Tumors of the Salivary Glands
Tumors of the salivary glands constitute a heterogeneous group of lesions of great morphologic variation, and for this reason, present many difficulties in classification. Since these tumors are relatively uncommon, early investigators were handicapped by insufficient material for study. With the publication of several large series of cases, accompanied by serious discussions of the nature of tumors of the salivary glands based upon a cumulative clinical experience of many years, considerable progress has been made in broadening our knowledge of these lesions. Among these studies have been those of Evans and Cruickshank, Thackray and Lucas, and WHO.
Foote and Frazell were among the first investigators to provide a usable classification of salivary gland tumors. Spiro and his associates, Thackray and Sobin, and Batsakis have proposed classifications for practical use that are based on clinical behavior or specific histologic criteria. However, Eversole has proposed a histogenetic classification of salivary gland tumors, implicating two cell types as possible progenitors: the intercalated duct cell and the excretory duct reserve cell. The various types of salivary gland tumors are best distinguished by their histologic patterns. The clinical behavior of these various lesions may be based, as in most tumors, on the type of tumor as well as on the method of treatment utilized.
It is important to recognize that neoplasms may arise not only from the major salivary glands, but also from any of the numerous, diffuse, intraoral accessory salivary glands. Thus one may expect to see tumors originating from the glands in the lip, palate, tongue, buccal mucosa, floor of the mouth and retromolar area. Salivary gland tumors are much more common on the hard palate than on the soft, probably because there are a greater number of gland aggregates on the hard palate than on the soft palate. With only occasional exceptions, any type of tumor which occurs in a major salivary gland may also arise in an intraoral accessory gland. Thus, in the following discussion, the general features described under each tumor will hold true for both major and minor salivary gland lesions. There appear to be no truly specific, recognized tumors native only to the intraoral glands. Annual incidence of salivary gland tumors around the world is stated to be 1–6.5 cases per 100,000 people. Most studies have shown that minor salivary gland tumors are more common in females than males, with a ratio range from 1.2 : 1–1.9 : 1. Eneroth has presented data on over 2,300 tumors of the major salivary glands (Table 3-1), while a complete review of the intraoral minor salivary gland tumors has been published by Chaudhry and his coworkers, with much valuable information obtained from the analysis of over 1,300 cases (Table 3-2).
Occurrence of major salivary gland tumors
Data from CM Eneroth: Salivary gland tumors in the parotid gland, submandibular gland and the palate region. Cancer, 27: 1415, 1971.
Occurrence of intraoral accessory salivary gland tumors
Data from AP Chaudhry, RA Vickers, and RJ Gorlin: Intraoral minor salivary gland tumors. Oral Surg, 14: 1194, 1961.
Benign tumors of the salivary gland need no treatment other than surgical removal. Malignant tumors, on the other hand, may require radiation or chemotherapy or both after surgery. Surgery for salivary gland tumors removes all or most of the affected glands, not just the tumor. When performing surgery on these glands, great care is taken to identify and protect the nerves that pass through or near these glands and supply the muscles of the face, mouth and tongue. These nerves are stretched during surgery, which results in a temporary weakness on part of the face in up to 15% of patients. This weakness is temporary and usually disappears in one to three months. Occasionally, malignant tumors invade the nerves that supply part or all of the muscles of the face. When this occurs, a portion of the nerve is surgically removed with the tumor, and a nerve graft is used to rebuild the nerve.
Benign Tumors of the Salivary Glands
Pleomorphic Adenoma (Mixed tumor)
Pleomorphic adenoma is a benign neoplasm consisting of cells exhibiting the ability to differentiate to epithelial (ductal and nonductal) cells and mesenchymal (chondroid, myxoid and osseous) cells. This tumor has been referred to by a great variety of names through the years (e.g. mixed tumor, enclavoma, branchioma, endothelioma, enchondroma), but the term ‘pleomorphic adenoma’ suggested by Willis characterizes closely the unusual histologic pattern of the lesion. It is almost universally agreed that this tumor is not a ‘mixed’ tumor in the true sense of being teratomatous or derived from more than one primary tissue. Its morphologic complexity is the result of the differentiation of the tumor cells, and the fibrous, hyalinized, myxoid, chondroid and even osseous areas are the result of metaplasia or are actually products of the tumor cells per se. Pleomorphic adenoma is the most common salivary gland tumor (Table 3-3).
Histological classification of salivary gland tumors (WHO 1991)
• Pleomorphic adenoma
• Myoepithelioma (myoepithelial adenoma)
• Basal cell adenoma
• Warthin’s tumor (adenolymphoma)
• Oncocytoma (oncocytic adenoma)
• Canalicular adenoma
• Sebaceous adenoma
• Ductal papilloma
▫ Inverted ductal papilloma
▫ Intraductal papilloma
▫ Sialadenoma papilliferum
▫ Papillary cystadenoma
▫ Mucinous cystadenoma
• Acinic cell carcinoma
• Mucoepidermoid carcinoma
• Adenoid cystic carcinoma
• Polymorphous low grade adenocarcinoma (terminal duct adenocarcinoma)
• Epithelial-myoepithelial carcinoma
• Basal cell adenocarcinoma
• Sebaceous carcinoma
• Papillary cystadenocarcinoma
• Mucinous adenocarcinoma
• Oncocytic carcinoma
• Salivary duct carcinoma
• Malignant myoepithelioma (myoepithelial carcinoma)
• Carcinoma in pleomorphic adenoma (malignant mixed tumor)
• Squamous cell carcinoma
• Small cell carcinoma
• Undifferentiated carcinoma
• Other carcinomas
3. Nonepithelial tumors
4. Malignant lymphomas
5. Secondary tumors
6. Unclassified tumors
7. Tumor like lesions
• Necrotizing sialometaplasia (salivary gland infarction)
• Benign lymphoepithelial lesion
• Salivary gland cysts
• Chronic sclerosing sialadenitis of submandibular gland (Küttner tumor)
• Cystic lymphoid hyperplasia in AIDS
Adapted from: Seifert G. Histological typing of salivary gland tumors, 2nd ed. Berlin, Springer-Verlag, 1991.
