Pediatric Hematology and Oncology, 31:681–686, 2014 C Informa Healthcare USA, Inc. Copyright  ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.942936

REVIEW

Salivary Gland Tumors in Children: A Retrospective Clinical Review

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2 ¨ 1 Erman Atas¸,1 Tas¸kın Yucel, ¨ Ali Varan,1 Canan Akyuz, Burc¸a Aydın,1 1 1 ¨ ¨ ukpamukc ¨ Bilgehan Yalc¸ın, Tezer Kutluk, and Munevver Buy ¸ u1 1

Department of Pediatric Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey; Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey 2

Seven patients with salivary gland tumors who underwent between 1972 and 2012 were retrospectively evaluated. The age of the patients ranged from 6.3 to 13 years old; five were females and two were males. Five patients had stage IVa, one patient had stage I, and one patient had stage II disease. The surgical margin was found to be positive in five cases. There were three adenoid cystic carcinoma, two adenocarcinoma, one anaplastic carcinoma, and one mucoepidermoid carcinoma. There were five parotid, one lacrimal gland, and one palatal involvement. Three patients who had low stage tumors were treated with surgery alone. Four of the cases received adjuvant radiation and chemotherapy. One patient with parotid tumor died with progressive disease. One case with lacrimal gland neoplasm was alive 48 months after discontinuation of treatment. The other palate case was lost to follow-up 1 month after the beginning of the treatment. Surgery is the primary treatment, with radiotherapy and chemotherapy used as adjuvant treatments. The treatment options need to be selected and planned for each individual patient. Keywords children, outcome, salivary gland tumors, treatment

INTRODUCTION Salivary gland malignancies (SGMs) represent 6–8% of all head and neck cancers, and 0.3% of all malignancies [1, 2]. Epithelial salivary gland tumors (SGTs) account for less than 3% of all head and neck tumors and about 5% of these tumors occur in the pediatric age group; childhood SGTs are malignant in 35–50% of cases [3–5]. Under 17 years of age, pleomorphic adenomas, mucoepidermoid carcinomas, and acinic cell carcinomas account for about 90% of epithelial tumors [6]. SGTs are classified as benign, malignant epithelial, soft tissue, hematolymphoid, or secondary tumors [6]. Tumors of the salivary glands may be located in the parotid, submandibular, sublingual, or other minor glands. The most common tumor site is the parotid gland, accounting for 79–85% of cases [7, 8]. Malignant tumors constitute 15–32% of all parotid tumors [6]. These are very rare malignancies in children and have been treated with surgery, chemotherapy, and radiotherapy. The clinical presentation is variable [9]. Some patients present with asymptomatic slow growing tumors and some patients have suffer late recurrence Received 19 February 2014; accepted 6 July 2014. Address correspondence to Ali Varan, Department of Pediatric Oncology, Cancer Institute, Hacettepe University, 06100 Ankara, Turkey. E-mail: [email protected]

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after treatment [9]. In this paper, we evaluate the clinical features, treatment outcome, and prognostic features of salivary gland neoplasms from 40 years of experience.

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MATERIAL AND METHODS This study was conducted at Hacettepe University Children’s Hospital on pediatric patients with parotid malignancies between 1972 and 2012. The file archives of rare tumor’s section were reviewed for salivary gland tumors. Demographic characteristics, histopathologic features, treatment details, and outcomes of seven consecutively diagnosed salivary gland malignancy patients younger than 18 years of age were recorded and analyzed among 449 rare tumor cases from the files’ clinical records of Department of Pediatric Oncology, surgeons’ operation records and pathologic results between 1972 and 2012. Statistical analyses were performed using SPSS software version 15. The effect of the tumor characteristics on survival was investigated using the log rank test. Kaplan–Meier survival statistics were calculated. Possible influencing factors identified by univariate analysis were entered into Cox regression analysis, with backward selection, to determine independent predictors of survival. A 5% Type I error level was used to infer statistical significance.

