SALIVARY GLAND CARCINOMAS IN CHILDREN AND ADOLESCENTS: A POPULATION-BASED STUDY, WITH COMPARISON TO ADULT CASES

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1 ORIGINAL ARTICLE SALIVARY GLAND CARCINOMAS IN CHILDREN AND ADOLESCENTS: A POPULATION-BASED STUDY, WITH COMPARISON TO ADULT CASES Iyad Sultan, MD, 1 Carlos Rodriguez Galindo, MD, 2 Sereen Al-Sharabati, DO, 3 Marco Guzzo, MD, 4 Michela Casanova, MD, 5 Andrea Ferrari, MD 5 1 Department of Pediatric Oncology, King Hussein Cancer Center, Amman, Jordan. isultan@khcc.jo 2 Department of Pediatric Oncology, Dana Farber Cancer Institute and Children s Hospital, Harvard Medical School, Boston, Massachusetts 3 Private Dental Clinic, Amman, Jordan 4 Otorhinolaryngology Unit, Istituto Nazionale Tumori, Milano, Italy 5 Pediatric Oncology Unit, Istituto Nazionale Tumori, Milano, Italy Accepted 31 August 2010 Published online 10 November 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. Salivary gland carcinomas are rare malignancies, particularly in young individuals in whom only scanty data are available from published studies. Methods. We searched the SEER database ( ) for patients with a reported diagnosis of salivary gland carcinoma; children/adolescents (<20 years old) were compared with adults. Results. We identified 263 children/adolescents (58% girls) and 12,571 adults (43% women). The most common histology was mucoepidermoid carcinoma in both groups, but the percentages of other histologies were different. Children/adolescents had more favorable features with most tumors being localized, with no extension to adjacent tissues or lymphatic spread (76% vs 50% in adults, p <.001). Also most tumors were well differentiated or moderately differentiated (88% vs 49% in adults, p <.001). The 5-year overall survival for children/adolescents was 95% 1.5%, compared with 59% 0.5% for adults (p <.001). Conclusion. When compared with adults, salivary gland carcinomas in children/adolescents are less advanced, and have more favorable features and better outcome. Head Neck 33: , 2011 Keywords: salivary glands; carcinoma; children; adolescents; SEER; prognosis Salivary gland carcinomas are rare neoplasms in adults but are exceedingly infrequent in children. 1 Only few single-institution series on epithelial salivary gland tumors have been reported in the literature, describing the clinical findings of less than 300 cases combined Published studies seem to indicate that the clinical characteristics in younger patients differ somewhat from those seen in their adult counterparts. However, the paucity of available Correspondence to: I. Sultan VC 2010 Wiley Periodicals, Inc. data on rare pediatric tumors limits the development of tailored treatment guidelines; therefore, pediatric oncologists and pediatric surgeons must follow adult recommendations. To better characterize the clinical features and outcomes of salivary gland carcinomas in children, we performed an analysis of cases registered in the Surveillance, Epidemiology, and End Results (SEER) public-access database. 18 MATERIALS AND METHODS Study Population. We used the case listing session of the SEER*Stat program to identify children/ adolescents (<20 years old) with a reported diagnosis of salivary gland carcinoma in the SEER 17 ( seer.cancer.gov/data/) database based on the International Classification of Childhood Cancer, version 3 (ICCC-3), group XI(f.1) carcinomas of salivary glands. 19 This definition includes all carcinomas in major salivary glands. Neoplasms of the minor salivary glands can be found anywhere in the oral cavity; hence there is no distinctive morphology code for this site in the SEER database. The query was set to exclude patients with follow-up in the form of a death certificate or autopsy only and those without microscopic confirmation of their disease. The survival session of the SEER*Stat software was used to calculate the relative survival of patients, which is based on calculated survival of studied patients with adjustment made for expected mortality in the general population. Relative survival rates provide better comparison of survival rates in young patients (low chance of death from other causes) to older patients (higher chance of death from cardiovascular disease and other causes). In addition, the rate session was used to calculate the incidence rates Salivary Gland Carcinoma in Children/Adolescents HEAD & NECK DOI /hed October 2011

