 cases. J Oral Maxillofac Surg 2005;63:805–810. 25. Pires FR, Pringle GA, de Almeida OP, Chen SY. Intra-oral minor salivary gland tumors: a clinicopathological study of 546 cases. Oral Oncol 2007;43:463–470. 26. Hannen EJ, Bulten J, Festen J, Wienk SM, de Wilde PC. Polymorphous low grade adenocarcinoma with distant metastases and deletions on chromosome 6q23-qter and 11q23-qter: a case report. J Clin Pathol 2000;53:942–945. 27. Tanaka F, Wada H, Inui K, et al. Pulmonary metastasis of polymorphous low-grade adenocarcinoma of the minor salivary gland. Thorac Cardiovasc Surg 1995;43:178–180. 28. Gonzalez-Garcia R, Rodriguez-Campo FJ, Munoz-Guerra MF, Nam-Cha SH, Sastre-Perez J, Naval-Gias L. Polymorphous low-grade adenocarcinoma of the palate: report of cases. Auris Nasus Larynx 2005;32:275–280.
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Rhinological and Otological Society, Inc.
Polymorphous Low-Grade Adenocarcinoma of the Head and Neck: A Population-Based Study of 460 Cases Tapan D. Patel, BS; Alejandro Vazquez, MD; Emily Marchiano, BA; Richard Chan Park, MD; Soly Baredes, MD, FACS; Jean Anderson Eloy, MD, FACS Objectives/Hypothesis: Polymorphous low-grade adenocarcinoma (PLGA) is a rare malignant neoplasm of the minor salivary glands. This study analyzes the demographic, clinicopathologic, incidence, and survival characteristics of head and neck PLGA (HN-PLGA). Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for HN-PLGA cases from 2001 to 2011 (460 cases). Data analyzed included patient demographics, incidence trends, and survival outcomes. Results: Head and neck PLGA occurred most frequently in the sixth and seventh decades of life. Mean age at diagnosis was 61.3 (6 15.0) years. There was a female predilection with a female-to-male ratio of 2.15:1. There was a predilection toward blacks among the US population, with black-to-white incidence rate ratio of 2.33:1. The most common site of HNPLGA was the palate (57.2%), followed by the lip (7.0%). Average tumor size was 2.1 (6 1.3) cm at presentation. The majority of cases were localized at the time of presentation (70.5%), with rare distant metastasis (4.3%). The most common treatment modality was surgery alone (77.9%), followed by surgery with radiotherapy (19.5%). Elective neck dissection was performed in 5.3% of the cases. Survival analysis showed excellent 10-year disease-specific (96.4%) and relative (94.7%) survival rates. Ten-year disease-specific survival was better among those treated with surgery alone (98.0%) or surgery with adjuvant radiotherapy (90.9%) than those treated with radiotherapy alone (75.0%) (P < 0.0001). Conclusion: This study represents the largest cohort of HN-PLGA cases. Head and neck PLGA shows a predilection for women and blacks in the US population. It has an excellent survival outcome with surgery being the treatment of choice. Key Words: Polymorphous low-grade adenocarcinoma, malignancy, SEER, demographic, incidence, disease-specific survival, relative survival, palate, minor salivary glands. Level of Evidence: 4. Laryngoscope, 125:1644–1649, 2015
INTRODUCTION Polymorphous low-grade adenocarcinoma (PLGA) is a salivary gland tumor first described by Evans and Batsakis in 1984.1 PLGAs usually arise from the minor salivary glands; however, there have been reports of these tumors within the major salivary glands.2 They most commonly occur in the palate, but also can occur at extrapalatal sites including the tongue base, buccal mucosa, and inner upper lip.3,4 They are slow-growing unencapsulated tumors that have characteristic nuclear
Additional Supporting Information may be found in the online version of this article. From the Department of Otolaryngology–Head and Neck Surgery (T.D.P., A.V., E.M., R.C.P., S.B., J.A.E.); the Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey (S.B., J.A.E.); and the Department of Neurological Surgery (J.A.E.), Rutgers New Jersey Medical School, Newark, New Jersey, U.S.A. Editor’s Note: This Manuscript was accepted for publication February 23, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jean Anderson Eloy, MD, FACS, Professor and Vice Chairman, Director, Rhinology and Sinus Surgery; Director, Otolaryngology Research; Co-Director, Endoscopic Skull Base Surgery Program, Department of Otolaryngology–Head and Neck Surgery, Neurological Institute of New Jersey, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ 07103. E-mail: [email protected] DOI: 10.1002/lary.25266