RESULTS There were seven children with parotid malignancy. The characteristics of these patients are shown in Table 1. Their age at diagnosis ranged from 6.3 to 13 years, with a mean of 10.2 years; there were five females and two males. The lag time between onset of symptoms and diagnosis ranged from 30 to 540 days, with a mean of 90 days. There were five cases of perineural, vascular, and stromal invasion. In four cases, tumor was located on the right side. Patient complaints included swelling at the posterior, anterior, and inferior side of the ear, jaw, cheek, or velum and prominence of the right eye. There was only one case of lymph node involvement. The size of the tumors ranged from 1×1 cm to 6×4 cm. There was a positive surgical margin in five cases. On pathologic examination, there were three adenoid cystic carcinomas, two adenocarcinomas, one anaplastic carcinoma, and one mucoepidermoid carcinoma. Pleomorphism was present in one case. Two cases were being followed-up for intraductal papilloma and monomorphic adenoma before the malignancy occurred. Tumors originated in the

TABLE 1 Clinical Characteristics of the Patients with Salivary Gland Tumor

1 2 3 4 5 6 7

Gender

Age (years)

Gland

TNM

Stage

Primary treatment

Outcome and followup time (months)

M F F M F F F

8 10.3 6.3 12 13 9 13

Parotid Parotid Palate Parotid Parotid Parotid Lacrimal

T1N0M0 T2N0M0 T4aN0M0 T4aN0M0 T4N1M0 T4aN0M0 T4aN0M0

I II IVa IVa IVa IVa IVa

Surgery Surgery Surgery Surgery-RT-MMR Surgery-RT-BEP Surgery-RT-MMR Surgery-RT-MMR

Alive (110) Died (81) Lost (1) Alive (38) Alive (196) Alive (10) Alive (48)

Note. M: male, F: female, RT: radiotherapy, BEP: Cisplatin, Etoposide, Bleomycin, MMR: Cisplatin, Doxorubicin, Cyclophosphamide, Vincristine, Actinomycin-D, Dacarbazine. Pediatric Hematology and Oncology

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Salivary Gland Tumors in Children

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parotid in five patients, and there was one case of lacrimal gland and one of palatal involvement. The palatal case presented to our hospital with swelling on the velum, and pathologic diagnosis was adenoid cystic carcinoma. Tumors were stage I, stage II, and stage IVa in one, one, and five cases, respectively. The first treatment strategy was surgery in all cases. Surgery was done in all patients. One patient underwent tru-cut biopsy, and then surgery was performed after the pathology revealed mucoepidermoid carcinoma. Others underwent surgical resection before having a final diagnosis. Residual disease was found after surgery in four cases: three of these underwent secondary surgery. Parotidectomy was undertaken in five patients. The mass near the lacrimal gland was excised. One case underwent excision of the velum, after which secondary surgery was conducted on the hard palate. There was one case of metastasis to cervical lymph nodes. According to histopathologic findings or the presence of residual disease, chemotherapy and/or radiotherapy were also used. Chemotherapy protocols were comprised of combination therapy (induction: cisplatin, cyclophosphamide, doxorubicin, vincristine; maintenance: cisplatin, doxorubicin, dacarbazine alternately with cyclophosphamide, actinomycin D, vincristine). Chemotherapy contained a cisplatin-based combination in three cases (42.8%); and one case was treated with bleomycin, etoposide, and cisplatin. Radiotherapy was given at doses between 56 and 60 Gy. It was given to four patients, at the doses of 6000 cGy in three cases and 5600 cGy in one case. Two cases were lost to follow-up before radiotherapy. The remaining patient suffered disease progression during chemotherapy and died after 5 months. This patient did not undergo radiotherapy as primary treatment, but was given 6000 cGy radiotherapy after the first recurrence in the mandible. The second recurrence comprised widespread bone involvement and was treated with cisplatin and etoposide and 2400 cGy radiotherapy to the sacrum. Event-free survival and overall survival rates were 67 and 80%. One patient with a lacrimal gland neoplasm was well in 48 months after discontinuation of treatment. The case with palate disease was lost to follow-up 1 month from the beginning of treatment. The median follow-up time was 51 months (1–196 months). Five patients were alive and one patient died from progressive disease. One patient had residual disease and underwent secondary surgery and afterward he was lost to follow-up. Relapse occurred in bone in one patient. The primary tumor area control rate was 71.4%. On univariate analysis, no one prognostic factor was found to affect survival (P > .25).

DISCUSSION Epithelial salivary gland neoplasms are uncommon in both adults and children. The mean age of pediatric patients has been reported 13.4 years, with a slight female predominance [10]. Risk factors in adults for SGM are exposure to ionizing radiation and occupations such as working with rubber products or asbestos, plumbing, and woodworking [11–13]. However, the etiology is usually not determined. In our study, the mean age was 10.2 years and the female:male ratio was 2.5. There were only seven cases, which is consistent with the rarity of these tumors in children. No relevant information about the etiology of SGM was available for our series. More females were affected than males. The parotid gland as a major gland and the palate as a minor gland are the most common site of SGT [14]. Guzzo et al. reported that the most common sites are the parotid, submandibular, and sublingual glands [3]. In our study, the parotid gland was the most common site at 71.4%, followed by the lacrimal gland and palate. C Informa Healthcare USA, Inc. Copyright 

