Salivary gland cancer

Acinic cell carcinoma of the salivary gland was initially considered a serous cell adenoma. However, in 1954, Foote and Frazel found that this tumor was aggressive, had infiltrative growth, and metastasized. They considered it a differentiated form of acinic cell adenocarcinoma of the SG and found that most acinic cell tumors were curable with adequate treatment.

In the subsequent WHO classification of 1972, it was considered an acinic cell tumor. Currently, the term "acinic cell tumor" is not correct, since the malignant potential of this neoplasm is clearly established. Acinic cell carcinoma is a malignant epithelial tumor of the SG in which some of the tumor cells demonstrate signs of serous acinar differentiation, which are characterized by cytoplasmic secretory granules of zymogen. Cells of the SG ducts are also a component of this neoplasm. Code - 8550/3.

Synonyms: acinar cell adenocarcinoma, acinar cell carcinoma.

Women are slightly more likely to develop salivary gland cancer than men. Patients with AK belong to a wide range of age groups - from small children to the elderly, with an almost equal distribution in the age groups from 20 to 70 years. Up to 4% of patients are under 20 years old. In the vast majority (over 80%) of cases, AK is localized in the parotid SG, followed by small SG of the oral cavity (about 1-7%), about 4% - submandibular SG and up to 1% - sublingual SG.

Clinically, salivary gland cancer usually manifests itself as a slowly growing, solid, non-fixed tumor in the parotid region, although in the case of multifocal growth, tumor fixation to the skin and/or muscle is observed. 1/3 of patients complain of intermittent or vague pain, and 5-10% have paresis or paralysis of the facial muscles. The duration of symptoms is on average less than a year, but in rare cases can reach several years.

Salivary gland cancer initially spreads with regional metastasis to the lymph nodes of the neck. Then distant metastases appear - most often in the lungs.

Macroscopically, it is a dense solitary tumor without clear demarcation from the surrounding glandular tissue. The size varies from 0.5 to 2, less often - up to 8 cm, on section - grayish-white, in places brown with cavities filled with brownish fluid, or with serous contents. Cystic formations of various sizes are surrounded by solid glandular loose tissue. In some cases, the tumor surface is solid, creamy-gray, without cystic cavities. The density of the node varies depending on the ratio of solid and cystic components. The tumor is in a capsule, but the capsule may not be along its entire length. Recurrent tumors are usually solid in nature, with foci of necrosis, do not have a capsule, on section the tumor surface does not resemble a pleomorphic adenoma with its slippery, shiny, bluish-translucent tissue. Multifocal tumor growth and vascular invasion were noted. Ultrastructural studies revealed the similarity of tumor cells with serous acinar elements of the terminal sections of the gastrointestinal tract.

Microscopic picture reveals signs of infiltrative growth. Round and polygonal cells have granular basophilic cytoplasm, well-defined cell membrane, some cells are vacuolated. Sometimes cells have cubic shape, and sometimes cells are so small that they lose clear contours; polymorphism of cells, mitotic figures are revealed. Tumor cells have characteristics of epithelial cells, chaotically forming a solid, trabecular pattern, stripes and nests, acinar and glandular formations. Cells form solid fields, less differentiated cells form follicle-like and glandular-like structures. Stromal fibrovascular layers are narrow, have thin-walled vessels, foci of necrosis and calcification are encountered. The main characteristic features of this form of tumor are a predominantly solid structure, similarity to serous acinar cells, homogeneity of tumor cells and the absence of glandular structures, and specific granularity of the cytoplasm.

Histologically, based on the differentiation of cells toward serous acini, a number of morphological growth patterns and tumor cell types are possible. Specific types are acinar, ductal, vacuolated, and clear cell. Nonspecific types are glandular, solid-lobular, microcystic, papillary-cystic, and follicular. Acinar cells are large, polygonal, with slightly basophilic granular cytoplasm and a rounded, eccentrically located nucleus. Cytoplasmic granules of zymogens give a positive PAS reaction, are resistant to diastase, and stain weakly or not at all with mucicarmine. However, the PAS reaction can sometimes be focal and not immediately visible. Ductal cells are smaller in size, eosinophilic, cubic in shape, with a centrally located nucleus. They surround lumens of various sizes. Vacuolated cells contain cytoplasmic PAS-negative vacuoles of various sizes and variable in number. Light cells resemble acinar cells in shape and size, but their cytoplasm is not stained by either routine methods or the PAS reaction. Glandular cells are round or polygonal, oxyphilic with a round nucleus and rather unclear borders. They often form syncytial bundles. The glandular-cellular variant is represented by predominant cells with very small cytoplasmic granularity. The intensity of cytoplasmic staining depends on the granularity of the cells, which have a close resemblance to the proenzyme granules of serous cells of the SG. This similarity is represented not only by the appearance, distribution, density of arrangement, but also by the ability to intensively stain with hematoxylin, eosin and PAS. These cells do not contain mucus, fat or silver granules; vacuoles, cysts and free spaces are present. The cells are located between the cysts in a solid mass or form lacy glandular and acinar structures. The scanty tumor stroma consists of richly vascularized connective tissue with rare accumulations of lymphatic elements.

In the solid type of structure, tumor cells are tightly adjacent to each other, forming bundles, nodes and aggregates. In the microcystic type, the presence of many small spaces (from several microns to millimeters) is characteristic. Pronounced cystic cavities, larger in diameter than in the microcystic type, partially filled with papillary proliferation of the epithelium, characterize the cystic-papillary (or papillary-cystic) type. In this variant, secondary changes are especially often visible in the form of pronounced vascularization, hemorrhages of varying duration, and even with signs of phagocytosis of hemosiderin by tumor cells of the cyst lumens. The follicular type is characterized by multiple cystic cavities lined with epithelium and filled with eosinophilic protein contents, which resembles thyroid follicles with colloid. Psammoma bodies may be seen, sometimes numerous, and are detected by cytological examination after fine-needle biopsy.

Although salivary gland cancer most often has a single cell type and growth pattern, in many cases there are combinations of both cell and morphological types. The acinar cell and ductal cell types are most common, while all other types are much less common. Thus, the clear cell variant occurs in no more than 6% of salivary gland cancer cases. It is usually focal in nature and rarely presents diagnostic difficulties. The clear cell variant has water-colored cytoplasm. The cells do not contain glycogen, fat, or PAB-positive material in the cytoplasm. The nucleus is centrally located, round, vesicular, and dark with indistinct nucleoli. Mitotic figures are absent. The cell membrane very clearly surrounds the cell. Clear cells form solid or trabecular clusters with a small number of glandular or acinar structures. Among the architectural types, the most common are solid-lobular and microcystic, followed by papillary-cystic and follicular.

