oral pathology 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 neoplasms of controversial histogenesis, accounting for 3% of all head and neck tumors.‘, 2 Clinicopathologic studies of these tumors have been influenced not only by their rarity but also by diverse clinical behavior and a wide spectrum of morphologic presentations, making their histologic classification problematic.2y 3 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 epi-

Presented 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 adoles- cents with a consecutive series of 24 cases represen- tative of the prevalence of these tumors in southern Portugal. It covers a 30-year period and attempts to contribute to establish their clinicoepidemiologic pro- file.

MATERIAL AND METHODS

Between 1959 and 1989,759 cases of salivary gland tumors were diagnosed at the Pathology Department of Instituto Portugub de Oncologia de Francisco Gentil (Lisbon Center). From this series 24 epithelial neoplasms (3.2%) occurred in children and adoles- cents less than 18 years of age. Hematoxylin-eosin- stained sections from each case were reviewed, and new sections were obtained when necessary. All cases were reclassified according to the modified World Health Organization histologic classification of sali- vary gland tumors3 We excluded from the study

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Salivary gland tumors in children 697

Table I. Clinical, morphologic, and follow-up data of whole series

Sex/age Major or Case No. (Yd minor Location Histology

Follow-up (mo)foutcome

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 16 F/8 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 Left parotid Major Right parotid Major Left parotid Major Right parotid Major Right parotid Major Left parotid Major Right submandibular Major Right parotid Major Right parotid Major Right parotid Major Left submandibular Major Left parotid Major Right parotid Minor Soft palate Major Left submandibular Minor Soft palate Major Right parotid

Minor Major Major Minor Major Major

Soft palate Left parotid Left parotid Soft palate Right parotid Left parotid Left 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

Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma

24/NED - - - -

12/NED 156/NED

- 72/NED 24/NED

- 84/NED 1 Z/NED 12/NED 1 Z/NED

- 144/NED

60/REC 120/REC

Z/NED 6/NED

36/NED 72/NED

2/DOD

DOD, Dead of disease; NED, no evidence of disease; REC. recurrence.

mesenchymal and metastatic tumors and lymphopro- liferative lesions.

The clinical charts of all patients were reviewed for age, sex, location of the tumor, and clinical status. Follow-up information was obtained in 16 cases and ranged from 2 to 156 months. The adult series of tu- mors (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 patients ranged between 3 months and 18 years (mean age 13.4 years). Four patients were less than 10 years of age, and in one instance the tumor was congenital. Fifteen patients were female; nine were male. The fe- male/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

Pleomorphic adenoma was diagnosed in all but one of the benign neoplasms. It corresponded to 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 occurred in the first decade of 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 pleomorphic adenoma presented as a well-circumscribed and encapsulated single nodule, varying between 2 and 8 cm. One case (No. 13) displayed a multinodular “recurrence type” presentation but was accepted as primary because the patient gave no history of previous surgery.

M icroscopically the pleomorphic adenomas were represented by a biphasic cellular proliferation with variable proportions of epithelial and mesenchymal elements (chondroid, collagenous, and mucoid stroma) (Fig. 1). Focal squamous differentiation was encountered in 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 ORAL SURG ORAL MED ORAL PAI’HOI December 199 I

Fig. 1. Pleomorphic adenoma of parotid gland. Tumor is circumscribed by thin fibrous capsule and composed of my- oepithelial cells with moderately dense stroma. (Hematox- ylin-eosin stain; original magnification, X 160.)

Fig. 3. Case 18. Mucoepidermoid carcinoma of soft pal- ate. Cystic spaces lined by mucus cells and small solid nests of intermediate-type cells (arrow). (Hematoxylin-eosin stain; original magnification, X 160.)

Fig. 2. Case 7. Papillary adenoma of parotid gland. Tu- 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 series was a papillary cystadenoma (Table I). It occurred in the right parotid gland of a 9-year-old girl, was encapsu- lated, and measured 5 cm. Microscopically it was formed by fibrovascular cores lined by cuboidal and cylindric cells, with areas of pseudostratification (Fig. 2). Few ductlike structures were 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 component was absent. No recurrence of the tumor was observed after 144 months of follow-up.

Malignant tumors

Mucoepidermoid carcinoma was the most frequent malignant histologic type, corresponding to five of

seven cases. One tumor occurred in a patient less than 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 presented as a nonencapsulated mass measuring between 1.5 and 5 cm. All tumors showed an expansive growth pattern and were classified as low-grade, well-differentiated neoplasms according to the criteria of Healey et a1.6 (Fig. 3). Vascular invasion, low-regional lymph node metastases, and distant metastases were not encoun- tered. Mitoses were less than 1 per 10 high-power fields, and necrosis was either absent or occurred as minute foci. All five patients were alive and free of disease at the end of the follow-up study. However, two cases recurred locally, one of them twice (case 9), 4 and 24 months after the first surgery. Both patients underwent a second surgery and now have no evidence of local or distant tumor.

