“Ameloblastoma” – A survey on the need for a multidisciplinary research approach to this biological enigma

Ikechukwu U. Madukwe

Department of Oral Surgery and Pathology School of Dentistry, College of Medical Sciences
University of Benin, Benin City, Nigeria

ABSTRACT
Background:  Ameloblastoma is a strange clinic-histologic contradiction, with an aggressive clinical behavior and benign histological feature.  Enamel organ responsible for the physiological tooth formation is equally responsible for extensive contributions to Oral pathologies.  These pathological processes and conditions range from simple periodontal cyst to odontogenictumours
Methodology:  This is a survey in multidisciplinary research approach to the study of ameloblastoma in the College of Medical Sciences, University of Benin.  This survey was interactive through telephone calls and direct interview.  Interaction was with 39 doctors, made up of 13 maxillofacial surgeons, 21 doctors in physiology and 5 doctors in medical biochemistry.
Result:  Out of 39 doctors interviewed, 5 (12.8%) maxillofacial surgeons, 8 (20.5%) physiologists and 3 (7.7%) medical biochemists indicated their interest to participate in the in vitro studies 16 (41%).
Conclusion:  We conclude that multidisciplinary approach to ameloblastoma research is over due.
Recommendation:  We therefore recommend a joint investigation of this enigma.

Keyword: Ameloblastoma, multidisciplinary, research, biological.

INTRODUCTION
Ameloblastoma considered by Campos1 as a behavioural and histological paradox, has bothered mankind since the time of Cusack[2] who first recognized it in 1827 and was called adamantinoma by Louis-Charles Malassez[3] in 1855 and finally renamed by Ivy and Churchill[4] in 1930.  Ameloblastoma because of its aggressive clinical behavior and its histological feature apparently benign, constitutes a puzzling paradox.  Some hypotheses concerning ameloblastoma as a strange clinico-histologic contradiction and well the additional paradox represented by this neoplastic parenchyme which is a tissue that consist of cells that can normally form enamel but do not elaborate any of the calcified dental tissue of that nature.[1] These odontogenictumours are complex group of lesions of diverse histopathological types and clinical behaviour[5], usually classified into four groups, and clinically presents more in the mandibular molar region, (70%), premolar region (20%) and anterior region (10%).[6] It has slight predilection to male in Nigeria[7] and females in Asia8-13 with an average age of about 32 years in Nigeria[7] and 40 years in Asia.[8]  It is a tumour of low socio-economic group[13-18].  The mandibule on which the tumourameloblastoma initiates, grows, and sustained has inferior alveolar artery as its main branch as it branches of the first part of the maxillary artery.  It is the major arterial supply, both in physiological and pathological states.  This inferior dental artery is the main arterial blood supply to the mandible from normalcy through tumour initiation to its growth and progression.  This raises the concern as to what local alterations occurred in the cellular environment of the arterial tree that is proxy to this tumuor initiation, growth and progression.[19] This is the main blood supply to the mandibule in what ever state.
The enamel organ responsible for the physiological tooth formation is equally responsible for extensive contributions to oral pathologies.  These pathological processes and conditions range from simple periodontal cyst to odontogenictumours of which ameloblastoma is one.[20]
This odontogenic organ considered from the moment of its normal and innocent formation, is usually made up of a variety of different cellular types which undergo series of morphological, physiological and biochemical modifications throughout the several phases of cellular development and differentiation.  These modificationsare known to mobilize complicated biological mechanism not yet completely explained or understood.  This renders tissue interactions very complex especially at the level of the ectodermal and mesodermal interface.1
These controlled modifications therefore command the biological process of physiological tooth formation.  The understanding of how these cellular modifications may be altered pathologically may suggest a rational explanation for the existence of this series of clinically and/or histologically different pathological conditions, inspite of the fact that they are derived from the same dental organ that form normal teeth.[21]
This raises the question of possible compromises in the vascular integrity that triggers of the initiation, growth and progression of ameloblastoma.19  Studies have demonstrated regional variations in responses of vascular smooth muscles to vesso-active agents.[22]  These agents may possibly exist in the inferior dental vessels environment, that may alter the behaviours of these rest cells and modify vascular integrity.
This may offer possible explanation as to why the rest cells of Malassez forms periodontal cysts, and lacking tumour forming characteristics.  While the rest cells of serres forms ameloblastoma.[1]
What therefore are these environmental changes in the arterial tree and ameloblastoma, determine these differences.  This survey though limited in scope was designed to sensitize the minds of both basic science and clinical researchers as to the need for studies aimed at exploring ameloblasoma clinically, histologically and in vitro, with the aim of establishing a possible nexus with changing physiological factors and progressing pathological tissue from tumor initiation, through growth to expansion and progression.  This multidisciplinary quest will center on vascular contribution via vascular structural modification that may have bearing on the initiation and tumour growth.  This is in the realm of physiological studies.  In addition biochemical studies will focus on changing ionic concentration in the blood and tissues; in addition to extra-cullular bye product of local tissue invasion by lytic ameloblastoma in line with Philipsen and Reichart5 studies that revealed increasing evidence that residues of odontogenic epithelium play major role in the pathogensis of human epithelial odontogenic neoplasms.  Therefore, raising further concern as to factors at submicroscopic levels that trigger off these changes.  The use of molecular methodologies in investigation of ameloblastoma is just emerging.  In years to come will change our views from pure clinical perspective to collaborative in-vitro focus.  Radical treatments (marginal or en-bloc segmental resection with safely margins)[23-24] have remain the treatment option in this environment as most ameloblastomas are massive due to late presentation (Fig. 1).  Therefore, making available large mandibular tissues for possible in vitro studies of vascular and extra-vascular contribution in the reactivation of these rest cells.
This is a multidisciplinary challenge, requiring a multidisciplinary approach by maxillofacial-surgeons, pathologists, biochemists and physiologists.