Numerous theories have been advanced in explaining the histogenesis of this bizarre tumor. Currently, these center around the myoepithelial cell and a reserve cell in the intercalated duct. Ultrastru ctural studies have confirmed the presence of both ductal and myoepithelial cells in pleomorphic adenomas. It follows that possibly either or both may play active roles in the histogenesis of the tumor. Hubner and his associates have postulated that the myoepithelial cell is responsible for the morphologic diversity of the tumor, including the production of the fibrous, mucinous, chondroid and osseous areas. Regezi and Batsakis postulated that the intercalated duct reserve cell can differentiate into ductal and myoepithelial cells and the latter, in turn, can undergo mesenchymal metaplasia, since they inherently have smooth muscle like properties. Further differentiation into other mesenchymal cells then can occur. Batsakis has discussed salivary gland tumorigenesis, and while still implicating the intercalated duct reserve cell as the histogenetic precursor of the pleomorphic adenoma, stated that the role of the myoepithelial cell is still uncertain and that it may be either an active or passive participant histogenetically. Finally, Dardick and his associates have questioned the role of both ductal reserve and myoepithelial cells. They state that a neoplastically altered epithelial cell with the potential for multidirectional differentiation may be histogenetically responsible for the pleomorphic adenoma.
Pleomorphic adenomas have shown consistent cytogenetic abnormalities, chiefly involving the chromosome region 12q13-15. The putative pleomorphic adenoma gene (PLAG1) has been mapped to chromosome 8q12. Many other genes have also been implicated; however, cytogenetic or molecular studies do not as yet have an established role in the diagnosis of pleomorphic adenoma.
Pleomorphic adenoma is the most common tumor of salivary glands. The parotid gland is the most common site of the pleomorphic adenoma; 90% of a group of nearly 1,900 such tumors reported by Eneroth. It may occur in any of the major glands or in the widely distributed intraoral accessory salivary glands; however its occurrence in the sublingual gland is rare. In the parotid this tumor most often presents in the lower pole of the superficial lobe of the gland, about 10% of the tumors arise in the deeper portions of the gland. Approximately 8% of pleomorphic adenomas involve the minor salivary glands, the palate is the most common site (60–65%) of minor salivary gland involvement. It occurs more frequently in females than in males, the ratio approximating 6 : 4. The majority of the lesions are found in patients in the fourth to sixth decades with the average age of occurrence of about 43 years, but they are also relatively common in young adults and have been known to occur in children. The clinical behavior of this tumor in children is similar to that in adults (Table 3-4).
TNM/AJCC 1997 staging (clinical staging)
TX: primary tumor cannot be assessed
• T0: No evidence of primary tumor
• T1: Tumor 2 cm or less in greatest dimension without extraparenchymal extension*
• T2: Tumor > 2 cm but < 4 cm in greatest dimension without extraparenchymal extension*
• T3: Tumor having extraparenchymal extension* without seventh nerve involvement and/or more than 4 cm but no more than 6 cm in greatest dimension
• T4: Tumor invades base of skull, seventh nerve, and/or exceeds 6 cm in greatest Dimension
• N0: No regional node metastasis
• Nx: Regional nodes cannot be assessed
• N1: Single ipsilateral node, < 3 cm
• N2a: Single ipsilateral node, > 3 cm and < 6 cm
• N2b: Multiple ipsilateral nodes, < 6 cm
• N2c: Contralateral or bilateral nodes, < 6 cm
• N3: Node > 6 cm
• MO: No distant metastasis
• Mx: Metastasis cannot be assessed
Minor salivary gland tumors are staged according to their site of origin.
Microscopic evidence alone does not constitute extraparenchymal extension for classification purpose.
*Extraparenchymal extension is clinical or macroscopic evidence of invasion of skin, soft tissues, bone or nerve.
The history presented by the patient is usually that of a small, painless, quiescent nodule which slowly begins to increase in size, sometimes showing intermittent growth (Fig. 3-1). The pleomorphic adenoma, particularly of the parotid gland, is typically a lesion that does not show fixation either to the deeper tissues or to the overlying skin (Fig. 3-2 A). It is usually an irregular nodular lesion which is firm in consistency, although areas of cystic degeneration may sometimes be palpated if they are superficial. The skin seldom ulcerates even though these tumors may reach a fantastic size, lesions having been recorded which weighed several kilograms (Fig. 3-2 B). Pain is not a common symptom of the pleomorphic adenoma, but local discomfort is frequently present. Facial nerve involvement manifested by facial paralysis is rare.
Figure 3-2 Pleomorphic adenoma of parotid gland.
(A) Typical appearance of pleomorphic adenoma of parotid gland. (B) The lesion here is used not to illustrate the usual clinical appearance of a pleomorphic adenoma of the parotid gland, but to demonstrate the size which these tumors may attain. This lesion was present for eighteen years A, Courtesy of Dr Neelakandan RS, Department of Oral and Maxillofacial Surgery, Meenakshi Ammal Dental College, Chennai.
