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Intraoral Minor Salivary Gland Neoplasms: Review of 213 Cases
J Oral Maxillofac Surg 63:805-810, 2005
Intraoral Minor Salivary Gland Neoplasms: Review of 213 Cases Wei-Yung Yih, DDS, MS,* F. James Kratochvil, DDS,† and Jeffery C.B. Stewart, DDS, MS‡ Purpose: Minor salivary gland tumors (MSGTs) constitute a heterogeneous group of neoplasms with
great histomorphologic variation. This study reviews a large series of benign and malignant salivary gland tumors of the oral region and determines the incidence and the correlation of the histopathologic features with the clinical characteristics. Materials and Methods: Two hundred thirteen cases of MSGT were retrospectively studied. Hematoxylin-eosin–stained slides were examined in all cases. Special stains and immunohistochemical stains were used in selected cases. Clinical characteristics of the neoplasms were also noted. Results: One hundred nineteen tumors were benign (56%), and 94 tumors were malignant (44%). Pleomorphic adenoma was the most common benign tumor (93 of 119). Canalicular adenoma was the second most common benign MSGT in our series (25 of 119). Of the 94 malignant MSGTs, mucoepidermoid carcinoma (MEC) (45 of 94), adenoid cystic carcinoma (22 of 94), and polymorphous low-grade adenocarcinoma (18 of 94) were the most common. Most MECs (34 of 45) were low-grade lesions. Of 5 central MECs, 3 cases occurred in the maxilla and 2 cases arose in the mandible. Conclusions: Benign intraoral MSGTs are slightly more common than malignant MSGTs. Pleomorphic adenoma is the most common MSGT, and MEC is the most common malignant variety. The palate is the most common site for minor gland neoplasms. Benign labial salivary gland neoplasms are more common in the upper lip, and malignant labial tumors are more common in the lower lip. © 2005 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 63:805-810, 2005 point of hybrid tumors with features of 2 different, well-defined tumor entities.1 With few immunohistochemical markers available for differentiation of tumors, accurate diagnosis of MSGTs may be quite difficult. In this study, MSGTs were retrospectively studied clinically and microscopically. The incidence of each category of tumors is demonstrated. Characteristic histopathologic features of MSGTs are discussed with an attempt to correlate the histopathologic findings with clinical presentation.
Neoplasms arising from the minor salivary glands are relatively common. The myriad of histologic types of minor salivary gland tumors (MSGTs) makes this the most heterogeneous group of neoplasms of the upper aerodigestive tract. Although some tumors of minor and major salivary glands may arise from the same progenitor cells, they may exhibit different biologic behavior related to anatomic site of occurrence. Characteristically, specific MSGTs have a tendency to occur in particular locations. Challenges to microscopic diagnosis include biphasic differentiation of salivary gland tumors even to the
Materials and Methods
Received from the Department of Pathology and Radiology, Oregon Health and Science University School of Dentistry, Portland, OR *Professor. †Associate Professor and Chairman. ‡Associate Professor. Address correspondence and reprint requests to Dr Yih: Department of Pathology and Radiology, Oregon Health and Science University School of Dentistry, 3181 SW Sam Jackson Park Rd, Portland, OR 97239-3098.
Two hundred eight cases from the Oral Pathology Service of Oregon Health and Science University (1964-2001) and 5 cases from the Oral Pathology Service of the University of Pennsylvania (1995-1999) were retrospectively studied. Hematoxylin and eosin– stained slides were examined in all cases. Special stains including Masson’s trichrome, mucicarmine, PAS (with and/or without digestion), and immunohistochemical stains for keratin, vimentin, muscle specific actin, S-100 protein, and desmin were used in selected cases to aid in the diagnosis.
© 2005 American Association of Oral and Maxillofacial Surgeons
0278-2391/05/6306-0021$30.00/0 doi:10.1016/j.joms.2005.02.021
805
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INTRAORAL MINOR SALIVARY GLAND NEOPLASMS
Table 3. LOCATIONS OF PLEOMORPHIC ADENOMAS
Table 1. BENIGN AND MALIGNANT GLAND TUMORS
Type of Tumor Benign salivary gland tumors Pleomorphic adenoma Canalicular adenoma Oxyphilic adenoma Total Malignant salivary gland tumors Mucoepidermoid carcinoma Adenocystic carcinoma Polymorphous low-grade adenocarcinoma Adenocarcinoma, NOS Carcinoma ex pleomorphic adenoma Acinic cell carcinoma Papillary cystadenocarcinoma Cystadenocarcinoma Total
Location
No. of Cases
Palate (soft and/or hard palate) Upper lip Buccal mucosa Retromolar region
50 25 16 2
No. of Cases 93 25 1 119 45 22 18 4 2 1 1 1 94
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
Results One hundred nineteen MSGTs were benign (56%) and 94 were malignant (44%) (Table 1). The most common tumor overall was pleomorphic adenoma (PA), followed by mucoepidermoid carcinoma (MEC) (Table 2). PA was the most common benign tumor (93 of 119) (78.2%). PAs occurred between ages 17 and 88 years (average age, 46 years). PAs in females (61 cases) were more common than in males (32 cases) with a ratio of 1.9:1. The location of occurrence of PAs is listed in Table 3. The diverse microscopic pattern of this neoplasm is one of its most characteristic features (Fig 1). Cuboidal epithelial cells are arranged in tubes
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
or ductlike structures. In other areas, the tumor cells assumed a stellate, polyhedral, or spindle form, and some cells had a “plasmacystoid” morphology. Squamous epithelial cells with typical intercellular bridges were relatively common, and sometimes actual keratin pearls were formed. Foci of hyalinized connective tissue, cartilage-like, and/or mucoid material also were seen. Seventy-two cases of PA were available for evaluation of encapsulation. Fifty-nine cases had a capsule, although most were incomplete or tumor cells were noted in the capsule. Thirteen cases were without a capsule. In 16 of 50 palatal PAs, which had an incomplete capsule or were without a capsule, tumor cells extended into the overlying lamina propria (Fig 2). Mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm and the second most common tumor overall, representing 45 of 94 malignancies (47.9%). The age range was from 25 to 90 years (average age, 55.6 years). Thirty-two cases of MEC were in females and 13 cases were in males, a ratio of 2.5:1. Locations of the MECs are listed in Table 4. Of interest are 5 central MECs, 3 that occurred in the maxilla and 2 that arose in the mandible. The reported duration of MECs was 1 week to 10 years, and the tumors ranged in size from 0.3 to 4 cm.
