SIALOBLASTOMA: A Case Report and Review of the Literature on Congenital Epithelial Tumors of Salivary Gland Origin
Chuen Hsueh, MD, and F. Gonzalez-Crussi, MD
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Department of Pathology, Children’s Memorial Hospital of Chicago, and Northwestern University Medical School, Chicago, Illinois 60614
The histologic, immunohistochemical, and ultrastructural features of a congenital epithelial tumor o j the parotid were studied. The tumor was characterized by solid nests of epithelial cells intermingled with proliferating ductal structures lined by a double layer of cells. Immunoperoxidase staining for cytokeratin, vimentin, actin, and 9 1 0 0 protein showed the presence of cytokeratin in the ductal cells as well as the presence of vimentin, actin, and S-100 protein in the outermost layer of the ducts. The solid nests were focally reactive to S-100 and vimentin. Ultrastructural examination revealed myoepithelial cells with replication of basement membrane material. The tumor recurred 17 months after excision without b m p h node involvement or metastasis. The term “sialoblastoma’’ is favored. Review of the literature on congenital, epithelial salivary gland tumors showed that a f e w cases recurred locally and only one case had regional lymph node involvement. No distant metastasis has been reported. 0
KEY WORDS: basal cell adenoma, congenital tumor, parotid gland, salivary gland.
It is well known that tumors primary of salivary gland are very uncommon during childhood. In most large series of salivary gland tumors that include patients of all ages, children represent less than 5% of the affected population (1, 2). Still more uncommon is the occurrence of a tumor of salivary gland detected at birth or in the first few months of life. When present, such tumors are likely to be primary of vasoformative tissue, that is, lymphangiomas or hemangiomas that arise incidentally within a salivary gland, most often the parotid. Epithelial neoplasms in this anatomic location, although very infrequent, generally occur in older children and adolescents (3, 4); congenital examples are truly exceptional. Nevertheless, congenital or neonatal tumors of the parotid gland present interesting clinicopathologic aspects that Address reprint requests to: Dr. F. G . Crussi, Department of Pathology, Box 1 7 , 2300 Children’s Plaza, Chicago, Illinois 60614.
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pathologists must be aware of. It is the purpose of the present article to report the histologic, immunohistochemical, and ultrastructural features of one such case and to review the existing literature on these rare tumors.
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CLINICAL HISTORY A Caucasian girl, born at 38 weeks of gestation by cesarean section because of fetal distress, was noted to have a mass on the right cheek. This lesion was firm, movable, and measured 1 cm in diameter. The postnatal physical examination was otherwise unremarkable. The mass was unchanged 24 days after birth, and a surgical exploration was performed at Children’s Memorial Hospital of Chicago. At operation, a well-circumscribed mass 2.2 cm in diameter was found along Stensen’s duct, appearing to arise from the superficial lobe of the parotid gland. The mass was completely excised with sparing of the facial nerve. The patient did well postoperatively, until a recurrence developed 17 months later. A second operation revealed a firm mass measuring 1.5 X 1.5 cm that extended into both superficial and deep parotid lobes. A total parotidectomy and excision of the facial nerve with nerve grafting were done. The patient had an uneventful postoperative course. She has been tumor free for 3 l/2 years since the second surgical procedure.
MATERIALS AND METHODS The tissue for light microscopy was fixed in 10% buffered formalin or B5 fixative, routinely processed, and stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) reagent with and without diastase digestion. For immunohistochemical study, we used an avidin-biotin-peroxidase complex (ABC) system (Vector Lab) following the manufacturer’s instructions. Sections were cut from formalin-fixed, paraffin-embedded tissue. The antisera used included cytokeratin (Becton Dickinson; mouse; prediluted), vimentin (Dako; mouse; 1:25), muscle-specific actin (HHF3J (Enzo Biochem; mouse; prediluted), myosin (Miles; rabbit; 1:3000), S-100 protein (Biomedia; rabbit; 1:3), and glial fibrillary acidic protein of GFAP (Labsystems; mouse; 1: 1000). For electron microscopy, the material was fixed in 3 % phosphatebuffered glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated in graded alcohols and propylene oxide, and embedded in Spurr’s plastic. Onemicrometer-thick sections were stained with toluidine blue. Ultrathin sections were studied with a Zeiss 10-A electron microscope.