The pleomorphic adenoma of intraoral accessory glands seldom is allowed to attain a size greater than 1–2 cm in diameter. Because this tumor causes the patient difficulties in mastication, talking and breathing, it is detected and treated earlier than tumors of the major glands. The palatal glands are frequently the site of origin of tumors of this type (Fig. 3-3), as are the glands of the lip (Fig. 3-4) and occasionally other sites. Except for size, the intraoral tumor does not differ remarkably from its counterpart in a major gland. The palatal pleomorphic adenoma may appear fixed to the underlying bone, but is not invasive. In other sites the tumor is usually freely movable and easily palpated. Recurrent lesions, however, occur as multiple nodules and are less mobile than the original tumor (Table 3-5).
Occurrence of major salivary gland tumors
Modified from: Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer Incidence in Five Continents, Volume VIII, IARC Scientific Publications No. 155, 2002, IARC, Lyon, France.
The mixed tumors generally appear as an irregular to ovoid mass with well-defined borders. The tumors in major glands have either an incomplete fibrous capsule or are unencapsulated whereas in the minor glands they are unencapsulated. The cut surface may be rubbery, fleshy, mucoid or glistening with a homogeneous tan or white color. Areas of hemorrhage and infarction may be noted occasionally.
Morphologic diversity is the most characteristic feature of this neoplasm. Microscopically, benign mixed tumors are characterized by variable, diverse, structural histologic patterns, seldom do individual cases resemble each other, considerable variation is also seen within a single tumor. Pleomorphic adenomas demonstrate combinations of glandular epithelium and mesenchyme like tissue and the proportion of each component varies widely among individual tumors. Foote and Frazell (1954) categorized the tumor into the following types:
Typical features of benign and malignant salivary gland tumors
|Benign salivary gland tumors||Malignant salivary gland tumors|
|• Slow growing||• Sometimes fast growing|
|• Soft or rubbery consistency||• Sometimes hard consistency|
|• 85% of parotid tumors are benign||• 45% of minor glands are malignant|
|• Do not ulcerate||• May ulcerate and invade bone|
|• No associated nerve signs||• May cause cranial nerve palsies (e.g. parotid tumor causes facial palsy, adenoid cystic carcinoma can cause multiple nerve lesions especially of lingual, facial or hypoglossal nerves)|
• Myxoid and cellular components present in equal proportion
The epithelial component forms ducts and small cysts that may contain an eosinophilic coagulum, the epithelium may also occur as small cellular nests, sheets of cells, anastomosing cords and foci of keratinizing squamous or spindle cells. Myoepithelial cells are a major component of pleomorphic adenoma. They have a variable morphology, sometimes appearing as angular or spindled, while some cells are more rounded with eccentric nuclei and hyalinized eosinophilic cytoplasm resembling plasma cells (earlier referred to as hyaline cells) (Fig. 3-5). Myoepithelial-cells are also responsible for the characteristic mesenchyme like changes; these changes are brought about by extensive accumulation of mucoid material around individual myoepithelial cells giving a myxoid appearance. Vacuolar degeneration of these myoepithelial cells then results in a cartilaginous appearance (Fig. 3-6). Foci of hyalinization, bone and even fat can be noted in the connective tissue stroma of many tumors. When the pleomorphic pattern of the stroma is absent, and the tumor is highly cellular, it is often referred to as a ‘cellular adenoma’. When myoepithelial proliferation predominates, the diagnosis of ‘myoepithelioma’ (q.v.) is generally made.
Figure 3-5 Pleomorphic adenoma.
Keratinizing epithelium in a background of plasmacytoid myoepithelial cells Courtesy of Dr Albert Abrams.
Treatment and Prognosis
The accepted treatment for this tumor is surgical excision. The intraoral lesions can be treated somewhat more conservatively by extracapsular excision. Since these tumors are radioresistant, the use of radiation therapy is of little benefit and is therefore contraindicated.
Rarely, a malignant tumor may arise within this tumor, a phenomenon known as carcinoma ex pleomorphic adenoma. There is a second class of tumors which are called metastasizing benign mixed tumors. These tumors have a histologically benign appearance but usually have a history of multiple local recurrences. Metastases occur several years after the initial diagnosis and may occur to the lungs, regional lymph nodes, skin, and bone. The usual clinical course is good but there are cases which have an aggressive clinical course leading to death in 22% of cases. Fortunately this last category of tumors is very rare.
Myoepithelioma: (Myoepithelial adenoma)
The term myoepithelioma was first used by Sheldon in 1943. The myoepithelioma is an uncommon salivary gland tumor which accounts for less than 1% of all major and minor salivary tumors. Nonetheless, it is important in that the component cell constitutes a prominent place in salivary gland neoplasia. Many authorities, including Batsakis, consider the myoepithelioma to be a ‘one-sided’ variant at the opposite end of the spectrum from the pleomorphic adenoma.
There are no clinical features which can serve to separate the myoepithelioma from the more common pleomorphic adenoma. It occurs in adults with an equal gender distribution. The parotid gland is most commonly involved and the palate is the most frequent intraoral site of occurrence. Sciubba and Brannon reported lesions in the retromolar glands and the upper lip.
The tumor is composed exclusively, or almost exclusively, of neoplastic myoepithelial cells. The neoplastic cells are predominantly spindle-shaped or plasma-cytoid. Epithelioid or clear cells may also be present (Figs. 3-7, 3-8). Either a single cell type predominates in a tumor or there may be a combination of cell types. The tumor is often difficult to diagnose definitively at the light microscopic level. Myoep-ithelioma does not contain the characteristic chondromyxoid stroma of pleomorphic adenoma. Myoepithelioma consisting predominantly of spindle cells tends to be more cellular than the tumor consisting of predominantly plasmacytoid cells. Definitive diagnosis lies in the ultrastructural identification of myoepithelial cells. The myoepithelial cell exhibits a basal lamina and fine intracytoplasmic myofilaments. Desmosomes are encountered between adjacent cells.