Table 2. ORDER OF INCIDENCE OF MINOR SALIVARY GLAND NEOPLASMS
Incidence Order Pleomorphic adenoma Mucoepidermoid carcinoma Canalicular adenoma Adenocystic carcinoma Polymorphous low-grade adenocarcinoma Adenocarcinoma, NOS Carcinoma ex pleomorphic adenoma Acinic cell carcinoma Cystadenocarcinoma Papillary cystadenocarcinoma Oxyphilic adenoma Total
No. of Cases (%) 93 (43.7) 45 (21.1) 25 (11.7) 22 (10.3) 18 (8.4) 4 (1.9) 2 (0.9) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 213
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
FIGURE 1. Photomicrograph showing a pleomorphic adenoma in the upper lip (hematoxylin and eosin stain, original magnification ⫻25). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
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YIH, KRATOCHVIL, AND STEWART
FIGURE 2. Photomicrograph of a palatal pleomorphic adenoma showing that the tumor cells were close to the mucosal epithelium (hematoxylin and eosin stain, original magnification ⫻25). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
FIGURE 3. Photomicrograph of a mucoepidermoid carcinoma composed of mucus-secreting cells and intermediate cells (hematoxylin and eosin stain, original magnification ⫻10). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
Microscopically, the tumors are composed of mucussecreting cells, epidermoid-type cells, and intermediate cells with different patterns and ratios (Fig 3). Clear cells were occasionally seen. Grading of MECs was based on the criteria of Auclair et al.2 Using these criteria, 38 cases of MEC were classified as low grade, 3 cases were intermediate grade, and 4 cases were high grade. Twenty-five cases were canalicular adenoma (CA), with 20 cases occurring in females and 5 cases in males. The age range was from 43 to 79 years (average age, 64 years). Sixteen cases of CA occurred in the upper lip, 7 cases were in the palate, and 2 cases were in the buccal mucosa. The sizes of the tumors ranged from 0.4 to 1 cm. The reported duration of CAs was from 2 months to 1 year. Microscopically, these CAs are typically composed of long strands or cords of epithelial cells that are arranged in a double row (Fig 4). The cords enclose some cystic spaces of varying sizes. The supporting stroma is loose and fibrillar with delicate vascularity. The tumors often have a thin
fibrous capsule. Six CAs in our series demonstrated multifocal microscopic features. Twenty-two cases were adenoid cystic carcinoma (ACC), and they occurred from age 19 to 94 years (average age, 58.6 years). Twelve ACCs were in females and 10 cases in males. Locations of ACCs were listed in Table 5. The sizes of the tumors were from 0.6 to 4 cm. Durations of ACCs were from 2 weeks to 6 years. Microscopically, the neoplasms are composed of small, deeply staining, uniform cells that are arranged in rounded islands, anastomosing cords, or with a ductlike pattern, the central portion of which may contain spaces with a mucoid material producing the typical cribriform pattern (Fig 5A). Spread of the tumor cells along the perineural spaces or in perineural sheaths is a common feature of this neoplasm. Growth of cells in a solid form sometimes occurs (Fig
Table 4. LOCATIONS OF MUCOEPIDERMOID CARCINOMAS
Location
No. of Cases
Palate Lower lip Retromolar region Buccal mucosa Maxilla Mandibular ridge Lower vestibule Floor of mouth Mandible Unknown
20 7 3 3 3 2 2 2 2 1
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
FIGURE 4. Photomicrograph of a canalicular adenoma showing cords of epithelial cells with loose supporting stroma (hematoxylin and eosin stain, original magnification ⫻100). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
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INTRAORAL MINOR SALIVARY GLAND NEOPLASMS
Table 5. LOCATIONS OF ADENOID CYSTIC CARCINOMAS
Table 6. LOCATIONS OF POLYMORPHOUS LOWGRADE ADENOCARCINOMAS
Location
No. of Cases
Location
No. of Cases
Palate Maxilla Buccal mucosa Mandibular vestibule Maxillary buccal vestibule Upper lip Floor of mouth Unknown
13 2 2 1 1 1 1 1
Palate Buccal mucosa Retromolar region Lower lip Upper lip Pillar of fauces Unknown
8 4 2 1 1 1 1
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
5B). In other instances, only thin, delicate anastomosing cords of neoplastic cells are dispersed throughout an abundant stroma. There were 18 cases of polymorphous low-grade adenocarcinoma (PLGA). Ten cases were in females and 8 cases were in males. PLGAs occurred from age 33 to 94 years (average age, 64 years). The sizes of the tumors were from 1 to 4.3 cm. Duration of the tumors
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
ranged from 6 months to 20 years. The locations of occurrence of PLGAs are listed in Table 6. Microscopically, cytologic uniformity and architectural diversity characterize the tumors. Growth patterns varied from solid, tubular, papillary, cribriform, to fascicular (Fig 6A), whereas the cells are always small to mediumsized, regular, and lacking in nuclear atypia (Fig 6B).