Two other malignant neoplasms in the present se- ries consisted of a case of adenoid cystic carcinoma and a congenital tumor. The adenoid cystic carcinoma (case 23) occurred in the left parotid gland of an 18- year-old adolescent. It measured 5 cm and micro- scopically had tubular pattern, compatible with a grade I carcinoma.7 There was perineural infiltration, but vascular invasion was not documented. The patient is now well and free of recurrence 72 months after parotidectomy.

In this series there was a congenital tumor resected at the age of 3 months. The tumor was present at birth and was the cause of a dystocia. It was located within the left parotid gland, measured 9 cm, and had an ex- pansive pattern of growth with a nodular arrange- ment. The nodules were separated by very thin fibrous

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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 nests ill-defined ductlike arrangements were ap- parent (Fig. 4, A). The cells lining the ductal spaces were cuboidal, had slightly dense cytoplasm, hyper- chromatic nuclei, and inconspicuous nucleoli. The mitotic index was 4 mitoses per 10 high-power fields. The ductlike cells that formed the central areas of the tumor nodules were positive for low-molecular-weight keratin antibody (AEl) (Fig. 4, B), whereas the pe- ripheral 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 differentia- tion.

The lesion recurred 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 re- gional spread of the disease.

DISCUSSION

The relative frequency of the epithelial salivary gland tumors occurring in children and adolescents ranges from 3.7% to 5.5%. 4, 5, &‘I However, the com- parison 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 a1.4 included patients under the age of 15, Nagao et a1.5 patients under 16 years, and Seifert et a1.8 patients 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 admit- ted to the pediatric ward of our hospital. The total number of cases (24) represented 3.2% of all the sal- ivary gland tumors treated in the hospital during the same period. Our finding of four cases (16.7%) in pa- tients less than 10 years of age stresses that tumors of salivary gland origin are extremely rare in the first decade of 1ife.s I4

In the present series the female/male ratio was 1.7: 1, similar to previous data from Seifert et al.* and Castro et a1.14 and confirms in the pediatric group the well-known predominance of the salivary gland tu- mors for the female sex. In the group of benign tumors, only 5 of the 17 cases (29.4%) occurred in male patients, analogous to that observed in adu1ts.s I5

Most tumors (70.8%) were located in the parotid gland; five of them (41.6%) were malignant. This percentage is similar to that obtained by Byars et a1.16 The majority of the tumors included in the studies of Seifert et al.* and of Bakshar and Lilly17 was also lo- cated in the major salivary glands. The relative distribution of benign and malignant epithelial tu-

Fig. 4. A, Case 21. Clear cell carcinoma of parotid gland. Tumor is multilobular and predominantly formed by clear cells. Ductal structures are apparent (arrow) (Hematoxy- lin-eosin stain; original magnification, X270.) B, Strong immunoreactivity of ductal component with anti-AEl an- tiserum. (Avidin-biotin complex method original magnifi- cation, X70.)

mors according to their origin from the major and minor salivary glands is similar to that generally de- scribed in adults.i5> ‘* Malignancy in the pediatric group is also more commonly associated with tumors arising within the minor salivary glands. In our series half the tumors occurring in the minor salivary gland were malignant as compared with 5 of the 13 primary tumors of the major glands (38.4%).

The most frequent histologic type in the present se- ries was pleomorphic adenoma. This observation agrees with the conclusions of Byars et a1.16 (17/23 cases), Seifert et a1.8 (65% of their series), and Mal- one and Baker.19 Alternatively, Jaques et a1.i3 and Nagao et a1.5 found a lower frequency for this tumor type in the pediatric age group, of 36.3% and 28.1%, respectively. These discrepancies may represent geo- graphic differences in the incidence of this tumor or may reflect either diverse criteria for the age limit of the pediatric group or institutional characteristics, because general hospitals usually have a higher per-

700 Fonseca, Martins, and Soares ORAL SURG ORAL MEU ORAL PATHOI. December 1991

centage of benign cases in comparison with cancer hospitals. All these reasons taken 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 recurrences were observed in 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 disease 7 years after the surgical resection of the parotid gland, the surrounding peri- glandular soft tissues, and the overlying skin.

The nonpleomorphic adenoma with a papillary or- ganization included in the present series occurred in the right parotid gland of a 9-year-old girl. The tumor was composed of true papillae lined by cuboidal and columnar cells without associated lymphoid elements. Krolls et al.4 and Jaques et al.r3 described in children an identical type of neoplasm “morphologically sim- ilar to Warthin’s tumor but lacking lymphoid stro- ma.” However, the cytologic features of the neoplas- tic cells of the case we report are clearly distinct from the classic oncocytic cells of Warthin’s tumor. Simi- larly, the same seems to be found in the cases described by Krolls et al.4 and Jaques et a1.13 when reference is made to the illustrations in their publica- tions. If one considers the new proposal of Seifert et al.3 for the World Health Organization histologic typing of salivary gland tumors, we should probably categorize this case among the very rare examples of papillary cystadenomas. Nevertheless, not all char- acteristics ascribed to that tumor variant are present in our case.

