|Year : 2015 | Volume
| Issue : 2 | Page : 76-79
Current concepts of salivary gland tumors
Raj Kumar Badam1, Sudheer Kanth2, Sugunakar Raju3, Sujan Kumar Kotha4, Madhusudhan Rao5, K Lalith Prakash Chandra6
1 Department of Oral Medicine and Radiology, Panineeya Institute of Dental Sciences and Research Centre, Dilsukhnagar, Hyderabad, Andhra Pradesh, India
2 Department of Oral and Maxillofacial Pathology, Mamatha Dental College and Hospital, Khammam, Andhra Pradesh, India
3 Department of Oral and Maxillofacial Pathology, Kamineni Institute of Dental Sciences, Narkatpally, Andhra Pradesh, India
4 Department of Orthodontics, MNR Dental College, Sangareddy, Telangana, Andhra Pradesh, India
5 Department of Oral and Maxillofacial Pathology, Lenore Institute of Dental Sciences, Rajanagaram, Rajamandry, Andhra Pradesh, India
6 Department of Oral and Maxillofacial Pathology, Sibar Institute of Dental Sciences, Guntur, Andhra Pradesh, India
|Date of Web Publication||17-Nov-2015|
Dr. Raj Kumar Badam
Department of Oral Medicine and Radiology, Panineeya Institute of Dental Sciences and Research Centre, Road No. 5, Kamala Nagar, Dilsukhnagar - 500 060, Hyderabad, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
The embryonic development of salivary glands is a complex process that creates compact, highly organized secretory organs with functions essential for oral health. The development is an example of branching morphogenesis, recent research found to involve unexpectedly dynamic cell motility, and novel regulatory pathways. Numerous growth factors, extracellular matrix molecules, gene regulatory pathways, and mechanical forces contribute to salivary gland morphogenesis, but local gene regulation and morphological changes appear to play particularly notable roles. Salivary gland tumors are one of the most complex and relatively rare groups of lesions encountered in oral pathology practice. Their complexity is attributed to the heterogeneity of the cells of origin of these lesions. Frequent overlap of microscopic features among various neoplasms makes us sometimes even to differentiate benign and malignant lesions leading to a diagnostic dilemma. Here, we review and summarize the current concepts regarding the histogenetic and morphogenetic concepts of salivary gland tumors and their relevance to routine diagnosis and classification of these lesions.
Keywords: Histogenetic concepts, morphogenetic concepts, salivary glands
|How to cite this article:|
Badam RK, Kanth S, Raju S, Kotha SK, Rao M, Chandra K L. Current concepts of salivary gland tumors. J Orofac Sci 2015;7:76-9
|How to cite this URL:|
Badam RK, Kanth S, Raju S, Kotha SK, Rao M, Chandra K L. Current concepts of salivary gland tumors. J Orofac Sci [serial online] 2015 [cited 2019 May 20];7:76-9. Available from: http://www.jofs.in/text.asp?2015/7/2/76/169751
| Introduction|| |
Histogenesis is the formation or development of tissues from the undifferentiated cells of the germ layers of the embryo. In pathology, this term has become synonymous with the "cell of origin" for a neoplasm rather than the developmental process underlying the tumor.
Morphogenesis is the evolution and development of form, as the development of the shape of a particular organ or part of the body, or the development undergone by individuals who attain the type to which the majority of the individuals of the species approximate. For pathologists, this definition represents the process of differentiation inherent in neoplasms and the resulting histopathology characteristic for that particular tumor.  Salivary gland development is an example of branching morphogenesis, a process fundamental to many developing organs, including lung, mammary glands, pancreas, and kidney.  During the 6-8 th embryonic week, the major salivary glands develop as outpouchings of oral ectoderm and grow inwardly into the surrounding mesenchyme.  For overall glandular growth, nervous system involvement and tightly regulated signaling pathways (sonic hedgehog [Shh] and the fibroblastic growth factor family of receptors) are crucial. , The basic secretory units of the salivary glands consist of the spherical acinus, the myoepithelial cell, the intercalated duct, the striated duct, and the excretory duct. The primary secretion is produced in the acini, and the duct system carries the saliva to the oral cavity. Myoepithelial cells embrace the secretory acini and the intercalated ducts while the striated ducts and the subsequent conducting portion are supported by basal cells. The secretory units are divided into three types:
- Serous (thin, watery, proteinaceous, and amylase secreted),
- Mucous (viscous, glycoprotein-rich, sialomucins secreted) and
- Mixed. 