FIGURE 5. (A) Photomicrograph showing a cribriform pattern of an adenoid cystic carcinoma (hematoxylin and eosin stain, original magnification ⫻25). (B) Photomicrograph showing a solid growth pattern of adenoid cystic carcinoma (hematoxylin and eosin stain, original magnification ⫻25).
FIGURE 6. (A) Photomicrograph of a polymorphous low-grade adenocarcinoma (hematoxylin and eosin stain, original magnification ⫻25). (B) Photomicrograph of a polymorphous low-grade adenocarcinoma composed of uniform cuboidal cells with pale-staining ovoidshaped nuclei (hematoxylin and eosin stain, original magnification ⫻25).
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
YIH, KRATOCHVIL, AND STEWART
Mitoses are infrequent. Clear cytoplasm, oxyphilic and mucinous metaplasia, and intratubular calcification are sometimes present. Perineural invasion of tumor cells was common. Mucinization and hyalinization of stroma were often seen. All of the tumors were nonencapsulated. Four cases were diagnosed as adenocarcinoma not otherwise specified (AC). Three ACs occurred in females and 1 case occurred in a male. ACs occurred between ages 37 to 87 years (average age, 61.2 years). The sizes of the tumors were 0.7 to 3 cm, and the duration of the tumors was from 3 weeks to several years. Two cases occurred in the hard palate, one was in the lower lip, and the other was from an unknown location. Microscopically, the neoplasms that were classified in this nonspecific category were a histologically heterogeneous group; they varied from highly anaplastic adenocarcinoma to moderately well-differentiated lesions. Two cases were diagnosed as carcinoma ex PA. One case occurred in the right buccal mucosa of a 37-year-old man; the other was in the right retromolar region of a 75-year-old man. Microscopically, the malignant foci appeared in the histologically benign PA or the malignant component overgrew the benign element but the PA pattern was still apparent (Figs 7A, B). An acinic cell carcinoma occurred in the junction of the hard and soft palate in a 25-year-old man. One case was diagnosed as papillary cystadenocarcinoma in the left buccal mucosa of a 35-year-old man. A cystadenocarcinoma occurred in the left hard palate in a 47-year-old woman. Finally, there was an oxyphilic adenoma in the lower lip of a 26-year-old man.
Discussion Epithelial neoplasms arising in minor salivary glands are relatively common, and they are regularly encountered in oral and maxillofacial surgical pathology services. They are a microscopically heterogeneous group of neoplasms, and some types have a propensity to develop in particular intraoral locations. There have been several relatively recent reports of significantly large series of these tumors, including Eveson and Cawson’s series of 336 tumors reported in 1985,3 Waldron et al’s series of 426 tumors in 1988,4 Neville et al’s series of 103 labial gland tumors in 1988,5, and Ellis et al’s textbook of Surgical Pathology of Salivary Glands in 1991,6 which included 3,355 cases of MSGTs. In addition, there were 165 cases reported by Loyola et al in 19957 and 129 cases reported by Kusama et al in 1997.8 Our findings most closely follow those of Waldron and colleagues, probably due to the fact that their
809
FIGURE 7. (A) Photomicrograph of a carcinoma ex pleomorphic adenoma showing pseudoductal structures formed by atypical epithelium and a hyalinized stroma (hematoxylin and eosin stain, original magnification ⫻100). (B) Photomicrograph showing nuclear pleomorphism, hyperchromatism, and increased mitosis in a carcinoma ex mixed tumor (hematoxylin and eosin stain, original magnification ⫻150). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
series best demonstrates biopsy submissions most commonly seen in an oral pathology biopsy service and that the diagnostic labels given to the lesions are representative of those commonly used at this time. In the Armed Forces Institute of Pathology series,6 adenocarcinoma NOS was the third most common tumor diagnosed in minor glands, exceeding CA, ACC, and PLGA. This likely does not represent the true incidence of these neoplasms due to the fact that the Armed Forces Institute of Pathology is a referral center for pathologists and often only problematic cases are submitted for consultation. Eveson and Cawson’s3 series of 336 MSGTs was published in 1985 and did not include PLGA as a recognized neoplasm. The current review of our series found 8 of 18 PLGAs had been diagnosed as PA prior to 1983. In our series, the ratio of incidence of benign and malignant MSGTs is consistent with other reports.3– 8 PA is the most common benign MSGT in our series (93 of 119). PAs clinically exhibit slow growth of an irregular or a well-circumscribed, sessile-based, firm mass that occasionally has an ulcerated surface. In this
