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DEVELOPMENT OF THE JAWS1ODONTOGENESIS

Similar to tumors of other organ systems, odontogenic neoplasms and cysts often recapitu-late the tissues seen in various stages of embryo-genesis. A basic understanding of the embryology of odontogenesis is essential for pathologists to understand the features of many lesions that occur in the jaws of children and adults.

All ectodermal organs, including hair, teeth, and exocrine glands, develop as a result of complex interactions between the primitive epithelium and mesenchyme (�). Tooth germs exhibit many features that are morphologically and molecularly similar to these other epithelial appendages (2). The pharyngeal (branchial) ap-paratus consists of a series of paired structures, including arches, pouches, grooves, and mem-branes, that are numbered in a cranial to caudal direction. The first branchial arch forms the mandible and maxilla (3). The arch is surfaced by ectoderm that covers mesoderm and neural crest ectomesenchyme. Neural crest cells are

central to the process of mammalian tooth de-velopment in heterodonts (4). They are the only source of mesenchyme able to sustain tooth development, and give rise not only to most of the dental tissues, but also to the periodontal tissues that hold teeth in position.

DEVELOPMENT OF THE TOOTH AND SUPPORTING TISSUES

At about 6 weeks’ gestation, tooth develop-ment begins as 20 separate invaginations of ecto-derm, termed buds, from the dental lamina. Sig-naling molecules secreted by the oral epithelium establish cellular fields which form specific teeth. The critical information to model tooth shape resides in the neural crest–derived mesenchyme. Neural crest cells ultimately differentiate into highly specialized cell types to produce mature dental organs (5). The enamel organs that even-tually form the crowns of each deciduous and permanent tooth develop through three identifi-able stages: bud, cap, and bell (fig. �-�).

Figure 1-1

ODONTOGENESIS: CAP STAGE

The early enamel organ is attached to the epithelial surface of the primitive stoma by the dental lamina.

Tumors and Cysts of the Jaws

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Each dental lamina proliferates apically, eventually taking on a bell shape (fig. �-2). At this time, the connection between the overlying stomodeum and the forming enamel organ frag-ments into small epithelial islands referred to as the epithelial rests of Serres (fig. �-3). The enamel organ consists of three cell layers: inner enamel epithelium, stellate reticulum, and outer enamel epithelium, and forms a cap over the dental pa-pillae. Together, the enamel organ and a dental papilla are referred to as the tooth germ.

The bell stage is notable for cellular histo-differentiation, morphologic alteration, and early mineralization. Cells of the enamel organ directly adjacent to the dental papillae, termed the inner enamel epithelium, transform into columnar ameloblasts. Through a subsequent process of induction, the ameloblasts cause cells in the periphery of the dental papillae to dif-ferentiate into columnar odontoblasts. At this

point only a basement membrane separates the ameloblasts from the odontoblasts.

With the apposition of predentin by the odontoblasts, the enamel organ begins to show a fourth cell layer, termed the stratum interme-dium, directly adjacent to the ameloblasts (fig �-4). Once the stratum intermedium forms, am-eloblasts become more columnar and the nuclei move away from the basement membrane, a process called reverse nuclear polarization (figs. �-5,�-6). Most other columnar secretory cells have nuclei located near the basement mem-brane and secrete their product at the opposite end of the cell, usually into a duct lumen. The presence of nuclei that are polarized away from the basement membrane is a feature of a variety of odontogenic tumors.

The terminal differentiation of odontoblasts is controlled by the inner enamel epithelium and occurs according to a tooth-specific pattern.

Figure 1-2

ODONTOGENESIS: BELL STAGE

The inner and outer enamel epithelium and induced dental papillae are no longer connected to the surface by the dental lamina.

Figure 1-3

ODONTOGENESIS

Epithelial rests of Serres persist in the connective tissue following the degeneration of the dental lamina.

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Development of the Jaws

Figure 1-4

ODONTOGENESIS

Early mineralization is seen at the interface of the inner enamel epithelium and the dental papillae.

Figure 1-5

ODONTOGENESIS

Early tooth mineralization is characterized, from bottom to top, by basophilic dental papillae, columnar odontoblasts, tall columnar ameloblasts with polarized nuclei and vesiculated cytoplasm, stratum intermedium, and stellate reticulum.

Figure 1-6

ODONTOGENESIS

Columnar odontoblasts adjacent to the dental papillae at the bottom lay down predentin matrix and tal l columnar ameloblasts at the top produce enamel matrix.