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homogeneity and histologic heterogeneity with multiple growth patterns, including solid, ductotubular, cribriform, trabecular, and single file growth.3–6 Although they are locally invasive, distant metastasis is rare.1,7–10 Treatment for PLGA is surgical resection with or without radiotherapy.11 Recurrence rates are as high as 33%, and recurrent disease tends to show a more aggressive histology with a higher number of mitoses, increased papillary component, and greater likelihood of classification as an intermediate-grade adenocarcinoma.11 Interestingly, recurrence has not been associated with the presence of perineural invasion.12 To date, scholarship on PLGA is limited to small, single-institutional series and case reports.1–4,9,11,13–18 Most of these studies have focused on histopathologic characterization of this tumor. The largest study to date by Castle et al.3 analyzed 164 cases of PLGA using files from the tumor registries of the Armed Forces Institute of Pathology. However, no large study thus far has analyzed incidence trends and survival outcomes of this tumor. Here, we present an epidemiologic analysis of PLGA using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Database. We analyzed 460 cases of head and neck PLGA (HNPLGA) from 18 SEER registries, representing the largest cohort of HN-PLGA patients studied so far. Our analysis includes demographic and clinicopathologic features Patel et al.: SEER Head and Neck PLGA
of this rare neoplasm, along with its incidence trends and survival outcomes.
MATERIALS AND METHODS Frequency, incidence, and survival data were obtained from the SEER 18 dataset for the years 2001 to 2011. We decided to restrict our search to this time period because the morphological code for PLGA was introduced in the year 2000 as part of the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3).19 The previous version of this classification scheme (ICD-O-2) did not have a code specifically for PLGA. For our study, institutional review board approval was not required because SEER does not report sensitive patient information. The SEER database was queried for patients diagnosed with HN-PLGA based on the ICD-O-3 code for PLGA (8525/3). Anatomic locations within the head and neck region were selected using the SEER “site and morphology/primary site-labeled” variable. We used the following ICD-O-3 topographical codes in our analysis: C00-C14, C30-C32, C41.0, C41.1, C44.0-C44.4, C47.0, C49.0, C69, C73.9, C75.0, C76.0, and C77.0. Frequency data were stratified and analyzed by age, gender, race, primary site, histologic grade, American Joint Committee on Cancer (AJCC) stage, tumor-node-metastasis classification, SEER LRD (local, regional, distant) stage, and treatment modality. Incidence data were age adjusted to the standard U.S. 2000 population and reported per 100,000 people at risk for cases diagnosed between 2001 and 2011. Five-year and 10-year survival rates were calculated using Kaplan-Meier analysis, yielding overall survival (OS) and disease-specific survival (DSS) rates. Relative survival (RS) for these time intervals were represented using the ratio between the observed survival rate and the expected age-adjusted survival rate for a similar segment of the population. SEER data were extracted using SEER*Stat 8.1.5 (National Cancer Institute, Bethesda, MD) software. Incidence data were analyzed via weighted least squares for annual percent change (APC) using 1-year end-points in SEER*Stat 8.1.5 software. Joinpoint Regression Program 4.1.1.1 (National Cancer Institute, Bethesda, MD) was used to calculate APC in incidence and assess the statistical significance of the trends observed. Survival data from SEER*Stat 8.1.5 were reorganized and reclassified in Microsoft Excel 2013 (Microsoft, Redmond, WA) and then imported into JMP Statistical Discovery 11 (SAS Institute, Cary, NC) for log-rank analysis to generate KaplanMeier curves and DSS rates. SEER*Stat 8.1.5 was also used to extract RS data. Probability values (P value) < 0.05 were considered statistically significant.