810 series, 16 cases of palatal PA demonstrated tumor cells that extended directly into the superficial lamina propria. However, in 17 other cases, the tumor cells were close to the mucosa with only a microscopic distance between (Fig 2). This finding would support the concept that the tumor and the overlying mucosa should be removed during complete excision of palatal mixed tumors. In this series, most of the PAs had an incomplete capsule with tumor cells in the capsule or tumor cells directly contacting the adjacent nonneoplastic tissue. CA was the second most common benign MSGT in this series (25 of 119). Surprisingly, Loyola et al7 and Kusama et al8 did not identify CAs in their publications. Six of our CAs (24%) were multifocal. This finding combined with a poorly developed, or absent, capsule could be misconstrued as an adenocarcinoma. In this series, labial CAs and PAs occurred only in the upper lip and were not found in the lower lip. Ninety-four MSGTs in this series were malignant (44%) with MEC (45 of 94), ACC (22 of 94), and PLGA (18 of 94) being the most common. Most MECs (38 of 45) were classified as low-grade lesions. The grading was based on the criteria created by Auclair et al.2 Of the 7 labial cases of MEC in our series, all of them occurred in the lower lip. These findings are consistent with those of Neville et al.5 In our series, 9 of the 10 lower lip salivary gland tumors (7 MEC, 1 PLGA, 1 adenocarcinoma, NOS) were malignant. ACC is a slowly growing malignancy. Early expression of nerve involvement is a characteristic of this tumor. Although the 5-year survival rate is high, the cure rate over 20 years is much lower.9 Microscopically, a solid growth pattern (Fig 6) usually carries a poor prognosis. Eight PLGAs were recognized in cases previously diagnosed before 1983 as PA and one case was previously diagnosed as ACC. Kusama et al8 noted that they did not identify any PLGAs in their series of 129 MSGTs. Possibly, PLGAs may have been included in their PAs and ACCs. Diagnosis of PLGA was based on cytologic uniformity and histologic diversity. PLGAs are usually slowly growing tumors and carry a relatively good prognosis.10 –13 Distinction of PLGA from ACC is sometimes difficult but important because
INTRAORAL MINOR SALIVARY GLAND NEOPLASMS
these 2 tumors pursue a significantly different clinical behavior. Adenocarcinoma NOS, tumors that could not be classified into a well-defined specific category, were a histologically heterogeneous group. Despite the microscopic variation in pattern, these tumors display the usual microscopic features of malignant neoplasms, including nuclear and cellular pleomorphism and invasive features. In our series, the relative incidence of benign and malignant MSGTs is consistent with previous reports. PA is the most common and MEC is the second most common MSGT. The palate is the most common site overall for MSGTs. The benign labial neoplasms are more common in the upper lip, whereas the malignant tumors are more common in the lower lip.
References 1. Seifert G, Donath K: Hybrid tumors of salivary glands. Definition and classification of five cases. Eur J Cancer B Oral Oncol 32B:251, 1996 2. Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of intraoral salivary glands. Evaluation and application of grading criteria in 143 cases. Cancer 69:2021, 1992 3. Eveson JW, Cawson RA: Salivary gland tumors: A review of 2410 cases with particular reference to histological types, site, age, and sex distribution. J Pathol 146:51, 1985 4. Waldron CA, el-Mofty SK, Gnepp DR: Tumors of the intraoral minor salivary glands: A demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol 66:323, 1988 5. Neville BW, Damm DD, Weir JC, et al: Labial salivary gland tumors. Cancer 61:2113, 1988 6. Ellis GL, Auclair PL, Gnepp DR: Surgical Pathology of the Salivary Glands. Philadelphia, PA, Saunders, 1991, pp 138 –146 7. Loyola AM, de Araujo VC, de Sousa SO, et al: Minor salivary gland tumors. A retrospective study of 164 cases in a Brazilian population. Eur J Cancer B Oral Oncol 31b:197, 1995 8. Kusama K, Iwanari S, Aisaki K, et al: Intraoral minor salivary gland tumors: A retrospective study of 129 cases. J Nihon Uni Sch Denti 39:128, 1997 9. Neville BW, Damm DD, Allen CM, et al: Oral and Maxillofacial Pathology (ed 2). Philadelphia, PA, Saunders, 2002, p 428 10. Batsakis JG, Pinkston GR, Luna MA, et al: Adenocarcinomas of the oral cavity: A clinico-pathologic study of terminal duct carcinomas. J Laryngol Otol 97:825, 1983 11. Freedman PD, Lummerman H: Lobular carcinoma of intraoral minor salivary glands. Oral Surg Oral Med Oral Pathol 56:157, 1983 12. Evans HL, Batsakis JG: Polymorphous low-grade adenocarcinoma of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Cancer 53:935, 1984 13. Vincent SD, Hammond HL, Finkelstein MW: Clinical and therapeutic features of polymorphous low-grade adenocarcinoma. Oral Surg Oral Med Oral Pathol 77:41, 1994
Intraoral Minor Salivary Gland Neoplasms: Review of 213 Cases Wei-Yung Yih, DDS, MS,* F. James Kratochvil, DDS,† and Jeffery C.B. Stewart, DDS, MS‡ Purpose: Minor salivary gland tumors (MSGTs) constitute a heterogeneous group of neoplasms with
great histomorphologic variation. This study reviews a large series of benign and malignant salivary gland tumors of the oral region and determines the incidence and the correlation of the histopathologic features with the clinical characteristics. Materials and Methods: Two hundred thirteen cases of MSGT were retrospectively studied. Hematoxylin-eosin–stained slides were examined in all cases. Special stains and immunohistochemical stains were used in selected cases. Clinical characteristics of the neoplasms were also noted. Results: One hundred nineteen tumors were benign (56%), and 94 tumors were malignant (44%). Pleomorphic adenoma was the most common benign tumor (93 of 119). Canalicular adenoma was the second most common benign MSGT in our series (25 of 119). Of the 94 malignant MSGTs, mucoepidermoid carcinoma (MEC) (45 of 94), adenoid cystic carcinoma (22 of 94), and polymorphous low-grade adenocarcinoma (18 