In many cases of AC, pronounced lymphoid infiltration of the stroma is detected. The presence and severity of this infiltration have no prognostic significance, but it is more often found in less aggressive and clearly demarcated AC with a microfollicular type of structure and a low proliferative index. Such salivary gland cancer is separated by a thin fibrous pseudocapsule and surrounded by lymphoid infiltrates with the formation of proliferation centers.

Electron microscopy reveals round, dense, multiple cytoplasmic secretory granules characteristic of acinar cells. The number and size of granules vary. Rough endoplasmic reticulum, numerous mitochondria, and rare microvilli are also characteristic ultrastructural features. Vacuoles of various sizes and shapes are found in some cells. The basement membrane separates groups of acinar and ductal cells from the stroma. It has been found that light cells at the light-optical level are the result of artificial changes or expansion of the endoplasmic reticulum, lipid inclusions, enzymatic degradation of secretory granules, etc.

Ultrastructural examination of the acinar cells of the tumor revealed a specific type of secretory granules in the cytoplasm of many cells, similar to the granules of normal serous cells of the salivary acini. Some investigators found two types of cells: those with secretory granules in the cytoplasm and those without them. The latter contained well-developed organelles. Secretory granules were localized in the apical part of the cytoplasm. The cytoplasm of some cells was almost completely filled with secretory granules, but in the cytoplasm of other cells they were very few. In such cells, organelles were rare, with a small number of mitochondria. The lamellar complex and endoplasmic reticulum were indistinguishable. However, neoplastic cells without secretory granules contained well-developed cytoplasmic organelles. They were abundant in endoplasmic reticulum and a number of mitochondria. The lamellar complex was visible in many cells. The surface of the cells filled with secretory granules was smooth, but their microvilli at the edge of the cell did not have secretory granules. Ribosomes were located opposite the cytoplasmic and nuclear membranes. A transition was observed between the clear cells and the grooved duct cells.

Histogenetically, acinar cells of the tumor originated from mature serous cells of the GS acini as a result of malignant transformation of terminal duct cells with histological differentiation towards acinar cells. However, it has been shown that normal acinar cells can undergo mitotic division and some salivary gland cancers can arise as a result of transformation of this cell type. Morphological, histochemical and ultrastructural studies have shown the similarity of tumor cells to serous cells, confirming theoretical concepts. The secretory activity of tumor cells is similar to that of normal serous cells of the GS acini. Clear cell carcinoma of the salivary gland, being a separate tumor in the morphological sense, probably develops from the striped cells of the duct.

Low-differentiated salivary gland cancer is characterized by pronounced cellular polymorphism, high proliferative activity, frequent mitotic figures, which is confirmed by their worse prognosis.

Most often, the best predictor than the tumor grade is the stage of the disease. Large tumor sizes, the spread of the process to the deep parts of the parotid gland, signs of incomplete and insufficiently radical tumor resection - all this indicates a poor prognosis. With regard to the proliferative activity of the neoplasm, the most reliable marker is the Ki-67 labeling index. When this indicator is less than 5%, tumor relapses are not observed. With a Ki-67 labeling index equal to or higher than 10%, most patients have a very poor prognosis.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ]

Mucoepidermoid carcinoma of the salivary gland

Mucoepidermoid carcinoma of the salivary gland has been known by various names since 1921. In 1945, F. W. Stewart et al. described the tumor under the term "mucoepidermoid tumor", reflecting its histological structure. It is a malignant glandular epithelial tumor characterized by mucous, intermediate and epidermoid cells with columnar, clear cell and oncocytic features. Code - 8430/0.

Synonyms: mixed epidermoid and mucinous carcinoma.

Research by foreign and domestic pathologists and clinicians served as the basis for including mucoepidermoid tumor in the group of carcinomas. According to the clinical and morphological features, a well-differentiated type with a low degree of malignancy and a poorly differentiated type with a high degree of malignancy are distinguished. Some researchers also distinguish an intermediate type - moderately differentiated with an average degree of malignancy. However, L. Sikorowa, J. W. Meyza (1982) believe that there are no sufficiently clear histological criteria for distinguishing an intermediate type.

Macroscopically, low-grade salivary gland cancer usually has a clear line of demarcation from the surrounding tissue, but does not have a capsule and shows signs of infiltrative growth. The tumor size is from 2 to 5 cm. The tumor node on the cut is with a mucous surface, cystic cavities are often revealed; sometimes the neoplasm is represented by one or more cystic cavities. A high-grade tumor has dimensions from 3 to 10 cm, is dense, immobile, infiltrates the surrounding tissues, without cystic cavities, with hemorrhages and areas of necrosis. Superficial salivary gland cancer has a bluish-reddish color and can simulate mucocele or vascular lesion. The mucous membrane over the tumor localized in the palate may have a papillary appearance. Sometimes the eroded surface of the bone is visible.

Microscopically, salivary gland cancer is represented by various cell types: undifferentiated, intermediate, epidermoid, clear, and mucus-producing cells. Undifferentiated cells are small, slightly larger than a lymphocyte, round or oval with a small round nucleus. Chromatin is intensely stained with hematoxylin. The cytoplasm is basophilic. These cells do not contain mucus and are PAB-negative. They form solid layers and cords, often on the periphery of the tubules and epithelial layers of more differentiated cells. Undifferentiated cells can differentiate into intermediate, clear, epidermoid, and mucus-producing cells in two directions - epidermoid and glandular. Differentiation into epidermoid cells is weak and indirect, through intermediate cells. Differentiation into glandular cells mainly occurs directly. Intermediate cells (cells lacking any specificity) are larger than undifferentiated cells. They have a small vesicular nucleus and eosinophilic cytoplasm. Their number varies, but in many cases they constitute the majority of the tumor component. The result of their pluripotent differentiation are goblet, clear and epidermoid cells.

Epidermoid cells are medium-sized, round or polyhedral. Their cytoplasm is acidophilic, the nucleus is vesicular, contains nucleoli. Just like undifferentiated cells, they form solid layers, cords, and can line cystic cavities. Keratohyalin and desmosomes make them similar to squamous epithelial cells.

