Tumors of the Salivary Glands

Histogenesis

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.

Clinical Features

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).

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.

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).

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.

Clinical Features

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.

Histologic Features

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.

Treatment and Prognosis

The tumor is treated by surgical excision. The same surgical principles apply as in treating pleomorphic adenomas. Only one recurrence was noted in 16 cases in which follow-up was available.

Clinical Features

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.

Treatment and Prognosis

The tumor is treated by excision and recurrences are seldom seen.

Histogenesis

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.

Clinical Features

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.

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.

Clinical Features

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.

Histologic Features

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.

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.

Clinical Features

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.

Histologic Features

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.

Treatment and Prognosis

The tumor can be treated by enucleation or simple surgical excision; recurrence is rare.

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

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

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.

Treatment

Surgical excision is curative and these tumors are not known to recur.

Clinical Features

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.

Histologic Features

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.

Treatment and Prognosis

No large series of cystadenoma with follow up information has been reported. At least one recurrence has been noted. The likelihood of recurrence is low. A conservative surgical procedure ensures complete removal.

Clinical Features

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.

Histologic Features

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.

Clinical Features

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).

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.

Histologic Features

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).

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).

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.

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.

Clinical Features

The salivary glands most commonly involved by this tumor are the parotid, the submaxillary and the accessory glands in the palate and tongue (Fig. 3-24). The adenoid cystic carcinoma occurs most commonly during the fifth and sixth decades of life, but it is by no means rare even in the third decade. It is seen more commonly in females. Many of the patients exhibit clinical manifestations of a typical malignant salivary gland tumor: early local pain, facial nerve paralysis in the case of parotid tumors, fixation to deeper structures and local invasion. Some of the lesions, particularly the intraoral ones, exhibit surface ulceration. There may be clinical resemblance in some cases to the pleomorphic adenoma. Adenoid cystic carcinoma has a marked tendency to spread through perineural spaces and usually invades well beyond the clinically apparent borders.

Histologic Features

Adenoid cystic carcinoma is composed of myoepithelial cells and ductal cells which have a varied arrangement. Morphologi cally, three growth patterns have been described: cribriform (classic), tubular, and solid (basaloid). The tumors are categorized according to the predominant pattern. The cribriform pattern shows basaloid epithelial cell nests that form multiple cylindrical cyst like patterns resembling a Swiss cheese or honey comb pattern, which is the most classic and best recognized pattern. The lumina of these spaces contain periodic acid-Schiff (PAS) positive mucopoly-saccharide secretion. The tubular pattern reveals tubular structures that are lined by stratified cuboidal epithelium. The solid pattern shows solid groups of cuboidal cells with little tendency towards duct or cyst formation. The cribriform pattern is the most common, whereas the solid pattern is the least common. Solid adenoid cystic carcinoma is a high-grade lesion with reported recurrence rates of up to 100% compared with 50–80% for the tubular and cribriform variants.

Treatment and Prognosis

The treatment of the adenoid cystic carcinoma is chiefly surgical, although in some cases surgery has been successfully coupled with X-ray radiation. Radiation alone is not recommended. In general, this tumor is a slowly growing lesion which tends to metastasize only late in its course. The cure rate for patients with this disease, though varying somewhat from series to series, is discouragingly low. Factors influencing prognosis are the site of occurrence and the histologic pattern of the tumor (Fig. 3-25). Conley and Dingman (1974) found that there is a marked difference in the clinical behavior of major and minor gland adenoid cystic carcinomas. Only 28% of 78 patients with minor gland tumors were alive with no evidence of disease in a 4–14-year follow-up study. Sixty-four percent of 54 patients with major gland tumors studied over a comparable period were alive and free of disease.

Clinical Features

In minor gland sites polymorphous lowgrade adenocarcinoma is twice as frequent as adenoid cystic carcinoma, and, among all benign and malignant salivary gland neoplasms, only pleomorphic adenoma and mucoepidermoid carcinoma are more common. The average age of patients is reported to be 59 years, with 70% of patients between the ages of 50 and 79 years. The female to male ratio is about 2 : 1. In the AFIP case files, over 60% of tumors occurred in the mucosa of either the soft or hard palates, approximately 16% occurred in the buccal mucosa, and 12% in the upper lip. Polymorphous low-grade adenocarcinoma typically presents as a firm, nontender swelling involving the mucosa of the hard and soft palates (often at their junction), the cheek, or the upper lip. Discomfort, bleeding, telangiectasia, or ulceration of the overlying mucosa may occasionally occur.

Histologic Features

Microscopically polymorphous low-grade adenocarcinoma is characterized by infiltrative growth with diverse morphology and uniform cytologic features. The tumors are well circumscribed but unencapsulated and infiltrate into adjacent structures. The polymorphic nature of the lesion refers to the variety of growth patterns it assumed which includes solid, ductal, cystic and tubular. In some tumors, a cribriform pattern can be produced, which resembles adenoid cystic carcinoma. The tumor is composed of cuboidal to columnar isomorphic cells that have uniform ovoid to spindle- shaped nuclei. Scant to moderate amounts of eosinophilic cytoplasm can be seen. The tumor stroma varies from mucoid to hyaline and in some cases, tumor nests are separated by fibrovascular stroma. Perineural invasion is common that makes this tumor mistaken as adenoid cystic carcinoma.