of 94) were the most common. Most MECs (34 of 45) were low-grade lesions. Of 5 central MECs, 3 cases occurred in the maxilla and 2 cases arose in the mandible. Conclusions: Benign intraoral MSGTs are slightly more common than malignant MSGTs. Pleomorphic adenoma is the most common MSGT, and MEC is the most common malignant variety. The palate is the most common site for minor gland neoplasms. Benign labial salivary gland neoplasms are more common in the upper lip, and malignant labial tumors are more common in the lower lip. © 2005 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 63:805-810, 2005 point of hybrid tumors with features of 2 different, well-defined tumor entities.1 With few immunohistochemical markers available for differentiation of tumors, accurate diagnosis of MSGTs may be quite difficult. In this study, MSGTs were retrospectively studied clinically and microscopically. The incidence of each category of tumors is demonstrated. Characteristic histopathologic features of MSGTs are discussed with an attempt to correlate the histopathologic findings with clinical presentation.
Neoplasms arising from the minor salivary glands are relatively common. The myriad of histologic types of minor salivary gland tumors (MSGTs) makes this the most heterogeneous group of neoplasms of the upper aerodigestive tract. Although some tumors of minor and major salivary glands may arise from the same progenitor cells, they may exhibit different biologic behavior related to anatomic site of occurrence. Characteristically, specific MSGTs have a tendency to occur in particular locations. Challenges to microscopic diagnosis include biphasic differentiation of salivary gland tumors even to the
Materials and Methods
Received from the Department of Pathology and Radiology, Oregon Health and Science University School of Dentistry, Portland, OR *Professor. †Associate Professor and Chairman. ‡Associate Professor. Address correspondence and reprint requests to Dr Yih: Department of Pathology and Radiology, Oregon Health and Science University School of Dentistry, 3181 SW Sam Jackson Park Rd, Portland, OR 97239-3098.
Two hundred eight cases from the Oral Pathology Service of Oregon Health and Science University (1964-2001) and 5 cases from the Oral Pathology Service of the University of Pennsylvania (1995-1999) were retrospectively studied. Hematoxylin and eosin– stained slides were examined in all cases. Special stains including Masson’s trichrome, mucicarmine, PAS (with and/or without digestion), and immunohistochemical stains for keratin, vimentin, muscle specific actin, S-100 protein, and desmin were used in selected cases to aid in the diagnosis.
© 2005 American Association of Oral and Maxillofacial Surgeons
0278-2391/05/6306-0021$30.00/0 doi:10.1016/j.joms.2005.02.021
805
806
INTRAORAL MINOR SALIVARY GLAND NEOPLASMS
Table 3. LOCATIONS OF PLEOMORPHIC ADENOMAS
Table 1. BENIGN AND MALIGNANT GLAND TUMORS
Type of Tumor Benign salivary gland tumors Pleomorphic adenoma Canalicular adenoma Oxyphilic adenoma Total Malignant salivary gland tumors Mucoepidermoid carcinoma Adenocystic carcinoma Polymorphous low-grade adenocarcinoma Adenocarcinoma, NOS Carcinoma ex pleomorphic adenoma Acinic cell carcinoma Papillary cystadenocarcinoma Cystadenocarcinoma Total
Location
No. of Cases
Palate (soft and/or hard palate) Upper lip Buccal mucosa Retromolar region
50 25 16 2
No. of Cases 93 25 1 119 45 22 18 4 2 1 1 1 94
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
Results One hundred nineteen MSGTs were benign (56%) and 94 were malignant (44%) (Table 1). The most common tumor overall was pleomorphic adenoma (PA), followed by mucoepidermoid carcinoma (MEC) (Table 2). PA was the most common benign tumor (93 of 119) (78.2%). PAs occurred between ages 17 and 88 years (average age, 46 years). PAs in females (61 cases) were more common than in males (32 cases) with a ratio of 1.9:1. The location of occurrence of PAs is listed in Table 3. The diverse microscopic pattern of this neoplasm is one of its most characteristic features (Fig 1). Cuboidal epithelial cells are arranged in tubes
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
or ductlike structures. In other areas, the tumor cells assumed a stellate, polyhedral, or spindle form, and some cells had a “plasmacystoid” morphology. Squamous epithelial cells with typical intercellular bridges were relatively common, and sometimes actual keratin pearls were formed. Foci of hyalinized connective tissue, cartilage-like, and/or mucoid material also were seen. Seventy-two cases of PA were available for evaluation of encapsulation. Fifty-nine cases had a capsule, although most were incomplete or tumor cells were noted in the capsule. Thirteen cases were without a capsule. In 16 of 50 palatal PAs, which had an incomplete capsule or were without a capsule, tumor cells extended into the overlying lamina propria (Fig 2). Mucoepidermoid carcinoma (MEC) was the most common malignant neoplasm and the second most common tumor overall, representing 45 of 94 malignancies (47.9%). The age range was from 25 to 90 years (average age, 55.6 years). Thirty-two cases of MEC were in females and 13 cases were in males, a ratio of 2.5:1. Locations of the MECs are listed in Table 4. Of interest are 5 central MECs, 3 that occurred in the maxilla and 2 that arose in the mandible. The reported duration of MECs was 1 week to 10 years, and the tumors ranged in size from 0.3 to 4 cm.