Light cells are variable in size and shape, have light, transparent ("empty") cytoplasm containing glycogen. The nucleus is small, vesicular or pycnotic, located in the center or on one side of the cell. These cells form solid fields adjacent to cysts or are located among groups of undifferentiated and intermediate cells.

The mucus-producing cells are large, cuboidal and cylindrical, but in most cases goblet-shaped. They usually make up no more than 10% of the tumor. The small nucleus is located eccentrically or on the periphery of the cell. The fibrillar or reticular cytoplasm is slightly basophilic and intensely stains with mucicarmine - the result of mucus secretion, which accumulates in the cellular cytoplasm. The mucus secretion, penetrating into the stroma, forms mucus lakes. Goblet cells line the salivary "tubes" and cysts, often being the only element of the lining. They differentiate from intermediate and undifferentiated cells. Mucus-producing cells are one of the variants of differentiation of tumor cells into the terminal mucous secretory sections of the SF.

In the more differentiated type with a low degree of malignancy, cystic structures of various sizes predominate, predominantly containing mucus penetrating the stroma. They are surrounded by intermediate, undifferentiated and clear cells. The stroma is generally abundant, fibrous, locally hyalinized. Nerve invasion, necrosis, high mitotic activity or cellular atypia are rare. Lymphoid infiltration at the tumor margin with the formation of proliferation centers may imitate lymph node invasion.

The microscopic appearance of the well-differentiated type is characterized by cellular polymorphism and predominantly cystic structures filled with mucus; the less differentiated type is more uniform. The proportion of different cell types may vary both among different MCs and within a single tumor. Salivary gland cancer usually has a multicystic structure with a solid component, which sometimes predominates. Some tumors have clear borders, but infiltration of the adjacent parenchyma is obvious. All the described cell types may be present in the tumor, but intermediate and epidermoid cells predominate. They form solid nests of various sizes and shapes with a uniform structure of small cells infiltrating the stroma. Cellular atypia is pronounced, mitotic figures are frequent. Areas of small cells with mitotic figures may be found among single goblet cells; areas of tiny cysts with mucus-secreting cells are also encountered. Rarely, oncocytic, clear, and/or columnar cell populations may predominate. Clear cells have little mucin, but glycogen content is detected. Focal sclerosis and/or mucous extravasates with inflammatory infiltration are common. Sclerosing carcinoma of the salivary gland has been described.

Considering the origin of mucoepidermoid tumors, it is important to know about the presence of goblet and epidermoid cells in the epithelium of the salivary ducts in both physiological and pathological conditions. According to ultrastructural studies, in the pathological state, epithelial ductal cells can differentiate in the glandular and epidermoid direction. The modification of spinous cells occurs through the formation of intermediate cells. Mucoepidermoid carcinoma is composed of cells that arise from the modification of undifferentiated cells. This is an indication that the mucoepidermoid tumor originates from salivary duct cells or develops as a result of the modification of cells located under the columnar cells of the interlobar or large salivary duct. Myoepithelial cells were not found in the MC, which confirms the concept that these tumors develop from large salivary duct cells, among which myoepithelial cells are not found.

Microscopic differential diagnosis between the cystic variant of MC and a cyst is based on the presence of homogeneity of the cystic lining and the absence of signs of infiltrative growth. The presence of mucus-forming cellular elements and the absence of signs of keratinization help in the differential diagnosis of the poorly differentiated variant of MC with a predominance of epidermoid cells.

Several systems for determining the degree of differentiation of MC have been proposed, but none of them is generally accepted. However, a system based on five histological features has proven its effectiveness.

Highly differentiated tumors behave more aggressively when localized in the submandibular gastrointestinal tract.

The reaction with high-molecular-weight cytokeratins in immunohistochemical studies can help in identifying epidermoid cells when their number is small in the tumor.

Adenoid cystic salivary gland cancer

Adenoid cystic salivary gland cancer develops in the salivary and mucous glands. In the literature, the tumor was described under the term "cylindroma", proposed in 1859 by Billroth, and reflecting the structure of the intercellular substance of the tumor. The term "adenoid cystic carcinoma", proposed by J. Eving, in the opinion of most clinicians and pathologists, takes into account the malignant nature of the tumor, reflects its clinical and morphological features.

Adenoid cystic salivary gland cancer is a basaloid tumor composed of epithelial and myoepithelial cells in various morphological configurations, including tubular, cribriform, and solid growth patterns. Code - 8200/3.

Macroscopically, the tumor may appear as a relatively limited node or infiltrate, usually unencapsulated. The tumor infiltrate extends into the surrounding tissue, and hemorrhages and cystic degeneration are present.

When cut, the tissue is homogeneous, partly moist, gray-white, yellow-gray or light brown.

Microscopically, perineural spread of the tumor is often detected. Cellular elements are mainly represented by small cells with round or oval nuclei, scanty cytoplasm and poorly distinguishable borders. Mitoses are rare. There are cells with a dark nucleus, slightly eosinophilic cytoplasm, forming glandular structures. Among the irregularly shaped cell masses, there are rows of cysts or alveolar spaces, creating the so-called cribriform areas, which characterize the direction of these tumors. The glandular structures are filled with hyaline, giving a PAB-positive reaction. Sometimes, cribriform structures alternate with solid or cystic areas. Cell cords and layers pass through the hyaline stroma and form round or oval cell masses of various sizes and shapes. Cribrous areas can be large and formed by small groups of cells scattered in fibrous and/or hyaline stroma. Depending on the infiltrative properties of the tumor cells, the following types are distinguished: when open spaces or cavities predominate over glandular or solid areas; when the tumor contains solid tissue (especially connective fibrous tissue) or infiltrated skeletal muscles; this type is common. The tumor stroma is hyaline and gives a positive metachromatin reaction. There are no chondroid or myxochondroid components.

Ultrastructural studies have shown that adenoid cystic carcinoma consists of two types of cells - epithelial secretory (ductal) and myoepithelial. Tumor myoepithelial cells are very similar to one of the types of normal cells of the intercalated duct. Altered myoepithelial cells usually have a hyperchromatic pointed nucleus and often clear cytoplasm. Serous cells, polyhedral in shape, are undifferentiated, with a rich nuclear-cytoplasmic ratio. RAB-positive, hyaline-containing cysts and pseudoglandular structures are represented by a reduplicated basement membrane produced by tumor cells.