RESULTS Analysis of Demographic and Clinicopathologic Factors A total of 460 cases of HN-PLGA were reported in the SEER database between 2001 and 2011. Table I describes the demographic and clinicopathologic factors of HN-PLGA cases extracted from the SEER database. The mean age at diagnosis was 61.3 years with a standard deviation of 15.0 years. Females accounted for 68.3% of the HN-PLGA cases. The female-to-male ratio was 2.15:1. Whites accounted for 76.6% of the cases and blacks accounted for 21.2%. The most common primary site for the tumor was the palate, specifically the hard palate (26.1%) followed by the soft palate (15.9%). A Laryngoscope 125: July 2015
total of 9.6% of the cases were recorded as overlapping lesion of the palate and 5.7% of the cases were recorded as palate, not otherwise specified (NOS). This ambiguity of the classification system led us to consider the “palate” as one combined entity (including soft palate; hard palate; overlapping lesion of palate; and palate, NOS). Grouping the palatal cases in this way, we found 57.2% of the cases involving the palatal region. Lip (7.0%) and buccal mucosa (6.1%) were the next common sites of involvement. As the name implies, histologically PLGA is a low-grade tumor. Out of the cases for which histologic grade information was available in the SEER database (422 cases), 37.2% were of well-differentiated type (histologic grade I), and the remaining 62.8% cases were of moderately differentiated type (histologic grade II). AJCC staging information was available for 319 cases (i.e., those diagnosed after 2004 only): stage I (46.7%), stage II (17.6%), stage III (5.6%), and stage IV (11.9%). The majority of the cases had localized disease (70.5%) at diagnosis based on the SEER LRD stage. Only 4.3% of the cases were diagnosed with distant metastasis. Table II shows the cases categorized by treatment modality and neck dissection information. Treatments were categorized as single-modality radiotherapy, combined surgery and radiotherapy, or surgery alone. Treatment data were available for 416 cases. The majority of the patients underwent surgical therapy alone (77.9%), followed by surgery and radiotherapy (19.5%). Only 2.6% of the patients received radiotherapy alone. Information on neck dissection was queried based on nodal involvement. In patients with N0 neck disease, neck dissection was performed in 5.3% of the cases; whereas, in patients with N1 or N2 neck disease, neck dissection was performed in 62.5% of the cases.
Incidence and Survival Analysis The incidence analysis was performed for the years 2001 to 2011 (Supp Table SI; online version only). Overall age-adjusted mean incidence rate of HN-PGLA was 0.051 cases per 100,000 of population at risk (95% confidence interval (CI), 0.046–0.056). The average incidence in males was 0.035 cases per 100,000 of male population (95% CI, 0.030–0.042), and the average incidence in females was 0.065 cases per 100,000 of female population (95% CI, 0.056–0.072), with a female-to-male incidence rate ratio of 1.82:1. The incidence analysis by race showed an overall age-adjusted mean incidence rate for blacks of 0.110 cases per 100,000 (95% CI, 0.088–0.135) and 0.047 cases per 100,000 for whites (95% CI, 0.042– 0.0524). The black-to-white incidence rate ratio was 2.33:1. In addition, the incidence trend analysis by race also showed decreasing trends for whites (APC of 22.33%) and blacks (APC of 21.42%) from 2001 to 2011, but these trends were not statistically significant. Overall, HN-PLGA rate in 2011 was 0.053 cases per 100,000 population at risk and decreased from 0.061 cases per 100,000 population in 2001 (Supp. Fig. S1; online version only). Joinpoint regression model revealed a decreasing incidence of HN-PLGA with the APC of Patel et al.: SEER Head and Neck PLGA
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TABLE I. Demographic and Clinicopathologic Characteristics of Head and Neck Polymorphous Low-Grade Adenocarcinoma (2001–2011). n
%
460
100
TABLE I. (Continued) n
%
282 11
88.4% 3.4%
N Classification* Total Mean Age at Diagnosis, Years (6 SD) Age Groups
61.3 (6 15.0)
N2
0–19 years
2
0.4%
20–29 years 30–39 years
6 28
1.3% 6.1%
40–49 years
69
15.0%
50–59 years 60–69 years
100 100
21.7% 21.7%
70–79 years
93
20.2%
53
11.5%
Male
146
31.7%
Female Race
314
68.3%
White
344
76.6%
Black Asian or Pacific Islander
95 8
21.2% 1.8%
801 years Gender
American Indian or Alaska Native
2
0.4%
11
–
Hard palate
120
26.1%
Soft palate Overlapping lesion of palate
73 44
15.9% 9.6%
Palate, NOS
26
5.7%
Lip Mouth, NOS
32 31
7.0% 6.7%
Buccal mucosa
28
6.1%
Parotid gland Other major salivary glands
24 19
5.2% 4.1%
Unknown Location
Nasal cavity and paranasal sinuses
22
4.8%
Tongue Other head and neck sites
10 31
2.2% 6.7%
Average Tumor Size, cm (6 SD)
2.1 (6 1.3)
Histologic Grade Well differentiated, grade I
157
37.2% 62.8%
38
–
I
149
46.7%
II III
56 18
17.6% 5.6%
IV
38
11.9%
58
18.2%
T1
153
48.0%
T2 T3
64 14
20.1% 4.4%
T4
32
10.0%
Tx
56
17.6%
Unknown/not recorded AJCC Stage†
Unknown T Classification†
5
1.6%
21
6.6%
M0
297
93.1%
M1 Mx
5 17
1.6% 5.3%
Localized Regional
309 110
70.5% 25.1%
Distant
19
4.3%
Unknown
22
–
Nx M Classification†
SEER LRD Stage
*Percentages are out of n 5 319 (cases diagnosed 2004 and onward). AJCC 5 American Joint Committee on Cancer; LRD 5 local, regional, distant; NOS 5 not otherwise specified; SD 5 standard deviation; SEER 5 Surveillance, Epidemiology, and End Results; TNM 5 tumor, node, metastasis.