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RESULTS
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Histopathological Findings The specimen from the first operation was composed of solid nests of epithelial cells separated from each other by bands of fibrous tissue. In some areas, these cell nests were intermingled with proliferating ductal structures (Fig. 1). Ducts appeared to bud from or were contained within some solid cell nests; the latter were sharply delineated from the surrounding stroma by a distinct basement membrane. The tumor cells showed some pleomorphism. The nuclei were round to oval, with dispersed chromatin and one or two moderately prominent nucleoli. The cytoplasm was clear to pale amphophilic with distinct cell borders. No obvious nuclear palisading was noted at the periphery of the cell nests, nor was there evidence of cystic formation or cribriform pattern. Coarse foci of calcification were present within the capsule and fibrous septa. Some PAS-positive and diastase-resistant secretory material was enclosed in the ductal lumens. The specimen from the second operation had histologic features identical to those of the first.
FIGURE 1. Histologic appearance of the tumor, characterized by densely aggregated epithelial cell masses with foci of ductal differentiation. X 50.
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lmmunohistochemistry Cytokeratin was expressed exclusively by the ductal component, including ducts budding from solid cell nests; the latter remained unstained (Fig. 2). Vimentin was expressed by most cells in both ductal structures and solid nests; the intensity, however, was not uniform. Cells constituting the solid nests showed focal cytoplasmic staining for this antigen, usually paranuclear, but not punctate in character. In ductal structures, the staining was greater in the abluminal portion of the ductal lining. Smooth-muscle actin (HHF3J antibody characteristically decorated spindly cells located external to ductal lining cells. The bilayered structure of many ducts, not readily apparent by other techniques, was advantageously revealed by the use of this antibody. In some cell nests, the staining with antiactin was present in the outermost cells (Fig. 3) but absent in the more centrally located cells. Myosin distributed in a fashion similar to actin, but reactivity was much weaker, and in our hands the results were sometimes ambiguous. S-100 protein also localized to the outer cell layer of bilayered ducts, as well as to outermost cells of many solid cell nests. Interestingly, reactivity was strongest in the nuclei. A few solid cell nests displayed diffuse, moderately intense cytoplasmic reactivity not confined to peripherally located cells (Fig. 4). The tumor cells did not demonstrate the presence of GFAP on immunostaining.
FIGURE 2. Immunostaining for cytokeratin shows strong reactivity confined to ductal cells. Note lack of expression in solid cell nests. X 50.
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FIGURE 3. Smooth muscle actin (HHF,,) antibody localizes primarily in outer cells of bilayered intercalated ducts, as well as in cells occupying a peripheral location in solid cell clusters. X 125.
FIGURE 4. S-100 protein immunostaining showing strong nuclear reactivity in both ducts and solid cell clusters. T h e bilayered nature of some ducts is revealed by this stain, because inner epithelial cells remain unreactive. X 300.
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Electron Microscopic Findings The ultrastructure of well-formed neoplastic ducts revealed epithelial cells lining the ductal lumen and spindly cells forming an outer thin layer just external to the epithelium, identifiable as myoepithelial cells (Fig. 5). The ductal epithelial cells were joined by tight junctions close to the lumen and manifested early formation of microvilli. These cells had a high nucleocytoplasmic ratio, irregularly contoured nuclei, intracytoplasmic small lipid droplets, frequent lysosomal electron-dense inclusions, and small deposits of glycogen; their embryonic nature was manifested by numerous free ribosomes with scant development of endoplasmic reticulum. The myoepithelial cells extended thin cytoplasmic projections, in some areas too small to be resolved by light microscopy, closely apposed to the abluminal surface of the ductal epithelial cells and separated from the surrounding stroma by a distinct basement membrane. In some areas, the basement membrane appeared incurved upon itself or many times replicated. The myoepithelial cells showed intracytoplasmic thin filaments and small subplasmalemmal densities; the cytoplasmic elec-
FIGURE 5. A neoplastic duct in cross section reveals a central lumen
(open arrow) bordered by few short microvilli. The epithelial cells have irregular nuclei and abundant lysosomal dense inclusions. The duct is partially surrounded by myoepithelial cells with an elongated nucleus (solid a row). Focal multiplication of basement lamina profiles (arrowhends) is evident. Electron micrograph, x 5000.