The myoepithelial cells (or "basket cells") are located between the basement membrane and the basal plasma membrane of the acinar cells. Besides the salivary glands, these cells are also found in breast, sweat, and lachrymal glands. , Myoepithelial cells are flat, variable, however, in morphology, and cannot be reliably identified by light microscopy. They possess dendritic processes that extend over the epithelial surface and embrace the secretory acini. The most profound characteristic of these cells is their dual basal epithelial-myxoid nature.  In addition to basal cytokeratin expression (i.e., cytokeratin 5 and 14), myoepithelial cells also contain cytoplasmic myofilaments, including actin, tropomyosin, and myosin.  These cytokeratins and cytoplasmic myofilaments act as specific immunohistochemical markers in differentiating salivary gland tumors.
Tumors of the salivary glands display one of the greatest diversities of histology among human cancers. A broad morphologic spectrum exists between different tumor types and sometimes even within an individual tumor mass. In addition, the occurrence of hybrid tumors, dedifferentiation and the propensity of some benign salivary gland tumors to progress to malignancy make this group of lesions one of the most interesting and challenging in the head and neck.
Classification of salivary gland tumors is essentially based on morphology, and histologic aspects of these tumors correlate with the normal salivary gland structure. However, this histologic similarity does not necessarily imply that a particular tumor arises from the structure it mimics. The morphologic complexity of salivary gland tumors is further illustrated by the fact that in the latest revision of the World Health Organization histological classification of salivary gland tumors nearly 40 different epithelial subtypes are recognized.
| Classification|| |
Histological classification of epithelial tumors of the salivary glands, given by World Health Organization (2005)
Benign epithelial tumors
- Pleomorphic adenoma
- Basal cell adenoma
- Warthin tumor
- Canalicular adenoma
- Sebaceous lymphadenoma
- Nonsebaceous lymphadenoma
- Inverted ductal papilloma
- Intraductal papilloma
- Sialadenoma papilliferum.
Malignant epithelial tumors
- Acinic cell carcinoma
- Mucoepidermoid carcinoma
- Adenoid cystic carcinoma
- Polymorphous low-grade adenocarcinoma
- Epithelial-myoepithelial carcinoma
- Clear cell carcinoma, NOS
- Basal cell adenocarcinoma
- Sebaceous carcinoma
- Sebaceous lymphadenocarcinoma
- Low-grade cribriform cystadenocarcinoma
- Mucinous adenocarcinoma
- Oncocytic carcinoma
- Salivary duct carcinoma
- Adenocarcinoma, NOS
- Myoepithelial carcinoma
- Carcinoma ex-pleomorphic adenoma
- Metastasizing pleomorphic adenoma
- Squalors cell carcinoma
- Small cell carcinoma
- Large cell carcinoma
- Lymphoepithelial carcinoma
| Histogenetic Concepts|| |
In the last decades, the numerous morphologic subtypes of salivary gland neoplasms have evoked considerable interest in their histogenetic origin. Determination of the cell type(s) involved in tumor induction in normal salivary gland tissue has led to the proposal of various theories.
The first hypothesis was based on the positioning of proliferating cells in the salivary glands. Histologic observations in fetal salivary gland tissue suggested that the outer (basal) layer of cells give rise to the inner (luminal) layer. This "semipluripotent bicellular reserve cell theory" was proposed by Eversole in 1971 and refined by Batsakis and colleagues 6 years later. ,, In this concept, excretory basal cells only give rise to mucoepidermoid and squamous carcinomas, whereas the intercalated luminal cells are responsible for lesions such as pleiomorphic and monomorphic adenomas, adenoid cystic carcinomas, and acinic cell carcinomas. The secretory acinar cells, being highly differentiated, are assumed to be incapable of cell division and thus play a minimal role in tumor formation.