There are three distinct patterns: tubular, cribriform, and solid or basaloid. In the tubular pattern, well-defined tubes and ducts with central lumens are lined by an inner layer of epithelial cells and an outer layer of myoepithelial cells. The cribriform pattern, the most common, is characterized by nests of cells with cylindromatous cystic cavities. These are filled with hyaline or basophilic mucous content. The solid or basaloid pattern is formed by bundles of uniform basaloid cells in the absence of tubular or microcystic formation. In the cribriform and solid patterns, small true ducts are always present but may not always be readily apparent. Each pattern may predominate or, more commonly, be part of a complex tumor structure. The tumor stroma is usually hyalinized and may show mucinous or mucinous features. In some tumors, there is marked stromal hyalinosis with compression of the epithelial component. Perineural or intraneural invasion is a common and frequent feature of ACC. The tumor may extend along a nerve for a considerable distance without clinically visible signs of neoplasm. In addition, the tumor may infiltrate bone before radiographic signs of its destruction appear.

Adenoid cystic salivary gland cancer is occasionally found together with other neoplasms (hybrid tumor). According to the results of the study of recurrent and metastatic tumors, the possibility of transformation of ACC into pleomorphic carcinoma or sarcoma is reported.

Prognostic and predictive factors - factors affecting survival - include for ACC: histological type, tumor localization, clinical stage, presence of bone lesions, and the state of surgical resection margins. In general, tumors consisting of cribriform and tubular structures are less aggressive than those with solid areas occupying 30% or more of the tumor area. Along with the histological type, the clinical stage of the disease has a significant impact on the prognosis. According to other researchers, attempts to confirm the prognostic value of the "grade" have failed. The prognostic value of the clinical stage and tumor size as the most constant factors of clinical outcome in these patients has been revised. Five-year survival is 35%, but more remote results are significantly worse: from 80 to 90% of patients die from the disease after 10-15 years. Local relapses, according to various data, occur in 16-85% of cases of these tumors. Relapse is a serious sign of incurability. Lymph node involvement is uncommon and ranges from 5-25%, usually more common in tumors localized in the submandibular SG, which is more likely to be due to direct tumor spread to the lymph node rather than metastasis. Distant metastases are observed in 25-55% of ACC cases, with the lungs, bones, brain, and liver most commonly affected. Only 20% of patients with distant metastases survive 5 years or more.

The impact of perineural invasion on survival is controversial. Wide radical local excision with or without subsequent irradiation is the treatment of choice. Radiotherapy alone or in combination with chemotherapy in the treatment of recurrence and/or metastases has limited success. However, radiotherapy improves outcomes when applied locally to microscopic residual disease. The value of chemotherapy in ACC is limited and requires further study.

[ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ], [ 11 ]

Epithelial-myoepithelial cancer of the salivary gland

Salivary gland cancer consisting of two cell types in varying proportions that usually form duct-type structures. Biphasic morphology is represented by an inner layer of duct lining - epithelial-type cells and an outer layer of clear myoepithelial-type cells. Code - 8562/3.

Synonyms: adenomyoepithelioma, clear cell adenoma, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell adenocarcinoma

Epithelial-myoepithelial cancer of the salivary gland occurs in 1% of all salivary gland tumors. Women are more often affected - 2:1. The age of patients ranges between 13 and 89 years; the peak incidence is observed in the age group of 60-70 years. In pediatric practice, 2 cases of the disease have been described. Epithelial-myoepithelial carcinoma is most often localized in large salivary glands, especially in the parotid salivary gland (60%), but small salivary glands of the oral cavity, upper respiratory and digestive tracts can also be affected.

The clinical picture of epithelial-myoepithelial salivary gland cancer is represented by a painless, slowly growing tumor. Arising in small SGs, salivary gland cancer often ulcerates, presenting as submucous nodes with unclear edges. Rapid growth and/or pain in the facial nerve suggest the presence of tumor areas with a low degree of differentiation.

Macroscopically, epithelial-myoepithepial salivary gland cancer is characterized as a multinodular formation with an expansive growth pattern at the edges and the absence of a true capsule. The tumor surface is lobular and solid. Cystic cavities may be present. The tumor of small SGs is poorly delineated from surrounding tissues.

Histologically, epithelial-myoepithepial salivary gland cancer has a lobular growth pattern with a mixed - tubular and solid - structure. Papillary and cystic areas can be identified in 20% of cases. Tumors of small SGs can infiltrate surrounding tissues. Ulceration of the mucous membrane covering the tumor occurs in approximately 40% of cases.

The pathognomonic histological feature of epithelial-myoepithelial carcinoma is the presence of two-layer ductal structures. The inner layer is formed by one row of cuboidal cells with dense fine-grained cytoplasm and central or basal arrangement of nuclei. The outer layer may be represented by one or several layers of polygonal cells with clearly defined borders. The cytoplasm has a characteristic light appearance, and the nucleus is slightly eccentric, vesicular. The two-layer type of structure is preserved in cystic and papillary areas, but solid areas may be formed exclusively by light cells. The hyaline basement membrane surrounding the lobules of the tumor gives them an organ-like appearance. Organ structures are of various sizes with tubules in the center, lined with very small, cuboidal and shapeless, dark epithelial cells. Their nuclei are large, dark-colored, containing two or three nucleoli. The cytoplasm is scanty, mitoses are rare. These cells resemble the interlobular duct cells of normal SG. They contain few organelles and produce little secretion. PAS-positive, hyaline, eosinophilic tufts of basement membrane-like material surround the ductal structures and separate the clear cells in solid areas. The cells of the outer layer are rich in glycogen and other organelles. They show myoepithelial differentiation. The nuclei of the clear cells are small, oval, or spindle-shaped, and are located near and parallel to the basement membrane. There are some tumors in which the clear cells predominate and their solid structure resembles hypernephroma, parathyroid adenoma, or the clear cell type of acinic cell carcinoma. These salivary gland cancers were previously classified as myoepithelial adenomas or ductal carcinomas. Infiltrative growth and metastasis are characteristic.

Coagulative necrosis in the central parts of tumor nodes is rare. In rare cases, squamous cell metaplasia and spindle cells, as well as oncocytic changes in the cells of the inner layer of ductal structures, may be observed.

Perineural and vascular invasion are common, and invasion into underlying bone may also occur.

In the clear cell population, epithelial-myoepithelial salivary gland cancer can be determined from 0 to 1-2 mitoses per field of view. Rare cases of dedifferentiation have been described

Prognostically, relapses occur in approximately 40%, and metastases in 14% of cases. The most common localization of metastases is the cervical lymph nodes, lungs, liver, and kidneys. Up to 10% of patients die from the disease and its complications. 5- and 10-year survival rates are 80 and 72%, respectively.