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tron density of these cells thus seemed greater than that of the adjacent epithelial cells. In some ducts, the electron density of the cytoplasm of myoepithelial cells was so great as to obscure all details of their fine structure. Cells composing solid clusters tended to have ovoid nuclei of smoother or more uniform shape than those of ductal cells. In general, the cytoplasm was more abundant, and in some of these cells ample development of endoplasmic reticulum profiles was visible. These cell masses were also surrounded by basement lamina, which was less apparent than in ducts because of its close contact with the external plasmalemma of the cells it encircled; only in focal areas did it show a clear lamina rara interna. The cytoplasm also contained abundant free ribosomes. Cell-to-cell attachments were reduced to small junctions of the macula adherens type. In contrast to ductal epithelium, cells of dense clusters showed no interdigitation of adjacent plasmalemmata. By electron microscopy, no well-formed myoepithelial cells could be identified at the periphery of the dense cell masses in the samples studied. The surrounding stroma showed fibroblast-like cells with distended endoplasmic reticulum in which flocculent material was contained; the stroma was rich in amorphous intercellular matrix but showed very few collagen fibers.
DISCUSSION Congenital tumors originating in the epithelial (ductal or secretory) cellular components of a salivary gland are exceedingly rare. Vawter and Tefft ( 5 ) reported in 1966 two such cases under the name “embryoma” of the parotid gland. Since then, morphologically and clinically similar or identical tumors have been variously named, depending on the histologic details that different authors chose to emphasize, in a somewhat arbitrary way. Thus, Thackray and Lucas (6) illustrated under the caption of “monomorphic adenoma” the histology of a parotid tumor of a 1%-month-old infant (see their figure 145) that seems virtually indistinguishable from the “congenital basal cell adenoma” of Canalis et al. (7), the “adenoma” of Krolls et al. (2), or, for that matter, the “embryoma” originally described by Vawter and Tefft ( 5 ) . Some authors preferred to emphasize cell palisading at the periphery of the epithelial nests and advocated use of the term “basal cell adenoma” (7) or “low-grade basaloid adenocarcinoma” (8). Others, pointing to the presence of perineural invasion and cystic spaces, favored “adenoid cystic carcinoma’’ (9, 10). Still others, upon encountering mixed patterns, used the descriptive, although awkward term “congenital hybrid basal cell adenoma-adenoid cystic carcinoma” (1 1) for a congenital parotid gland tumor that does not seem to be essentially different from the others mentioned above. It is testimony to the lack of consistency of the nomenclature of these neoplasms that the two original cases of parotid “embryoma” in the report by Vawter and Tefft ( 5 ) reap-
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peared recently as “congenital carcinoma” in a retrospective review of salivary gland tumors of childhood from the same institution in which the prototypic description originated (3). We believe that our insistence on nomenclature is warranted because salivary gland carcinomas, that is, malignant epithelial neoplasms, do occur in children, and their treatment and outcome are in great measure subordinate to the histopathologic type. Mucoepidermoid carcinoma, acinic cell carcinoma, and undifferentiated carcinoma are the most common epithelial malignancies in children (1, 3). Because these tumors appear to be clinically and histopathologically distinct from “congenital carcinoma,” we think it is advisable to discourage use of the latter term. No case of congenital epithelial malignancy of salivary gland origin appears to have had a fatal course, although local recurrence may be seen. One poorly documented exception is on record in which a 2-year-old black girl died of an adenocarcioma of parotid gland due to direct invasion of the brain and skull by the tumor, which also had lung metastases (12). Because the congenital origin of this case is questionable, we have not included it in our tabulation (Table 1). Avoidance of the term “carcinoma” in clearly congenital cases would serve the purpose of focusing the oncologist’s attention on the uniqueness of congenital epithelial malignancy and thereby would enhance caution in devising appropriate therapeutic strategies. Among the alternative nomenclatures that may be proposed for these tumors, “embryoma” has much to recommend it, because that tumor seems to arise in the course of embryogenesis. However, it has been pointed out that this term resembles “dysembryoma,” a word that has been used as synonymous with teratoma, to which this tumor is not related (13). Moreover, further qualification as to site is required in order to distinguish the tumor from “embryomas” primary of other anatomic structures. “Epithelialmyoepithelial