2 We selected the following age groups to categorize patients (<10 years old, 10 to 14, 15 to 19, 20 to 40, 40 to 60, and more than 60 years old). The historic SEER stage was used; according to this system, tumors are labeled as localized (confined to gland/ duct of origin), regional (extension to surrounding tissue, including facial nerve involvement), or distant (distant spread including supraclavicular lymph node involvement). Data on regional lymph node involvement were extracted from 3 items: 4-digit extent of disease (diagnosis year, ), 10-digit extent of disease (diagnosis year, ), and collaborative stage ( ). Because regional lymph node status was not coded homogenously, we selected to label lymph node status as N0 (reported to have no involvement), N1 to 3 (any reported regional involvement), and NX (regional lymph node not reported [blank] or reported to be unknown [codes 9 or 99]). Statistical Analysis. MedCalc for Windows version (MedCalc Software, Mariakerke, Belgium) was used to perform statistical calculations on the pediatric population. The chi-square test was used to compare categorical variables. The Kaplan Meier method was used to calculate survival estimates for children/adolescents using all-cause mortality as an endpoint. The log-rank test was used to compare survival curves. The Mann Whitney (rank-sum test for independent variables) was used to compare the tumor size in children/ adolescents and adults. A Cox proportional hazards regression model was constructed using the following variables: sex, grade, histology, size, lymph node status, and SEER stage. Blank/empty records were excluded from the analysis and all-cause mortality was chosen as an endpoint. Results are presented as hazard ratios (HRs) followed by the 95% confidence intervals (CIs). RESULTS Patient Characteristics and Comparison to Adults. From 1973 to 2006, there were 263 children/ adolescents with a reported diagnosis of carcinoma of the salivary glands (0.5% of all malignancies reported in children/adolescents). Another 17 cases with mesenchymal tumors arising from salivary glands (16 from the parotid gland) were registered: 14 rhabdomyosarcoma, 1 fibrosarcoma, 1 peripheral primitive neuroectodermal tumor, and 1 malignant myoepithelioma. On the other hand, 12,571 adult cases were reported (0.3% of all malignancies reported in adults). The annual incidence of this malignancy was 0.8 and 15 per million in children/adolescents and adults, respectively. There was a slight female predominance in children/adolescents and male predominance in adults (Table 1). Male predominance was seen in patients older than 40 years at diagnosis (Figure 1). The majority of Table 1. Patient characteristics with comparison between children/ adolescents (<20 years old) and adults. Characteristic No. of patients (%) Children/ adolescents Adults p value Sex Female 153 (58.2) 5451 (43.4) <.001 Male 110 (41.8) 7120 (56.6) Age (years) <10 23 (8.7) (35.0) (56.3) (12.1) (29.6) > (58.3) Race Black 39 (14.8) 935 (7.4) <.001 White 204 (77.6) 10,685 (85.0) Other 20 (7.6) 951 (7.6) Stage Localized 192 (75.9) 5867 (50.0) <.001 Regional 51 (20.2) 4475 (38.2) Distant 10 (4.0) 1381 (11.8) Unstaged 10 ( ) 848 ( ) Regional lymph nodes N0 178 (89.4) 6072 (69.2) <.001 N (10.6) 2703 (30.8) NX 64 ( ) 3796 ( ) Site Parotid gland 228 (86.7) 992 (78.9).0087 Submandibular gland 27 (10.3) 1972 (15.7) NOS, overlapping, sublingual 8 (3.0) 678 (5.4) Histology Mucoepidermoid carcinoma 129 (49.0) 3067 (24.4) <.001 Acinar cell carcinoma 91 (34.6) 1373 (10.9) Adenoid cystic carcinoma 14 (5.3) 1639 (13.0) Adenocarcinoma 13 (4.9) 1878 (14.9) Squamous cell carcinoma 2 (0.8) 2279 (18.1) Others 14 (5.3) 2335 (18.6) Grade (I) Well differentiated 40 (25.8) 1161 (15.6) <.001 (II) Moderately differentiated 97 (62.6) 2515 (33.7) (III) Poorly differentiated 6 (3.9) 2556 (34.3) (IV) Undifferentiated/ anaplastic 12 (7.7) 1222 (16.4) Unknown 108 ( ) 5117 ( ) Note: ( ), Data were not used in calculating total percentage. patients were white, with a higher percentage of blacks in children/adolescents (14.8%) in comparison to adults (7.4%). The parotid gland was the most common site of origin in children/adolescents and in adults. A different distribution of histiotypes was observed. Most of the tumors in children/adolescents were mucoepidermoid and acinar cell carcinomas (84%). Adenoid cystic carcinoma, adenocarcinoma, and squamous cell carcinoma were rare in children but more commonly reported in adults (Figure 2A). Almost three-fourths of the tumors in children/adolescents were localized (confined to Salivary Gland Carcinoma in Children/Adolescents HEAD & NECK DOI /hed October