Basal Cell Adenoma
Basal cell adenoma is a neoplasm of a uniform population of basaloid epithelial cells arranged in solid, trabecular, tubular, or membranous patterns. The basal cell adenoma was first reported as distinct entity by Kleinsasser and Klein in 1967. Batsakis is credited with reporting the first case in the American literature in 1972, and suggested that the intercalated duct or reserve cell is the histogenetic source of the basal cell adenoma.
Basal cell adenomas tend to occur primarily in the major salivary glands, particularly the parotid gland. In the series reported by Batsakis and associates, 48 of 50 tumors were in the parotid gland and two were in the submaxillary gland. The tumors are usually painless and are characterized by slow growth. They occur chiefly in adults, the average age of the patients is 57.7 years with the peak of incidence seen in the sixth decade. However, the tumor can occur in younger persons, Canalis and his coworkers reported a basal cell adenoma in the submaxillary gland of a newborn male. There is a 2 : 1 female predilection for the occurrence of this tumor. These tumors appear as a firm swelling which may be cystic and compressible. These tumors are clinically indistinguishable from mixed tumors and their greatest dimension is usually less than 3 cm.
Basal cell adenoma occurs as a single well-defined nodule, the membranous type may be multifocal. Tumors in major salivary gland have a well defined capsule, whereas intraoral tumors are less well defined. The cut surface often is homogeneous with gray to brown in color, and may have cystic areas.
The basal cells that make up this lesion are fairly uniform and regular; two morphologic forms can be seen. One is a small cell with scanty cytoplasm and round deeply basophilic nucleus. The other cell is large with eosinophilic cytoplasm and an ovoid pale staining nucleus. Basal cell adenomas can be divided on the basis of their morphologic appearances into four subtypes:
The most common type of basal cell adenoma is the solid variant. The basaloid cells form islands and cords that have a broad, rounded, lobular pattern. These cells are sharply demarcated from the connective tissue stroma by basement membrane. This feature contrasts with the melting type of growth characteristic of pleomorphic adenoma.
This pattern exhibits multiple small, round duct like structures. These tubules are lined by two distinct layers of cells, with inner cuboidal ductal cells surrounded by an outer layer of basaloid cells. The tubular variant is the least common; however, tubule formation either alone or with basal cell masses, can be found in most basal cell adenomas, at least focally (Fig. 3-9).
This subtype has the same cytologic features as the solid type, but the epithelial islands are narrower and cord like and are interconnected with one another, producing a reticular pattern (Fig. 3-10).
This is a distinct subtype of basal cell adenoma characterized by the presence of abundant, thick, eosinophilic hyaline layer that surrounds and separates the epithelial islands. Electron microscopy has shown that this hyaline material is reduplicated basement membrane. The epithelial islands are arranged in large lobules and appear to mould to the shape of other lobules to resemble a jigsaw puzzle pattern.
Warthin’s Tumor: (Papillary cystadenoma lymphomatosum, adenolymphoma)
Warthin’s tumor is the second most common tumor in the salivary glands. This tumor was first recognized by Albrecht in 1910 (quoted by Ellis and Auclair 1991) and later described by Warthin in 1929. This unusual type of salivary gland tumor occurs almost exclusively in the parotid gland, although occasional cases have been reported in the submaxillary gland. The intraoral accessory salivary glands are rarely affected.
Numerous theories have been advanced to account for the peculiar nature of this tumor. The currently accepted theory is that the tumor arises in salivary gland tissue entrapped within paraparotid or intraparotid lymph nodes during embryogenesis. However, Allegra has suggested that the Warthin’s tumor is most likely a delayed hypersensitivity disease, the lymphocytes being an immune reaction to the salivary ducts which undergo oncocytic change. Hsu and coworkers recently studied the tumor immunohistochemically and have suggested that the lymphoid component of the tumor is an exaggerated secretory immune response.
A strong association between development of this tumor and smoking is documented. The exact mechanism by which smoking may predispose patients to Warthin’s tumor is unclear. However, several studies have shown that a high percentage of Warthin’s tumor patients smoke. Epstein-Barr virus has also been implicated in the pathogenesis of this tumor; however there are many conflicting reports.
Warthin’s tumor was traditionally considered a disease of men. However, recent reports have identified a substantial percentage of patients who are women. This tumor commonly presents in the sixth and seventh decades and average age of the patients at the time of diagnosis of the lesion was 62 years. The tumor is generally superficial, lying just beneath the parotid capsule or protruding through it. Seldom does the lesion attain a size exceeding 3–4 cm in diameter. It is not painful, is firm to palpation and is clinically indistinguishable from other benign lesions of the parotid gland.
It is a smooth, some what soft parotid mass and is well encapsulated when located in the parotid. The tumor contains variable number of cysts that contains a clear fluid. Areas of focal hemorrhage may also be seen.
This tumor is made up of two histologic components: epithelial and lymphoid tissue. As the name would indicate, the lesion is essentially an adenoma exhibiting cyst formation, with papillary projections into the cystic spaces and a lymphoid matrix showing germinal centers (Fig. 3-11). The cysts are lined by papillary proliferations of bilayered oncocytic epithelium. The inner layer cells are tall columnar with finely granular and eosinophilic cytoplasm due to presence of mitochondria and slightly hyperchromatic nuclei. The outer layer cells are oncocytic triangular and occasionally fusiform basaloid cells. Focal areas of squamous metaplasia and mucous cell prosoplasia may be seen. There is frequently an eosinophilic coagulum present within the cystic spaces, which appears as a chocolate-colored fluid in the gross specimen. The abundant lymphoid component may represent the normal lymphoid tissue of the lymph node within which the tumor developed or it may actually represent a reactive cellular infiltrate which involves both humoral and cell mediated mechanisms (Fig. 3-12).