MATERIALS AND METHODS
This survey is on multidisciplinary research approach to the study of ameloblastoma in the College of Medical Sciences, University of Benin.  The treatment of advanced ameloblastoma is surgical resection of the mandible or maxillary by the maxillofacial surgeons after due confirmation by the oral pathologists (Fig. 1).  The resected mandible is of no further clinical value.  The level of resection is guided by the size of ameloblastoma and in large Amelobastoma. Before resection the inferior dental bundle is ligated from its emergency from the cranial base “F”, and a second intraossios ligature is made at “C”, just 1-2cm off the tumour margin “B”.  “D” is the experimental artery with the tumour mass “A”, and any part of “E” to “F” is the control arterial tissue (Fig. II).  Both will be preserved in physiological salt solution for in vitro study by physiologist.  Most participating physiologists are dental surgeon in the Department of Physiology.  Before surgery medical biochemists are expected to have taken blood sample for analysis of calcium level and local lytic products influx to the blood.  Intra-tumour artery “D” is the experimental tissue, andany of the arterial segment from the ligated cranial base “F” to the intraossios second ligation “E” is the control. The inclusion criteria are the large ameloblastomas of the mandibule extending to the molar areas and the exclusion criteria are the early ameloblastomas. This survey was a telephone and face to face survey on the need and usefulness of a collaborative, multidisciplinary research to ameloblastoma in the college of medical sciences.  Interaction with the surgeons was by phone with their numbers[22] in the Department of Oral and Maxillofacial Surgery, University of Benin Teaching Hospital and oral interview with the Dental Surgeons and Medical Doctors in both the Departments of Physiology and Medical Biochemistry.  There are 13 doctors in maxillofacial surgery, 21 doctors in physiology (8 dental surgeons, 13 medical doctors) and 5 medical doctors in medical biochemistry.  Making the total number of participants 39.

AMELOBLASTOMA_Pic01

RESULTS
Out of 39 doctors interviewed, maxillofacial surgeons 5 (12.8%), Physiologist 8 (20.5%) and Medical Biochemist 3 (7.7%) indicated their willingness to participate in the in-vitro studies making a total of 16 (41%).In-vitro studies is to allow for enough control and enable the precise effect of an agent or factor to be properly investigated outside the varying influence of hormones, nervous and chemical agents in the body. Experimental protocols specific to each participating unit will be specific to them and will be presented to the Ethics Committee of the University of Benin Teaching Hospital for approval in line with the declaration of Helsinki.