carcinoma” adequately describes the dual cellular composition of the tumor (see below). However, this term is applied currently to an uncommon salivary gland tumor of elderly patients, with more variable histologic appearances than those of the entity under discussion (14, 15). For these reasons our preference is “sialoblastoma,” a term first used by Taylor (16); both the dysontogenetic character and the site of the tumor are conveyed in a single word. In Table 1 we have summarized information pertaining to 14 cases, including our own, of congenital epithelial neoplasms of salivary gland origin. The tumor size ranged from 1.5 to 15 cm. The parotid gland, as is true of tumors of older patients, was the most frequent site of origin, although the submandibular gland was affected in three cases (7, 9, 10) and the site was not specified in one case (6). In no case did the disease progress to cause death by extensive dissemination. However, in three cases the tumor recurred locally
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(5, 16), and in one case the regional lymph nodes were involved by metastases (1 1). Admittedly, the tabulated cases may not be histologically homogenous, because of the above mentioned difficulties of nomenclature. Nevertheless, this compilation substantiates the conclusion that local control is the main problem attending epithelial neoplasms of congenital or neonatal origin, not distant dissemination. It is also apparent from Table 1 that the risk for local recurrence is high and that recurrence may be delayed for several months, or up to 11/2years after excision. Local tumor extension may be life-threatening, as illustrated by Taylor’s case (16) (case 12, Table l ) , in which recurrence was accompanied by tumor extension into the skull. All of this emphasizes the crucial role of surgery as the primary treatment modality and the need for complete excision with a safety margin on initial approach. Simple enucleation of apparently well-circumscribed solid tumors is definitely insufficient to control the disease. The published illustrations of congenital parotid tumors showed a repetitive histopathology. However, some departures were noted. Cases 1, 2, and 11 (Table 1) showed the cribriform pattern characteristic of adenoid cystic carcinoma (9-11) and case 10 represented a sebaceous adenoma with a predominant benign sebaceous component. There is enough published information to be certain that a subset of congenital epithelial tumors of the parotid gland exhibit fairly consistent pathologic features (13). Nests or lobules of poorly differentiated cells, sometimes related to slender ducts with a discernible lumen, and other areas comprised of closely aggregated tubules were the main features of these cases. This structural organization is said to resemble the developing gland, and thus the name sialoblastoma may be applied (16). By conventional histology the appearance suggests monomorphic adenoma. However, combined ultrastructural and immunohistologic study shows that the tumor is not made of a single cell type but that myoepithelial cells are a component of the neoplasm, which is therefore “bimorphic,” to use the terminology of Dardick et al. (17). The significance of myoepithelial cells in salivary gland tumors is still controversial, although a widely held hypothesis maintains that their presence is associated with a low ability to metastasize and a relatively torpid clinical course (18). In our material, spindly cells reactive to actin, myosin, and S-100 protein were interpreted as myoepithelial cells of “mesenchymal” appearance (19). Presumably, myoepithelial or precursor cells of “epithelial” morphology occur at the periphery of the epithelial cell nests of the tumor, because reactivity to S-100 (and weakly to vimentin) was confined to these peripherally situated epithelial cells in close relationship to basement lamina. Myoepithelial cells are known to vary widely in their antigenic expression (20). Although S-100 reactivity was marked in peripherally situated cells of the epithelial clusters, the significance of this finding is unclear because the bio-
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logic function of S-100 protein is still uncertain. Reactivity was frequently intranuclear. It has been suggested that pregnancy hormones may interact with the S-100 protein gene (21), and such interaction may conceivably take place in tumors that develop antenatally.