21.55%. However, this trend was not statistically significant (P 5 0.3838). The incidence trend analysis by gender showed a decreasing trend in incidence for females initially from 2001 to 2004 (APC of 218.52%), followed by an increasing trend from 2004 to 2011 (APC of 5.41%). These trends were found to be statistically significant (P < 0.05). Supporting Figure S2 (online version only) shows the incidence trend curve for females. For males, the incidence trend analysis showed a decreasing trend (APC of 22.63%) from 2001 (0.033 per 100,000) to 2011 (0.030 per 100,000); however, this trend was not found to be statistically significant.
TABLE II. Treatment of Head and Neck Polymorphous Low-Grade Adenocarcinoma (2001–2011).
265
Moderately differentiated, grade II
N0 N1
n
%
Surgery Radiotherapy
324 11
77.9% 2.6%
Surgery and radiotherapy
81
19.5%
44
–
15 266
5.3% 94.7%
1
–
10
62.5%
6
37.5%
Treatment
None/unknown Neck Dissection No nodal involvement ND No ND Unknown Nodal involvement (N1) ND No ND ND 5 neck dissection.
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TABLE III. Five-Year Survival Analysis for Head and Neck Polymorphous Low-Grade Adenocarcinoma. 5 Years n
All Cases Location
378
Hard palate
OS
P Value
–
98.6%
–
0.0266*
100.0%
1.0000
100
91.5%
61
100.0%
< 2 cm
161
94.8%
2 cm AJCC Stage
144
90.6%
168
93.6%
42
85.4%
Advanced (stages III and IV) Treatment Modality
DSS
91.1%
Soft palate Tumor Size
Early (stages I and II)
P Value
Surgery
273
92.0%
Radiotherapy Surgery and radiotherapy
6 65
75.0% 94.5%
100.0% 0.2802
100.0%
0.2750
98.6% 0.0475*
100.0%
0.0039*
94.4% 0.2964
99.3%
< 0.0001*
75.0% 100.0%
RS
95% CI
98.8%
84.8%–99.9%
96.6%
78.6%–99.5%
100.0%
–
99.5%
83.9%–100.0%
99.1%
86.3%–99.9%
99.7%
84.9%–100.0%
88.8%
67.5%–96.5%
98.9%
94.3%–99.8%
– 98.4%
– 39.3%–100.0%
*Statistical significance AJCC 5 American Joint Committee on Cancer; CI 5 confidence interval; DSS 5 disease-specific survival; OS 5 overall survival; RS 5 relative survival.
Tables III and IV show 5- and 10-year survival analyses for 378 HN-PLGA cases, respectively, for which survival data was available in SEER. Overall survival, DSS, and RS were calculated. Overall survival takes into account two causes of deaths: deaths due to disease of interest and deaths due to all other causes. Diseasespecific survival takes into account only deaths attributable to the cancer of interest.20 Relative survival is obtained by dividing the OS by the expected survival of a comparative segment of the population. Relative sur-
vival is the standard measure of net survival in population-based cancer studies.20,21 Overall survival for all cases was 91.1% at 5 years and 72.7% at 10 years. The 5- and 10-year DSS were found to be 98.6% and 96.4%, respectively. The 5- and 10-year RS were 98.8% (95% CI, 84.8%–99.9%) and 94.7% (95% CI, 60.9%–99.4%), respectively. Survival analysis was also carried out comparing the two most common HN-PLGA tumor sites, namely the hard and the soft palate. The 5-year OS was 91.5% for the hard
TABLE IV. Ten-Year Survival Analysis for Head and Neck Polymorphous Low-Grade Adenocarcinoma.