Mucoepidermoid carcinoma is the prevalent ma- lignant neoplasm of the salivary glands among chil- dren and adolescents. Its frequency in our series (20.8%) is similar to that reported by Krolls et al.4 and Seifert et al.8 The relative frequency of mucoepider- moid carcinoma is higher in the children and adoles- cents than in adults (5.7%), a finding similar to that found by Seifert et al.8 It is generally observed that most if not all mucoepidermoid carcinomas occurring in the childhood and adolescent group are well differentiated (grade I, low grade) and moderately differentiated (grade II, intermediate grade) tu- mors.9, i4, 20, 21 Concerning the influence of the grade of differentiation on the prognosis of the mucoepider- moid carcinomas, our results confirm the usefulness of the classification of Healey et a1.6 because all neo- plasms were classified as grade I tumors and followed a relative benign course, in agreement with the obser- vations of Castro et ali4 and Nascimento et a1.21 The favorable prognosis of mucoepidermoid carcinoma as verified in the younger patients seems to be related

with a higher incidence of well-differentiated grade I tumors in this age group. *O However, different results were given by Seifert et al.,8 who reported a relatively high frequency of poorly differentiated, grade III mucoepidermoid carcinomas among children and ad- olescents (15% of their series). These variations stress the difficulties for comparing data biased by different classification criteria, distinct characteristics of the series, and geographic factors.

Very few cases of congenital salivary gland tumors have been reported; most of them exhibited a uniform embryonic pattern. 22 Recently Lack and Upton23 de- scribed a case with histologic characteristics similar to those observed in case 21 of this series. Both tumors were biphasic neoplasms and had a multinodular ar- rangement formed by solid nests of clear cells some- times with groups of smaller dark cells in the center. A dual differentiation pattern was demonstrated in our case by immunocytochemistry, with expression of both epithelial and myoepithelial phenotypes. Parotid congenital neoplasms with apparently similar struc- ture were reported by Vawter and Tefft24 and Tay- lor25 and received the designation of “sialoblastoma.” As in our case, these tumors showed ductal structures immunoreactive for cytokeratins in the center of nod- ules formed by clear cells exhibiting antiactin immu- noreactivity. In contrast to the congenital case of our series, their patients followed a favorable course.

If one ascribes to the statement of Batsakis et al.** that the perinatal neoplasms should be classified as their adult counterpart whenever possible, it is tempt- ing to classify the tumor we report as an instance of epithelial-myoepithelial carcinoma of high-grade ma- lignancy. The youngest patient bearing a tumor of such type described in the literature was a woman in the third decade of life.26 Furthermore, in adults, epi- thelial-myoepithelial carcinomas usually do not fol- low such an aggressive behavior as our case did.

In conclusion, our series confirms the rarity of sal- ivary gland neoplasms among children and adoles- cents. The series covers a 30-year period and includes most cases occurring in southern Portugal so that it can be representative of these tumors in that part of Europe. The epidemiologic profile of the tumors fol- lows that of adults. They mostly affect females, have a prevalent location in the major glands, and are pre- dominantly benign. The clinical behavior of pediatric mucoepidermoid carcinoma, however, is more favor- able 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

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Salivary gland tumors in children 701

tumors. Geneva: World Health Organization, 1972. 3. Seifert G, Brocheriou C, Cardesa A, Eveson JW. WHO inter-

national histological classification of tumors. Path01 Res 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 Japanese children. Virchows Arch [A] 1980;388:263-72.

6. Healey WV, Perzin KH, Smith L. Mucoepidermoid carcinoma of salivary gland origin: classification, clinico-pathologic cor- relation 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 malignancies in children. Cancer 1985;55:1730-6.

10. Myer C, Cotton RT. Salivary gland disease in children: a re- view. 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 mucoepi- dermoid carcinoma in the pediatric age group. Arch Otolaryn- go1 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. Fonseca I, Soares J. Tumores des gllndulas sahvares: estudo clinicopatologico de 213 cases. J Sot Cien Med 1987;151:316- 26.

16. Byars LT, Ackerman LV, Peacock E. Tumors of salivary gland origin in children: a clinicopathologic appraisal of 24 cases. Ann Surg 1957;146:40-51.

17. Bakshar SN, Lilly GE. Salivary gland tumors of infancy: re- port of twenty cases. J Oral Surg 1963;21:306-13.

18. Sharkey FE. Systematic evaluation of the World Health Or- ganization classification of salivary gland tumors: a clinico- pathologic study of 366 cases. Am J Clin Path01 1977;67:272- 80.

19. Malone B, Baker SR. Benign pleomorphic adenomas in chil- dren. Ann Otol Rhino1 Laryngol 1984;93:210-4.

20. Clode AL, Fonseca I, Santos JR, Soares J. Mucoepidermoid carcinoma of the salivary glands: a reappraisal of 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, Sil- veira 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 sali- vary 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-sialo- blastoma. Pediatr Path01 1988;8:447-52.

26. Hamper K, Brugman M, Koppermann R, et al. Epithelial- myoepithelial 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