Table 2. ORDER OF INCIDENCE OF MINOR SALIVARY GLAND NEOPLASMS
Incidence Order Pleomorphic adenoma Mucoepidermoid carcinoma Canalicular adenoma Adenocystic carcinoma Polymorphous low-grade adenocarcinoma Adenocarcinoma, NOS Carcinoma ex pleomorphic adenoma Acinic cell carcinoma Cystadenocarcinoma Papillary cystadenocarcinoma Oxyphilic adenoma Total
No. of Cases (%) 93 (43.7) 45 (21.1) 25 (11.7) 22 (10.3) 18 (8.4) 4 (1.9) 2 (0.9) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 213
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
FIGURE 1. Photomicrograph showing a pleomorphic adenoma in the upper lip (hematoxylin and eosin stain, original magnification ⫻25). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
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YIH, KRATOCHVIL, AND STEWART
FIGURE 2. Photomicrograph of a palatal pleomorphic adenoma showing that the tumor cells were close to the mucosal epithelium (hematoxylin and eosin stain, original magnification ⫻25). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
FIGURE 3. Photomicrograph of a mucoepidermoid carcinoma composed of mucus-secreting cells and intermediate cells (hematoxylin and eosin stain, original magnification ⫻10). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
Microscopically, the tumors are composed of mucussecreting cells, epidermoid-type cells, and intermediate cells with different patterns and ratios (Fig 3). Clear cells were occasionally seen. Grading of MECs was based on the criteria of Auclair et al.2 Using these criteria, 38 cases of MEC were classified as low grade, 3 cases were intermediate grade, and 4 cases were high grade. Twenty-five cases were canalicular adenoma (CA), with 20 cases occurring in females and 5 cases in males. The age range was from 43 to 79 years (average age, 64 years). Sixteen cases of CA occurred in the upper lip, 7 cases were in the palate, and 2 cases were in the buccal mucosa. The sizes of the tumors ranged from 0.4 to 1 cm. The reported duration of CAs was from 2 months to 1 year. Microscopically, these CAs are typically composed of long strands or cords of epithelial cells that are arranged in a double row (Fig 4). The cords enclose some cystic spaces of varying sizes. The supporting stroma is loose and fibrillar with delicate vascularity. The tumors often have a thin
fibrous capsule. Six CAs in our series demonstrated multifocal microscopic features. Twenty-two cases were adenoid cystic carcinoma (ACC), and they occurred from age 19 to 94 years (average age, 58.6 years). Twelve ACCs were in females and 10 cases in males. Locations of ACCs were listed in Table 5. The sizes of the tumors were from 0.6 to 4 cm. Durations of ACCs were from 2 weeks to 6 years. Microscopically, the neoplasms are composed of small, deeply staining, uniform cells that are arranged in rounded islands, anastomosing cords, or with a ductlike pattern, the central portion of which may contain spaces with a mucoid material producing the typical cribriform pattern (Fig 5A). Spread of the tumor cells along the perineural spaces or in perineural sheaths is a common feature of this neoplasm. Growth of cells in a solid form sometimes occurs (Fig
Table 4. LOCATIONS OF MUCOEPIDERMOID CARCINOMAS
Location
No. of Cases
Palate Lower lip Retromolar region Buccal mucosa Maxilla Mandibular ridge Lower vestibule Floor of mouth Mandible Unknown
20 7 3 3 3 2 2 2 2 1
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
FIGURE 4. Photomicrograph of a canalicular adenoma showing cords of epithelial cells with loose supporting stroma (hematoxylin and eosin stain, original magnification ⫻100). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
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INTRAORAL MINOR SALIVARY GLAND NEOPLASMS
Table 5. LOCATIONS OF ADENOID CYSTIC CARCINOMAS
Table 6. LOCATIONS OF POLYMORPHOUS LOWGRADE ADENOCARCINOMAS
Location
No. of Cases
Location
No. of Cases
Palate Maxilla Buccal mucosa Mandibular vestibule Maxillary buccal vestibule Upper lip Floor of mouth Unknown
13 2 2 1 1 1 1 1
Palate Buccal mucosa Retromolar region Lower lip Upper lip Pillar of fauces Unknown
8 4 2 1 1 1 1
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
5B). In other instances, only thin, delicate anastomosing cords of neoplastic cells are dispersed throughout an abundant stroma. There were 18 cases of polymorphous low-grade adenocarcinoma (PLGA). Ten cases were in females and 8 cases were in males. PLGAs occurred from age 33 to 94 years (average age, 64 years). The sizes of the tumors were from 1 to 4.3 cm. Duration of the tumors
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
ranged from 6 months to 20 years. The locations of occurrence of PLGAs are listed in Table 6. Microscopically, cytologic uniformity and architectural diversity characterize the tumors. Growth patterns varied from solid, tubular, papillary, cribriform, to fascicular (Fig 6A), whereas the cells are always small to mediumsized, regular, and lacking in nuclear atypia (Fig 6B).