10 Years P Value
RS
95% CI
96.4%
–
94.7%
60.9%–99.4%
0.2527
96.3% 100.0%
0.5050
96.6% 99.2%
78.6%–99.5% 0.0–100.0%
80.3% 62.2%
0.0210*
98.0% 94.2%
0.3691
99.5% 83.0%
83.9%–100.0% 49.7%–95.1%
168 42
86.7% 85.4%
0.1316
100.0% 94.4%
0.0039*
– –
– –
Surgery Radiotherapy
273 6
74.1% 75.0%
0.3215
98.0% 75.0%
< 0.0001*
96.7% –
12.4%–99.9% –
Surgery and radiotherapy
65
70.5%
85.3%
38.1%–97.4%
All Cases
n
OS
P Value
378
72.7%
–
100 61
81.2% 83.0%
161 144
DSS
Location Hard palate Soft palate Tumor Size < 2 cm 2 cm AJCC Stage Early (stages I and II) Advanced (stages III and IV) Treatment Modality
90.9%
*Statistical significance. AJCC 5 American Joint Committee on Cancer; CI 5 confidence interval; DSS 5 disease-specific survival, OS 5 overall survival; RS 5 relative survival.
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Fig. 1. Kaplan-Meier analysis of 10-year disease-specific survival (DSS) for HN-PLGA by treatment modality. Note: A small sample size of six cases was found for the radiotherapy (RT) alone group. The maximum follow-up period of this group was 56 months.
palate and 100.0% for the soft palate (P 5 0.0266). The 5-year DSS was 100.0% for both locations (P < 0.0001). Five-year RS was 96.6% for hard palate and 100.0% for the soft palate. Better survival outcomes were observed for tumors with size smaller than 2 cm compared to the tumors with size 2 cm. The 10-year OS for tumors less than 2 cm was 80.3%, whereas the OS for tumors 2 cm was 62.2% (P 5 0.0210). Similarly, the 10-year RS for tumors smaller than 2 cm (99.5%) was found to be better than that for tumors 2 cm (83.0%). When stratified by AJCC stage, patients with advanced stage disease (i.e., AJCC stage III or IV) had poorer overall survival outcomes at 5 and 10 years compared to patients with early-stage disease (i.e., AJCC stage I or II). At 5 years, the OS was 93.6% for patients with early stage disease and 85.4% for patients with advanced stage disease (P 5 0.0475). The 5- and 10-year DSS also showed worse survival for patients with advanced-stage disease compared to patients with early-stage disease (P 5 0.0039). Figures 1 and 2 show 10-year OS and DSS KaplanMeier survival curves grouped by treatment modality. The 10-year OS was 74.1% for surgery alone, 70.5% for surgery with radiotherapy, and 75.0% for radiotherapy alone (P 5 0.3215). The 10-year DSS was 98.0% for surgery alone, 90.9% for surgery and radiotherapy, and 75.0% for radiotherapy alone (P < 0.0001). The treatment modality did show some impact on survival outcomes; a trend toward poor DSS outcome was seen for patients receiving radiotherapy alone. However, in our analysis it should be noted that survival information was available only for six patients out of the 11 patients who received radiotherapy alone. The 10-year DSS for these patients was 75.0%. Of these 6 patients, two patients were older than 75 years, and the remaining four had an advanced stage disease (AJCC stage III or IV).
