Pathogenesis of salivary gland neoplasms: The concepts of histogenesis and morphogenesis

The “histogenesis” concept

This concept of the development of SGNs is based on the putative cells of origin involved in the formation of specific structures of the fetal salivary gland system. The histogenic concept of salivary gland tumors has usually relied on histologic observations of the fetal salivary gland and the cellular differentiation involved in particular segments of the duct system.

Over the years, several theories involving the histogenesis concept in SGNs have been put forth:^[3,6,7]

1. Basal reserve cell theory (Eversole, 1971):

   Also called as “progenitor cell” theory. It is based on the hypothesis that the basal cells function as reserve cells that eventually give rise to its derivates of the luminal layer of the intercalated and the excretory ducts. The hypothesis was formulated after observation of the embryonic palatal minor salivary glands and bilayered major ducts in the human fetal salivary gland. The tumors that most appropriately fit into the hypothesis include pleomorphic adenoma, basal cell adenoma, and canalicular adenoma.

2. Pluripotent unicellular reserve cell theory (Batsakis, 1977):

   This theory is another type of reserve cell theory; however, it states that only the basal cells of the excretory duct are responsible for the development of all the other salivary gland structures. The theory eliminated any implication of the intercalated duct reserve cells in the development of salivary gland units or neoplasms.

3. Semi-pluripotent bicellular reserve cell theory (Dardick, 1981):

   This theory is a more elaborative and refined version of the reserve cell theories. The basal cells of the intercalated and excretory ducts were still implicated in the development of luminal structures; however, a distinction was made between the derivatives of the two types. The first type, basal cells of the intercalated ducts, gives rise to acini and the luminal cells of the intercalated and striated ducts. The second type of basal cells, excretory duct reserve cells, give rise to squamous or mucin-producing columnar cells.^[6,7]

   Based on this theory, it could be interpreted that mucoepidermoid carcinoma and squamous cell carcinoma arose from the excretory duct reserve cells, whereas the intercalated duct reserve cells formed all the other tumors.

   It was also pointed out that the myoepithelial cells were responsible, in part, for the morphologic diversity of the neoplasms. Although the “bicellular theory of origin” has been well accepted, there has been little or no direct evidence to support the hypothesis.

4. Multicellular histogenesis concept (Dardick et al., 1989):

   The theory suggests that the differentiated luminal and abluminal cells of the mature salivary glands are capable of proliferating into neoplasms [Figure 1]. It was demonstrated that the basal cells of the ducts, luminal cells, as well as acinar cells were capable of DNA synthesis and mitosis. In adult rats, when hyperplasia was induced in the salivary glands, it was found that more acinar cells were found in the S-phase of the cell cycle as compared to the intercalated ductal cells. It was, thus, evident from these observations that the proliferative compartment in the salivary glands was not restricted only to the ductal basal cells.^[6,7]

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Figure 1:

Multicellular histogenesis concept of salivary gland neoplasms.

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In terms of tumor induction, it should be appreciated that “differentiated cells are capable of metaplastic alterations’ epidermoid metaplasia has been demonstrated in acinar and myoepithelial cells of the salivary gland of the rat and secretory cells of hamster tracheal mucosa. The role of repair and replenishment could be assumed only by uncommitted stem (reserve cell) cells and by inference such as cells are solely at risk for neoplastic induction. Epithelialmyoepithelial carcinoma and the newly described entities of intercalated duct adenoma and striated duct adenoma are aptly supported by this hypothesis.

The “Morphogenesis” concept

Studies have revealed the previously unrecognized complexity of the salivary ductal epithelium and some aspects of the cellular organization of these ducts. The morphogenetic approach focuses on tumor differentiation and other cellular processes that critically influence histomorphology. They are unconcerned with the tumor initiation processes, even though these are of primary importance and are likely to influence many aspects of tumor development. The morphogenic process determines the specific features allowing recognition of each normal organ as well as differentiation of SGNs.^[3,6]

The importance of this concept is that it relates the histology of the neoplastic processes directly to the classification of SGNs rather than designing a special cell of origin that are generally impossible to precisely identify once the tumor is clinically overt, thus, having better practical applications compared to the histogenesis concepts. Understanding the ductoacinar concept helps to appreciate the evolution of histological features in salivary gland tumors, which is essential for proper morphological classification.

Pleomorphic adenoma

The term “pleomorphic adenoma” suggested by Willis characterizes closely the unusual histologic pattern of the lesion. The neoplastic cells exhibit an ability to differentiate into epithelial (luminal and abluminal) cells and mesenchymal (chondroid, myxoid, and osseous) cells. Many theories have been put forward in explaining the histogenesis of this bizarre tumor.^[3,11]

At present, these are centered around myoepithelial cells and a reserve cell in the intercalated duct. Regezi and Batsakis postulated that the intercalated duct reserve cells differentiate into ductal and myoepithelial cells and later, in turn, can exhibit metaplasia into mesenchymal phenotype as demonstrated by the expression of vimentin and smooth muscle actin. Hubner, and more recently, Brodetskyi et al. suggested that these myoepithelial cells are responsible for the production of the fibrous, mucinous, chondroid, and osseous tissue accounting for the histomorphologic diversity of the tumor.^[11]

Even so, the role of the myoepithelial cell in the histogenesis of PA is uncertain and it may only be a passive participant in the process. Dardick et al. questioned the role of intercalated duct (ICD) cells and myoepithelial cells. They stated that a neoplastically altered epithelial cell with the potential for multidirectional differentiation may be responsible for the PA.^[6]

Warthin’s tumor

Warthin’s tumor is the second most common tumor in the salivary glands, almost invariably occurring in the parotid gland. This tumor was first recognized by Albrecht in 1910 and later described by Warthin in 1929.^[12] The histologic appearance leaves no doubt that Warthin’s tumor differentiates both basal and luminal cells in the development of its characteristic epithelium. Unlike either normal luminal or basal/myoepithelial cells, both cell types in Warthin’s tumor are packed with mitochondria and, therefore, show oncocytic differentiation.