In 1989, Batsakis et al. evoked a "pluripotent stem cell model" to explain the phenotypic heterogeneneity seen within salivary gland neoplasms.  In this postulate, salivary gland tumors arise from a population of pluripotent stem cells present in the intercalated duct system where they are responsible both for the regeneration within the gland and for the development of metaplasia.
Recent investigations, however, provided accumulating evidence that all mature cell types in salivary gland tissue are capable of proliferation, , giving rise to the "multicellular concept" of tumor histogenesis.  This latest concept suggests that any of the cell types in salivary gland tissue is capable of giving rise to any of the various types of tumor in this organ.
To prove multicellular concept autoradiography study was done in neonatal and adult rat salivary glands by administration of tritiated thymidine. Electron microscopy of these tissues in neonates revealed that duct basal cells, luminal cells at all levels of the duct system and even acinar cells were capable of DNA synthesis and mitosis. Indeed, in these studies, more luminal than basal cells were seen in mitosis. , When hyperplasia was induced in adult rats more acinar cells than intercalated duct cells were found in S-phase of the cell cycle. Similar findings were also reported in fetal and adult human salivary gland. , These results proves that dividing cells were not limited to basal cells of excretory ducts and, luminal cells of intercalated ducts thus disproving semi-pluripotential bicellular reserve cell hypothesis.
| Morphogenetic Concepts|| |
A number of factors affect the final hlstologic features of salivary gland tumors. However, these factors interact results in the histology and therefore, the criteria used for diagnosis. In many cases, patterns of tumor differentiation reflect the bilayered cellular makeup of all levels of the normal salivary gland, that is, composed of inner luminal or acinar cells and outer basal and/or myoepithelial cells, this histologic aspect is embodied in the ducto-acinar concept for appreciating one facet of tumor differentiation in salivary gland tumors. This ducto-acinar unit is a stylization representing the continuum of acinar/duct luminal cells on the one hand and basal/myoepithelial cells on the other, again from distal acinar to proximal excretory duct. This model provides a basis for outlining potential differentiation pathways in salivary gland tumors. As such it has no histogenetic implications, that is, does not imply one or other cell type as potential progenitors for neoplasms.
Model for morphogenetic concepts
In the simplest possible scenario based on the ducto-acinar unit, tumor cell differentiation results in three basic models of benign or malignant salivary gland neoplasms.
In one form of differentiation, tumor cell production results in a dual population that combines recognizable luminal and/or acinar cells with myoeplthellal and/or basal cells.
A second differentiation pattern results primarily in luminal/glandular cells that resemble to some extent normal duct epithelial and/or acinar cells while the third process produces tumor cells resembling normal myoepithelial and/or basal cells. ,
Evaluation of tumors on the basis of tumor cell phenotype(s), their arrangement, and the unique production of stromal materials that influences the final histology in these tumors allows for the establishment of improved diagnostic criteria. 
Selecting various combinations of luminal and myoepithelial/basal cells and coupling them with differing amounts and arrangements of extracellular materials serve to design models for each of the variants of these three salivary gland tumors. Although pleomorphic adenoma and adenoid cystic carcinoma may appear morphologically distinct by light microscopy, both share many common features, including luminal cells forming duct-like structures. In the case of the cribriform variant of adenoid cystic carcinoma, however, these are usually insignificant and wedged between the more obvious neoplastic myoepithelial/basal cell component and well delineated foci of extracellular matrix responsible for the cribriform appearance. 
In pleomorphic adenoma, on the other hand, duct-like structures are generally more prominent, and the myoepithelial/basal type cells have a wider range of cytology and exhibit potential to gradually transform both to either squamous cell and/or chondrocytes, the latter at times still cytokeratin positive and having desmosomes, tonofilaments, and basal lamina. By comparing differentiation of tumor cell types and their arrangement ultrastructurally the considerable similarities between pleomorphic adenoma and adenoid cystic carcinoma readily become apparent. The apparent increased production of extracellular materials and the resulting isolation of modified myoepithelial cells result in the myxoid stroma. Although the underlying processes are the same in these two tumors, the genetic mechanisms responsible for the final morphology of each of them must differ, which even applies to the recognized variants within each subtype. 
| Conclusion|| |
Salivary gland tumors are relatively rare and diverse group of lesions with unresolved intricacies from its development to maturation. The modern approach is more realistic, in that histological typing is based on cellular differentiation rather than the cell of origin. It is important for the pathologist to assess the cytoarchitectural features and cytoarchitectural profile of these neoplasms and correlate them with histognetic concepts for better understanding which in turn will help in diagnosis and management of these lesions.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Dardick I, Burford-Mason AP. Current status of histogenetic and morphogenetic concepts of salivary gland tumorigenesis. Crit Rev Oral Biol Med 1993;4:639-77.