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Pleomorphic adenoma is the most common SGT and mucoepidermoid carcinoma is the most common malignant tumor, followed by adenocarcinoma, acinic cell carcinoma, and adenoid cystic carcinoma [14]. The percentage of malignant tumors was comparable with the study of Speight et al. [14]. Baker et al. [15] reported adenoid cystic carcinoma to be the most common pathologic subtype. In our study, adenoid cystic carcinoma was the most common subtype followed by adenocarcinoma, anaplastic carcinoma, and mucoepidermoid carcinoma. Painless swelling, numbness, parapharyngeal fullness, weakness, and pain in the facial cranial nerve area are the most common signs of SGTs [15]. In our study, patients complained of swelling in the posterior, anterior, and inferior side of the ear, jaw, cheek, and velum and prominence of the right eye. These signs are usually compatible with mass effects and invasion around nerve tissue. There were five cases of nerve, stromal, and vascular invasion in our study, consistent with facial nerve paralysis with the parotid subtype in 28.6% and fixation to surrounding tissue in 85.7%. The overall 5 year survival of patients with parotid carcinoma is reported to be almost 62% [16]. In our study, this rate was similar at 67%. Some patients present with asymptomatic slow growing tumors and some patients have suffer late recurrence after treatment [9]. Lag time sometimes may be long. In our series, the 540 days lag time seems like an extreme for progression of an actual malignancy. This patient was followed by different center as monomorphic adenoma. Nearly 19 months later from first complaint of swelling under ear, this patient was admitted with complaints of sudden increase in swelling. Due to progression, new biopsy was performed. Anaplastic carcinoma was revealed. Surgery is the initial and mainstay of treatment for SGTs. Superficial or total parotidectomy should be performed for malignant parotid tumor according to tumors extent [3]. One patient underwent to tru-cut biopsy, however surgery was performed after result of mucoepidermoid carcinoma. Others underwent to surgery before diagnosis first. Three of seven cases underwent to second surgery owing to residue. Lymph node excision was performed. Only one patient had lymph node positivity. Lymph node metastasis rates are low at 14–20% [17]. Neck dissection is recommended only for clinically detected neck metastases [5, 18, 19]. We found only one patient with lymph node metastasis (14%). This rate was compatible with the rate mentioned in the preceding paragraph. However, this rate of lymph node metastasis is high enough to dramatically influence surgical approach and staging in our opinion. Salivary gland tumors are staged according to size, extraparenchymal extension, lymph node involvement, and metastasis. Stage is more important factor for outcome than histologic grade [20]. Patients with localized tumors may be cured by radical surgery alone. We should use radiologic diagnostic tests such as magnetic resonance and computed tomography for extension of disease to make decision on treatment. We do not know which tumors come to us with lymph node metastasis. Radiotherapy is recommended for microscopic residual tumor, lymphatic/vascular invasion, and nodal involvement [19]. Radiotherapy can also be used in patients with undifferentiated and high-grade tumors, perineural invasion, advanced disease such as facial nerve involvement, or deep lobe involvement [21–26]. In our study, four cases who received radiotherapy had perineural invasion. One patient with perineural invasion did not undergo radiotherapy due to lost to follow-up. Cisplatin, doxorubicin, and cyclophosphamide are the most common chemotherapeutic agents in advanced salivary gland carcinoma [27]. We used cisplatin-based chemotherapy protocols. In our experience, surgery was chosen as a first treatment. Also, we preferred secondary surgery for residual tumors. Only one neck dissection was performed for lymph node involvement.