A more unfavorable prognosis is associated with the size of the tumor and its rapid growth. The main prognostic factor is the state of the wound edges after tumor excision. In small SGs, the prognosis is worse, which is probably due to the difficulties and sometimes impossibility of radical tumor removal. Atypia worsens the prognosis if its signs are present in 20% or more of tumor cells. Aneuploidy, high mitotic index, areas of dedifferentiation predict a worse outcome, metastases and relapses develop in 70% or more patients.

[ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ]

Clear cell carcinoma of the salivary gland

A malignant epithelial tumor consisting of a homogeneous population of cells that have optically clear cytoplasm when stained with hematoxylin and eosin. Since salivary gland cancer often has a clear cell component, clear cell carcinoma is distinguished from them by the monomorphism of the clear cell population and the absence of any features characteristic of other tumors of the SG. Code - 8310/3.

Synonyms: clear cell adenocarcinoma, hyalinizing clear cell carcinoma.

Clear cell carcinoma of the salivary gland can be confused with epithelial-myoepithelial carcinoma, which has even been described as clear cell carcinoma.

The peak incidence is between 40 and 70 years of age, the tumor is almost never found in children. There is no gender predisposition.

Clear cell carcinoma is most often localized in the small glands of the oral cavity. The palate is most often affected, although the tumor can be found in the glands of the mucous membrane of the cheeks, tongue, floor of the mouth, lips, retromolar and tonsillar region.

Clinically, the only constant sign is the appearance of swelling; pain and ulceration of the mucous membrane are much less common. It is reported that the tumor may exist in the patient from 1 month to 15 years before diagnosis.

Macroscopically, salivary gland cancer, despite its relatively small size (usually no more than 3 cm in diameter), the tumor does not have clear boundaries, and there are often signs of infiltration of surrounding tissues - salivary gland, mucous membrane, soft tissues, bones and nerves. The cut surface is grayish-whitish.

Histologically, clear cell carcinoma of the salivary gland is characterized by a uniform population of round or polygonal cells with clear cytoplasm. In rare cases, a small percentage of cells have pale oxyphilic cytoplasm. The nuclei are eccentrically located, have a rounded shape, and often contain small nucleoli. Using the PAS reaction, it is possible to detect varying amounts of glycogen in the cytoplasm of tumor cells. Some authors distinguish, according to this feature, the so-called "clear cell carcinoma rich in glycogen." When stained with mucicarmine, cytoplasmic mucins are usually absent. Tumor cells form bundles, nests, solid foci - ductal structures are absent in clear cell carcinoma. Fission figures are rare, but signs of moderate nuclear polymorphism are noted in some tumors. In the hyalinizing type of clear cell carcinoma, the stroma consists of broad collagen bundles, while in other types it is represented by thin fibrous septa, which may be cellular or weakly collagenous. Clear cell carcinoma has no capsule and has features of an infiltrative tumor.

Clear cell salivary gland carcinoma is immunohistochemically positive for cytokeratin, at least focally. The expression of B-100 protein, vimentin, CPAP, and actin is variable. In the presence of histologic and immunohistochemical signs of myoepithelial differentiation, the tumor is best classified as a clear cell variant of myoepithelioma or myoepithelial carcinoma.

Electron microscopy reveals tight junctions, desmosomes, tonofilaments, microvilli, and basement membrane, i.e., signs of ductal differentiation.

Thus, the histogenesis of clear cell carcinoma, as confirmed by ultrastructural data, is associated with ductal rather than myoepithelial differentiation.

The prognosis for clear cell carcinoma is very good. A small number of tumors metastasize to regional lymph nodes and, much less frequently, to the lungs. No fatal cases have been reported from this disease.

[ 18 ], [ 19 ], [ 20 ], [ 21 ]

Mucinous salivary gland cancer

A rare malignant tumor consisting of epithelial clusters with large lakes of extracellular mucin. The mucinous component usually occupies the bulk of the tumor mass. Code - 8480/3.

Macroscopically, mucinous salivary gland cancer has a nodular structure and poorly defined borders. The cut surface is grayish-whitish, contains numerous cystic cavities filled with viscous jelly-like contents.

Histologically, salivary gland cancer consists of irregular nests and groups of neoplastic cells floating in mucus-filled cystic cavities separated by connective tissue bundles. The tumor cells are cuboidal, cylindrical, or irregular in shape, with usually clear cytoplasm and centrally located hyperchromatic nuclei. Tumor cell nuclei may show atypia, but division figures are very rare. The tumor cells are collected in groups (clusters) and tend to form secondary lumens or incomplete ductal-type structures. Mucus-forming cells may construct papillary structures projecting into lakes of mucus. Islands of tumor mucus-forming cells of the acinar type may also be present. The intracellular and extracellular mucus contents are PAS-positive and also stain with Alcian blue and mucicarmine.

The immunoprofile of mucinous adenocarcinoma cells is pancytokeratin, as well as cytokeratins 7, 8, 18 and 19, i.e. those that are usually found in simple epithelium. In approximately 10-20% of cases, a positive reaction is found with cytokeratins 4 and 13. Tumor cells are negative for the expression of cytokeratins 5/6, 10, 14, 17 and smooth muscle actin.

Electron microscopy reveals numerous mucus droplets of low electron density in the densely packed cytoplasm of tumor cells. Serous-mucous droplets are also detected. Randomly arranged microvilli can be seen on the side of the cells facing the lumen.

The differential diagnosis for mucinous adenocarcinoma includes mucoepidermoid salivary gland carcinoma, mucin-rich variant of ductal carcinoma of the SG, and cystadenocarcinoma. Mucus extravasates may be seen in MC, but the tumor itself consists of epidermoid and intermediate cells. Cystadenocarcinoma and AC have cystic cavities lined by epithelium, but lakes of extracellular mucus are not characteristic of these tumors.

In terms of prognosis, it should be noted that mucinous salivary gland cancer is not sensitive to radiation therapy and has a tendency to relapse and metastasize to regional lymph nodes.

Oncocytic salivary gland cancer

Characterized by proliferation of cytomorphologically malignant oncocytic and adenocarcinomatous structural phenotype, including its infiltrative properties. This tumor may arise de novo, but is usually detected in association with a pre-existing oncocytoma. It metastasizes and recurs, and is designated as oncocytic carcinoma despite the absence of cellular features of malignancy. Code - 8290/3.