Numerous theories have been advanced to account for the peculiar histomorphology of this tumor. Thompson and Bryant in their study described that tumors with typical epithelial elements showed no evidence of normal lymph node architecture, and they suggested that it involved a neoplastic proliferation of parotid ductal epithelium and concomitant secondary formation of lymphoid tissue. Histochemical investigations have indicated that Warthin’s tumor most likely arose from salivary ducts in the lymphoid stroma.^[13]

It was also suggested that Warthin’s tumor is most likely a delayed hypersensitivity disease, the lymphocytes being an immune reaction to the salivary ducts which undergo oncocytic change. Recent immunohistochemistry (IHC)-based studies have suggested that the lymphoid component of the tumor is an exaggerated secretory immune response. The currently accepted theory is that the tumor arises in salivary gland tissue entrapped within paraparotid or intraparotid lymph nodes during embryogenesis.

Acinic cell carcinoma (ACC)

Neoplastic acinar cells constitute an integral component of ACC.^[13] In most cases of the microcystic variant of ACC, what have been referred to as vacuoles within the tumor cells, implying a degenerative process in this tumor, are in reality smaller versions of true intercellular lumens.^[14]

Oncocytoma and oncocytic adenocarcinoma

The name “oncocytoma” is derived from the resemblance of these tumor cells to apparently normal cells which have been termed “oncocytes.”^[15] These cells are not only limited to salivary glands but may also be found in the breast, thyroid, parathyroid, pituitary, and other glands. The phenomenon of “oncocytosis” occurs as a result of an aberrant increase in the number of mitochondria in the cells. There may represent age-related changes or occur as a result of an increase in the metabolic activity of the cells.^[6]

In addition to luminal cell differentiation in oncocytomas, myoepithelial-type cells have been reported ultrastructurally, such dual differentiation is theoretically possible and would not differ from the neoplastic myoepithelium shown in otherwise classical ACC.

Adenoid cystic carcinoma

Emulation of the ductoacinar unit is complete in three model diagrams representing the recognized growth patterns, cribriform, tubular, and solid.^[6,13]

1. In the cribriform variant, some balance exists between the differentiation of luminal cells-forming ductal structures-and basal/myoepithelial cells.^[13]

2. Tubular variant results when luminal cells forming ducts are surrounded by a single to a few layers of basal/myoepithelial cells without intercellular materials accumulating.

3. The solid variant develops from an exuberant proliferation of neoplastic basal/myoepithelial cells.

Mucoepidermoid carcinoma

Tumor cell differentiation based on the organization of the normal ductoacinar unit results in a variety of cell types and a considerable spectrum of histology in mucoepidermoid carcinoma. The differentiation potential of luminal cells can produce goblet cells, non-descript cuboidal to columnar cells, glycogen-laden clear cells, and squamous cells.^[16] Similarly, differentiation in abluminal cells can be seen as myoepithelial cells, intermediate cells, squamous cells, glycogen-rich clear cells, and non-specific basal cells. By mixing the cell types, it is possible to develop the range of histology both within and between cases of mucoepidermoid carcinoma, as well as various grades of the tumor.

Epithelial-myoepithelial carcinoma

As the name suggests, the tumor exhibits a bidifferential cell population comprising epithelial as well as myoepithelial cells. In this case, an apparent “inverse ductal” arrangement is noted, wherein the central luminal cells are small with eosinophilic cytoplasm and the outer myoepithelial cells appear clear due to their rich glycogen content.^[17] Histogenically, the tumor may exhibit an epithelial-dominant or a myoepithelial-dominant picture or an almost equal proportion of both as noted in the classic variant. Solid, tubular, cribriform, and papillary architectures add to the histomorphologic spectrum of epithelial-myoepithelial carcinoma.

Polymorphous adenocarcinoma

The tumor exhibits a cytologically uniform yet architecturally diverse histopathological picture; thus, the name “polymorphous.” The tumor is also called “terminal duct carcinoma” indicating the putative cells of origin to be from the terminal excretory ducts.^[18] The myriad histologic patterns result from the controlled development of tumor cells with varying arrangements from region to region, as well as variation between individual cases. In some examples, this consists of regions composed exclusively or predominantly of luminal cells; in other cases, as a combination of luminal and abluminal cells while in some cases, largely as basal/ myoepithelial cells.^[6] Depending on the location and amounts of extracellular materials, histopathology may exhibit myxoid stroma and/or areas with a cribriform growth pattern. Combinations of these cell types and growth patterns commonly occur in individual cases.^[13]

The advent of IHC has confirmed much of the assumptions on which the histogenic and morphogenic concepts of SGN pathogenesis were based. These are summarized in brief in [Table 2].^[19-21]