3 gland/duct of origin). Extension to surrounding tissues (regional stage) and distant spread (distant stage) was observed mainly in adults (Figure 2B). Regional nodal involvement was reported more frequently in adults (31%) than in children (10.6%; p <.001). In addition, a higher percentage of tumors in children/adolescents were reported to be well differentiated or moderately differentiated (grade I and II) when compared to adults (Figure 2C). The median diameter of tumors with reported size was 21 mm in children/adolescents (n ¼ 181) and 25 mm in adults (n ¼ 8423; p ¼.0038). FIGURE 1. Sex distribution of patients with salivary gland carcinomas in the SEER 17 database (1973 to 2006). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Distinct Clinical Features in Children. The median age of children/adolescents with salivary gland carcinomas was 15 years. Most cases were adolescents; only 8.7% were below the age of 10, and 35% were 10 to 14 years old. Mucoepidermoid carcinoma was the most common histology in all sites, and particularly in the parotid gland. Other histologies represented a higher fraction in sites other than the parotid gland (Figure 3). In the youngest group of patients (<10 year, n ¼ 23), the majority of tumors were reported in FIGURE 2. Bar histograms indicating percentages of patients with salivary gland tumors in different age groups according to histologic subtypes (A), grades (B), and SEER stages (C). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1478 Salivary Gland Carcinoma in Children/Adolescents HEAD & NECK DOI /hed October 2011

4 FIGURE 3. The percentages of different histologies in the parotid gland, submandibular gland, and major salivary glands (not otherwise specified) in children/adolescents (<20 years old at diagnosis). Ca, carcinoma. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] the parotid gland (n ¼ 22); the histologic types were mucoepidermoid carcinoma (n ¼ 15), acinar cell carcinoma (n ¼ 5), adenocarcinoma (n ¼ 2), and undifferentiated carcinoma (n ¼ 1). No tumors with distant stage were reported. Local Control. The majority of patients (88%) in both the children/adolescents and adult groups had cancer-directed surgery. The SEER database reported that surgery was not recommended in 728 patients (4 children/adolescents), whereas it was recommended but not performed in 664 patients (1 child; for the following reasons: refused by the patient, contraindicated for other conditions, or for unknown reason). Surgical details were available for patients diagnosed after 1998 as a new coding system was used and surgeries for salivary glands were specifically coded. Among 128 pediatric patients, 17 patients (13%) underwent tumorectomy or excisional biopsy; 53 (41%) underwent subtotal parotidectomy, and 51 (40%) underwent total or radical parotidectomy (Table 2). Among the 65 patients with facial nerve status recorded, two-thirds (n ¼ 44) had their facial nerve spared during surgery. Details of regional lymph node surgery were captured for patients diagnosed after 2002 and were available for 74 pediatric patients: 21 cases did not undergo any nodal surgery, 19 had removal of 1 to 3 nodes, and 27 had removal of 4 nodes or more. Nodal biopsy or aspiration was performed in 3 cases (type of nodal surgery was unknown in 4 patients). In comparison to adults, children/adolescents received radiation less frequently (27% of children/adolescents vs 51% of adults, p <.001). In the majority of cases in which both modalities were used (n ¼ 6027), radiotherapy was given after primary site surgery (95%). Survival. The median follow-up of all patients in the study cohort was 3.4 years (range, 0 34 years). The 5-year and 10-year overall survival for children/adolescents were 95% 1.5% and 94% 1.6%, respectively, compared to 59% 0.5% and 46% 0.5%, respectively, for adults (log-rank test, p <.001; Figure 4). The relative survival, which takes into account the natural decrease in survival in older individuals, declined gradually in successive age groups (Table 3). Among 16 children/adolescents who were reported dead at study cut-off, 13 were reported to have cancerrelated mortality. Among those 13 patients, 4 had distant spread at diagnosis and 2 were reported to have second malignancies as causes of death (acute lymphoblastic leukemia and osteosarcoma). The following factors were found to be associated with a significantly worse outcome in Cox proportional hazards regression multivariate model when tested on the entire population (all age groups): male sex (HR, 1.3; 95% CI, ), lymph node involvement (HR, 1.6; 95% CI, ), distant stage (HR, 1.6; 95% CI, ), grade III or IV (HR, 1.8; 95% Table 2. Surgical details of 128 children/adolescents diagnosed after No. of patients FN spared FN sacrificed FN status not recorded Total Local tumor excision/excisional biopsy Less than total parotidectomy NOS Superficial lobe only Deep lobe with or without superficial lobe Total parotidectomy Radical parotidectomy Parotidectomy, NOS No surgery Total Abbreviations: FN, facial nerve; NOS, not otherwise specified. Salivary Gland Carcinoma in Children/Adolescents HEAD & NECK DOI /hed October