Treatment

Polymorphous low-grade adenocarcinoma is best treated by conservative wide surgical excision. This neoplasm typically runs a moderately indolent course. Although the tumor can recur, sometimes multiple times over many years, distant metastases have not been reported. The overall prognosis is good. Perineural invasion does not appear to affect the prognosis.

Clinical Features

This is predominantly a tumor of the parotid gland. In the AFIP case files, the mean age of patients is about 60 years and women are more often affected than men. Localized swelling with a history of steady increase in size over a period of time is the common symptom, but occasionally patients experience facial weakness or pain. Nasal obstruction and facial deformity may represent major complaints of patients with maxillary involvement. Some studies have suggested that patients with these tumors are at increased risk for a second primary malignancy—either in the salivary glands or in a separate site (breast and thyroid have been reported).

Histologic Features

The histologic features of this tumor may vary greatly from solid lobules that are separated by bands of hyalinized fibrous tissue to irregular, papillary cystic arrangements with tumor cells which partially or completely fill cystic spaces but most tumors show a multinodular growth pattern with islands of tumor cells separated by dense bands of fibrous connective tissue. The islands of tumor cells are composed of small ducts lined by cuboidal epithelium that is surrounded by clear cells which interface with a thickened, hyaline-like basement membrane. The inner luminal cuboidal cells have finely granular, dense eosinophilic cytoplasm and central or basally located nucleus. The outer, clear myoepithelial cells vary in shape from columnar to ovoid and have a vesicular nucleus located towards the basement membrane.

Treatment

Surgery is considered the primary mode of treatment. Even with complete surgical resection recurrences and distant metastases remain a concern and may occur from a few months to years after initial surgery.

Clinical Features

In AFIP case files spanning almost 11 years, basal cell carcinoma comprised 1.6% of all salivary gland neoplasms and 2.9% of salivary gland malignancies. Nearly 90% of tumors occurred in the parotid gland. The average age of patients is reported to be 60 years. Basal cell adenocarcinoma predominantly occurs at the seventh decade without gender preference. The tumors affecting the minor salivary glands occur most frequently at the oral cavity (buccal mucosa, palate) and the upper respiratory tract. Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom experienced. A sudden increase in size may occur in a few patients.

Histologic Features

As seen with basal cell adenoma, basal cell adenocarcinoma can also be histologically divided into four subtypes: (1) solid, (2) ductal, (3) trabecular, and (4) membranous.

The prevalent histologic tumor pattern is represented by solid neoplastic aggregates with a peripheral cell palisading arrangement frequently delineated by basement membrane like material. Few areas with trabecular or membranous arrangement may be seen. The neoplastic clusters are formed by two cell populations: the small dark cell type, which is predominant and a large pale cell type. Generally, the small dark cells are present peripherally to the larger paler cells. The tumor extends into the surrounding tissues by local infiltration as nodules, nests and cords. Perineural and vascular invasion is noticed in a few cases.

Treatment and Prognosis

Basal cell carcinomas are low-grade carcinomas that are infiltrative, locally destructive, and tend to recur. They only occasionally metastasize. Surgical excision with a wide enough margin to ensure complete removal of the tumor is the primary treatment. Regional lymph node dissection is recommended only if there is evidence of metastatic disease. The overall prognosis for patients with this tumor is good.

Clinical Features

This tumor shows bimodal age distribution, peak incidence of tumor occurrence is found in the third decade and seventh and eighth decades of life (range 17–93 years). The male and female incidence of occurrence is almost equal. Most of the reported cases have arisen in the parotid gland. The chief complaint is that of painful masses, with varying degrees of facial nerve paralysis, and occasionally, fixation of the skin is present. Tumors range in size from 0.6–8.5 cm in greatest dimension.

Histologic Features

Tumors are well circumscribed or partially encapsulated, with pushing or locally infiltratingmargins. Cellular pleomorphism and cellular atypia are uniformly present and are more prevalent than in sebaceous adenomas. Tumor cells may be arranged in multiple lare focior in sheets and have hyperchromatic nuclei surrounded by abundant clear to eosinophilic cytoplasm (Fig. 3-26 A). Areas of cellular necrosis and fibrosis are commonly found. Perineural invasion has been observed in more than 20% of tumors. Vascular invasion is extremely unusual. Rare oncocytes and foreign body giant cells with histiocytes may be observed.

Treatment

It varies from local excision and parotidectomy to preoperative and postoperative radiotherapy, with or without chemotherapy. Patient survival ranged from 8 months to 13 years (mean is 4.5 years).