FIGURE 5. (A) Photomicrograph showing a cribriform pattern of an adenoid cystic carcinoma (hematoxylin and eosin stain, original magnification ⫻25). (B) Photomicrograph showing a solid growth pattern of adenoid cystic carcinoma (hematoxylin and eosin stain, original magnification ⫻25).
FIGURE 6. (A) Photomicrograph of a polymorphous low-grade adenocarcinoma (hematoxylin and eosin stain, original magnification ⫻25). (B) Photomicrograph of a polymorphous low-grade adenocarcinoma composed of uniform cuboidal cells with pale-staining ovoidshaped nuclei (hematoxylin and eosin stain, original magnification ⫻25).
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
YIH, KRATOCHVIL, AND STEWART
Mitoses are infrequent. Clear cytoplasm, oxyphilic and mucinous metaplasia, and intratubular calcification are sometimes present. Perineural invasion of tumor cells was common. Mucinization and hyalinization of stroma were often seen. All of the tumors were nonencapsulated. Four cases were diagnosed as adenocarcinoma not otherwise specified (AC). Three ACs occurred in females and 1 case occurred in a male. ACs occurred between ages 37 to 87 years (average age, 61.2 years). The sizes of the tumors were 0.7 to 3 cm, and the duration of the tumors was from 3 weeks to several years. Two cases occurred in the hard palate, one was in the lower lip, and the other was from an unknown location. Microscopically, the neoplasms that were classified in this nonspecific category were a histologically heterogeneous group; they varied from highly anaplastic adenocarcinoma to moderately well-differentiated lesions. Two cases were diagnosed as carcinoma ex PA. One case occurred in the right buccal mucosa of a 37-year-old man; the other was in the right retromolar region of a 75-year-old man. Microscopically, the malignant foci appeared in the histologically benign PA or the malignant component overgrew the benign element but the PA pattern was still apparent (Figs 7A, B). An acinic cell carcinoma occurred in the junction of the hard and soft palate in a 25-year-old man. One case was diagnosed as papillary cystadenocarcinoma in the left buccal mucosa of a 35-year-old man. A cystadenocarcinoma occurred in the left hard palate in a 47-year-old woman. Finally, there was an oxyphilic adenoma in the lower lip of a 26-year-old man.
Discussion Epithelial neoplasms arising in minor salivary glands are relatively common, and they are regularly encountered in oral and maxillofacial surgical pathology services. They are a microscopically heterogeneous group of neoplasms, and some types have a propensity to develop in particular intraoral locations. There have been several relatively recent reports of significantly large series of these tumors, including Eveson and Cawson’s series of 336 tumors reported in 1985,3 Waldron et al’s series of 426 tumors in 1988,4 Neville et al’s series of 103 labial gland tumors in 1988,5, and Ellis et al’s textbook of Surgical Pathology of Salivary Glands in 1991,6 which included 3,355 cases of MSGTs. In addition, there were 165 cases reported by Loyola et al in 19957 and 129 cases reported by Kusama et al in 1997.8 Our findings most closely follow those of Waldron and colleagues, probably due to the fact that their
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FIGURE 7. (A) Photomicrograph of a carcinoma ex pleomorphic adenoma showing pseudoductal structures formed by atypical epithelium and a hyalinized stroma (hematoxylin and eosin stain, original magnification ⫻100). (B) Photomicrograph showing nuclear pleomorphism, hyperchromatism, and increased mitosis in a carcinoma ex mixed tumor (hematoxylin and eosin stain, original magnification ⫻150). Yih, Kratochvil, and Stewart. Intraoral Minor Salivary Gland Neoplasms. J Oral Maxillofac Surg 2005.