5 FIGURE 4. Kaplan Meier curves indicating overall survival for children/adolescents and adults with salivary gland carcinomas; the log-rank test was used to compare the curves. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] CI, ), size more than the median (25 mm; HR, 1.7; 95% CI, ), and histologies other than mucoepidermoid/acinar cell carcinoma (HR, 1.8; 95% CI, ). This model was not reproducible when restricted to children due to the small sample size and the small number of events. When the whole group was analyzed to study the effect of the extent of surgery on survival, it was observed that those patients who had complete resection of the salivary gland (vs partial resection) and those with facial nerve sacrifice had worse survival (p <.001 using log-rank tests). However, it was of note that the median size of tumors that were completely resected (n ¼ 2123) was larger (25 mm) than that of the tumors that were partially resected (n ¼ 2572, 20 mm) with a statistically significant difference (Mann Whitney test, p <.001). Similarly, patients with a reported facial nerve sacrifice (n ¼ 871) had larger tumors (median 25 mm) than those with reported preservation of the facial nerve (n ¼ 1639, 21 mm; p <.001). Due to the small sample size, the relationship between the tumor size and surgical outcome was not analyzed separately in children/adolescents. Table 3. Relative survival of patients with salivary gland tumors. No. of y 5-year RS SE 10-year RS SE < % 1.4% 95.4% 1.6% % 0.7% 90.2% 1.0% % 0.8% 70.9% 1.0% 60þ 63.4% 1% 55.7% 1.4% Abbreviation: RS, relative survival. DISCUSSION The present study confirms that malignant epithelial tumors of the salivary glands are extremely rare in children, in particular in prepubertal age. The SEER database indicated an annual incidence of 0.8 per million in 0 to 19 year olds, similar to that reported by the Italian Study on Rare Tumours in Paediatric Age (TREP) project on rare pediatric tumors. 20 The TREP project was launched in Italy in 2000 with the goal of improving the clinical management and enhancing basic research on the most uncommon pediatric cancers, salivary gland tumors among them. 21 However, only 6 cases of carcinoma of the salivary glands were registered in the first 7 years of the activity (out of 336 patients with rare pediatric tumors), compared to 48 expected cases. Because the project involved all the pediatric oncology centers and most of the pediatric surgery units in Italy, these data would suggest that the majority of children and adolescents with salivary gland tumors were treated by other specialists (ie, otorhinolaryngologists or adult surgeons). Scanty data are available in the literature on pediatric carcinoma of the salivary glands. Therefore, the SEER database offers an interesting opportunity to collect data on a large series of pediatric cases and compare their clinical findings and outcomes to those observed in adults. Although retrospective data coming from a population-based registry may have some limitations and should be interpreted with caution, the current analysis suggests some differential features for the pediatric cases. Pediatric carcinomas were mainly mucoepidermoid or acinar cell carcinomas, well differentiated or moderately differentiated, and usually arising in the parotid gland. When compared to adults, a slight female predominance and a relatively higher occurrence in black children/adolescents were observed. More importantly, pediatric tumors were diagnosed at a low stage. Some of these findings were variously reported by other small single-institution series. Survival analysis showed that outcome was significantly better for children, particularly when compared to adults older than 40 years old. These data might be partially related to the more favorable clinical presentation observed in children. However, whether age-related differences in biology exist remains unclear; the small number of events in the pediatric cohort hindered further survival analysis controlled for the different clinical characteristics. The treatment of salivary gland carcinomas is mainly surgical. Parotidectomy (superficial or total) with the attempt to identify and preserve the facial nerve should be the mainstay of therapy. Our data suggest that postoperative facial nerve injury is a critical risk in parotid surgery. Other studies have reported a greater risk of facial weakness in children compared with adults. 4,5,10,22 Furthermore, in relation to this finding, we would recommend that children and adolescents with salivary gland tumors be referred to specialized centers, preferably in whom cooperation between pediatric oncologists, surgeons, and adult experts may optimize the chances for young patients to be cured with limited morbidity Salivary Gland Carcinoma in Children/Adolescents HEAD & NECK DOI /hed October 2011