Figure 3-11 Warthin’s tumor.
Figure shows cystic spaces partially filled with homogeneous fluid circumscribed by double rows of oncocytes having a stroma richly infiltrated by lymphoid tissue.
Treatment and Prognosis
The accepted treatment of the papillary cystadenoma lymphomatosum is surgical excision. This can almost invariably be accomplished without injury to the facial nerve, particularly since the lesion is usually small and superficial. These tumors are well encapsulated and seldom recur after removal.
Malignant transformation is exceedingly rare in either the epithelial or lymphoid component. Cases of mucoepidermoid carcinoma involving Warthin’s tumor of the parotid gland have been reported; however, a direct transition from Warthin’s tumor to mucoepidermoid carcinoma was not identified.
Oncocytoma: (Oncocytic adenoma, oxyphilic adenoma, acidophilic adenoma)
Oncocytoma is a rare benign tumor composed of oncocytes with granular eosinophilic cytoplasm and a large number of atypical mitochondria. This rare salivary gland tumor is a small benign lesion, which usually occurs in the parotid gland. Except that it does not generally attain any great size, it does not differ in its clinical characteristics from other benign salivary gland tumors. For this reason, a clinical diagnosis is difficult if not impossible to establish. The name ‘oncocytoma’ is derived from the resemblance of these tumor cells to apparently normal cells which have been termed ‘oncocytes’ and which are found in a great number of locations, including the salivary glands, respiratory tract, breast, thyroid, pancreas, parathyroid, pituitary, testicle, fallopian tube, liver and stomach. These cells are predominantly seen in duct linings of glands in elderly persons, but little is actually known of their mode of development or significance (Fig. 3-13). Electron microscopic studies have shown that the cytoplasm of the oncocyte is choked with mitochondria. Ionizing radiation is the predisposing condition.
Figure 3-13 Oxyphilic adenoma.
(A) Normal oncocytes in accessory salivary gland ducts of elderly patient. (B) High-power photomicrograph. (C) Low-power photomicrograph of oncocytoma.
The oncocytoma is somewhat more common in women than in men and occurs almost exclusively in elderly persons. Chaudhry and Gorlin, who reviewed the literature, found 29 cases of oncocytoma and added four new cases to those reported. Only occasionally does this tumor arise before the age of 60 years, 80% of cases occurring between the ages of 51 and 80 years. The tumor usually measures 3–5 cm in diameter and appears as a discrete, encapsulated mass which is sometimes nodular. Pain is generally absent.
An interesting condition called diffuse multi nodular oncocytoma or ‘oncocytosis’ of the parotid gland has been described by Schwartz and Feldman. This condition is characterized by nodules of oncocytes which involve the entire gland or large portions of it.
The oxyphilic adenoma is characterized microscopically by large cells which have an eosinophilic cytoplasm and distinct cell membrane and which tend to be arranged in narrow rows or cords (Fig. 3-13). The oncocytes are arranged in sheets or nests and cords, which form alveolar or organoid pattern. Some degree of cellular atypia, nuclear hyperchromatism and pleomorphism is accepted as compatible with benignancy in oncocytoma. These cells, exhibiting few mitotic figures, are closely packed, and there is little supportive stroma (Fig. 3-14). Lymphoid tissue is frequently present, but does not appear to be an integral part of the lesion. Ultrastructural studies of parotid oncocytomas by Tandler and associates and Kay and Still have shown that the cells are engorged with enlarged and morphologically altered mitochondria.
Figure 3-14 Oncocytoma alveolar pattern.
Illustrated by clusters of oncocytes that are supported by thin, fibrous connective tissue septa and small blood vessels. Note oncocytes have clear cytoplasm that is interspersed with cytoplasmic granularity.
A variant of the oxyphilic adenoma is sometimes seen in intraoral salivary glands, particularly in the buccal mucosa and upper lip. This has been termed, an oncocytic cystadenoma since it is a tumor like nodule composed chiefly of numerous dilated duct like or cyst like structures lined with oncocytes. In recurrent tumors, there may be marked clear cell change and these tumors may be referred to as clear-cell oncocytoma. Treatment and Prognosis. The treatment of choice is surgical excision, and the tumor does not tend to recur. Malignant transformation is uncommon, but malignant oncocytoma is now a well-established entity. Johns and associates reviewed the literature on malignant oncocytomas and reported three additional cases. Other well-documented cases have been those of Lee and Roth, and Gray and his coworkers.
Canalicular adenoma is an uncommon neoplasm composed of columnar epithelial cells arranged in a single or double layer forming branching cords in a loose stroma. The bilayer shows an intermittent separation, which forms structures resembling lumen or canaliculi.
This lesion originates primarily in the intraoral accessory salivary glands, and in the vast majority of cases, it occurs in the upper lip. However, cases are known in which the lesion occurred in the palate, buccal mucosa and lower lip. Only one was noted in the parotid gland in the series reported by Nelson and Jacoway. The tumor occurs in adults far more common in patients of age 34–65 years; this tumor is seen more commonly in females with a ratio of 1.8 : 1. The tumor generally presents as a slowly growing, well-circumscribed, firm nodule which, particularly in the lip, is not fixed and may be moved through the tissue for some distance. Occasionally, two separate and distinct tumors may occur in the upper lip of an individual.