series best demonstrates biopsy submissions most commonly seen in an oral pathology biopsy service and that the diagnostic labels given to the lesions are representative of those commonly used at this time. In the Armed Forces Institute of Pathology series,6 adenocarcinoma NOS was the third most common tumor diagnosed in minor glands, exceeding CA, ACC, and PLGA. This likely does not represent the true incidence of these neoplasms due to the fact that the Armed Forces Institute of Pathology is a referral center for pathologists and often only problematic cases are submitted for consultation. Eveson and Cawson’s3 series of 336 MSGTs was published in 1985 and did not include PLGA as a recognized neoplasm. The current review of our series found 8 of 18 PLGAs had been diagnosed as PA prior to 1983. In our series, the ratio of incidence of benign and malignant MSGTs is consistent with other reports.3– 8 PA is the most common benign MSGT in our series (93 of 119). PAs clinically exhibit slow growth of an irregular or a well-circumscribed, sessile-based, firm mass that occasionally has an ulcerated surface. In this
810 series, 16 cases of palatal PA demonstrated tumor cells that extended directly into the superficial lamina propria. However, in 17 other cases, the tumor cells were close to the mucosa with only a microscopic distance between (Fig 2). This finding would support the concept that the tumor and the overlying mucosa should be removed during complete excision of palatal mixed tumors. In this series, most of the PAs had an incomplete capsule with tumor cells in the capsule or tumor cells directly contacting the adjacent nonneoplastic tissue. CA was the second most common benign MSGT in this series (25 of 119). Surprisingly, Loyola et al7 and Kusama et al8 did not identify CAs in their publications. Six of our CAs (24%) were multifocal. This finding combined with a poorly developed, or absent, capsule could be misconstrued as an adenocarcinoma. In this series, labial CAs and PAs occurred only in the upper lip and were not found in the lower lip. Ninety-four MSGTs in this series were malignant (44%) with MEC (45 of 94), ACC (22 of 94), and PLGA (18 of 94) being the most common. Most MECs (38 of 45) were classified as low-grade lesions. The grading was based on the criteria created by Auclair et al.2 Of the 7 labial cases of MEC in our series, all of them occurred in the lower lip. These findings are consistent with those of Neville et al.5 In our series, 9 of the 10 lower lip salivary gland tumors (7 MEC, 1 PLGA, 1 adenocarcinoma, NOS) were malignant. ACC is a slowly growing malignancy. Early expression of nerve involvement is a characteristic of this tumor. Although the 5-year survival rate is high, the cure rate over 20 years is much lower.9 Microscopically, a solid growth pattern (Fig 6) usually carries a poor prognosis. Eight PLGAs were recognized in cases previously diagnosed before 1983 as PA and one case was previously diagnosed as ACC. Kusama et al8 noted that they did not identify any PLGAs in their series of 129 MSGTs. Possibly, PLGAs may have been included in their PAs and ACCs. Diagnosis of PLGA was based on cytologic uniformity and histologic diversity. PLGAs are usually slowly growing tumors and carry a relatively good prognosis.10 –13 Distinction of PLGA from ACC is sometimes difficult but important because
INTRAORAL MINOR SALIVARY GLAND NEOPLASMS
these 2 tumors pursue a significantly different clinical behavior. Adenocarcinoma NOS, tumors that could not be classified into a well-defined specific category, were a histologically heterogeneous group. Despite the microscopic variation in pattern, these tumors display the usual microscopic features of malignant neoplasms, including nuclear and cellular pleomorphism and invasive features. In our series, the relative incidence of benign and malignant MSGTs is consistent with previous reports. PA is the most common and MEC is the second most common MSGT. The palate is the most common site overall for MSGTs. The benign labial neoplasms are more common in the upper lip, whereas the malignant tumors are more common in the lower lip.
References 1. Seifert G, Donath K: Hybrid tumors of salivary glands. Definition and classification of five cases. Eur J Cancer B Oral Oncol 32B:251, 1996 2. Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of intraoral salivary glands. Evaluation and application of grading criteria in 143 cases. Cancer 69:2021, 1992 3. Eveson JW, Cawson RA: Salivary gland tumors: A review of 2410 cases with particular reference to histological types, site, age, and sex distribution. J Pathol 146:51, 1985 4. Waldron CA, el-Mofty SK, Gnepp DR: Tumors of the intraoral minor salivary glands: A demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol 66:323, 1988 5. Neville BW, Damm DD, Weir JC, et al: Labial salivary gland tumors. Cancer 61:2113, 1988 6. Ellis GL, Auclair PL, Gnepp DR: Surgical Pathology of the Salivary Glands. Philadelphia, PA, Saunders, 1991, pp 138 –146 7. Loyola AM, de Araujo VC, de Sousa SO, et al: Minor salivary gland tumors. A retrospective study of 164 cases in a Brazilian population. Eur J Cancer B Oral Oncol 31b:197, 1995 8. Kusama K, Iwanari S, Aisaki K, et al: Intraoral minor salivary gland tumors: A retrospective study of 129 cases. J Nihon Uni Sch Denti 39:128, 1997 9. Neville BW, Damm DD, Allen CM, et al: Oral and Maxillofacial Pathology (ed 2). Philadelphia, PA, Saunders, 2002, p 428 10. Batsakis JG, Pinkston GR, Luna MA, et al: Adenocarcinomas of the oral cavity: A clinico-pathologic study of terminal duct carcinomas. J Laryngol Otol 97:825, 1983 11. Freedman PD, Lummerman H: Lobular carcinoma of intraoral minor salivary glands. Oral Surg Oral Med Oral Pathol 56:157, 1983 12. Evans HL, Batsakis JG: Polymorphous low-grade adenocarcinoma of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Cancer 53:935, 1984 13. Vincent SD, Hammond HL, Finkelstein MW: Clinical and therapeutic features of polymorphous low-grade adenocarcinoma. Oral Surg Oral Med Oral Pathol 77:41, 1994