Macroscopically, salivary gland cancer has a dense consistency, is homogeneous, lacks a capsule, and on section is gray to brown and red-brown in color, sometimes with foci of necrosis.

Histologically, oncocytic salivary gland cancer is foci, islets, and nests of large round or polygonal cells with delicate granular oxyphilic cytoplasm and a round centrally located nucleus, often with a pronounced nucleolus. Multinucleated cells are sometimes encountered. In some tumors, ductal structures of various calibers may be encountered. Tumor cells form layers, columnar formations, trabeculae, and additionally glandular and pseudoglandular fields. The hyaline stroma of the tumor is infiltrated with oxyphilic granular cells. Oncocytic salivary gland cancer has no capsule and often infiltrates adjacent muscle, lymphatic vessels, and nerves. Cellular and nuclear atypia and polymorphism are characteristic. Tumor cells capture perineural structures, infiltrate tissues, skeletal muscles, and vessels. They have little keratinization or mucin production; the PAS reaction and Alcian blue reaction are negative.

Ultrastructural studies by Lee and Roth (1976) showed that the structure of malignant oncocytoma does not differ from the structure of the benign tumor variant. Only the basement membrane is absent and the intercellular spaces are sometimes widened. The diagnosis of malignant oncocytoma is based on the presence of an encapsulation defect, local, perineural and vascular invasion, regional and distant metastases.

The oncocytic nature of the cells can be determined by various histochemical staining methods that reveal mitochondria, as well as by using the immunohistochemical method with antimitochondrial antibodies.

Immunohistochemical method helps to differentiate oncocytic carcinoma from benign oncocytoma. Antibodies Ki-67, alpha-1-antitrypsin are used.

Electron microscopy reveals large numbers of mitochondria, often of abnormal shape and size. The intracytoplasmic spaces are lined with microvilli, and lipid droplets are also present. Other ultrastructural features include a nearly continuous basal lamina, regularly spaced desmosomes, and abnormal cristae within the mitochondria.

Prognostically, oncocytic salivary gland cancer is a highly malignant tumor. It is characterized by multiple local relapses, the presence of regional and distant metastases. Apparently, the most significant prognostic factor is the presence or absence of distant metastases.

Myoepithelial carcinoma of the salivary gland

A tumor consisting almost exclusively of tumor cells with myoepithelial differentiation, characterized by an infiltrative growth pattern and the ability to metastasize. This tumor is a malignant analogue of myoepithelioma. Code - 8982/3.

Synonym: malignant myoepithelioma.

Macroscopically, myoepithelial cancer of the salivary gland lacks a capsule, but can grow as a nodule and have very clear boundaries. The size of the tumor varies widely - from 2 to 10 cm. The surface of the tumor on the section has a grayish-whitish color, can be shiny. In some tumors, fields of necrosis and cystic degeneration are visible.

Regarding the spread of myoepithelial carcinoma, it should be said that the tumor can affect the adjacent bone. Perineural and vascular invasion occurs. Regional and distant metastases are rare, but may appear later, as the disease progresses.

Histologically, myoepithelial carcinoma of the salivary gland is characterized by a multilobular structure. The cell type of myoepithelial carcinoma mirrors its benign counterpart in myoepithelioma. The tumor cells are often spindle-shaped, stellate, epithelioid, plasmacyte-like (hyaline), or, rarely, vacuolated in a signet-ring cell pattern. Other tumors tend to have an increased cellular component consisting of spindle cells resembling sarcomas. Very rarely, myoepithelial carcinoma consists of a monomorphic population of clear cells with myoepithelial features.

The tumor cells may form solid or tufted structures, and the type of structure may also be trabecular or reticular. But the tumor cells may also be separated from each other by abundant myxoid or hyalinized stroma. Cystic or pseudocystic degeneration may occur. Small areas with squamous differentiation may be found. Rarely, myoepithelial carcinoma of the salivary gland contains ductal structures with lumens lined by nonluminal cells. A tumor consisting of a fairly large number of ductal structures lined by a large number of true luminal cells should not be included in the category of a "pure" myoepithelial neoplasm.

Within the same tumor, various types of structure and various cell types are found. Indeed, most myoepithelial carcinomas are less monomorphic than benign myoepithelioma. They may also show increased mitotic activity. Cellular polymorphism may also be noticeable, and necrosis may be detected. However, the main requirement for establishing the diagnosis is the detection of signs of infiltrative and destructive growth, and this is precisely the property that distinguishes myoepithelial carcinoma from benign myoepithelial tumor.

It is believed that myoepithelial cancer of the salivary gland can arise de novo, but it should be emphasized that in half of the cases it develops from a previous pleomorphic adenoma or benign myoepithelioma, especially from a recurrent one.

Genetic studies have revealed rare abnormalities in this tumor - approximately 25% of cases, mainly in the form of various chromosomal aberrations. The most common changes are in chromosome 8.

Myoepithelial carcinoma of the salivary gland is a tumor with an aggressive growth pattern, and the clinical results of its treatment are variable. Approximately 1/3 of patients die from this disease, another third suffer from tumor relapses, often repeated, and, finally, another third are completely cured. Expressed cellular polymorphism and high proliferative activity correlate with a poor prognosis. There are no differences in the clinical behavior of myoepithelial carcinomas growing de novo and those that develop from pleomorphic adenomas and benign myoepitheliomas.

Molecular genetic methods show chromosomal abnormalities in myoepithelial carcinomas in 20-25% of cases, most often related to changes in chromosome 8.

Salivary gland cancer from pleomorphic adenoma

It is defined by the current WHO classification as "pleomorphic adenoma from which a malignant tumor arose." Code - 8941/3.

Synonyms: salivary gland cancer from benign mixed tumor, cancer in pleomorphic adenoma, malignant mixed tumor.

Macroscopically, salivary gland cancer looks like a clearly defined node, has a capsule, which in some places can be defective, infiltrated or destroyed by tumor masses. The average size of carcinoma from pleomorphic adenoma is usually twice that of its benign analogue, varying, according to various sources, from 1.5 to 25 cm. The tumor does not have clear boundaries, signs of invasive growth may be expressed. Sometimes carcinoma from pleomorphic adenoma has clear boundaries, grows in the form of a scar or appears completely encapsulated.

On section, the surface of the tumor is solid, resembling a mixed tumor, but there are foci of hemorrhage, cystic degeneration and necrotic areas characteristic of a malignant tumor.