Clinical Features

Cystadenocarcinoma is considered to be a low-grade neoplasm. Most of the cases, about 65%, occurred in the major salivary glands (primarily in the parotid). Among the reported cases men and women are found to be affected equally and the average age at presentation is about 59 years. Patients present with a slowly growing asymptomatic mass. Clinically, this neoplasm is rarely associated with pain or facial paralysis.

Histologic Features

A cystic growth pattern must dominate the histologic appearance for the diagnosis to be considered (Fig. 3-26 B). These cystic spaces vary in size between tumors as well as within the same tumor. These neoplasms may appear circumscribed or reveal haphazard growth throughout the gland. The lumina often are filled with mucus and hemorrhage and dystrophic calcifications are sometimes evident focally. The lining cells vary from cuboidal to tall columnar, and often a single tumor contains basaloid, oncocytic, clear, and occasionally, mucus cells that form adenomatous or nodular, solid epithelial areas. These solid areas usually occupy the space between the cystic structures. Nuclear hyperchromatism and nuclear variability are subtle, and only rare mitotic figures are present. Nucleoli may be obvious. Encapsulation is incomplete, and infiltration into either salivary gland parenchyma or fibrous or adipose tissue is seen. The tumor may infiltrate either as cyst like structures or as solid islands. Although the vast majority of cystadenocarcinomas are low-grade lesions, moderate/intermediate-grade tumors do exist.

Treatment and Prognosis

No information is currently available that pertains specifically to the prognosis of the salivary gland cystadenocarcinomas. Currently the treatment principles for low-grade cystadenocarcinomas are similar to the principles applied for other low-grade salivary gland adenocarcinomas. These include consideration of the site, the clinical extent of the disease and the histologic grade prior to institution of therapy. Radical neck dissection should be preserved only to deal with obvious metastases.

Clinical Features

Clinically, these lesions are soft, spongy masses that may be thought to be cysts.

Histologic Features

The gross specimens are very mucoid, with a slimy texture and they may actually ooze mucoid material. These tumors are circumscribed but not encapsulated. Low magnification reveals islands and cords of tumor cells that appear to be floating within pools of pale staining mucin. The pools of mucin may be divided into irregular lobules by fibrous connective tissue septa that course through the tumor, which is unencapsulated. The tumor cells are moderately large, cuboidal, and polygonal cells with eosinophilic to amphophilic cytoplasm. The nuclei are vesicular, and scattered mitotic figures may be found. The tumor islands are surrounded by pale-staining mucoid substance. The mucoid substance stains with mucicarmine, periodic acid-Schiff, and alcian blue at pH 2.0. Mucicarmine stain also reveals that many tumor cells contain intracytoplasmic mucin.

Treatment and Prognosis

Complete excision with the care to avoid seeding the surgical site would seem to be a satisfactory mode of treatment for these salivary gland tumors.

Clinical Features

Oncocytic carcinoma may be considered to be a high-grade carcinoma. Most cases occur in the parotid gland but recent reports have described tumors that involved the submandibular gland and minor glands of the palate, nasal cavity, and ethmoid and maxillary sinuses. The average age of patients in one series was 63 years. Patients usually develop parotid masses that cause pain or paralysis. The skin overlying the gland is occasionally discolored or wrinkled.

Histologic Features

All types of benign or malignant salivary gland tumors may have foci of oncocytic cells, but the oncocytic component usually contains such a small portion that it is unlikely to be confused with oncocytic carcinoma. Tumors with a significant oncocytic component include Warthin’s tumor, oncocytoma, and oncocytic carcinoma. They are characterized by oncocytes with marked cellular atypia, frequent mitosis, destruction of adjacent structures, perineural or vascular invasion, and distant or regional lymph node metastasis. Histochemical or electron microscopic confirmation of the oncocytic (mitochondrial) nature of the cytoplasm is necessary because cytoplasmic accumulation of smooth endoplasmic reticulum, lysosomes, or secretory granules may have a similar appearance.

Treatment and Prognosis

Oncocytic carcinoma is considered to be a high-grade neoplasm and aggressive initial surgery seems to have a significantly better overall prognosis. Radiation does not appear to favorably alter the biologic behavior of this tumor. Prophylactic neck dissection may be indicated for tumors that are larger than 2 cm in diameter.

Clinical Features

Parotid swelling is the most common sign. Facial nerve dysfunction or paralysis occurs in over one-fourth of patients and may be the initial manifestation. The high-grade variant of this neoplasm is one of the most aggressive types of salivary gland carcinomas and is typified by local invasion, lymphatic and hematogenous spread with poor prognosis.

Histologic Features

The infiltrative tumor elements are typically composed of clusters of tumor cells that may have small lumina or cribriform arrangements, but solid, irregularly shaped tumor cell aggregates are frequently present. The neoplastic epithelial cells are cuboidal and polygonal with a moderate amount of eosinophilic cytoplasm and are accompanied by a dense fibrous connective tissue stroma that may be hyalinized in some areas. Invasion of the nerves and blood vessels is frequent in addition to infiltration of salivary gland lobules and extra-salivary gland tissues, such as fat, muscle, and bone. Mucicarmine and Alcian blue stains are generally negative, except, perhaps, for a small amount of luminal staining. Immuno histochemical and ultrastructural studies have identified ductal cells but no myoepithelial cells.