Arey LB. Developmental Anatomy. Philadelphia: WB Saunders; 1974.
Denny PC, Ball WD, Redman RS. Salivary glands: A paradigm for diversity of gland development. Crit Rev Oral Biol Med 1997;8:51-75.
Jaskoll T, Leo T, Witcher D, Ormestad M, Astorga J, Bringas P Jr, et al.
Sonic hedgehog signaling plays an essential role during embryonic salivary gland epithelial branching morphogenesis. Dev Dyn 2004;229:722-32.
Jaskoll T, Witcher D, Toreno L, Bringas P, Moon AM, Melnick M. FGF8 dose-dependent regulation of embryonic submandibular salivary gland morphogenesis. Dev Biol 2004;268:457-69.
Martinez-Madrigal F, Micheau C. Histology of the major salivary glands. Am J Surg Pathol 1989;13:879-99.
Hamperl H. The myothelia (myoepithelial cells). Normal state; regressive changes; hyperplasia; tumors. Curr Top Pathol 1970;53:161-220.
Lakhani SR, O′Hare MJ. The mammary myoepithelial cell - Cinderella or ugly sister? Breast Cancer Res 2001;3:1-4.
Eversole LR. Histogenic classification of salivary tumors. Arch Pathol 1971;92:433-43.
Regezi JA, Batsakis JG. Histogenesis of salivary gland neoplasms. Otolaryngol Clin North Am 1977;10:297-307.
Batsakis JG. Salivary gland neoplasia: An outcome of modified morphogenesis and cytodifferentiation. Oral Surg Oral Med Oral Pathol 1980;49:229-32.
Batsakis JG, Regezi JA, Luna MA, el-Naggar A. Histogenesis of salivary gland neoplasms: A postulate with prognostic implications. J Laryngol Otol 1989;103:939-44.
Dardick I, Byard RW, Carnegie JA. A review of the proliferative capacity of major salivary glands and the relationship to current concepts of neoplasia in salivary glands. Oral Surg Oral Med Oral Pathol 1990;69:53-67.
Attie JN, Sciubba JJ. Tumors of major and minor salivary glands: Clinical and pathologic features. In: Current Problems in Surgery. Vol. 18. Chicago: Year Book Medical Publishers Inc.; 1981. p. 80-1.
Denny PC, Chai Y, Pimprapaiporn W, Denny PA. Three-dimensional reconstruction of adult female mouse submandibular gland secretory structures. Anat Rec 1990;226:489-500.
Denny PC, Chai Y, Klauser DK, Denny PA. Three-dimensional localization of DNA synthesis in secretory elements of adult female mouse submandibular gland. Adv Dent Res 1990;4:34-44.
Walker NI, Gobé GC. Cell death and cell proliferation during atrophy of the rat parotid gland induced by duct obstruction. J Pathol 1987;153:333-44.
Walker NI, Pound AW. An autoradiographic study of the cell proliferation during involution of the rat pancreas. J Pathol 1983;139:407-18.
Dardick I. A Color Altlas of Salivary Gland Tumor Pathology. 1 st
ed. New York: Igaku-Shoin Medical Publishers; 1996.
Chaudhry AP, Leifer C, Cutler LS, Satchidanand S, Labay GR, Yamane GM. Histogenesis of adenoid cystic carcinoma of the salivary glands. Light and electronmicroscopic study. Cancer 1986;58:72-82.
Mills SE, Cooper PH. An ultrastructural study of cartilaginous zones and surrounding epithelium in mixed tumors of salivary glands and skin. Lab Invest 1981;44:6-12.