oralpathology Editor: LEWIS R. EVERSOLE,
DDS, MSD, MA
Oral Diagnosis, Medicine & Pathology School of Dentistry 53-058 UCLA Health Sciences Center Los Angeles, California 90024
Epithelial salivary gland tumors of children and adolescents in southern Portugal A clinicopathologic
study of twenty-four
cases
Isabel Fonseca, MD,a A. Gentil Martins, MD,b and Jorge Soares, MD, PhD,a Lisbon, Portugal INSTITUTO
PORTUGU&
DE ONCOLOGIA
DE FRANCISCO
GENTIL
During a 30-year period 24 epithelial salivary gland tumors were diagnosed in children and adolescents less than 18 years of age. The cases were retrieved from a series of 759 consecutive cases of salivary gland tumors (3.2%) from the area corresponding to southern Portugal during the same period of time. The mean age of the patients was 13.4 years, and one case was congenital. There was a slight female predominance (male/female ratio 1: 1.7). The parotid gland was affected in most cases (70.8%). Seventeen neoplasms were benign, and the remaining seven were malignant. As in the adult group, pleomorphic adenoma was the most frequent benign tumor (68.8%), with similar histologic findings and clinical course. Mucoepidermoid carcinoma was the prevalent malignant tumor (20.8%), had a high grade of differentiation, and had a favorable outcome. The histologic pattern of the congenital neoplasm was similar to that of adult epithelial-myoepithelial carcinoma. (ORAL SURC ORAL MED ORAL PATHOL 1991;72:696-701)
S
alivary gland tumors are infrequent neoplasmsof controversial histogenesis,accounting for 3% of all head and neck tumors.‘, 2 Clinicopathologic studiesof these tumors have been influenced not only by their rarity but also by diverseclinical behavior and a wide spectrum of morphologic presentations,making their histologic classification problematic.2y3 Particularly in children and adolescents,salivary gland tumors, especially those of epithelial origin, are exceedingly rare; most of the tumors occurring in this age group are benign nonepithelial neoplasms.4,5 This work was undertaken to study retrospectively the primary epiPresented in part at the Twelfth European Congress of Pathology. Supported by a grant from the Nticleo Regional do Sul da Liga Portuguesa contra 0 Cancro. “Morphologic Pathology Department. bOncology Clinic IV. 7/U/29127 696
thelial salivary gland tumors in children and adolescents with a consecutive series of 24 casesrepresentative of the prevalenceof these tumors in southern Portugal. It covers a 30-year period and attempts to contribute to establish their clinicoepidemiologic profile. MATERIAL
AND METHODS
Between 1959and 1989,759 casesof salivary gland tumors were diagnosedat the Pathology Department of Instituto Portugub de Oncologia de Francisco Gentil (Lisbon Center). From this series24 epithelial neoplasms (3.2%) occurred in children and adolescents less than 18 years of age. Hematoxylin-eosinstained sections from each case were reviewed, and new sectionswere obtained when necessary.All cases were reclassified according to the modified World Health Organization histologic classification of salivary gland tumors3 We excluded from the study
Salivary gland tumors in children 697
Volume 72 Number 6
Table I. Clinical, morphologic, and follow-up data of whole series Case No.
Sex/age (Yd
Benign tumors 1 M/14 2 F/17 3 F/15 4 F/18 5 F/l2 6 F/l8 7 F/15 8 M/14 9 M/16 10 F/15 11 M/17 12 M/14 13 F/IO 14 F/16 15 F/14 F/8 16 17 F/9 Malignant tumors 18 M/14 19 M/14 20 M/13 21 F/14 22 F/7 23 F/18 24 M/3 mo
Major or minor
Histology
Location
Follow-up (mo)foutcome
24/NED -
Major Major Major Major Major Major Major Major Major Major Major Major Major Minor Major Minor Major
Left parotid Right parotid Left parotid Right parotid Right parotid Left parotid Right submandibular Right parotid Right parotid Right parotid Left submandibular Left parotid Right parotid Soft palate Left submandibular Soft palate Right parotid
Pleomorphic adenoma Pleomorphic adenoma Pleomorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Pleomorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Pleomorphic adenoma Pleomorphic adenoma Pleomorphic adenoma Papillary cystadenoma
12/NED 156/NED 72/NED 24/NED 84/NED 1Z/NED 12/NED 1Z/NED 144/NED
Minor Major Major Minor Major Major
Soft palate Left parotid Left parotid Soft palate Right parotid Left parotid Left parotid
Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma
60/REC 120/REC Z/NED 6/NED 36/NED 72/NED 2/DOD
-
DOD, Deadof disease;NED, no evidenceof disease;REC. recurrence.
mesenchymaland metastatic tumors and lymphoproliferative lesions. The clinical charts of all patients were reviewedfor age, sex, location of the tumor, and clinical status. Follow-up information was obtained in 16 casesand ranged from 2 to 156 months. The adult seriesof tumors (n = 735) was used for comparison of the sex distribution and the relative frequency of the benign and the malignant tumors. RESULTS
Table I summarizes the clinical, histologic, and follow-up data of the whole series. The ages of the patientsrangedbetween3 monthsand 18 years(mean age 13.4 years). Four patients were lessthan 10 years of age, and in one instancethe tumor was congenital. Fifteen patients were female; nine were male. The female/male ratio was 1.7:1 in the pediatric group and 2.5: 1 in the adult group. Twenty tumors were located within major salivary glands (eight in the left parotid gland, nine in the right parotid gland, and three in the submandibular gland). The remaining four cases originated in the m inor glands of the oral cavity. Of the 24 neoplasms,17 (70.8%) were benign and seven (29.2%) malignant.