Treatment and Prognosis

Salivary duct carcinoma is a high-grade malignancy that must be treated aggressively. Complete local excision with radical neck dissection and postoperative radiation therapy seems to offer the maximum benefit for the patient.

Clinical Features

They tend to be present in patients over 40 years of age and occur with nearly equal frequency in men and women. About half of these tumors present in the parotid glands, the minor salivary glands, particularly the palate, lip and tongue are the next most commonly affected sites. Clinical presentation again most often involves an enlarging mass. Adenocarcinoma is different from other salivary gland neoplasms in that as many as 25% of patients will complain of pain or facial weakness at presentation.

Histologic Features

Gross pathology reveals a firm mass with irregular borders and infiltration into surrounding tissue. It is generally a solid tumor without any cystic spaces. These malignancies can demonstrate a wide range of growth patterns, and for this reason, can be somewhat difficult to classify. However, all adenocarcinomas have in common the formation of glandular structures and they are described as grades I, II or III based upon the degree of cellular differentiation. Grade I lesions have well formed ductal structures while grade III lesions have a more solid growth pattern with few glandular characteristics (Figs. 3-27, 3-28).

Treatment and Prognosis

Because these are more aggressive tumors, treatment for adenocarcinoma is aggressive. Complete local excision is the mainstay of therapy. In the parotid this may include facial nerve sacrifice. In the minor salivary glands, a portion of the maxilla or mandible may have to be resected with the tumor. Postoperative radiation therapy does seem to be of some benefit. Lymph node metastasis is not uncommon and in patients with palpable neck disease neck dissection is warranted. Local recurrence rates vary in the literature but have been cited as high as 51%.

Clinical Features

The majority of patients present with the primary complaint of a painless mass. This is an intermediateto high-grade carcinoma. Histologic grade does not appear to correlate well with clinical behavior; tumors with a low-grade histologic appearance may behave aggressively.

Histologic Features

The cytologic features of individual cells and the general morphologic features resemble tumor cells in benign myoepithelioma and the myoepithelial cells of mixed tumor. The tumor cells may be spindle shaped or plasmacytoid cells (Fig. 3-29). The cell types are often intermixed but usually one or the other cell type predominates. The tumors may be quite cellular and more suggestive of sarcoma than carcinoma. The stroma in other areas of the tumors may be more conspicuous and myxoid. These tumors are distinguished from benign myoepithelial neoplasms by their infiltrative, destructive growth. They usually demonstrate increased mitotic activity and cellular pleomorphism. Some tumor cell should be immunoreactive for cytokeratin, S100 protein, smooth muscle actin, and occasionally, glial fibrillary acidic protein.

Treatment

Wide surgical excision seems to be preferred.

Carcinoma ex Pleomorphic Adenoma (Carcinoma exmixed tumor)

Carcinoma ex pleomorphic adenoma is the most common of the three salivary neoplasms that are broadly referred to as malignant mixed tumors. It occurs when a carcinoma develops from the epithelial component of a preexisting pleomorphic adenoma. Diagnosis requires the identification of benign tumor in the tissue sample. The incidence or relative frequency of this tumor may vary considerably depending on the study cited. A review of material at the AFIP showed carcinoma ex pleomorphic adenoma to comprise 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors, ranking it as the sixth most common malignant salivary gland tumor after mucoepidermoid carcinoma; adenocarcinoma; acinic cell carcinoma; polymorphous low-grade adenocarcinoma; and adenoid cystic carcinoma.

Clinical Features

The neoplasm occurs primarily in the major salivary glands. It occurs most often in the parotid, followed by the submandibular gland and palate. It presents in the sixth to eighth decade of life with patients averaging 10 years older than those with pleomorphic adenomas. Presentation is usually a painless mass but some patients will report recent rapid enlargement of a long-standing nodule. Approximately one-third of patients may experience facial paralysis.

Histologic Features

Gross pathology of carcinoma ex pleomorphic adenoma often shows a poorly circumscribed, infiltrative, hard mass. Micro scopically malignant appearing cells are present adjacent to a typical appearing pleomorphic adenoma. The malignant portion of the tumor can take the form of any epithelial malignancy except acinic cell (Fig. 3-30). Most commonly this will be in the form of an undifferentiated carcinoma (30%) or adenocarcinoma (25%). This tumor tends to be more aggressive than other salivary malignancies and about 25% of patients will have lymph node metastasis on presentation.

Treatment and Prognosis

Treatment includes radical surgical resection, often in conjunction with neck dissection, and postoperative radiation therapy. Prognosis appears to be related to the local extent of disease and the histologic type of the carcinoma component.