those reported in other published studies.3,4,9,11,17,22–24 Head and neck PLGA occurs over a wide age range; however, it tends to occur more frequently in the sixth and seventh decades of life.22–24 In our study, the mean age at diagnosis was 61.3 years, and 43.4% of the cases were found in the age range of 50 to 69 years. There appears to be a female preponderance in PLGA, with a female-tomale ratio of 2:1.3,4,22,23 We also found a similar female predilection in our cohort of 460 patients, with our female-to-male ratio of 2.15:1. Based on the results of our incidence analysis, we found a predilection toward blacks, with a black-to-white incidence rate ratio of 2.33:1. Consistent with prior studies,4,17,22–25 we found the palate to be the most common site for the tumor origin. It accounted for 57.2% of the cases in our study. The second most common site was the lip, followed by the buccal mucosa. Because there is a preponderance of minor salivary gland tissues in these sites, PLGA can be considered primarily a neoplasm of minor salivary gland tissue. Prior studies have reported an average tumor size at diagnosis between 2 cm and 2.5 cm.3,4,9 In our study, we found an average tumor size of 2.1 cm at presentation among 361 cases for whom size information was available in SEER. Although a malignant neoplasm, PLGA exhibits limited metastatic behavior, differentiating it from other malignant salivary gland tumors. Regional metastasis rates of 5% to 15% have been reported in prior studies.4,9,17 However, we found a regional spread in 25.1% cases at the time of presentation. Distant metastasis is rare. Earlier studies have reported distant metastasis rates between 0.6 to 7.5%.3,4,26,27 Consistent with these reports, our distant metastasis rate at diagnosis was 4.3%. Complete surgical resection of the tumor was the treatment of choice in this current analysis. A total of 77.9% of the patients received surgery alone for the management of the tumor. Surgery with radiotherapy was the second most common treatment. Pogodzinski et al.9 and Gonzalez-Garcia et al.28 have recommended against elective neck dissections unless major resection or reconstruction is planned. Consistent with this recommendation, neck dissections were not performed in the
DISCUSSION Polymorphous low-grade adenocarcinoma is a rare neoplasm of minor salivary glands that exhibits slow growth and indolent behavior. The demographic and clinicopathologic features in our study generally match Laryngoscope 125: July 2015
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Fig. 2. Kaplan-Meier analysis of 10-year overall survival (OS) for HN-PLGA by treatment modality. Note: A small sample size of six cases was found for the radiotherapy (RT) alone group. The maximum follow-up period of this group was 56 months.
Patel et al.: SEER Head and Neck PLGA
majority of patients with N0 disease (94.7%) in this analysis. Head and neck PLGA has an excellent prognosis. The 5- and 10-year RS were 98.8% and 94.7%, respectively. As expected, patients with tumors 2 cm in size had worse 5- and 10-year RS compared to patients with tumors less than 2 cm at presentation. In the study by Castle et al.,3 DSS of 97.6% was reported, without evidence of recurrence nearly a decade after surgical management. Similarly in our analysis, the 10-year DSS for patients receiving surgery alone was 98.0%, matching the DSS rate reported by Castle et al. Only 11 patients received radiotherapy alone, and the survival data was available for only six of these patients. The 10-year DSS for these patients was found to be significantly lower (75.0%) than that for surgery alone (98.0%) or surgery combined with radiotherapy (90.9%, P < 0.0001). The reasons for the poor survival outcomes for the radiotherapy alone group may be that these patients had an advanced stage disease (AJCC stage III or IV) or that surgery was not advised due to their mature age. Furthermore, given the small sample size for the radiotherapy group, a strong conclusion that radiotherapy alone leads to poor prognosis cannot be drawn. Because our study was a population-based analysis of HN-PLGA, there are certain limitations inherent to this type of study. We used ICD-O-3 morphological and topographical codes to select HN-PLGA cases from the SEER database. However, one limitation of using such a coding system is that it introduces the possibility of inaccuracy through the miscoding of cases. Retrospective population-based studies are dependent on accurate coding and consistent data collection among numerous sites. In addition, SEER does not contain complete information regarding the extent of therapeutic intervention, such as the number of cycles of radiotherapy applied or the specific surgical techniques utilized. Furthermore, SEER does not currently have information on tumor recurrence, which precludes us from reporting on the recurrence and disease-free survival rates on this tumor. Likewise, data about chemotherapy was unavailable for our analysis, even though some of the patients in our study might have received chemotherapy. Consequently, the results should be interpreted with these limitations in mind. Despite such limitations, a cohort of this magnitude has not been previously analyzed, and as such it provides important information on this tumor.
CONCLUSION Polymorphous low-grade adenocarcinoma is a slowgrowing malignant tumor that is predominantly found in the minor salivary glands of the oral cavity. It has a predilection for females and blacks in the US population. The palate is the most common site for this neoplasm. This tumor has an excellent survival outcome, with surgery being the treatment of choice. The role of radiotherapy currently remains unclear in the management of this tumor.
Laryngoscope 125: July 2015
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