26-week-old male Tg.AC hemizygous mouse (Mus musculus).Mouse had a steadily enlarging mandibular mass.
Firm pale 1 centimeter mass adjacent to the incisors.
Mandible: Odontogenic tumor, ameloblastic, tooth.
The mandibular bone contains an invasive neoplasm that is composed of thin irregular
anastomosing cords of cuboidal to low columnar pallisading epithelial cells separated by a loose undifferentiated
spindle cell stroma resembling ameloblastoma (figures 2-1 and 2-2).Â The stroma contains cells with oval nuclei with finely stippled
chromatin and indistinct cytoplasmic borders, consistent with ameloblasts.
Odontogenic neoplasms are the most common spontaneous neoplasms in Tg.AC mice occurring at an incidence of approximately 13% in males and 17% in females.(2) Grossly, they occur as firm masses in the maxilla or mandible. Microscopically, 3 morphologic types occur the most frequent of which is the ameloblastic type as in the present case submission.(2,3) The second type, which appears to arise from the periodontal ligament, is the mesenchymal type which is composed of mesenchymal cells embedded in a dense eosinophilic matrix.Â The third morphologic type resembles odontomas and is composed largely of irregular abortive tooth structures formed by enamel, dentin and well differentiated ameloblasts and odontoblasts.
Other common neoplasms of Tg.AC transgenic mice include squamous papillomas of the forestomach, skin papillomas, alveolar/bronchiolar adenoma, salivary gland duct carcinoma and erythroleukemia seen primarily in the liver with involvement of the spleen, bone marrow and lymph nodes.
Mandible: Odontogenic tumor, ameloblastic.
Conference participants discussed odontogenesis and the distinguishing characteristics of
odontogenic epithelium: 1) peripheral palisading of epithelial cells, 2) location of the nucleus at the apical pole in
the palisaded cells, 3) cytoplasmic clearing at the basilar pole in the palisaded cells, and 4) prominent intercellular
bridging among the internal epithelial cells.(1)
All participants slides contained a pre-existing tooth at the periphery of the neoplasm.Â In addition, some participants slides contained a smaller tooth-like structure within the neoplasm.Â Considerable discussion centered on the origin of this structure, with some participants interpreting it as tooth recapitulation by neoplastic cells, while other participants favored a pre-existing structure.Â The classification of odontogenic tumors in transgenic mice, as summarized by the contributor, is convenient and avoids the problem of interpreting this tooth-like structure. However, participants noted that classification using the World Health Organizations (WHOs) scheme for domestic animals would hinge on interpretation of this structure.Â If this structure is interpreted as recapitulation by the neoplasm, the diagnosis would be ameloblastic fibro-odontoma, while the absence of this feature would make the tumor consistent with an ameloblastic fibroma using the WHO scheme.(1)
While in domestic species most odontogenic tumors have similar biological behavior (i.e.Â local destruction by expansion, amenable to surgical excision), there are two notable exceptions.Â Canine acanthomatous ameloblastoma is aggressive, locally infiltrative, and prone to recurrence; fibromatous epulis of periodontal ligament origin is benign, and a surgical cure is often achieved despite incomplete surgical margins.(1)
The high incidence of odontogenic tumors in Tg.AC transgenic mice is attributed to the expression of the ras oncogene.Â Odontogenic tumors appear in up to 100% of dual transgenic mice expressing both ras and myc oncogenes, and appear as early as 4 weeks of age.(3) Oncogenes are constitutively active genes that promote autonomous cell growth in cancer cells in the absence of normal growth-promoting signals.Â Oncogenes result from mutations in proto-oncogenes, and their products are called oncoproteins.Â Normal ras proteins are bound to the cytoplasmic aspect of the plasma membrane, and are activated only upon growth factor binding to plasma membrane receptors.Â Activated ras stimulates the mitogen-activated protein kinase cascade, resulting in signals to the nucleus for cell proliferation.Â Mutated ras proteins are continually activated, usually due to point mutations that impair guanosine trhiphosphate (GTP) hydrolysis, resulting in continuous stimulation of downstream proliferation signals. The mechanisms by which myc oncogene expression influences cell proliferation are less clear.Â Myc modulates myriad cellular activities, and is thought to be involved in carcinogenesis via some of its many targets, including ornithine decarboxylase and cyclin D2.(5)
1.Â Head KW, Cullen JM, Dubielzig RR, Else RW, Misdorp W, Patnaik AK, Tateyama S, van der Gaag I:
Histological Classification of Tumors of the Alimentary System of Domestic Animals, 2nd series, vol.Â X, ed.
Schulman YF, pp.Â 47-54.Â Armed Forces Institute of Pathology (in cooperation with the ARP and the WHO
Collaborating Center for Worldwide Reference on Comparative Oncology), Washington, DC, 20306
2.Â Mahler JF, Flagler ND, Malarkey DE, Mann PE, Haseman JK, Eastin W.Â Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice.Â Toxicologic Pathology 26(4):501-511, 1998
3.Â Mahler M, Rozell, Mahler JF, Merlino G, Devor-Hennemn D, Ward JM, Sundberg JP.Â In: Pathology of Genetically Engineered Mice.Â Eds.Â Ward JM, Mahler JF, Maronpot RR, Sundberg JP, Fredrickson RM, 1st edition. Iowa State University Press, Ames, IA, 2000
4.Â National Toxicology Program CD-Rom, Laboratory of Experimental Pathology.Â Lesions of Genetically Altered Mice, 2001 (http://dir.niehs.nih.gov/dirlep/genmice2/open_me.htm)
5.Â Stricker TP, Kumar V: Neoplasia: In: Robbins and Cotran Pathologic Basis of Disease, eds.Â Kumar V, Abbas AK, Fausto N, Aster JC, 8th ed., pp.Â 279-286.Â Saunders Elsevier, Philadelphia, PA, 2010