The canalicular adenoma has a strikingly characteristic picture. It is composed of long columns or cords of cuboidal or columnar cells in a single layer. These single layers of cells are parallel, forming long canals. Some-times rows of cells are closely approximated and appear as a double row of cells showing a ‘party wall’. In some instances, cystic spaces of varying sizes are enclosed by these cords. The cystic spaces are usually filled with an eosinophilic coagulum. The supporting stroma is loose and fibrillar with delicate vascularity (Fig. 3-15). The tumor has, at times, been mistaken for an adenoid cystic carcinoma and care should be taken to prevent this error (Fig. 3-16). As Mader and Nelson have pointed out, the adenoid cystic carcinoma rarely occurs in the upper lip and is seldom freely movable. Occasionally the tumor may be multifocal and foci of tumor cells are found outside the main lesion.
Sebaceous adenoma is a rare benign tumor that accounts for 0.1% of all salivary gland neoplasms and slightly less than 0.5% of all salivary adenomas. The mean age at initial clinical presentation was 58 years (range 22–90 years). This tumor is more common in men. In a series of cases reported by Ellis et al (1991), 12 tumors were located in the parotid gland, 4 in the buccal mucosa, two in the submandibular gland, and three in the area of lower molars or retromolar region. The tumors ranged in size from 0.42–3.0 cm in diameter.
The tumors are commonly encapsulated or sharply circumscribed, and they vary in color from grayish-white to pinkish-white to yellow or yellowish gray. These tumors are composed of sebaceous cell nests with minimal atypia and pleomorphism and no tendency to invade local structures. Many tumors are microcystic or may be composed predominantly of ectatic salivary ducts with focal sebaceous differentiation. The sebaceous glands may vary markedly in size and in tortuosity and are usually embedded in a fibrous stroma. Occasionally tumors demonstrate marked oncocytic metaplasia, and histiocytes and/or foreign body giant cells may be seen focally. Lymphoid follicles, cytologic atypia, cellular necrosis, and mitosis are not observed in sebaceous adenomas.
Conservative excision seems to be the treatment of choice. No recurrences have been reported.
The term ductal papilloma is used to identify a group of three rare benign papillary salivary gland tumors. They represent adenomas with unique papillary features and arise from the salivary gland duct system. There are three types with unique histopathological features. These are inverted ductal papilloma, intraductal papilloma, and sialadenoma papilliferum.
Inverted Ductal Papilloma
Inverted ductal papilloma was first described by White et al, in 1982. It is a very rare tumor and has been described only in minor salivary glands of adults. The lower lip is the most frequently involved site followed by buccal vestibular mucosa. Inverted ductal papillomas appear to arise from the excretory ducts near the mucosal surface. Clinically, these tumors are seen as submucosal nodules which may have a pit or indentation in the overlying surface mucosa. These tumors do not show any gender predilection.
Histologically, it consists of basaloid and squamous cells arranged in thick, bulbous papillary proliferations that project into the ductal lumen. The lumen of the tumor is often narrow and in some tumors communicates with the exterior of the mucosal surface through a constricted opening.
Intraductal papilloma is an ill-defined lesion that often is confused with papillary cystadenoma. It usually occurs in adults, with a mean age of occurrence being 54 years and is common in the minor salivary glands. The lower lip is the most frequently involved site followed by upper lip, palate and buccal mucosa. No gender predilection has been noted. Intraductal papilloma presents clinically as a submucosal swelling. These tumors appear to arise from the excretory ducts at a deeper level than the inverted ductal papilloma.
Microscopically, it exhibits a unicystic dilated structure. The cyst wall is lined by a single or double row of cuboidal and columnar cells, which extend into the cyst lumen as papillary projections having thin fibrovascular cores.
Sialadenoma papilliferum most commonly involves the minor salivary gland. This has a more complex histology, with a biphasic growth pattern of exophytic papillary and endophytic components. This tumor usually affects adults, the average age of the patients is 56 years. A male predilection is seen. The clinical presentation is unique as nearly all salivary gland neoplasms manifest as subsurface nodular swellings whereas sialadenoma papilliferum occurs as an exophytic, papillary surface lesion. The clinical impression in most cases is squamous papilloma of the mucosa.
Microscopically, these tumors display both an exophytic and an endophytic proliferation of ductal epithelium. The surface of the lesion is formed of papillary projections of epithelium supported by fibrovascular cores, covered by parakeratotic stratified squamous epithelium. The fibrovascular cores have an inflammatory cell infiltrate of lymphocytes, plasma cells and neutrophils. The ductal epithelium continues downwards into the deeper connective tissues. Multiple ductal lumina are seen, which are lined by a double row of cells consisting of a luminal layer of tall columnar cells resting on a cuboidal basal layer.
Cystadenomas of the salivary glands are benign neoplasms in which the epithelium demonstrates adenomatous proliferation that is characterized by formation of multiple cystic structures. Several morphologic variants of cystadenoma have been described of which papillary cystadenoma and mucinous cystadenoma are important. The papillary cystadenoma (PC) is defined as a cystadenoma in which the cystic space is filled with papillary projections. WHO described papillary cystadenoma as “a tumor that closely resembles Warthin’s tumor but without the lymphoid elements, constituting multiple papillary projections and a greater variety of epithelial lining cells.” If mucous cells predominate in the cell population of the lining epithelial cells, the tumor is termed as mucinous cystadenoma.
Cystadenoma is widely distributed among major and minor salivary glands. Most of the minor salivary gland tumors are seen in lips, buccal mucosa, palate and the tonsillar area. This is more common in females than males (2:1) and occurs in older age, most common in the eighth decade of life. Clinically, it presents as a slow growing painless slightly compressible swelling. Some of the nodules are clinically similar to mucocele.