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Gland type, histology, grade, stage, tumor involvement of the facial nerve, fixation to the skin or deep structures, and spread to lymph nodes or distant areas are the most important prognostic factors [28, 29]. In our study, one patient died due to disease progression and another was lost to follow-up. There was deep lobe invasion of the parotid and palate, anaplastic, and adenoid cystic histopathology, perineural invasion, stage IVa characteristics, residual after surgery, and mandibular invasion in these patients. It would be more useful and valuable to present this study with a larger number of cases and pathological subtype of salivary gland tumors as adenoid cystic carcinoma rather than totally. In this way, we may evaluate the survival rates more uniformly in further studies. Low number and heterogenous group of our cases were the limitation of our study. CONCLUSIONS This rare tumor should be evaluated carefully by pediatric oncology, pediatric surgery, radiology, and pathology departments. Surgery is more important as a primary treatment option than radiotherapy or chemotherapy. Radiotherapy is a prominent adjuvant therapy for local control of residual tumor, local spread, and recurrent tumors. Cisplatin, doxorubicin, and cyclophosphamide are some of the chemotherapeutic options that have been used in advanced salivary gland carcinoma, generally reserved for advanced and recurrent disease. Individual treatment options should be selected and planned for each patients. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. REFERENCES [1] Ries LAG, Hankey BF, Miller BA, et al. Cancer Statistics Review. Bethesda, MD: National Cancer Institute; 1991:1973–1988. [2] Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005;114(5):806–816. [3] 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(6):806–810. [4] Luna MA, Batsakis JG, el-Naggar AK. Salivary gland tumors in children. Ann Otol Rhinol Laryngol. 1991;100(10):869–871. [5] 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(6):594–600. [6] Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005:254–258. [7] Guzzo M, Locati LD, Prott FJ, et al. Major and minor salivary gland tumors. Crit Rev Oncol Hematol. 2010;74(2):134–148. [8] Shikhani AH, Johns ME. Tumors of the major salivary glands in children. Head Neck Surg. 1988;10(4):257–263. [9] Copelli C, Bianchi B, Ferrari S, et al. Malignant tumors of intraoral minor salivary glands. Oral Oncol. 2008;44(7):658–663. [10] 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(6):696–701. [11] Ellis GL, Auclair PL. Tumors of the Salivary Glands. Atlas of Tumor Pathology, 3rd series, fascicle 17. Washington DC: Armed Forces Institute of Pathology; 1996. [12] van der Laan BF, Baris G, Gregor RT, et al. Radiation-induced tumours of the head and neck. J Laryngol Otol. 1995;109(4):346–349. C Informa Healthcare USA, Inc. Copyright 

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[13] Horn-Ross PL, Ljung BM, Morrow M. Environmental factors and the risk of salivary gland cancer. Epidemiology. 1997;8(4):414–419. [14] Speight PM, Barrett AW. Salivary gland tumours. Oral Dis. 2002;8(5):229–240. [15] Baker SR, Malone B. Salivary gland malignancies in children. Cancer. 1985;55(8):1730–1736. [16] Amirlak B. Malignant parotid tumors. http://emedicine.medscape.com/article/1289616-overview. Accessed 27 February 2013. [17] Stennert E, Kisner D, Jungehuelsing M, et al. High incidence of lymph node metastasis in major salivary gland cancer. Arch Otolaryngol Head Neck Surg. 2003;129(7):720–723. [18] Callender DL, Frankenthaler RA, Luna MA, et al. Salivary gland neoplasms in children. Arch Otolaryngol Head Neck Surg. 1992;118(5):472–476. [19] 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(3):195–202. [20] American Joint Committee on Cancer. Major salivary glands (parotid, submandibular, and sublingual). In: Edge SB BD, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. New York, NY: Springer; 2010:79–82. [21] Borthne A, Kjellevold K, Kaalhus O, Vermund H. Salivary gland malignant neoplasms: treatment and prognosis. Int J Radiat Oncol Biol Phys. 1986;12(5):747–754. [22] Elkon D, Colman M, Hendrickson FR. Radiation therapy in the treatment of malignant salivary gland tumors. Cancer. 1978;41(2):502–506. [23] Fitzpatrick PJ, Theriault C. Malignant salivary gland tumors. Int J Radiat Oncol Biol Phys. 1986;12(10):1743–1747. [24] Harrison LB, Armstrong JG, Spiro RH, et al. Postoperative radiation therapy for major salivary gland malignancies. J Surg Oncol. 1990;45(1):52–55. [25] McNaney D, McNeese MD, Guillamondegui OM, et al. Postoperative irradiation in malignant epithelial tumors of the parotid. Int J Radiat Oncol Biol Phys. 1983;9(9):1289–1295. [26] North CA, Lee DJ, Piantadosi S, et al. Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1990;18(6):1319–1326. [27] Licitra L, Cavina R, Grandi C, et al. Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients. Ann Oncol. 1996;7(6):640–642. [28] Vander Poorten VL, Balm AJ, Hilgers FJ, et al. The development of a prognostic score for patients with parotid carcinoma. Cancer 1999;85(9):2057–2067. [29] Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck. 2004;26(8):681–692; discussion 692–3.

Pediatric Hematology and Oncology

Salivary gland tumors in children: a retrospective clinical review.

Seven patients with salivary gland tumors who underwent between 1972 and 2012 were retrospectively evaluated. The age of the patients ranged from 6.3 ...
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