Carcinosarcoma (True malignant mixed tumor)

Carcino-sarcoma is a rare malignant salivary gland neoplasm that contains both carcinoma and sarcoma components. In a carcinosarcoma, the metastatic lesions contain both the stromal and epithelial elements. Some carcinosarcomas develop de novo while others develop in association with benign mixed tumor.

This neoplasm is rare in occurrence; there are only eight cases in the AFIP case files. Only 11 cases were recorded at MD Anderson over a 32-year period. The majority of tumors occur in the major salivary glands. The parotid is the most frequent site of occurrence. Average age at presentation is about 60 years and men and women appear to be equally affected. Clinically, swelling, pain, nerve palsy, and ulceration have been frequent findings.

Histologic Features

Microscopically, these tumors have both sarcomatous and carcinomatous elements. In the majority, the sarcoma is the dominating component and chon-drosarcoma is the most common cell type. The carcinoma element is usually an undifferentiated or high-grade ductal adenocarcinoma.

Treatment and Prognosis

This is also an aggressive tumor. In the largest series reported (12 cases), the average survival period was 3.6 years and it is not uncommon for patients to have distant metastasis on presentation. Currently, recommended treatment includes radical surgery, neck dissection for palpable nodes and postoperative radiotherapy. Although efficacy has yet to be proven, chemotherapy is likely to have a role in the treatment of this disease given the high rate of distant metastasis.

Metastasizing Mixed Tumor

Metastasizing mixed tumor is a very rare histologically benign salivary gland neoplasm. The meta stasizing mixed tumor refers to an otherwise benign acting pleomorphic adenoma that develops metastatic deposit. There is often a long interval between the diagnosis of the primary tumor and the metastases. The histologic features are within the spectrum of features that typify pleomorphic adenoma. The majority occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have been reported to occur up to 26 years after excision of the primary neoplasm.

Clinical Features

The reported frequency of this tumor among all major salivary gland tumors has varied from 0.9–4.7%. There is a 2 : 1 male-to-female ratio of occurrence and patients are usually over age 60. This neoplasm occurs in the parotid gland almost nine times more often than in the submandibular gland. This tumor is graded in a way similar to the extra salivary lesions according to the degree of differentiation (low, intermediate, and high). Previous exposure to ionizing radiation appears to increase the risk for developing this neoplasm. The median time between irradiation and diagnosis of the neoplasm is approximately 15.5 years. These tumors present as firm enlarging masses that are not uncommonly fixed to surrounding tissue and associated with pain or facial weakness.

Histologic Features

The gross and microscopic appearance is similar to squamous cell carcinoma of other primary sites and varies from well-differentiated to poorly differentiated. Salivary gland squamous cell carcinoma displays aggressive behavior with rapid growth and early spread to regional lymph nodes (Fig. 3-32).

Treatment and Prognosis

Treatment consists of surgical resection, neck dissection and postoperative radiation. The prognosis for this neoplasm is poor. In a 30-year retrospective analysis of 50 cases of squamous cell carcinoma of the salivary glands, survival rates at five and 10 years were 24% and 18%, respectively.

Histologic Features

Microscopically, the tumor cells have oval, hyperchromatic nuclei and scant amount of cytoplasm and are organized in sheets, strands, and nests. Small cell carcinoma of major salivary glands is a highly aggressive tumor, although the prognosis may be better than that for extra-salivary neoplasms. Studies also suggest that most salivary gland small cell carcinomas exhibit neuroendocrine differentiation. Neuroendocrine carcinomas are more frequently found in the minor salivary glands and have a better survival rate compared with small cell carcinomas of the lung. The undifferentiated counterpart of this neoplasm is the small cell undifferentiated carcinoma.

Treatment and Prognosis

The treatment of choice is wide surgical excision, possibly with radiation and/or chemotherapy. The prognosis for patients with small cell carcinomas arising in the major or minor salivary glands is better than that for patients with small cell carcinomas of the lung or larynx.

Treatment and Prognosis

The treatment consists of surgery alone or of surgery in combination with radiotherapy. Very little data is available concerning the behavior of these rare tumors.

Clinical Features

Characterized mainly by the presence of chronic, afebrile salivary gland enlargement, usually of the parotid glands. The enlargement is described as slowly evolving, indolent, undulating, and recurrent. Persons in the later decades of life (4th decade or beyond) are most afflicted. De-creased salivary secretion occurs, and sialochemistry generally demonstrates increased levels of potassium and decreased levels of sodium. Hypertrophy of acinar cells crowds and compresses the finer terminal ducts, thereby yielding the sialographic ‘leafless tree’ pattern (Table 3-7).

Histologic Features

The parotid swelling is due to acinar enlargement. The diameter of the acinar cell increases two to three times that of normal. The nuclei tend to be basally situated, and the cytoplasm tends to be packed with granules. Inflammatory cells are absent but individual fat cells may be seen in the interstitial tissue. Batsakis (1988) suggests that long standing uncorrected autonomic neuropathy, such as occurs in alcoholism or diabetes mellitus eventually leads to acinar atrophy and replacement with fat.