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Figure 1-7

EPITHELIAL RESTS OF MALASSEZ

Epithelial rests, remnants of the Hertwig epithelial root sheath, persist in the periodontal ligament which attaches the tooth root cementum to the surrounding cortical bone. Inset shows rest of Malassez at higher power.

During the cap-bell transition, cells from the in-ner enamel epithelium segregate to form single or multiple cusps (6). When crown formation is completed, the enamel organ degenerates into a thin layer of cuboidal or squamous cells, referred to as the reduced enamel epithelium. Like the rests of Serres, the reduced enamel epithelium retains the potential to form odontogenic cysts and tumors.

Tooth root formation continues through the apposition of dentin tubules, which are eventually sheathed in cementum, necessary for attachment to bone via Sharpey fibers of the periodontal ligament. For the apposition of root dentin to occur, the odontoblasts require an induction effect from cells of the enamel organ. The enamel epithelium forms a collar of cells known as Hertwig epithelial root sheath, which proliferates apically and induces the dif-ferentiation of odontoblasts. As it proliferates through the forming jaw bone, the root sheath apically leaves behind residual epithelial islands known as rests of Malassez (fig. �-7). These rests persist in the periodontal ligament and provide an additional source of odontogenic epithelium capable of forming cysts and tumors. Even though they appear inactive microscopically, experimental evidence has shown that the rests of Malassez continue to have low levels of mitotic activity, indicating that cellular

proliferation is responsible for the formation and enlargement of cysts and neoplasms under certain physiologic conditions (7).

Dentin that is not covered by enamel is cov-ered by cementum which is a form of modified osteoid produced by cementoblasts that are indistinguishable from osteoblasts. The cemen-tum is attached via Sharpey fibers through the periodontal ligament to a thin layer of cortical bone termed the lamina dura.

Because the mineralized tooth constitutes the hardest substance in humans and is resistant to the natural forces of decomposition after death, the features of tooth development also play an instrumental role in forensic identification, and in the evolutionary classification of our hominid ancestors (8).

While normal tooth development usually ends by about age 2�, the potential for the development of reactive, cystic, or neoplastic lesions of the jaws persists in the remnants of odontogenesis that are left behind. In addition to the reduced enamel epithelium and un-named rests often found in the tooth follicle, as well as the rests of Serres or Malassez, the original basal epithelium, which in the adult is represented by the gingiva and alveolar mucosa, retains the capability to form odontogenic tis-sue. This capability is supported by the forma-tion of peripheral odontogenic tumors, such as

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Development of the Jaws

the ameloblastomas that appear to bud directly from the basal cells of the gingiva.

RECENT ADVANCES

While the process of odontogenesis has been characterized for decades, recent research has shed more light on this process at the molecular level. More than 300 genes have so far been as-sociated with tooth development. Most of these genes are associated with signaling pathways mediating cellular communication between epi-thelial and mesenchymal tissues (9). Recently, micro-RNA pathways have emerged as impor-tant regulators of various aspects of embryonic development including odontogenesis (�0).

Restriction of the signaling peptide encoded by the sonic hedgehog gene in localized thick-enings of oral epithelium has been shown to play a crucial role during the initiation of odontogenesis (��). While the sonic hedgehog gene helps regulate tooth growth and helps to determine the shape of the tooth, signaling is not essential for differentiation of ameloblasts or odontoblasts (�2).

Members of the Msx homeobox gene family are expressed at sites of epithelial-mesenchymal interaction during tooth formation. Msx1-defi-cient mice exhibit an arrest in tooth develop-ment at the bud stage, while Msx2-deficient mice exhibit defects in later stages of tooth development. (�3).

Nestin, one of the intermediate filaments constituting the cytoskeleton, is a marker of neural stem cells or progenitor cells. Nestin is also involved in the differentiation of odon-togenic ectomesenchyme to odontoblasts and in the formation of mesenchymal tissues in odontogenic tumors (�4).

The genetic causes of most cases of abnormal enamel development, such as amelogenesis imperfecta, are associated with mutations in enamel matrix specific genes. Recent evidence, however, has shown that mutations in genes involved in pH regulation may affect enamel structure as well (�5).

New treatments for systemic disease also effect tooth development. The use of oral and intravenous bisphosphonates in young children with diseases such as osteogenesis imperfecta inhibits tooth formation and eruption, and has induced several types of dental abnormalities, which may be attributed to altered osteoclastic activities (�6).

By combining the knowledge of molecular regulation of tooth development with the re-cent breakthroughs in stem cell research, tooth regeneration may someday be possible (�7). The transfer of embryonic tooth primordia into the adult jaw has resulted in the formation of tooth structures, indicating that embryonic primordia can continue to develop in an adult environ-ment (�8).

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