Epithelial proliferation (Fig. 3-17) results in various sized cystic structures. The lining of these cystic structures varies from flattened to tall columnar cells, and cuboidal, mucous and oncocytic cells may also be seen. The lining thickness varies from one to three epithelial cells. Limited papillary growth with central connective tissue core is seen. Eosinophilic or slightly hematoxyphilic secretions are seen in the stroma. Dense fibrous connective tissue stroma with scattered inflammatory cells is present.
Malignant Tumors of the Salivary Glands
Acinic Cell Carcinoma: (Acinar cell or serous cell adenoma, adenocarcinoma)
Most salivary gland tumors arise from the epithelium of the duct apparatus, but occasionally lesions seem to show acinar cell differentiation. Acinic cell carcinoma is a malignant epithelial neoplasm in which the neoplastic cells express acinar differentiation. Some authors advocate the existence of both benign and malignant acinic cell neoplasms, whereas others are of the opinion that all acinic cell neoplasms are malignant. Unfortunately, the criteria for distinguishing between benign and malignant acinar cell tumors, if such a distinction exists, have not been clearly established. In an extensive study of acinic cell tumors of the major salivary glands by Abrams and his coworkers, it was concluded that most investigators believe that all tumors of this type have at least a low-grade malignant potential. By conventional use, the term acinic cell carcinoma is defined by cytologic differentiation towards serous acinar cells (as opposed to mucous acinar cells), whose characteristic feature is cytoplasmic PAS-positive zymogen-type secretory granules. In AFIP data of salivary gland neoplasms, acinic cell carcinoma is the third most common malignant salivary gland epithelial neoplasm after mucoepidermoid carcinoma and adenocarcinoma. In this data, acinic cell carcinoma comprised 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms (cited by Ellis GL, Auclair PL, Gnepp DR, 1991).
The acinic cell carcinoma closely resembles the pleomorphic adenoma in gross appearance, tending to be encapsulated and lobulated. Although this tumor has been reported occurring chiefly in the parotid, with more than 80% of the cases occurring in the parotid gland, it does occur occasionally in the other major glands and in the accessory intraoral glands (Fig. 3-18). The most common intraoral sites are the lips and buccal mucosa. The acinic cell carcinoma occurs predominantly in persons in middle age or somewhat older, the mean age being 44 years. It has also been encountered in 12% of the patients before the age of 20 years. Women were affected more than men (3 : 2). This tumor presents as a slowly growing, mobile or fixed mass of various durations. Usually asymptomatic but pain or tenderness is seen in over one third of the patients. Facial muscle weakness may be seen. Patients with bilateral synchronous tumors have been reported.
The acinic cell carcinoma, which is frequently surrounded by a thin capsule, may be composed of cells of varying degrees of differentiation. Well-differentiated cells bear remarkable resemblance to normal acinar cells, whereas less differentiated cells resemble embryonic ducts and immature acinar cells. Abrams and his associates have described four growth patterns: (1) solid, (2) papillary-cystic, (3) follicular, and (4) microcystic. In general, one pattern predominates, although combinations can occur. The most characteristic cell seen has the features of the serous acinar cells, with abundant granular basophilic cytoplasm and a round darkly stained eccentric nucleus. Other cells seen are the intercalated duct like cells, which are smaller and the vacuolated cells which seem to be unique to acinic cell carcinomas among salivary gland neoplasms.
Connective tissue stroma is delicately fibro vascular collagenous tissue. Lymphoid elements are commonly found in parotid acinic cell carcinomas, a feature which is helpful in the diagnosis. Such features are not found in the intraoral tumors. Apparently the acinic cell carcinoma can arise from embryologically entrapped salivary gland tissue in lymph nodes in or near the parotid compartment. Although ‘clear cells,’ have been described in acinic cell carcinomas, they most likely represent cells altered by fixation or they may actually represent the component cells of a clear cell carcinoma (q.v.), a recently recognized entity (Figs. 3-19, 3-20).
Treatment and Prognosis
The treatment of the acinic cell carcinoma in most cases has been surgical. Perzin and LiVolsi recommend total excision of parotid gland tumors with preservation of the facial nerve unless it is involved. Lymph node dissection is indicated only in the presence of clinical involvement and not as a routine procedure. Radiation therapy has not been shown to be of therapeutic value. Intraoral tumors are treated by surgical excision. Poor prognostic features included pain or fixation; gross invasion; and microscopic features of desmoplasia, atypia, or increased mitotic activity. Neither morphologic pattern nor cell composition was a predictive feature.
Mucoepidermoid carcinoma is a malignant epithelial tumor, first studied and described as a separate entity by Stewart, Foote and Becker in 1945. As the name implies, the tumor is composed of both mucus-secreting cells and epidermoid-type cells in varying proportions. Columnar and clear cells are also seen, and often demonstrate prominent cystic growth. It is the most common malignant neoplasm observed in the major and minor salivary glands. Mucoepidermoid carcinoma represents 29–34% of malignant tumors originating in both major and minor salivary glands. This carcinoma of the salivary glands accounts for 5% of all salivary gland tumors. The parotid gland is the most common site of occurrence. Intraorally, mucoepidermoid carcinoma shows a strong predilection for the palate.
Mucoepidermoid carcinoma occurs with a slight female predilection. It occurs primarily in the third or fifth decades of life, with an average age of 47 years, but can occur in virtually all decades. It is the most common malignant salivary gland tumor of children. Prior exposure to ionizing radiation appears to substantially increase the risk of developing mucoepidermoid carcinoma.