Treatment

Treatment is generally unsatisfactory and depends on correcting the underlying cause. Subtotal parotidectomy may be considered as a last resort.

Histologic Features

Oncocytosis may present as scattered foci of enlarged, eosinophilic epithelial cells or a solitary focus of metaplastic oncocytes. The cells may retain an acinar arrangement and form sheets, trabeculae, or duct like structures surrounded by fine collagen septa. The cytologic features consist of large, eosinophilic, polyhedral epithelial cells with fine granular cytoplasm and a centrally placed pyknotic nucleus (Fig. 3-34). Oncocytes occasionally show transition to clear cells as a result of intracytoplasmic glycogen.

Ultrastructural findings are characterized by cytoplasm that is packed with large, pleomorphic mitochondria containing filamentous, tubular, and vesicular cristae. The oncocytes have been considered a product of degenerative changes.

Etiology

Most cases of NS appear to arise spontaneously, whereas others are associated with a history of trauma, radiation therapy, or surgery. In most cases of NS, the etiology is believed to be related to vascular ischemia. The association of adjacent neoplasia that results in ischemic necrosis of the glandular elements and the histologic features of NS supports this pathogenic mechanism. Tobacco use is suggested as a possible etiologic risk factor for NS.

Clinical Features

NS is generally reported to involve the minor salivary glands of the oral cavity, particularly those of the palate. Reports of this entity in the minor glands of the retromolar pad area, buccal mucosa, tongue, incisive canal, and labial mucosa have also been reported. In addition, NS is recognized in the parotid and submandibular salivary glands, minor mucous glands in the lung, nasal cavity, larynx, trachea, nasopharynx, and maxillary sinus. Similar lesions are identified in the breast; the condition is referred to as posttraumatic lobular metaplasia of the breast. Lesions in the skin are referred to as syringometaplasia. The male-to-female ratio is approximately 2 : 1. The average age of patients with NS is 47.9 years, with a range of 17–80 years.

The lesions of NS often are painless; less frequently, they cause pain and numbness. NS manifests as a swelling with or without ulceration in anatomic sites that have mucous or serous glandular tissue. The typical clinical presentation of NS is that of a crateriform ulcer of the palate that simulates a malignant process. These ulcerated lesions are 1–3 cm and are usually unilateral, but bilateral synchronous lesions and metachronous lesions can occur. Some lesions of NS may present as a submucosal swelling, without ulceration of the overlying mucosa. An intact surface mucosa may be noted in an evolving lesion at the time of diagnosis, although most cases are accompanied by mucosal ulceration. Erosion of the palatal bone may occur in either ulcerated or nonulcerated lesions. Examination of a biopsy specimen is usually required to establish the correct diagnosis and to exclude a malignant or infectious process or an inflammatory condition such as Wegener granulomatosis. Extranodal lymphoma also may be considered in the clinical differential diagnosis of a palatal swelling or ulceration.

Histologic Features

The microscopic features of NS include coagulative necrosis of glandular acini and squamous metaplasia of its ducts. Mucin pooling is present, and an associated inflammatory infiltrate consists of macrophages, neutrophils, and less commonly, lymphocytes, plasma cells, and eosinophils (Fig. 3-35).

Pseudoepitheliomatous hyperplasia of the overlying mucosa can also be present, but the cytologic features of the epithelial atypia are usually absent. Occasionally, isolated mucous cells may be entrapped within the squamous islands; these cells should not be confused with those of mucoepidermoid carcinoma. The microscopic differential diagnosis for NS includes mucoepidermoid carcinoma and squamous cell carcinoma. Some believe that subacute necrotizing sialadenitis is yet another entity that occurs within the spectrum of NS; it should be distinguished from NS.

Treatment and Prognosis

NS resolves spontaneously. No treatment is necessary. Surgical care consists of incisional biopsy for diagnostic purposes. Periodic evaluation of the affected site is recommended until spontaneous resolution occurs. The prognosis for NS is excellent. Spontaneous resolution usually occurs within weeks. The average healing time for NS of the minor salivary glands of the hard and soft palates is approximately five weeks. The size of the lesion and whether or not bony perforation has occurred are clinical parameters that may influence the healing time.

Etiology

The exact cause of Mikulicz disease is not known, although it is suspected to be an autoimmune disorder. The symptoms of Mikulicz disease may occur due to the excessive accumulation of lymphocytes into the involved glands.

Clinical Features

Mikulicz disease affects more females than males and most often presents during the middle adult years. It often occurs in combination with Sjögren syndrome. Mikulicz disease is characterized by the sudden onset of xerostomia that may lead to difficulty in swallowing and result in tooth decay. Other symptoms include enlarged lacrimal glands, leading to absent or decreased tears; painless swellings (tumefactions) of the salivary glands (parotid, submaxillary) are noticed. The symptoms of Mikulicz disease are very similar to those of Sjögren syndrome and some researchers suspect that they may be the same disorder. Some people with Mikulicz disease may experience recurring fevers. The fever may be accompanied by dry eyes, diminished lacrimation, and uveitis. Lacrimal gland enlargement, parotid gland enlargement, dry mouth and dry eyes are the classic signs.