Histologically, salivary gland cancer has the appearance of a pleomorphic adenoma with components of the structure of various carcinomas. The areas of growth have the appearance of solid, glandular carcinoma or epidermoid carcinoma, but most often it is necessary to differentiate it from adenocarcinoma and squamous carcinoma. In some places, salivary gland cancer differentiates as squamous epithelium, taking the picture of primary mucoepidermoid carcinoma of intermediate and high malignancy. In addition, glandular carcinoma tends to form papillary, cystic or trabecular structures.

Malignant transformation of pleomorphic adenoma is characterized by the appearance of hyperchromatic, cytologically distinguishable epithelial cells in the hyaline stroma. The cells infiltrate and destroy the structure of the pleomorphic adenoma, capturing nerves and vessels. In some places, the tumor has a benign character, but cellular polymorphism and mitotic figures in other areas indicate a malignant character.

In some cases, myxoid substance predominates, chondroid nests consist of large hyperchromic chondroblasts mixed with the epithelial component of pleomorphic adenoma in varying proportions. Chondroid and myxoid zones can be mistakenly assessed as elements of adenocarcinoma. Areas of necrosis, hemorrhage and calcifications are encountered.

In some areas, spindle cells with elongated nuclei and usually scanty cytoplasm are visible in the stroma. The spindle cells are diffusely distributed or mixed with giant cells, forming pseudosarcomatous areas.

Histologically, the ratio of benign and malignant components in a tumor varies significantly from case to case. Sometimes it is necessary to carefully examine the entire material to find the benign component, which in some cases may not be detected at all. However, if there is documentary evidence of a surgically removed pleomorphic adenoma in the same place, the tumor should still be classified as a carcinoma from a pleomorphic adenoma.

The malignant component of pleomorphic adenoma carcinoma is most often poorly differentiated adenocarcinoma (such as ductal carcinoma of the SG or NDC) or undifferentiated carcinoma. However, any form of SG cancer may be observed.

The most reliable diagnostic criterion is invasive and destructive tumor growth. Nuclear atypia and hyperchromasia are common, but sometimes there are types of carcinoma from pleomorphic adenoma in which atypia is minimal. This sign - atypia - determines the "grade" of the tumor and most significantly affects the prognosis. Necrotic fields are usually present and mitoses are also easily detected.

Salivary gland cancer from pleomorphic adenoma should be divided into non-invasive, minimally invasive (less than 1.5 mm invasion into “extracapsular” tissues), invasive (more than 1.5 mm tumor invasion into surrounding tissues). 

The first two groups have a very good prognosis, while the third is very questionable. The distinction between invasive and noninvasive pleomorphic adenoma carcinoma is based on the detection of signs of tumor invasion into surrounding tissues.

Undifferentiated salivary gland cancer in morphological presentation is a malignant epithelial tumor of round or spindle-shaped cells, which cannot be attributed to any of the groups of salivary gland tumors. This salivary gland cancer does not have any structures and signs of functional differentiation. Microscopically, cancer subtypes are distinguished depending on the cell type. Currently, subtypes of undifferentiated cancer are considered as independent types.

Salivary gland cancer consists of round, small to medium-sized anaplastic cells arranged in layers or nests separated by fibrous hyaline stroma. There are also round, uniform cells lying freely in the stroma, resembling malignant lymphoma or reticulosarcoma. This is the so-called solid globular cell carcinoma of the salivary gland.

The spindle-shaped type of tumor is represented by small or medium-sized spindle-shaped cells, combined into groups or rows, which are additionally intertwined with each other. Sometimes giant cells are present. The tumor resembles spindle-cell sarcoma or germinal myomatous tissue, but the cells are capable of differentiation. There are mitoses, necrotic zones. The stroma is scanty and usually hyaline. This variant of the tumor may be similar to small-cell carcinoma, described by Koos et al. in 1972.

Polymorphonuclear salivary gland carcinoma consists of anaplastic cells of various sizes and shapes, diffusely scattered throughout the affected area. The tumor stroma is loose and hyaline. Tumor cells infiltrate tissues, spreading to adjacent structures, penetrating into vessels and perineural spaces.

Lymphoepithelial carcinoma of the salivary gland

Undifferentiated cancer of the salivary gland, accompanied by pronounced non-neoplastic lymphoplasmacytic infiltrates. Code - 8082/3.

Synonyms: lymphoepithelial-like cancer of the salivary gland, malignant lymphoepithelial tumor, undifferentiated cancer with lymphoid stroma, undifferentiated cancer, cancer from lymphoepithelial tumor.

As a variant of undifferentiated cancer, some consider it a malignant analogue of benign lymphoepithelial lesion, others - as a poorly differentiated squamous cell carcinoma with lymphoid stroma.

Macroscopically, salivary gland cancer may be clearly demarcated or have pronounced signs of invasion into the surrounding tissue of the gland and adjacent soft tissues. Tumor nodes have a dense consistency and sizes from 1 to 10 cm (on average 2-3 cm).

Histologically, salivary gland cancer grows in the form of infiltrative foci, bundles, islands, separated by lymphoid stroma. Tumor cells have unclear borders, light oxyphilic cytoplasm and an oval bubble-shaped nucleus with a clearly visible nucleolus. Nuclei usually vary moderately in size, although in rare cases they are completely monomorphic. Necrotic fields and numerous mitotic figures are usually easily detected. Sometimes tumor cells have a "plump" and spindle-shaped form and form characteristic bundles. Sometimes there are foci of squamous cell differentiation in the form of an increase in the volume of oxyphilic cytoplasm of tumor cells and the appearance of unclearly expressed intercellular bridges.

Salivary gland cancer is densely infiltrated with lymphocytes and plasma cells, often with the formation of reactive lymphoid follicles. The lymphoid component may be so pronounced that it masks the epithelial nature of the tumor. In some cases, histiocytes are found in large numbers in the tumor islands, creating a picture of the so-called "starry sky". Other inconstant features include the formation of "noncaseating" granulomas with or without giant multinucleated cells, amyloid deposits, cyst formation in the islands of some tumors, perineural or lymphovascular invasion.

Tumor cells are immunoreactive for pancytokeratin and EMA. Lymphoid cells are a mixture of T and B cells. Electron microscopy reveals signs of squamous differentiation in the form of desmosomes and tonofilaments.

In tumor cells, FISH or CISH methods can detect viral RNA and DNA belonging to the Epstein-Barr virus. Immunohistochemical determination of the membrane protein 1 of the Epstein-Barr virus is more variable.