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REFERENCES 1. Schuller DE, McCabe BF. Salivary gland neoplasms in children. Otolaryngol Clin North Am 1977;10:399-412. 2. Krolls SO, Trodahl JN, Boyers RC. Salivary gland lesions in children. A survey of 430 cases. Cancer 1972;30:459-69. 3. Lack EE, Upton MP. Histopathologic review of salivary gland tumors in childhood. Arch Otolaryngol Head Neck Surg 1988; 114:898-906. 4. Bianchi A, Cudmore RE. Salivary gland tumors in children. J Pediatr Surg 1978;13:519-21. 5. Vawter GF, Tefft M. Congenital tumors of the parotid gland. Arch Pathol 1966;82:242-5. 6. Thackray AC, Lucas RB. Tumors of the major salivary glands. Atlas of Tumor Pathology. Second series, fasc. 10. Washington, D.C.: Armed Forces Institute of Pathology, 1974;125-6. 7. Canalis RF, Mok MW, Fishman SM, Hemenway WG. Congenital basal cell adenoma of the submandibular gland. Arch Otolaryngol 1980;106:284-6. 8. Adkins GF. Low grade basaloid adenocarcinoma of salivary gland in childhood: The so-called hybrid basal cell adenoma-adenoid cystic carcinoma. Pathology 1990;22:187-90. 9. Danziger H. Adenoid cystic carcinoma of the submaxillary gland in an 8 month old infant. Can Med ASSOC J 1964;91:759-61. 10. Willis RA. The Pathology of Tumors of Children, Edinburgh: Oliver & Boyd, 1962;174. 11. Simpson PR, Rutledge JC, Schaefer SD, Anderson RC. Congenital hybrid basal cell adenomaadenoid cystic carcinoma of the salivary gland. Pediatr Pathol 1986;6:199-208. 12. McKnight HA. Malignant parotid tumor in the newborn. Am J Surg 1939;45:128-30. 13. Roth A, Micheau C . Embryoma (or embryonal tumor) of the parotid gland: Report of two cases. Pediatr Pathol 1986;5:9-15. 14. Morrow TA, Chun T, Mirani N. Epithelial myoepithelial carcinoma of the parotid gland. Ear Nose Throat J 1990;69(9):646-8. 15. Stiernberg CM, Batsakis JG, Bailey BJ, Clark WD. Epithelial-myoepithelial carcinoma of the parotid gland. Otolaryngol Head Neck Surg 1986;94:240-2. 16. Taylor GP. Congenital epithelial tumor of the parotid-sialoblastoma. Pediatr Pathol 1988;8:447-52. 17. Dardick I, Kahn HJ, Van Nostrand AW, Baumal R. Salivary gland monomorphic adenoma: Ultrastructural, immunoperoxidase and histogenetic aspects. Am J Pathol 1984;115:334-48. 18. BatsakisJG, Regezi JA, Lund MA, el-Nagar A. Histogenesis of salivary gland neoplasms: A postulate with prognostic implications. J Laryngol Otol 1989;103(10):939-44. 19. Martinez-Madrigal F, Micheau C . Histology of the major salivary glands. Am J Surg Pathol 1989;13(10):879-99. 20. Morinaga S, Nakajima T, Shimosato Y. Normal and neoplastic myoepithelial cells in salivary glands: An immunohistochemical study. Hum Pathol 1987;18(12):1218-26. 21. Hakamura Y, Moritsuka Y, Ohta Y, et al. S-100 protein in glands within decidua and cervical glands during early pregnancy. Hum Pathol 1989;20(12):1204-9. Received April 15, I991 Revision accepted August 14, 1991
Chuen Hsueh, MD, and F. Gonzalez-Crussi, MD
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Department of Pathology, Children’s Memorial Hospital of Chicago, and Northwestern University Medical School, Chicago, Illinois 60614
The histologic, immunohistochemical, and ultrastructural features of a congenital epithelial tumor o j the parotid were studied. The tumor was characterized by solid nests of epithelial cells intermingled with proliferating ductal structures lined by a double layer of cells. Immunoperoxidase staining for cytokeratin, vimentin, actin, and 9 1 0 0 protein showed the presence of cytokeratin in the ductal cells as well as the presence of vimentin, actin, and S-100 protein in the outermost layer of the ducts. The solid nests were focally reactive to S-100 and vimentin. Ultrastructural examination revealed myoepithelial cells with replication of basement membrane material. The tumor recurred 17 months after excision without b m p h node involvement or metastasis. The term “sialoblastoma’’ is favored. Review of the literature on congenital, epithelial salivary gland tumors showed that a f e w cases recurred locally and only one case had regional lymph node involvement. No distant metastasis has been reported. 0
KEY WORDS: basal cell adenoma, congenital tumor, parotid gland, salivary gland.
It is well known that tumors primary of salivary gland are very uncommon during childhood. In most large series of salivary gland tumors that include patients of all ages, children represent less than 5% of the affected population (1, 2). Still more uncommon is the occurrence of a tumor of salivary gland detected at birth or in the first few months of life. When present, such tumors are likely to be primary of vasoformative tissue, that is, lymphangiomas or hemangiomas that arise incidentally within a salivary gland, most often the parotid. Epithelial neoplasms in this anatomic location, although very infrequent, generally occur in older children and adolescents (3, 4); congenital examples are truly exceptional. Nevertheless, congenital or neonatal tumors of the parotid gland present interesting clinicopathologic aspects that Address reprint requests to: Dr. F. G . Crussi, Department of Pathology, Box 1 7 , 2300 Children’s Plaza, Chicago, Illinois 60614.
Pediatric Pathology, 12:205-214, 1992 Copyight @ 1992 by Hemasphue Publishing Corporation
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pathologists must be aware of. It is the purpose of the present article to report the histologic, immunohistochemical, and ultrastructural features of one such case and to review the existing literature on these rare tumors.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 05/21/15 For personal use only.