Histologic Features

The disease is characterized by an orderly lymphocytic infiltration of the salivary gland tissue, destroying or replacing the acini, with the persistence of islands of epithelial cells which probably represent residua of gland ducts (Fig. 3-36 B). Although the lymphoid element is usually diffuse, actual germinal centers are occasionally present. The epithelium may consist of ducts showing cellular proliferation and loss of polarity, or as the disease persists, solid nests or clumps of poorly defined epithelial cells which Morgan and Castleman termed ‘epimyoepithelial islands’. These sometimes seem to form a syncytium. It has been suggested that such islands arise as a result of proliferation of both ductal cells and peripheral myoepithelial cells. A characteristic change also found in advanced lesions is the deposition of eosinophilic, hyaline material in the epithelial islands.

Great care must be taken in differentiating between the benign lymphoepithelial tumor and a malignant lymphoma involving the salivary glands. In the latter disease, epimyoepithelial islands are not present, the lymphoid element is atypical, and there is infiltration of the interlobular septa by lymphoid tissue. The epithelial islands, on the other hand, may be mistaken for metastatic carcinoma. Other histologically similar lesions which must be considered in the differential diagnosis are chronic sialadenitis, papillary cystadenoma lymphomatosum and uveoparotitis.

Treatment and Prognosis

Biopsy of one of the swollen glands is key to the diagnosis of Mikulicz disease. An ultrasonographic examination of the area may help to rule out other reasons for gland swelling. Treatment of this disorder is symptomatic. Artificial tears may be used to maintain moisture in the eyes, and artificial saliva may be used to treat oral symptoms. Some individuals with Mikulicz disease may be instructed to follow a soft moist diet. This may help to reduce the pain caused by chewing and swallowing.

Etiology

Various causes of this disease have been suggested: genetic, hormonal, infectious and immunologic, among others. It may well be that a combination of factors, both extrinsic and intrinsic, play a role in the etiology of this condition. Most authorities consider an altered immunologic response to be the main intrinsic factor which is responsible for the disease. Laboratory findings support the autoimmune etiologic role (q.v.). Bertram has reported that 75% of a series of 35 patients with Sjögren’s syndrome had in their sera antisalivary duct antibody. Similar antibody was found in the sera of 24% of a group of 29 patients with systemic lupus erythematosus, a documented autoimmune disease. In addition, the sicca complex and Sjogren’s syndrome have been found to be associated with the HLA system, specifically HLA-DR3 and HLA-B8 which are associated with primary form of the disease and HLA-DRw52 seen to be associated with both the forms of Sjögren’s syndrome. Cytomegalovirus, paramyxo virus and Epstein-Barr virus have all been implicated in the pathogenesis of this condition but have not been proven conclusively.

Clinical Features

This disease occurs predominantly in women over 40 years of age, although children or young adults may be affected. The female: male ratio is approximately 10 : 1. The typical features of the disease are dryness of the mouth and eyes as a result of hypofunction of the salivary and lacrimal glands. This often results in painful, burning sensations of the oral mucosa. In addition, various secretory glands of the nose, larynx, pharynx and tracheobronchial tree (buccopharyngolaryngitis sicca), as well as of the vagina, are involved with this dryness. Schall and his associates have evaluated the degree of xerostomia by means of sequential salivary scintigraphy. Chisholm and Mason have quantified saliva production in patients with the sicca complex and Sjögren’s syndrome. Reduced salivary flow was noted in both groups. Sialochemistry studies by Ben-Aryeh and coworkers have demonstrated significantly elevated levels of IgA, potassium and sodium in the saliva of patients with the sicca complex. Moutsopoulos has reported that 80% of patients with primary Sjögren’s syndrome have parotid enlargement in contrast to only 14% with secondary Sjögren’s syndrome. Lymph adenopathy is more than twice as common in the primary form of the disease.

Rheumatoid arthritis, as mentioned, is an integral part of secondary Sjögren’s syndrome. It has been shown that patients with Sjögren’s syndrome with rheumatoid arthritis have certain different clinical manifestations than patients with sicca complex, despite similar histologic findings and some laboratory findings. In this regard, patients without rheumatoid arthritis, that is, sicca complex or primary Sjögren’s syndrome, more frequently manifest parotid gland enlargement, lymphadenopathy, purpura, Raynaud’s phenomenon, kidney involvement and myositis.

Histologic Features

Three types of histologic alterations in the major salivary glands have been described. In one case, there may be intense lymphocytic infiltration of the gland replacing all acinar structures although the lobular architecture is preserved. In another, there may be proliferation of ductal epithelium and myoepithelium to form ‘epimyoepithelial islands’. Both of these histologic changes are identical with those occurring in the benign lymphoepithelial lesion in Mikulicz’s disease. The third alteration may be simply an atrophy of the glands sequential to the lymphocytic infiltration.