Benign tumors
Pleomorphicadenomawas diagnosedin all but one of the benign neoplasms.It correspondedto the most frequent tumor type, with a total number of 16 cases (66.6%). Eleven patients were female and five were male. The mean age of the patients was 14.5 years; only one tumor occurredin the first decadeof life. The tumors were located in the parotid gland (11 cases), the submandibular gland (three cases),and the soft palate (two cases).All but one pleomorphicadenoma presentedas a well-circumscribed and encapsulated single nodule,varying between2 and 8 cm. One case (No. 13) displayeda multinodular “recurrence type” presentationbut was acceptedas primary becausethe patient gave no history of previous surgery. M icroscopically the pleomorphic adenomaswere representedby a biphasic cellular proliferation with variable proportions of epithelial and mesenchymal elements (chondroid, collagenous, and mucoid stroma) (Fig. 1). Focal squamousdifferentiation was encounteredin two cases. M itoses were extremely rare, and necrotic foci were not detected. Follow-up information was obtained in nine cases and ranged from 12 to 156 months (mean 45.3 months) without tumor recurrence.
696
Fonseca, Martins, and Soares
Fig. 1. Pleomorphic adenoma of parotid gland. Tumor is circumscribed by thin fibrous capsule andcomposed of myoepithelial cells with moderately dense stroma. (Hematoxylin-eosin stain; original magnification, X 160.)
of parotidgland.TuFig. 2. Case7. Papillaryadenoma mor is capsulated and composed of well-formed papillae lined by cuboidal cells. (Hematoxylin-eosin stain; original magnification, X 160.)
The other benign tumor found in this serieswas a papillary cystadenoma(Table I). It occurred in the right parotid gland of a 9-year-old girl, was encapsulated, and measured 5 cm. Microscopically it was formed by fibrovascular cores lined by cuboidal and cylindric cells, with areasof pseudostratification(Fig. 2). Few ductlike structureswere in continuity with the papillary surface fronds. The cells had oval nuclei, and the cytoplasm was eosinophilic. There was no atypicality, mitoses, or necrosis, and a lymphoid stroma componentwas absent.No recurrenceof the tumor was observedafter 144 months of follow-up. Malignant
tumors
Mucoepidermoidcarcinoma was the most frequent malignant histologic type, corresponding to five of
ORAL SURGORAL MED ORAL PAI’HOI December 199I
Fig. 3. Case 18. Mucoepidermoid carcinoma of soft palate. Cystic spaces lined by mucus cells and small solid nests of intermediate-typecells (arrow). (Hematoxylin-eosin stain; original magnification, X 160.)
sevencases.One tumor occurredin a patient lessthan 10 years of age, and the remaining four tumors affected patients aged 13 and 14 years (Table I). The tumors were located in the parotid gland (four cases) and the soft palate (one case). They presentedas a nonencapsulatedmass measuring between 1.5 and 5 cm. All tumors showedan expansivegrowth pattern and were classified as low-grade, well-differentiated neoplasmsaccording to the criteria of Healey et a1.6 (Fig. 3). Vascular invasion, low-regional lymph node metastases,and distant metastaseswere not encountered. Mitoses were less than 1 per 10 high-power fields, and necrosiswas either absent or occurred as minute foci. All five patients were alive and free of diseaseat the end of the follow-up study. However, two casesrecurred locally, one of them twice (case9), 4 and 24 months after the first surgery. Both patients underwenta secondsurgery and now haveno evidence of local or distant tumor. Two other malignant neoplasmsin the present series consistedof a case of adenoid cystic carcinoma and a congenitaltumor. The adenoidcystic carcinoma (case23) occurred in the left parotid gland of an 18year-old adolescent. It measured 5 cm and microscopically had tubular pattern, compatible with a grade I carcinoma.7There was perineural infiltration, but vascular invasion was not documented. The patient is now well and free of recurrence72 months after parotidectomy. In this seriesthere was a congenital tumor resected at the ageof 3 months. The tumor was presentat birth and was the causeof a dystocia. It was located within the left parotid gland, measured9 cm, and had an expansive pattern of growth with a nodular arrangement. The noduleswere separatedby very thin fibrous
Volume72 Number 6
Salivary gland tumors in children
699
septa,were formed by large cells of clear cytoplasm, with well-defined limits. In the center of some of the solid nestsill-defined ductlike arrangementswere apparent (Fig. 4, A). The cells lining the ductal spaces were cuboidal, had slightly densecytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli. The mitotic index was 4 mitosesper 10 high-power fields. The ductlike cells that formed the central areasof the tumor noduleswere positive for low-molecular-weight keratin antibody (AEl) (Fig. 4, B), whereasthe peripheral cells were either faintly positive or negative. The clear cell population was immunoreactive for S-100 protein, with both cytoplasmic and nuclear staining, supporting a myoepithelial cell differentiation. The lesionrecurred 4 months after surgery and was histologically identical to that of the primary lesion. The child died 2 months later as a result of local regional spread of the disease. DISCUSSION
The relative frequency of the epithelial salivary gland tumors occurring in children and adolescents rangesfrom 3.7% to 5.5%.4,5,&‘I However, the comparison between series is made difficult by the fact that different authors consider diverse age limits for the adolescent group. For instance, in their series, Krolls et a1.4included patients under the age of 15, Nagao et a1.5patients under 16 years, and Seifert et a1.8patients under 20 years. In other series the age limits are not even mentioned.12y l3 In the present study we adopted 18 years as the upper limit because it is the age limit criterion for a patient being admitted to the pediatric ward of our hospital. The total number of cases(24) represented3.2% of all the salivary gland tumors treated in the hospital during the sameperiod. Our finding of four cases(16.7%) in patients lessthan 10 yearsof age stressesthat tumors of salivary gland origin are extremely rare in the first decadeof 1ife.s I4 In the present series the female/male ratio was 1.7:1, similar to previousdata from Seifert et al.* and Castro et a1.14and confirms in the pediatric group the well-known predominanceof the salivary gland tumors for the female sex. In the group of benign tumors, only 5 of the 17 cases (29.4%) occurred in male patients,analogousto that observedin adu1ts.sI5 Most tumors (70.8%) were located in the parotid gland; five of them (41.6%) were malignant. This percentageis similar to that obtainedby Byars et a1.16 The majority of the tumors included in the studiesof Seifert et al.* and of Bakshar and Lilly17 was also located in the major salivary glands. The relative distribution of benign and malignant epithelial tu-
Fig. 4. A, Case21. Clear cell carcinoma of parotid gland. Tumor is multilobular and predominantly formed by clear cells. Ductal structures are apparent (arrow) (Hematoxylin-eosin stain; original magnification, X270.) B, Strong immunoreactivity of ductal component with anti-AEl antiserum. (Avidin-biotin complex method original magnification, X70.)