CLINICAL HISTORY A Caucasian girl, born at 38 weeks of gestation by cesarean section because of fetal distress, was noted to have a mass on the right cheek. This lesion was firm, movable, and measured 1 cm in diameter. The postnatal physical examination was otherwise unremarkable. The mass was unchanged 24 days after birth, and a surgical exploration was performed at Children’s Memorial Hospital of Chicago. At operation, a well-circumscribed mass 2.2 cm in diameter was found along Stensen’s duct, appearing to arise from the superficial lobe of the parotid gland. The mass was completely excised with sparing of the facial nerve. The patient did well postoperatively, until a recurrence developed 17 months later. A second operation revealed a firm mass measuring 1.5 X 1.5 cm that extended into both superficial and deep parotid lobes. A total parotidectomy and excision of the facial nerve with nerve grafting were done. The patient had an uneventful postoperative course. She has been tumor free for 3 l/2 years since the second surgical procedure.
MATERIALS AND METHODS The tissue for light microscopy was fixed in 10% buffered formalin or B5 fixative, routinely processed, and stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) reagent with and without diastase digestion. For immunohistochemical study, we used an avidin-biotin-peroxidase complex (ABC) system (Vector Lab) following the manufacturer’s instructions. Sections were cut from formalin-fixed, paraffin-embedded tissue. The antisera used included cytokeratin (Becton Dickinson; mouse; prediluted), vimentin (Dako; mouse; 1:25), muscle-specific actin (HHF3J (Enzo Biochem; mouse; prediluted), myosin (Miles; rabbit; 1:3000), S-100 protein (Biomedia; rabbit; 1:3), and glial fibrillary acidic protein of GFAP (Labsystems; mouse; 1: 1000). For electron microscopy, the material was fixed in 3 % phosphatebuffered glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated in graded alcohols and propylene oxide, and embedded in Spurr’s plastic. Onemicrometer-thick sections were stained with toluidine blue. Ultrathin sections were studied with a Zeiss 10-A electron microscope.
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RESULTS
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Histopathological Findings The specimen from the first operation was composed of solid nests of epithelial cells separated from each other by bands of fibrous tissue. In some areas, these cell nests were intermingled with proliferating ductal structures (Fig. 1). Ducts appeared to bud from or were contained within some solid cell nests; the latter were sharply delineated from the surrounding stroma by a distinct basement membrane. The tumor cells showed some pleomorphism. The nuclei were round to oval, with dispersed chromatin and one or two moderately prominent nucleoli. The cytoplasm was clear to pale amphophilic with distinct cell borders. No obvious nuclear palisading was noted at the periphery of the cell nests, nor was there evidence of cystic formation or cribriform pattern. Coarse foci of calcification were present within the capsule and fibrous septa. Some PAS-positive and diastase-resistant secretory material was enclosed in the ductal lumens. The specimen from the second operation had histologic features identical to those of the first.
FIGURE 1. Histologic appearance of the tumor, characterized by densely aggregated epithelial cell masses with foci of ductal differentiation. X 50.
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lmmunohistochemistry Cytokeratin was expressed exclusively by the ductal component, including ducts budding from solid cell nests; the latter remained unstained (Fig. 2). Vimentin was expressed by most cells in both ductal structures and solid nests; the intensity, however, was not uniform. Cells constituting the solid nests showed focal cytoplasmic staining for this antigen, usually paranuclear, but not punctate in character. In ductal structures, the staining was greater in the abluminal portion of the ductal lining. Smooth-muscle actin (HHF3J antibody characteristically decorated spindly cells located external to ductal lining cells. The bilayered structure of many ducts, not readily apparent by other techniques, was advantageously revealed by the use of this antibody. In some cell nests, the staining with antiactin was present in the outermost cells (Fig. 3) but absent in the more centrally located cells. Myosin distributed in a fashion similar to actin, but reactivity was much weaker, and in our hands the results were sometimes ambiguous. S-100 protein also localized to the outer cell layer of bilayered ducts, as well as to outermost cells of many solid cell nests. Interestingly, reactivity was strongest in the nuclei. A few solid cell nests displayed diffuse, moderately intense cytoplasmic reactivity not confined to peripherally located cells (Fig. 4). The tumor cells did not demonstrate the presence of GFAP on immunostaining.
FIGURE 2. Immunostaining for cytokeratin shows strong reactivity confined to ductal cells. Note lack of expression in solid cell nests. X 50.
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FIGURE 3. Smooth muscle actin (HHF,,) antibody localizes primarily in outer cells of bilayered intercalated ducts, as well as in cells occupying a peripheral location in solid cell clusters. X 125.
FIGURE 4. S-100 protein immunostaining showing strong nuclear reactivity in both ducts and solid cell clusters. T h e bilayered nature of some ducts is revealed by this stain, because inner epithelial cells remain unreactive. X 300.