Differential diagnosis of salivary gland cancer includes metastasis of undifferentiated cancer, malignant lymphoma, lymphoepithelial sialadenitis, lymphadenoma, and large cell undifferentiated cancer. In lymphoepithelial sialadenitis, there is no pronounced cellular atypia, a basement membrane is present, there is no desmoplastic stromal reaction, and there is no connection with Epstein-Barr virus infection. Lymphoid carcinoma is characterized by more or less pronounced formation of glandular structures, no cellular atypia, no desmoplastic stroma, and no connection with Epstein-Barr virus infection. Most lymphoepithelial carcinomas grow de nоvо, but sometimes they can develop into lymphoepithelial sialadenitis (formerly called myoepithelial sialadenitis). A familial predisposition to lymphoepithelial carcinoma of the GS has been reported with dominantly inherited trichoepithelioma, which is presumably associated with common suppressor genes.

Lymphoepithelial carcinoma

A rare tumor, accounting for less than 1% of all tumors of the gastrointestinal tract. There is a racial predisposition to the disease: Eskimos in Arctic regions (Greenland, Canada, Alaska), southeastern Chinese and Japanese are more often affected. The Eskimo Inuit tribe has the highest incidence of gastrointestinal tumors in the world, most of which are lymphoepithelial carcinoma. A slight predominance of women, frequent involvement of the parotid gland, more frequent observation of advanced stages of the disease and, probably, a more aggressive clinical course of the disease - all this is noted in the Inuit. The age of patients with lymphoepithelial carcinoma varies widely - 10-90 years, with people aged 40-50 years most often affected.

Etiologically, salivary gland cancer in almost 100% of cases is associated with lymphoepithelial carcinoma of the GS with the Epstein-Barr virus in endemic areas, which suggests an important role of this virus in oncogenesis. Serological testing reveals elevated titers of antibodies to the capsid and / or nuclear antigen of the Epstein-Barr virus in more than 50% of patients with lymphoepithelial carcinoma in endemic areas. In patients from non-endemic areas, the Epstein-Barr virus is rarely detected. These data indicate a whole complex of interactions of ethnic, geographic and viral factors in the pathogenesis of lymphoepithelial carcinoma of the GS.

The localization of lymphoepithelial carcinoma in 80% of cases is associated with the parotid GC, followed by the submandibular GC. Rarely, lymphoepithelial carcinoma occurs in the small GC of the oral cavity and oropharynx.

Clinically, lymphoepithelial carcinoma is an enlargement of the parotid and submandibular scrotum, often long-standing, but with sudden rapid growth. Pain may be absent. In advanced stages, the tumor may be fused with surrounding tissues or skin. Facial nerve involvement occurs in no more than 20% of cases. Metastases in the lymph nodes are observed in 10-40% of cases. There are no clinical or serological data confirming the association of the disease with Sjogren's syndrome.

Because lymphoepithelial carcinoma of the salivary gland is morphologically indistinguishable from nasopharyngeal carcinoma (which is much more common), it is also important to obtain and examine a nasopharyngeal biopsy before confirming the primary nature of the tumor as lymphoepithelial carcinoma of the GS.

Lymphoepithelial carcinoma of the salivary gland has a tendency to metastatic spread to regional lymph nodes. In approximately 20% of cases, distant metastases are found, with the most common sites being the lungs, liver, bones, and brain. The characteristic lymphoplasmacytic infiltration seen in the primary tumor may be weak or absent in metastases.

Prognostically, in patients with combined treatment (surgery with radiation therapy), 5-year survival reaches 75-86%, despite the possibility of local relapse. The main and most significant prognostic factor is the stage of the disease. Attempts have been made to classify the "grade" of lymphoepithelial carcinoma depending on the number of mitoses and the degree of cellular polymorphism, but at present there is no such system for subdividing lymphoepithelial carcinoma by the degree of malignancy that would be generally accepted or even widely used.

Small cell carcinoma of the salivary gland

A rare salivary gland cancer characterized by proliferation of small anaplastic cells with scanty cytoplasm, delicate nuclear chromatin, and inconspicuous nucleoli. Code - 8041/3.

Synonyms: small cell undifferentiated salivary gland cancer, small cell anaplastic cancer, oat cell carcinoma, neuroendocrine cancer.

Small cell salivary gland cancer accounts for less than 1% of all salivary gland tumors and approximately 2% of malignant salivary gland tumors. Most patients are over 50 years of age at diagnosis, but the tumor has also been described in younger individuals. This tumor affects men somewhat more often.

The tumor localization is associated with large and small SG and is most often found in the parotid SG.

Clinically, patients with salivary gland cancer complain of a painless, rapidly growing tumor over several months. Enlarged cervical lymph nodes and paralysis of facial muscles are common findings. Paraneoplastic syndrome associated with the production of ectopic hormones is not typical.

Macroscopically, small cell carcinoma of the salivary gland is a dense tumor with unclear borders, often with signs of infiltration of the adjacent parenchyma of the salivary gland and adjacent soft tissues. The tumor is usually grayish or whitish in color, usually with areas of hemorrhage and necrosis.

Histologically, small cell carcinoma of the salivary gland is characterized by fascicles, nests of irregular shape, consisting of anaplastic cells and variable amounts of fibrous stroma. Nests of tumor cells may form palisade structures along the tumor periphery. Rosette-like structures are occasionally seen. Tumor cells are usually 2-3 times larger than mature lymphocytes and have a round or oval nucleus with scanty cytoplasm. Occasionally, single polygonal and large cells are encountered. Chromatin in the nuclei is delicate, and nucleoli are inconspicuous or absent. Cell boundaries are poorly defined, and “layering” of nuclei on top of each other is often observed. Numerous mitotic figures are found. The tumor may have small and rare foci of ductal differentiation. Foci of squamous differentiation have also been described. A common occurrence is extensive areas of necrosis, hemorrhage, and signs of perineural invasion.

Small cell carcinoma of the salivary gland has an unfavorable prognosis in general: local relapses and distant metastases occur in more than 50% of patients. Metastasis to regional lymph nodes of the neck is less common than distant metastasis. The 5-year survival rate for small cell carcinoma ranges from 13 to 46%, according to various authors. The survival rate is even lower in patients with a primary tumor larger than 3 cm, negative staining for cytokeratin 20, and decreased immunoreactivity to neuroendocrine markers.