mors according to their origin from the major and minor salivary glands is similar to that generally described in adults.i5>‘* Malignancy in the pediatric group is also more commonly associatedwith tumors arising within the minor salivary glands.In our series half the tumors occurring in the minor salivary gland were malignant as comparedwith 5 of the 13 primary tumors of the major glands (38.4%). The most frequent histologic type in the presentseries was pleomorphic adenoma. This observation agreeswith the conclusionsof Byars et a1.16(17/23 cases),Seifert et a1.8(65% of their series),and Malone and Baker.19Alternatively, Jaques et a1.i3 and Nagao et a1.5found a lower frequency for this tumor type in the pediatric age group, of 36.3% and 28.1%, respectively.These discrepanciesmay representgeographic differencesin the incidence of this tumor or may reflect either diversecriteria for the age limit of the pediatric group or institutional characteristics, becausegeneral hospitals usually have a higher per-
700
Fonseca, Martins, and Soares
centage of benign casesin comparison with cancer hospitals. All these reasonstaken together may also eventually explain the unusual high incidence of mixed tumors in the pediatric age group reported by Krolls et al.4 (91.6%). No recurrenceswere observedin any of our cases; this probably relates to the type of surgery used:total excision of the involved gland. Even the patient who had a multinodular recurrent pattern of mixed tumor is well and free of disease7 years after the surgical resectionof the parotid gland, the surrounding periglandular soft tissues,and the overlying skin. The nonpleomorphicadenomawith a papillary organization included in the present seriesoccurred in the right parotid gland of a 9-year-oldgirl. The tumor was composedof true papillae lined by cuboidal and columnar cells without associatedlymphoid elements. Krolls et al.4 and Jaqueset al.r3 describedin children an identical type of neoplasm“morphologically similar to Warthin’s tumor but lacking lymphoid stroma.” However, the cytologic features of the neoplastic cells of the casewe report are clearly distinct from the classic oncocytic cells of Warthin’s tumor. Similarly, the same seems to be found in the cases described by Krolls et al.4 and Jaqueset a1.13when referenceis made to the illustrations in their publications. If one considersthe new proposal of Seifert et al.3 for the World Health Organization histologic typing of salivary gland tumors, we should probably categorizethis caseamong the very rare examplesof papillary cystadenomas.Nevertheless,not all characteristics ascribedto that tumor variant are present in our case. Mucoepidermoid carcinoma is the prevalent malignant neoplasmof the salivary glands among children and adolescents. Its frequency in our series (20.8%) is similar to that reportedby Krolls et al.4and Seifert et al.8 The relative frequency of mucoepidermoid carcinoma is higher in the children and adolescents than in adults (5.7%), a finding similar to that found by Seifert et al.8 It is generally observedthat most if not all mucoepidermoidcarcinomasoccurring in the childhood and adolescent group are well differentiated (grade I, low grade) and moderately differentiated (grade II, intermediate grade) tumors.9,i4, 20,21Concerning the influence of the grade of differentiation on the prognosisof the mucoepidermoid carcinomas,our resultsconfirm the usefulnessof the classification of Healey et a1.6becauseall neoplasmswere classifiedas grade I tumors and followed a relative benign course,in agreementwith the observations of Castro et ali4 and Nascimento et a1.21The favorable prognosisof mucoepidermoidcarcinoma as verified in the younger patients seemsto be related
ORAL SURG ORAL MEU ORAL PATHOI. December 1991