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Electron Microscopic Findings The ultrastructure of well-formed neoplastic ducts revealed epithelial cells lining the ductal lumen and spindly cells forming an outer thin layer just external to the epithelium, identifiable as myoepithelial cells (Fig. 5). The ductal epithelial cells were joined by tight junctions close to the lumen and manifested early formation of microvilli. These cells had a high nucleocytoplasmic ratio, irregularly contoured nuclei, intracytoplasmic small lipid droplets, frequent lysosomal electron-dense inclusions, and small deposits of glycogen; their embryonic nature was manifested by numerous free ribosomes with scant development of endoplasmic reticulum. The myoepithelial cells extended thin cytoplasmic projections, in some areas too small to be resolved by light microscopy, closely apposed to the abluminal surface of the ductal epithelial cells and separated from the surrounding stroma by a distinct basement membrane. In some areas, the basement membrane appeared incurved upon itself or many times replicated. The myoepithelial cells showed intracytoplasmic thin filaments and small subplasmalemmal densities; the cytoplasmic elec-
FIGURE 5. A neoplastic duct in cross section reveals a central lumen
(open arrow) bordered by few short microvilli. The epithelial cells have irregular nuclei and abundant lysosomal dense inclusions. The duct is partially surrounded by myoepithelial cells with an elongated nucleus (solid a row). Focal multiplication of basement lamina profiles (arrowhends) is evident. Electron micrograph, x 5000.
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tron density of these cells thus seemed greater than that of the adjacent epithelial cells. In some ducts, the electron density of the cytoplasm of myoepithelial cells was so great as to obscure all details of their fine structure. Cells composing solid clusters tended to have ovoid nuclei of smoother or more uniform shape than those of ductal cells. In general, the cytoplasm was more abundant, and in some of these cells ample development of endoplasmic reticulum profiles was visible. These cell masses were also surrounded by basement lamina, which was less apparent than in ducts because of its close contact with the external plasmalemma of the cells it encircled; only in focal areas did it show a clear lamina rara interna. The cytoplasm also contained abundant free ribosomes. Cell-to-cell attachments were reduced to small junctions of the macula adherens type. In contrast to ductal epithelium, cells of dense clusters showed no interdigitation of adjacent plasmalemmata. By electron microscopy, no well-formed myoepithelial cells could be identified at the periphery of the dense cell masses in the samples studied. The surrounding stroma showed fibroblast-like cells with distended endoplasmic reticulum in which flocculent material was contained; the stroma was rich in amorphous intercellular matrix but showed very few collagen fibers.
DISCUSSION Congenital tumors originating in the epithelial (ductal or secretory) cellular components of a salivary gland are exceedingly rare. Vawter and Tefft ( 5 ) reported in 1966 two such cases under the name “embryoma” of the parotid gland. Since then, morphologically and clinically similar or identical tumors have been variously named, depending on the histologic details that different authors chose to emphasize, in a somewhat arbitrary way. Thus, Thackray and Lucas (6) illustrated under the caption of “monomorphic adenoma” the histology of a parotid tumor of a 1%-month-old infant (see their figure 145) that seems virtually indistinguishable from the “congenital basal cell adenoma” of Canalis et al. (7), the “adenoma” of Krolls et al. (2), or, for that matter, the “embryoma” originally described by Vawter and Tefft ( 5 ) . Some authors preferred to emphasize cell palisading at the periphery of the epithelial nests and advocated use of the term “basal cell adenoma” (7) or “low-grade basaloid adenocarcinoma” (8). Others, pointing to the presence of perineural invasion and cystic spaces, favored “adenoid cystic carcinoma’’ (9, 10). Still others, upon encountering mixed patterns, used the descriptive, although awkward term “congenital hybrid basal cell adenoma-adenoid cystic carcinoma” (1 1) for a congenital parotid gland tumor that does not seem to be essentially different from the others mentioned above. It is testimony to the lack of consistency of the nomenclature of these neoplasms that the two original cases of parotid “embryoma” in the report by Vawter and Tefft ( 5 ) reap-
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peared recently as “congenital carcinoma” in a retrospective review of salivary gland tumors of childhood from the same institution in which the prototypic description originated (3). We believe that our insistence on nomenclature is warranted because salivary gland carcinomas, that is, malignant epithelial neoplasms, do occur in children, and their treatment and outcome are in great measure subordinate to the histopathologic type. Mucoepidermoid carcinoma, acinic cell carcinoma, and undifferentiated carcinoma are the most common epithelial malignancies in children (1, 3). Because these tumors appear to be clinically and histopathologically distinct from “congenital carcinoma,” we think it is advisable to discourage use of the latter term. No case of congenital epithelial malignancy of salivary gland origin appears to have had a fatal course, although local recurrence may be seen. One poorly documented