AMELOBLASTOMA_Table01

DISCUSSION
This study though very limited in scope is to elicit a multidisciplinary interest in the study of ameloblastoma, by exploring the tumour and extra-tumour environments given the advantage of patients that presents late to the clinic (Fig. 1).  The common treatment option is resection.  In mandibule,ameloblastoma resection can be hemi or complete mandibulectomy by the maxillofacial surgeons.  This makes study-tissue available, especially the inferior dental vessels by ligating it below the cranial base“F” (Fig. II) and storing the resulted part in a physiological salt solution (PSS).  The physiologist will use their experimental protocol to investigate the vascular integrity of the inferior dental vessels using the glass model FT.03 isometric tranducer coupled to Grass Model 7, 10 channel grass polygraph and Ugo-basil for recording Isometric contraction.  It has been established in animal experiments that regional variations do exist in the vascular smooth muscle to vaso-active agents.[19] In investigating the vascular integrity of the inferior dental vessels,emphasis will be on the investigation on role of vascular supply and vascular structural modifications that may have bearing to the tumour environment.  This may throw more light on the possible transitory role of vascular tissues in the initiation, growth and expansion of this tumour.  In addition, explore the answer to “What at the submicroscopic levels triggers off various changes especially in the reactivation of the rest cells?”Letiti et al[23] demonstrated that matrix metalloproteinases are known to promote cellular de-differentiation in the vascular smooth muscles and are involved in matrix degradation and cellular migration.  This triadfavours development and advancement of tumours.[27]  In the vascular smooth muscle cells, matrix metalloproteinase-2 are expressed especially in response to growth factors28 (platelate derived growth factor).  Studies have shown that thrombin generated at the sites of vascular injury not only participate in the coagulation cascade but signal other events related to development and complication of atherosclerotic plaque.  While the non-thrombic action of thrombin as investigated by Galiset al[29] revealed that at the site of vascular injury thrombin may activate locally produced matrix metalloproteinase-2 thereby facilitate cell migration and proliferation and influence the expression or activation of matrix metalloproteinase production by vascular smooth muscle cells.  This is a matrix degrading proteinase and contributes to several aspects of vascular lesion development.  Lee et al30 revealed that macrophages and vascular smooth muscles cells are potential sources of matrix metalloproteinase.  There is growing evidence that matrix metalloproteinase and α[5]β[1] integrin in vascular smooth muscle cells participate in the local invasiveness of ameloblastoma[31-32].  Therefore, physiological investigation of vascular integrity of the inferior dental vessels using the extra-tumour artery as control will no doubt open a flood gate of knowledge at the microscopic level, more so when the average age of occurrence of ameloblastoma in Nigeria is 32 years[12] and 40 years in Asia.[13]  Biochemical analysis of blood samples becomes necessary in the light of recent findings by McGuirt et al,[33] Ohtguru,[34] Iko et al,[35] and Havada et al[36] that serium calcium level is elevated in patients with ameloblastoma. What is the sources of this elevation of calcium?
This study therefore aims at a call for multidisciplinary investigation of vascular contributions in ameloblastic state.  Specifically, the inferior alveolar artery using extra-tumour artery as control and intra-tumour artery as study sample.  This is the major arterial supply to the tumuor cells from initiation, through progression to expansion.  In addition, this finding of elevated serium calcium blood levels in ameloblatoma patients may suggest compromised vascular integrity and therefore reflux of calcium or re-entry from lytic ameloblastoma environment made possible by matrix metalloproteinase-2 within the tumour environment.  Current view points on the cyto-differentiation and histopathogenesis of these lesions are today still largely based on clinical morphology.  An approach along the line of investigating molecular regulations controlling the physiological development of odontogenic organ on one hand and pathological odontogenic neoplasms on the other, will enlarge our knowledge in this field.
We conclude that multidisciplinary approach to ameloblastoma research is over due.  We therefore recommend a joint investigation of this enigma.

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