with a higher incidenceof well-differentiated grade I tumors in this age group.*OHowever, different results were given by Seifert et al.,8who reported a relatively high frequency of poorly differentiated, grade III mucoepidermoidcarcinomasamong children and adolescents(15% of their series).Thesevariations stress the difficulties for comparing data biasedby different classification criteria, distinct characteristics of the series,and geographicfactors. Very few casesof congenital salivary gland tumors have beenreported; most of them exhibited a uniform embryonic pattern.22Recently Lack and Upton23described a case with histologic characteristics similar to thoseobservedin case21 of this series.Both tumors were biphasic neoplasmsand had a multinodular arrangement formed by solid nests of clear cells sometimes with groups of smaller dark cells in the center. A dual differentiation pattern was demonstrated in our caseby immunocytochemistry,with expressionof both epithelial and myoepithelial phenotypes.Parotid congenital neoplasmswith apparently similar structure were reported by Vawter and Tefft24 and Taylor25and receivedthe designationof “sialoblastoma.” As in our case,thesetumors showedductal structures immunoreactivefor cytokeratins in the center of nodules formed by clear cells exhibiting antiactin immunoreactivity. In contrast to the congenital caseof our series,their patients followed a favorable course. If one ascribesto the statement of Batsakis et al.** that the perinatal neoplasmsshould be classified as their adult counterpart wheneverpossible,it is tempting to classify the tumor we report as an instance of epithelial-myoepithelialcarcinomaof high-grademalignancy. The youngest patient bearing a tumor of such type describedin the literature was a woman in the third decadeof life.26Furthermore, in adults, epithelial-myoepithelial carcinomas usually do not follow such an aggressivebehavior as our case did. In conclusion,our seriesconfirms the rarity of salivary gland neoplasmsamong children and adolescents. The seriescoversa 30-year period and includes most casesoccurring in southern Portugal so that it can be representativeof these tumors in that part of Europe. The epidemiologicprofile of the tumors follows that of adults. They mostly affect females, have a prevalent location in the major glands, and are predominantly benign. The clinical behaviorof pediatric mucoepidermoidcarcinoma, however,is more favorable than in adults. REFERENCES 1. Spiro RH. Salivary neoplasms: overview of 35year experience with 2807 patients. Head Neck Surg 1986;8:177-84. 2. Thackray AC, Sobin LH. Histological typing of salivary gland
Salivary gland tumors in children
Volume 72 Number 6 tumors. Geneva: World Health Organization, 1972. 3. Seifert G, Brocheriou C, CardesaA, EvesonJW. W H O international histological classification of tumors. Path01Res Pratt 1990;186:555-81. 4. Krolls SO, Trodahl JN, Boyers RC. Salivary gland lesions in children: a survey of 430 cases.Cancer 1972;30:459-69. 5. Nagao K, Matsuzaki 0, Saiga H, et al. Histopathologic studies on parotid gland tumors in Japanesechildren. Virchows Arch [A] 1980;388:263-72. 6. Healey WV, Perzin KH, Smith L. Mucoepidermoid carcinoma of salivary gland origin: classification, clinico-pathologic correlation and results of treatment. Cancer 1970;26:368-88. 7. Szanto PA, Luna MA, Tortoledo E, White RA. Histological grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984;54:1062-9. 8. Seifert G, Okabe H, Caselitz J. Epithelial salivary gland tumors in children and adolescents:analysis of 80 cases J Otorhinolaryngol Relat Spec 1986;3:137. 9. Baker SR, Malone B. Salivary gland malignanciesin children. Cancer 1985;55:1730-6. 10. Myer C, Cotton RT. Salivary gland diseasein children: a review. Part 2. Congenital and neoplastic disease.Clin Pediatr 1986;7:353-7. 11. Shikhani AH, Johns ME. Tumors of the major salivary glands in children. Head Neck Surg 1988;10:257-63. 12. Conley J, Tinsley PP. Treatment and prognosis of mucoepidermoid carcinoma in the pediatric age group. Arch Otolaryngo1 1985;111:322-4. 13. Jaques DA, Krolls SO, Chambers RG. Parotid gland tumors in children. Am J Surg 1976;132:469-7. 14. Castro EB, Huvos AG, Strong EW, Foote FW. Tumors of the maior salivarv alands in children. Cancer 1972:29:312-7. 15. FonsecaI, Soares J. Tumores des gllndulas sahvares:estudo clinicopatologico de 213 cases.J Sot Cien Med 1987;151:31626.
16. Byars LT, Ackerman LV, PeacockE. Tumors of salivary gland origin in children: a clinicopathologic appraisal of 24 cases. Ann Surg 1957;146:40-51.
701
17. Bakshar SN, Lilly GE. Salivary gland tumors of infancy: report of twenty cases.J Oral Surg 1963;21:306-13. 18. Sharkey FE. Systematic evaluation of the World Health Organization classification of salivary gland tumors: a clinicopathologic study of 366 cases.Am J Clin Path011977;67:27280.