The tumor of low-grade malignancy usually appears as a slowly enlarging, painless mass which simulates the pleomorphic adenoma. Unlike the pleomorphic adenoma; however, the low-grade mucoepidermoid carcinoma seldom exceeds 5 cm in diameter, is not completely encapsulated and often contains cysts which may be filled with a viscid, mucoid material. In addition to palate intraoral tumors occur on the buccal mucosa, tongue and retromolar areas. Because of their tendency to develop cystic areas, these intraoral lesions may bear close clinical resemblance to the mucous retention phenomenon or mucocele, especially those in the retromolar area (Fig. 3-21).
Figure 3-21 Mucoepidermoid carcinoma of palate. Courtesy of Dr Neelakandan RS, Department of Oral and Maxillofacial Surgery, Meenakshi Ammal Dental College, Chennai.
The tumor of high-grade malignancy grows rapidly and does produce pain as an early symptom. Facial nerve paralysis is frequent in parotid tumors. The patient may also complain of trismus, drainage from the ear, dysphagia, numbness of the adjacent areas and ulceration, noted particularly in tumors of the minor salivary glands. The mucoepidermoid carcinoma is not encapsulated, but tends to infiltrate the surrounding tissue, and in a large percentage of cases, it metastasize to regional lymph nodes. Distant metastases to lung, bone, brain and subcutaneous tissues are also common.
The mucoepidermoid carcinoma is composed of mucous secreting cells, epidermoid type (squamous) cells and intermediate cells. The mucous cells are of various shapes and have abundant, pale, foamy cytoplasm that stains positively for mucin stains. The epidermoid cells have squamoid features, demonstrate a polygonal shape, intercellular bridges and rarely keratinization. A population of cells that is often more important in recognizing mucoepidermoid carcinoma is a group of highly prolific, basaloid cells referred to as the intermediate cells. These cells are larger than basal cells and smaller than the squamous cells and are believed to be the progenitor of epidermoid and mucous cells. Occasionally clusters of clear cells can be present. These clear cells are generally mucin and glycogen free. Epidermoid cells, together with intermediate and mucous cells line cystic spaces or form solid masses or cords. Epidermoid and mucous cells may be arranged in a glandular pattern. The cysts may rupture liberating mucus which may pool in the connective tissue and evoke an inflammatory reaction (Fig. 3-22).
Figure 3-22 Mucoepidermoid carcinoma.
(A, B) Photomicrographs illustrate the association of the pale-staining, mucus-containing cells associated with darker staining epidermoid cells in a moderately high-grade mucoepidermoid carcinoma. (C) In one duct like structure the lining consists partially of squamous epithelium and partially of mucous cells From F Vellios: Am J Clin Pathol, 25: 147, 1955.
Mucoepidermoid carcinomas are graded as low-grade, intermediate-grade, and high-grade.
Low-grade tumors show well formed glandular structures and prominent mucin filled cystic spaces, minimal cellular atypia and a high proportion of mucous cells (Fig. 3-23).
Figure 3-23 Mucoepidermoid carcinoma.
(A) Mucicarmine stain. (B) PAS stain. The two components of the tumor are large, pale, mucous secreting cells, which typically surround large or small cystic spaces and sheets of epidermoid cells.
Intermediate-grade tumors have solid areas of epidermoid cells or squamous cells with intermediate basaloid cells. Cyst formation is seen but is less prominent than that observed in low-grade tumors. All cell types are present, but intermediate cells predominate.
High-grade tumors consist of cells present as solid nests and cords of intermediate basaloid cells and epidermoid cells. Prominent nuclear pleomorphism and mitotic activity is noted. Cystic component is usually very less (<20%). Glandular component is rare although occasionally it may predominate. Necrosis and perineural invasion may be present.
Variants of Tumor
Sclerosing mucoepidermoid carcinoma
Although mucoepidermoid carcinoma is the most common primary malignancy of the salivary glands, the sclerosing morphologic variant of this tumor is extremely rare, with only six reported cases. As its name suggests, sclerosing mucoepidermoid carcinoma is characterized by an intense central sclerosis that occupies the entirety of an otherwise typical tumor, frequently with an inflammatory infiltrate of plasma cells, eosinophils, and/ or lymphocytes at its peripheral regions.
The sclerosis associated with these tumors may obscure their typical morphologic features and result in diagnostic difficulties. Tumor infarction and extravasation of mucin resulting in reactive fibrosis are two mechanisms that have been suggested as the cause of this morphologic variant.
Intraosseous mucoepidermoid carcinoma
Mucoepidermoid carcinoma may originate within the jaws. This tumor type is known as central mucoepidermoid carcinoma. It is thought to form by the malignant transformation of the epithelial lining of odontogenic cysts. The tumor presents as an asymptomatic radiolucent lesion and is histologically of low-grade malignancy. The mandible is three times more commonly affected than the maxilla.
Treatment and Prognosis
Conservative excision with preservation of the facial nerve, if possible, is recommended for low- and intermediate-grade mucoepidermoid carcinomas of the parotid gland. The affected submandibular gland should be removed entirely. Radical neck dissection is performed in patients with clinical evidence of cervical node metastasis and is considered in any patient with a T3 lesion. Treatment for the minor glands is also primarily surgical. Some investigators have recommended postoperative irradiation only for high-grade malignancies, including high-grade mucoepidermoid carcinomas of the parotid glands. Few studies have assessed the role of chemotherapy and showed that high-grade mucoepidermoid carcinoma may show sensitivity similar to that of squamous cell carcinoma. Low-grade lesions had a five-year cure rate of 92%, whereas the intermediate-grade and high-grade lesions had a 49% 5-year cure rate.