exception is on record in which a 2-year-old black girl died of an adenocarcioma of parotid gland due to direct invasion of the brain and skull by the tumor, which also had lung metastases (12). Because the congenital origin of this case is questionable, we have not included it in our tabulation (Table 1). Avoidance of the term “carcinoma” in clearly congenital cases would serve the purpose of focusing the oncologist’s attention on the uniqueness of congenital epithelial malignancy and thereby would enhance caution in devising appropriate therapeutic strategies. Among the alternative nomenclatures that may be proposed for these tumors, “embryoma” has much to recommend it, because that tumor seems to arise in the course of embryogenesis. However, it has been pointed out that this term resembles “dysembryoma,” a word that has been used as synonymous with teratoma, to which this tumor is not related (13). Moreover, further qualification as to site is required in order to distinguish the tumor from “embryomas” primary of other anatomic structures. “Epithelialmyoepithelial carcinoma” adequately describes the dual cellular composition of the tumor (see below). However, this term is applied currently to an uncommon salivary gland tumor of elderly patients, with more variable histologic appearances than those of the entity under discussion (14, 15). For these reasons our preference is “sialoblastoma,” a term first used by Taylor (16); both the dysontogenetic character and the site of the tumor are conveyed in a single word. In Table 1 we have summarized information pertaining to 14 cases, including our own, of congenital epithelial neoplasms of salivary gland origin. The tumor size ranged from 1.5 to 15 cm. The parotid gland, as is true of tumors of older patients, was the most frequent site of origin, although the submandibular gland was affected in three cases (7, 9, 10) and the site was not specified in one case (6). In no case did the disease progress to cause death by extensive dissemination. However, in three cases the tumor recurred locally
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(5, 16), and in one case the regional lymph nodes were involved by metastases (1 1). Admittedly, the tabulated cases may not be histologically homogenous, because of the above mentioned difficulties of nomenclature. Nevertheless, this compilation substantiates the conclusion that local control is the main problem attending epithelial neoplasms of congenital or neonatal origin, not distant dissemination. It is also apparent from Table 1 that the risk for local recurrence is high and that recurrence may be delayed for several months, or up to 11/2years after excision. Local tumor extension may be life-threatening, as illustrated by Taylor’s case (16) (case 12, Table l ) , in which recurrence was accompanied by tumor extension into the skull. All of this emphasizes the crucial role of surgery as the primary treatment modality and the need for complete excision with a safety margin on initial approach. Simple enucleation of apparently well-circumscribed solid tumors is definitely insufficient to control the disease. The published illustrations of congenital parotid tumors showed a repetitive histopathology. However, some departures were noted. Cases 1, 2, and 11 (Table 1) showed the cribriform pattern characteristic of adenoid cystic carcinoma (9-11) and case 10 represented a sebaceous adenoma with a predominant benign sebaceous component. There is enough published information to be certain that a subset of congenital epithelial tumors of the parotid gland exhibit fairly consistent pathologic features (13). Nests or lobules of poorly differentiated cells, sometimes related to slender ducts with a discernible lumen, and other areas comprised of closely aggregated tubules were the main features of these cases. This structural organization is said to resemble the developing gland, and thus the name sialoblastoma may be applied (16). By conventional histology the appearance suggests monomorphic adenoma. However, combined ultrastructural and immunohistologic study shows that the tumor is not made of a single cell type but that myoepithelial cells are a component of the neoplasm, which is therefore “bimorphic,” to use the terminology of Dardick et al. (17). The significance of myoepithelial cells in salivary gland tumors is still controversial, although a widely held hypothesis maintains that their presence is associated with a low ability to metastasize and a relatively torpid clinical course (18). In our material, spindly cells reactive to actin, myosin, and S-100 protein were interpreted as myoepithelial cells of “mesenchymal” appearance (19). Presumably, myoepithelial or precursor cells of “epithelial” morphology occur at the periphery of the epithelial cell nests of the tumor, because reactivity to S-100 (and weakly to vimentin) was confined to these peripherally situated epithelial cells in close relationship to basement lamina. Myoepithelial cells are known to vary widely in their antigenic expression (20). Although S-100 reactivity was marked in peripherally situated cells of the epithelial clusters, the significance of this finding is unclear because the bio-
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logic function of S-100 protein is still uncertain. Reactivity was frequently intranuclear. It has been suggested that pregnancy hormones may interact with the S-100 protein gene (21), and such interaction may conceivably take place in tumors that develop antenatally.
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