19. Malone B, Baker SR. Benign pleomorphic adenomasin children. Ann Otol Rhino1 Laryngol 1984;93:210-4. 20. Clode AL, FonsecaI, Santos JR, Soares J. Mucoepidermoid carcinoma of the salivary glands: a reappraisalof the influence of the grade of differentiation on prognosis. J Surg Oncol 1991;46:100-6. 21. Nascimento AG, Amaral ALP, Prado LAF, Kligerman J, Silveira TRP. Mucoepidermoid carcinoma of salivary glands: a clinicopathologic study of 46 cases.Head Neck Surg 1986; 8:409-17. 22. Batsakis JG, Mackay B, Ryka F, Seifert RW. Perinatal salivary gland tumors (embryomas). J Laryngol Otol 1988; 102:1007-11. 23. Lack EE, Upton MP. Histopathologic review of salivary gland tumors in childhood. Arch Otolaryngol Head Neck Surg 1988;114:898-906. 24. Vawter GF, Tefft M. Congenital tumors of the parotid gland. Arch Path01 1966;82:242-5. 25. Taylor GP. Congenital epithelial tumor of the parotid-sialoblastoma. Pediatr Path01 1988;8:447-52. 26. Hamper K, Brugman M, Koppermann R, et al. Epithelialmyoepithelial duct carcinoma of salivary glands: a follow-up and cytophotometric study of 21 cases. J Oral Path01 Med 1989;18:299-9. Reprint requests:
Isabel Fonseca,MD Servipo de Patologia Morfolbgica Instituto Portugub de Oncologia Rua Prof. Lima Basto 1093 Lisbon, Portugal
DDS, MSD, MA
Oral Diagnosis, Medicine & Pathology School of Dentistry 53-058 UCLA Health Sciences Center Los Angeles, California 90024
Epithelial salivary gland tumors of children and adolescents in southern Portugal A clinicopathologic
study of twenty-four
cases
Isabel Fonseca, MD,a A. Gentil Martins, MD,b and Jorge Soares, MD, PhD,a Lisbon, Portugal INSTITUTO
PORTUGU&
DE ONCOLOGIA
DE FRANCISCO
GENTIL
During a 30-year period 24 epithelial salivary gland tumors were diagnosed in children and adolescents less than 18 years of age. The cases were retrieved from a series of 759 consecutive cases of salivary gland tumors (3.2%) from the area corresponding to southern Portugal during the same period of time. The mean age of the patients was 13.4 years, and one case was congenital. There was a slight female predominance (male/female ratio 1: 1.7). The parotid gland was affected in most cases (70.8%). Seventeen neoplasms were benign, and the remaining seven were malignant. As in the adult group, pleomorphic adenoma was the most frequent benign tumor (68.8%), with similar histologic findings and clinical course. Mucoepidermoid carcinoma was the prevalent malignant tumor (20.8%), had a high grade of differentiation, and had a favorable outcome. The histologic pattern of the congenital neoplasm was similar to that of adult epithelial-myoepithelial carcinoma. (ORAL SURC ORAL MED ORAL PATHOL 1991;72:696-701)
S
alivary gland tumors are infrequent neoplasmsof controversial histogenesis,accounting for 3% of all head and neck tumors.‘, 2 Clinicopathologic studiesof these tumors have been influenced not only by their rarity but also by diverseclinical behavior and a wide spectrum of morphologic presentations,making their histologic classification problematic.2y3 Particularly in children and adolescents,salivary gland tumors, especially those of epithelial origin, are exceedingly rare; most of the tumors occurring in this age group are benign nonepithelial neoplasms.4,5 This work was undertaken to study retrospectively the primary epiPresented in part at the Twelfth European Congress of Pathology. Supported by a grant from the Nticleo Regional do Sul da Liga Portuguesa contra 0 Cancro. “Morphologic Pathology Department. bOncology Clinic IV. 7/U/29127 696
thelial salivary gland tumors in children and adolescents with a consecutive series of 24 casesrepresentative of the prevalenceof these tumors in southern Portugal. It covers a 30-year period and attempts to contribute to establish their clinicoepidemiologic profile. MATERIAL
AND METHODS
Between 1959and 1989,759 casesof salivary gland tumors were diagnosedat the Pathology Department of Instituto Portugub de Oncologia de Francisco Gentil (Lisbon Center). From this series24 epithelial neoplasms (3.2%) occurred in children and adolescents less than 18 years of age. Hematoxylin-eosinstained sections from each case were reviewed, and new sectionswere obtained when necessary.All cases were reclassified according to the modified World Health Organization histologic classification of salivary gland tumors3 We excluded from the study
Salivary gland tumors in children 697
Volume 72 Number 6
Table I. Clinical, morphologic, and follow-up data of whole series Case No.
Sex/age (Yd
Benign tumors 1 M/14 2 F/17 3 F/15 4 F/18 5 F/l2 6 F/l8 7 F/15 8 M/14 9 M/16 10 F/15 11 M/17 12 M/14 13 F/IO 14 F/16 15 F/14 F/8 16 17 F/9 Malignant tumors 18 M/14 19 M/14 20 M/13 21 F/14 22 F/7 23 F/18 24 M/3 mo
Major or minor
Histology
Location
Follow-up (mo)foutcome
24/NED -
Major Major Major Major Major Major Major Major Major Major Major Major Major Minor Major Minor Major
Left parotid Right parotid Left parotid Right parotid Right parotid Left parotid Right submandibular Right parotid Right parotid Right parotid Left submandibular Left parotid Right parotid Soft palate Left submandibular Soft palate Right parotid
Pleomorphic adenoma Pleomorphic adenoma Pleomorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Pleomorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Plwmorphic adenoma Pleomorphic adenoma Pleomorphic adenoma Pleomorphic adenoma Papillary cystadenoma
12/NED 156/NED 72/NED 24/NED 84/NED 1Z/NED 12/NED 1Z/NED 144/NED
Minor Major Major Minor Major Major
Soft palate Left parotid Left parotid Soft palate Right parotid Left parotid Left parotid
Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma
60/REC 120/REC Z/NED 6/NED 36/NED 72/NED 2/DOD
-
DOD, Deadof disease;NED, no evidenceof disease;REC. recurrence.
mesenchymaland metastatic tumors and lymphoproliferative lesions. The clinical charts of all patients were reviewedfor age, sex, location of the tumor, and clinical status. Follow-up information was obtained in 16 casesand ranged from 2 to 156 months. The adult seriesof tumors (n = 735) was used for comparison of the sex distribution and the relative frequency of the benign and the malignant tumors. RESULTS
Table I summarizes the clinical, histologic, and follow-up data of the whole series. The ages of the patientsrangedbetween3 monthsand 18 years(mean age 13.4 years). Four patients were lessthan 10 years of age, and in one instancethe tumor was congenital. Fifteen patients were female; nine were male. The female/male ratio was 1.7:1 in the pediatric group and 2.5: 1 in the adult group. Twenty tumors were located within major salivary glands (eight in the left parotid gland, nine in the right parotid gland, and three in the submandibular gland). The remaining four cases originated in the m inor glands of the oral cavity. Of the 24 neoplasms,17 (70.8%) were benign and seven (29.2%) malignant.