6 The need for limiting long-term morbidity in young patients has to be taken into consideration. As for the indication of radiotherapy, its role in salivary gland tumors remains controversial. The presence of high-grade or large and incompletely resected tumors and the involvement of cervical lymph nodes at multiple levels are generally considered the main indications for irradiation. However, in children, given the higher risk of postirradiation complications, such as facial growth retardation and second malignant neoplasms, radiotherapy is usually recommended in highly selected cases. In this SEER series, radiotherapy was administered less frequently to children/adolescents (27%) than to adults (51%; p <.001). In conclusion, this analysis provides additional epidemiological, clinical, and outcome data on pediatric salivary gland carcinomas. However, further research is warranted to better investigate the biology and clinical history of these neoplasms. Pediatric oncologists and pediatric surgeons should establish active cooperation with head and neck specialists, and international collaborations should be implemented. Acknowledgment. The authors thank Dr. Hyveen Ramadan for reviewing and editing this manuscript. REFERENCES 1. Boukheris H, Curtis RE, Land CE, Dores GM. Incidence of carcinoma of the major salivary glands according to the WHO classification, 1992 to 2006: a population-based study in the United States. Cancer Epidemiol Biomarkers Prev 2009;18: Bradley P, McClelland L, Mehta D. Paediatric salivary gland epithelial neoplasms. ORL J Otorhinolaryngol Relat Spec 2007; 69: Védrine PO, Coffinet L, Temam S, et al. Mucoepidermoid carcinoma of salivary glands in the pediatric age group: 18 clinical cases, including 11 second malignant neoplasms. Head Neck 2006;28: Guzzo M, Ferrari A, Marcon I, et al. Salivary gland neoplasms in children: the experience of the Istituto Nazionale Tumori of Milan. Pediatr Blood Cancer 2006;47: Ethunandan M, Ethunandan A, Macpherson D, Conroy B, Pratt C. Parotid neoplasms in children: experience of diagnosis and management in a district general hospital. Int J Oral Maxillofac Surg 2003;32: Ribeiro Kde C, Kowalski LP, Saba LM, de Camargo B. Epithelial salivary glands neoplasms in children and adolescents: a forty-four-year experience. Med Pediatr Oncol 2002;39: Winslow CP, Batuello S, Chan KC. Pediatric mucoepidermoid carcinoma of the minor salivary glands. Ear Nose Throat J 1998;77: , Rogers DA, Rao BN, Bowman L, et al. Primary malignancy of the salivary gland in children. J Pediatr Surg 1994;29: Kessler A, Handler SD. Salivary gland neoplasms in children: a 10-year survey at the Children s Hospital of Philadelphia. Int J Pediatr Otorhinolaryngol 1994;29: Callender DL, Frankenthaler RA, Luna MA, Lee SS, Goepfert H. Salivary gland neoplasms in children. Arch Otolaryngol Head Neck Surg 1992;118: Luna MA, Batsakis JG, el-naggar AK. Salivary gland tumors in children. Ann Otol Rhinol Laryngol 1991;100: Fonseca I, Martins AG, Soares J. Epithelial salivary gland tumors of children and adolescents in southern Portugal. A clinicopathologic study of twenty-four cases. Oral Surg Oral Med Oral Pathol 1991;72: Shikhani AH, Johns ME. Tumors of the major salivary glands in children. Head Neck Surg 1988;10: Lack EE, Upton MP. Histopathologic review of salivary gland tumors in childhood. Arch Otolaryngol Head Neck Surg 1988;114: Gustafsson H, Dahlqvist A, Anniko M, Carlsöö B. Mucoepidermoid carcinoma in a minor salivary gland in childhood. J Laryngol Otol 1987;101: Seifert G, Okabe H, Caselitz J. Epithelial salivary gland tumors in children and adolescents. Analysis of 80 cases (Salivary Gland Register ). ORL J Otorhinolaryngol Relat Spec 1986; 48: Baker SR, Malone B. Salivary gland malignancies in children. Cancer 1985;55: Surveillance, Epidemiology, and End Results (SEER) Program ( SEER*Stat Database: survival-seer17 Regs Limited-Use, Nov 2008 Sub ( ) <Katrina/Rita Population Adjustment> - Linked To County Attributes - Total U.S., Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2009, based on the November 2008 submission. 19. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International Classification of Childhood Cancer, third edition. Cancer 2005;103: Pastore G, De Salvo GL, Bisogno G, et al. Evaluating access to pediatric cancer care centers of children and adolescents with rare tumors in Italy: the TREP project. Pediatr Blood Cancer 2009;53: Ferrari A, Bisogno G, De Salvo GL, et al. The challenge of very rare tumours in childhood: the Italian TREP project. Eur J Cancer 2007;43: Orvidas LJ, Kasperbauer JL, Lewis JE, Olsen KD, Lesnick TG. Pediatric parotid masses. Arch Otolaryngol Head Neck Surg 2000;126: Salivary Gland Carcinoma in Children/Adolescents HEAD & NECK DOI /hed October