Interestingly, Bertram and Hjoting-Hansen have reported that 85% of a group of patients with Sjögren’s syndrome exhibited alterations in the accessory salivary glands of the lip characteristically similar to those in the major glands; they also have suggested biopsy of the labial mucosa as an aid in establishing the diagnosis of the disease. Similar findings in accessory glands, as well as the demonstration of antisalivary duct antibody by an immunofluorescent technique, have been reported by Tarpley, Anderson and White.

Laboratory Findings

Over 75% of patients with primary Sjögren’s syndrome have a polyclonal hyperglobulinemia and many develop cryoglobulins. Multiple organ- or tissue-specific antibodies are found, including antisalivary duct antibodies, rheumatoid factor and antinuclear antibodies. An increased sedimentation rate is present in 80% of these patients. Interestingly, the presence of antisalivary duct antibody is three times more common in those with secondary Sjögren’s syndrome as compared to those with the sicca complex.

Radiographic Features

Sialography may be of diagnostic value in Sjögren’s syndrome. Sialographs demonstrate the formation of punctate, cavitary defects which are filled with radiopaque contrast media. These filling defects have been said to produce a ‘cherry blossom’ or ‘branchless fruit-laden tree’ effect radiographically. Som and his associates have suggested that the contrast material actually extravasates through the weakened salivary gland ducts to produce the sialographic features. Poor elimination of contrast media is noted, as might be expected, with retention of the material for over a month.

Treatment and Prognosis

There is no satisfactory treatment for Sjögren’s syndrome. Most patients are treated symptomatically. Keratocon junctivitis is treated by instillation of ocular lubricants such as artificial tears containing methylcellulose, and xerostomia is treated by saliva substitutes such as those used in the treatment of person with xerostomia secondary to radiation therapy. Extensive dental caries is a complication which is quite common, and scrupulous oral hygiene and frequent fluoride application is indicated to reduce this problem. There is no specific treatment for enlargement of the salivary glands. Surgery has been employed but is generally recommended only in patients with discomfort. Although radiation therapy has been recommended in the past, its use is not advocated currently.

A major complicating factor in patients with Sjögren’s syndrome is the development of pseudolymphoma and malignant lymphoma. In an extensive National Institutes of Health (NIH) study, 136 patients with Sjögren’s syndrome were followed for an average period of over eight years. Nonlymphoma malignancies were no more common than would be expected, whereas lymphomas were observed in nearly 44 times the expected incidence rate. The risk of lymphoma in Sjögren’s patients is 6.4 cases per 100 cases per year. Most lymphomas are non-Hodgkin’s types and are B-cell in origin. Macroglobulinemia of Waldenstrom also has been noted to develop in these patients.

The relation between the benign lymphoepithelial lesion, Mikulicz’s disease and Sjögren’s syndrome is possibly a very close one. Mikulicz’s disease, but not Mikulicz’s syndrome, is probably identical with the lymphoepithelial lesion. This entity shares several features in common with Sjögren’s syndrome. Both diseases are manifested, often but not invariably, by a swelling of the major salivary glands and lacrimal glands, singly or in pairs. In both diseases the patient has xerostomia, which probably is related to the displacement and destruction of acinar tissue. Finally, both diseases occur chiefly in middleaged or elderly women.

It is likely that the benign lymphoepithelial lesion is a mild form of Sjögren’s syndrome, but it should not be inferred that lymphoepithelial lesions will eventually terminate in Sjögren’s disease. More aptly, the two diseases may be considered two forms of the same disease with a probably common etiology.

Clinical Features

Salivary duct cysts of the parotid gland are unilateral painless swellings with no involvement of facial nerve and no fixation to the overlying skin. The majority of the affected patients are over 40 years of age. The cysts range in size from 0.8–10.0 cm with an average size of approximately 1–3 cm.

Histologic Features

Typically, these unilocular cysts are lined by single or multilayered cuboidal or columnar epithelium. Occasional mucus containing goblet cells and areas of oncocytic differentiation may be seen. It may be completely or partially lined by squamous epithelium. A sparse to moderate lymphocytic infiltration is present in the cyst wall.

Treatment

Simple surgical resection is curative.

Histologic Features

Histologic examination of the excised submandibular glands revealed preserved lobular architecture, thickening of interlobular septa by sclerotic tissue, dense lymphoplasmacytic infiltrate, preservation of ducts with periductal fibrosis, and variable loss of acini. Fine-needle aspiration cytologic findings were characterized by scattered tubular ductal structures often enveloped by collagen bundles or lymphoplasmacytic infiltrate, isolated fragments of fibrous stroma, a background rich in lymphoid cells, and paucity or absence of acini.

Treatment and Prognosis

The treatment of sialadenitis includes appropriate antibiotic therapy and rehydration of the patient to stimulate salivary flow. Surgical drainage may be needed if there is abscess formation.