Benign tumors
Pleomorphicadenomawas diagnosedin all but one of the benign neoplasms.It correspondedto the most frequent tumor type, with a total number of 16 cases (66.6%). Eleven patients were female and five were male. The mean age of the patients was 14.5 years; only one tumor occurredin the first decadeof life. The tumors were located in the parotid gland (11 cases), the submandibular gland (three cases),and the soft palate (two cases).All but one pleomorphicadenoma presentedas a well-circumscribed and encapsulated single nodule,varying between2 and 8 cm. One case (No. 13) displayeda multinodular “recurrence type” presentationbut was acceptedas primary becausethe patient gave no history of previous surgery. M icroscopically the pleomorphic adenomaswere representedby a biphasic cellular proliferation with variable proportions of epithelial and mesenchymal elements (chondroid, collagenous, and mucoid stroma) (Fig. 1). Focal squamousdifferentiation was encounteredin two cases. M itoses were extremely rare, and necrotic foci were not detected. Follow-up information was obtained in nine cases and ranged from 12 to 156 months (mean 45.3 months) without tumor recurrence.
696
Fonseca, Martins, and Soares
Fig. 1. Pleomorphic adenoma of parotid gland. Tumor is circumscribed by thin fibrous capsule andcomposed of myoepithelial cells with moderately dense stroma. (Hematoxylin-eosin stain; original magnification, X 160.)
of parotidgland.TuFig. 2. Case7. Papillaryadenoma mor is capsulated and composed of well-formed papillae lined by cuboidal cells. (Hematoxylin-eosin stain; original magnification, X 160.)
The other benign tumor found in this serieswas a papillary cystadenoma(Table I). It occurred in the right parotid gland of a 9-year-old girl, was encapsulated, and measured 5 cm. Microscopically it was formed by fibrovascular cores lined by cuboidal and cylindric cells, with areasof pseudostratification(Fig. 2). Few ductlike structureswere in continuity with the papillary surface fronds. The cells had oval nuclei, and the cytoplasm was eosinophilic. There was no atypicality, mitoses, or necrosis, and a lymphoid stroma componentwas absent.No recurrenceof the tumor was observedafter 144 months of follow-up. Malignant
tumors
Mucoepidermoidcarcinoma was the most frequent malignant histologic type, corresponding to five of
ORAL SURGORAL MED ORAL PAI’HOI December 199I
Fig. 3. Case 18. Mucoepidermoid carcinoma of soft palate. Cystic spaces lined by mucus cells and small solid nests of intermediate-typecells (arrow). (Hematoxylin-eosin stain; original magnification, X 160.)
sevencases.One tumor occurredin a patient lessthan 10 years of age, and the remaining four tumors affected patients aged 13 and 14 years (Table I). The tumors were located in the parotid gland (four cases) and the soft palate (one case). They presentedas a nonencapsulatedmass measuring between 1.5 and 5 cm. All tumors showedan expansivegrowth pattern and were classified as low-grade, well-differentiated neoplasmsaccording to the criteria of Healey et a1.6 (Fig. 3). Vascular invasion, low-regional lymph node metastases,and distant metastaseswere not encountered. Mitoses were less than 1 per 10 high-power fields, and necrosiswas either absent or occurred as minute foci. All five patients were alive and free of diseaseat the end of the follow-up study. However, two casesrecurred locally, one of them twice (case9), 4 and 24 months after the first surgery. Both patients underwenta secondsurgery and now haveno evidence of local or distant tumor. Two other malignant neoplasmsin the present series consistedof a case of adenoid cystic carcinoma and a congenitaltumor. The adenoidcystic carcinoma (case23) occurred in the left parotid gland of an 18year-old adolescent. It measured 5 cm and microscopically had tubular pattern, compatible with a grade I carcinoma.7There was perineural infiltration, but vascular invasion was not documented. The patient is now well and free of recurrence72 months after parotidectomy. In this seriesthere was a congenital tumor resected at the ageof 3 months. The tumor was presentat birth and was the causeof a dystocia. It was located within the left parotid gland, measured9 cm, and had an expansive pattern of growth with a nodular arrangement. The noduleswere separatedby very thin fibrous
Volume72 Number 6
Salivary gland tumors in children
699
septa,were formed by large cells of clear cytoplasm, with well-defined limits. In the center of some of the solid nestsill-defined ductlike arrangementswere apparent (Fig. 4, A). The cells lining the ductal spaces were cuboidal, had slightly densecytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli. The mitotic index was 4 mitosesper 10 high-power fields. The ductlike cells that formed the central areasof the tumor noduleswere positive for low-molecular-weight keratin antibody (AEl) (Fig. 4, B), whereasthe peripheral cells were either faintly positive or negative. The clear cell population was immunoreactive for S-100 protein, with both cytoplasmic and nuclear staining, supporting a myoepithelial cell differentiation. The lesionrecurred 4 months after surgery and was histologically identical to that of the primary lesion. The child died 2 months later as a result of local regional spread of the disease. DISCUSSION
The relative frequency of the epithelial salivary gland tumors occurring in children and adolescents rangesfrom 3.7% to 5.5%.4,5,&‘I However, the comparison between series is made difficult by the fact that different authors consider diverse age limits for the adolescent group. For instance, in their series, Krolls et a1.4included patients under the age of 15, Nagao et a1.5patients under 16 years, and Seifert et a1.8patients under 20 years. In other series the age limits are not even mentioned.12y l3 In the present study we adopted 18 years as the upper limit because it is the age limit criterion for a patient being admitted to the pediatric ward of our hospital. The total number of cases(24) represented3.2% of all the salivary gland tumors treated in the hospital during the sameperiod. Our finding of four cases(16.7%) in patients lessthan 10 yearsof age stressesthat tumors of salivary gland origin are extremely rare in the first decadeof 1ife.s I4 In the present series the female/male ratio was 1.7:1, similar to previousdata from Seifert et al.* and Castro et a1.14and confirms in the pediatric group the well-known predominanceof the salivary gland tumors for the female sex. In the group of benign tumors, only 5 of the 17 cases (29.4%) occurred in male patients,analogousto that observedin adu1ts.sI5 Most tumors (70.8%) were located in the parotid gland; five of them (41.6%) were malignant. This percentageis similar to that obtainedby Byars et a1.16 The majority of the tumors included in the studiesof Seifert et al.* and of Bakshar and Lilly17 was also located in the major salivary glands. The relative distribution of benign and malignant epithelial tu-
Fig. 4. A, Case21. Clear cell carcinoma of parotid gland. Tumor is multilobular and predominantly formed by clear cells. Ductal structures are apparent (arrow) (Hematoxylin-eosin stain; original magnification, X270.) B, Strong immunoreactivity of ductal component with anti-AEl antiserum. (Avidin-biotin complex method original magnification, X70.)
mors according to their origin from the major and minor salivary glands is similar to that generally described in adults.i5>‘* Malignancy in the pediatric group is also more commonly associatedwith tumors arising within the minor salivary glands.In our series half the tumors occurring in the minor salivary gland were malignant as comparedwith 5 of the 13 primary tumors of the major glands (38.4%). The most frequent histologic type in the presentseries was pleomorphic adenoma. This observation agreeswith the conclusionsof Byars et a1.16(17/23 cases),Seifert et a1.8(65% of their series),and Malone and Baker.19Alternatively, Jaques et a1.i3 and Nagao et a1.5found a lower frequency for this tumor type in the pediatric age group, of 36.3% and 28.1%, respectively.These discrepanciesmay representgeographic differencesin the incidence of this tumor or may reflect either diversecriteria for the age limit of the pediatric group or institutional characteristics, becausegeneral hospitals usually have a higher per-
700
Fonseca, Martins, and Soares
centage of benign casesin comparison with cancer hospitals. All these reasonstaken together may also eventually explain the unusual high incidence of mixed tumors in the pediatric age group reported by Krolls et al.4 (91.6%). No recurrenceswere observedin any of our cases; this probably relates to the type of surgery used:total excision of the involved gland. Even the patient who had a multinodular recurrent pattern of mixed tumor is well and free of disease7 years after the surgical resectionof the parotid gland, the surrounding periglandular soft tissues,and the overlying skin. The nonpleomorphicadenomawith a papillary organization included in the present seriesoccurred in the right parotid gland of a 9-year-oldgirl. The tumor was composedof true papillae lined by cuboidal and columnar cells without associatedlymphoid elements. Krolls et al.4 and Jaqueset al.r3 describedin children an identical type of neoplasm“morphologically similar to Warthin’s tumor but lacking lymphoid stroma.” However, the cytologic features of the neoplastic cells of the casewe report are clearly distinct from the classic oncocytic cells of Warthin’s tumor. Similarly, the same seems to be found in the cases described by Krolls et al.4 and Jaqueset a1.13when referenceis made to the illustrations in their publications. If one considersthe new proposal of Seifert et al.3 for the World Health Organization histologic typing of salivary gland tumors, we should probably categorizethis caseamong the very rare examplesof papillary cystadenomas.Nevertheless,not all characteristics ascribedto that tumor variant are present in our case. Mucoepidermoid carcinoma is the prevalent malignant neoplasmof the salivary glands among children and adolescents. Its frequency in our series (20.8%) is similar to that reportedby Krolls et al.4and Seifert et al.8 The relative frequency of mucoepidermoid carcinoma is higher in the children and adolescents than in adults (5.7%), a finding similar to that found by Seifert et al.8 It is generally observedthat most if not all mucoepidermoidcarcinomasoccurring in the childhood and adolescent group are well differentiated (grade I, low grade) and moderately differentiated (grade II, intermediate grade) tumors.9,i4, 20,21Concerning the influence of the grade of differentiation on the prognosisof the mucoepidermoid carcinomas,our resultsconfirm the usefulnessof the classification of Healey et a1.6becauseall neoplasmswere classifiedas grade I tumors and followed a relative benign course,in agreementwith the observations of Castro et ali4 and Nascimento et a1.21The favorable prognosisof mucoepidermoidcarcinoma as verified in the younger patients seemsto be related
ORAL SURG ORAL MEU ORAL PATHOI. December 1991
with a higher incidenceof well-differentiated grade I tumors in this age group.*OHowever, different results were given by Seifert et al.,8who reported a relatively high frequency of poorly differentiated, grade III mucoepidermoidcarcinomasamong children and adolescents(15% of their series).Thesevariations stress the difficulties for comparing data biasedby different classification criteria, distinct characteristics of the series,and geographicfactors. Very few casesof congenital salivary gland tumors have beenreported; most of them exhibited a uniform embryonic pattern.22Recently Lack and Upton23described a case with histologic characteristics similar to thoseobservedin case21 of this series.Both tumors were biphasic neoplasmsand had a multinodular arrangement formed by solid nests of clear cells sometimes with groups of smaller dark cells in the center. A dual differentiation pattern was demonstrated in our caseby immunocytochemistry,with expressionof both epithelial and myoepithelial phenotypes.Parotid congenital neoplasmswith apparently similar structure were reported by Vawter and Tefft24 and Taylor25and receivedthe designationof “sialoblastoma.” As in our case,thesetumors showedductal structures immunoreactivefor cytokeratins in the center of nodules formed by clear cells exhibiting antiactin immunoreactivity. In contrast to the congenital caseof our series,their patients followed a favorable course. If one ascribesto the statement of Batsakis et al.** that the perinatal neoplasmsshould be classified as their adult counterpart wheneverpossible,it is tempting to classify the tumor we report as an instance of epithelial-myoepithelialcarcinomaof high-grademalignancy. The youngest patient bearing a tumor of such type describedin the literature was a woman in the third decadeof life.26Furthermore, in adults, epithelial-myoepithelial carcinomas usually do not follow such an aggressivebehavior as our case did. In conclusion,our seriesconfirms the rarity of salivary gland neoplasmsamong children and adolescents. The seriescoversa 30-year period and includes most casesoccurring in southern Portugal so that it can be representativeof these tumors in that part of Europe. The epidemiologicprofile of the tumors follows that of adults. They mostly affect females, have a prevalent location in the major glands, and are predominantly benign. The clinical behaviorof pediatric mucoepidermoidcarcinoma, however,is more favorable than in adults. REFERENCES 1. Spiro RH. Salivary neoplasms: overview of 35year experience with 2807 patients. Head Neck Surg 1986;8:177-84. 2. Thackray AC, Sobin LH. Histological typing of salivary gland
Salivary gland tumors in children
Volume 72 Number 6 tumors. Geneva: World Health Organization, 1972. 3. Seifert G, Brocheriou C, CardesaA, EvesonJW. W H O international histological classification of tumors. Path01Res Pratt 1990;186:555-81. 4. Krolls SO, Trodahl JN, Boyers RC. Salivary gland lesions in children: a survey of 430 cases.Cancer 1972;30:459-69. 5. Nagao K, Matsuzaki 0, Saiga H, et al. Histopathologic studies on parotid gland tumors in Japanesechildren. Virchows Arch [A] 1980;388:263-72. 6. Healey WV, Perzin KH, Smith L. Mucoepidermoid carcinoma of salivary gland origin: classification, clinico-pathologic correlation and results of treatment. Cancer 1970;26:368-88. 7. Szanto PA, Luna MA, Tortoledo E, White RA. Histological grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984;54:1062-9. 8. Seifert G, Okabe H, Caselitz J. Epithelial salivary gland tumors in children and adolescents:analysis of 80 cases J Otorhinolaryngol Relat Spec 1986;3:137. 9. Baker SR, Malone B. Salivary gland malignanciesin children. Cancer 1985;55:1730-6. 10. Myer C, Cotton RT. Salivary gland diseasein children: a review. Part 2. Congenital and neoplastic disease.Clin Pediatr 1986;7:353-7. 11. Shikhani AH, Johns ME. Tumors of the major salivary glands in children. Head Neck Surg 1988;10:257-63. 12. Conley J, Tinsley PP. Treatment and prognosis of mucoepidermoid carcinoma in the pediatric age group. Arch Otolaryngo1 1985;111:322-4. 13. Jaques DA, Krolls SO, Chambers RG. Parotid gland tumors in children. Am J Surg 1976;132:469-7. 14. Castro EB, Huvos AG, Strong EW, Foote FW. Tumors of the maior salivarv alands in children. Cancer 1972:29:312-7. 15. FonsecaI, Soares J. Tumores des gllndulas sahvares:estudo clinicopatologico de 213 cases.J Sot Cien Med 1987;151:31626.
16. Byars LT, Ackerman LV, PeacockE. Tumors of salivary gland origin in children: a clinicopathologic appraisal of 24 cases. Ann Surg 1957;146:40-51.
701
17. Bakshar SN, Lilly GE. Salivary gland tumors of infancy: report of twenty cases.J Oral Surg 1963;21:306-13. 18. Sharkey FE. Systematic evaluation of the World Health Organization classification of salivary gland tumors: a clinicopathologic study of 366 cases.Am J Clin Path011977;67:27280.
19. Malone B, Baker SR. Benign pleomorphic adenomasin children. Ann Otol Rhino1 Laryngol 1984;93:210-4. 20. Clode AL, FonsecaI, Santos JR, Soares J. Mucoepidermoid carcinoma of the salivary glands: a reappraisalof the influence of the grade of differentiation on prognosis. J Surg Oncol 1991;46:100-6. 21. Nascimento AG, Amaral ALP, Prado LAF, Kligerman J, Silveira TRP. Mucoepidermoid carcinoma of salivary glands: a clinicopathologic study of 46 cases.Head Neck Surg 1986; 8:409-17. 22. Batsakis JG, Mackay B, Ryka F, Seifert RW. Perinatal salivary gland tumors (embryomas). J Laryngol Otol 1988; 102:1007-11. 23. Lack EE, Upton MP. Histopathologic review of salivary gland tumors in childhood. Arch Otolaryngol Head Neck Surg 1988;114:898-906. 24. Vawter GF, Tefft M. Congenital tumors of the parotid gland. Arch Path01 1966;82:242-5. 25. Taylor GP. Congenital epithelial tumor of the parotid-sialoblastoma. Pediatr Path01 1988;8:447-52. 26. Hamper K, Brugman M, Koppermann R, et al. Epithelialmyoepithelial duct carcinoma of salivary glands: a follow-up and cytophotometric study of 21 cases. J Oral Path01 Med 1989;18:299-9. Reprint requests:
Isabel Fonseca,MD Servipo de Patologia Morfolbgica Instituto Portugub de Oncologia Rua Prof. Lima Basto 1093 Lisbon, Portugal
