Ameloblastoma, a Behavioral and Histologic Paradox - (A Philosophical Approach)
Geraldo MAIA CAMPOS
Faculdade de Odontologia de Ribeirão Preto Universidade
de São Paula Ribeirão Preto, SP Brasil
Braz Dent J (1990) 1(1): 5-15 ISSN 0103-6440
| Introduction | The enamel
organ | Ameloblastoma: benign or malignant tumor?
| Why is hard tissue not formed in ameloblastoma? |
Epithelium/mesenchyme interaction | Morphodifferentiation
| Odontoblastic differentiation | Ameloblastic
differentiation | Stratum intermedium
| The role of connective stroma | References
The ameloblastoma, because of its aggressive clinical behavior and its
histological feature apparently benign, constitutes a puzzling paradox.
Some hypotheses concerning this strange clinical-histologic contradiction
are analyzed, as well as the additional paradox represented by the neoplastic
parenchyma itself, in which a tissue consisting of cells nominally able
to form enamel do not elaborate any of the calcified dental tissues.
Key words: ameloblastoma, odontogenic tumors.
In Brazil, when a politician is asked to voice his opinion about a controversial
matter, he usually avoids answering, alleging that "one does not reason
about hypotheses". Perhaps this is why politicians do not resolve any problem,
for in fact there is no other manner of reasoning if not this. Thus it
may often be healthy to reason freely about hypotheses, giving wings to
the imagination, only to see where it will lead. This is the objective
of the present philosophical remarks on some of the characteristic features
of that which is perhaps the most intriguing of all odontogenic neoplasms
- the ameloblastoma. The hypotheses presented will be nothing more than
flights of the imagination, but the premises on which they are founded
are common well-known facts, generally accepted scientifically.
The enamel organ
Any student who begins a course in dentistry recognizes the structure shown
in Figure 1A What few perhaps will know, at this point in their studies,
is that this structure - the enamel organ - is responsible for an extensive
chapter of Oral Pathology. This chapter deals with odontogenic pathologic
processes which include conditions ranging from a simple periodontal cyst
to the worst of all odontogenic tumors, the ameloblastoma.
The enamel organ is a structure comparable to the dermal appendages,
i.e., the hair follicle, the sweat gland and the sebaceous gland, or to
those derived from the oral mucous membrane, i.e., the accessory salivary
Amongst the skin appendages, perhaps the one that most resembles the
teeth is the hair, with the main difference being the latter's continual
growth, whereas the tooth has limited growth. However, there are some animals
- the rodents - in which growth of several teeth (the incisors) is equally
continuous, a fact which narrows even more this analogy.
The odontogenic organ considered from the moment of its formation, although
appearing to be a simple structure when analyzed superficially, in fact
is composed of a variety of different cellular types which undergo a series
of morphological, physiological and biochemical modifications throughout
the several phases of cellular development and differentiation. These modifications
mobilize a complicated biological mechanism (not yet completely explained
or understood) which renders the tissue inter-relations in which it is
involved very complex, principally at the level of the ectodermal/mesodermal
interface of the tissues which constitute the developing dental organ.
Thus, considering the ectodermal component of the odontogenic organ,
the dental lamina (which marks the beginning of tooth formation) presents
a histological appearance very similar to the deeper cellular layers of
the epithelium seen in the primordium of the oral mucosa. The outer epithelium
of the enamel organ is composed of short cells, while the inner enamel
epithelium is composed of tall cells. The stratum intermedium is formed
of flat cells, while the stellate reticulum exhibits a polygonal pattern
In regard to the mesodermic component of the odontogenic organ, the
dental papilla shows a mesenchymal aspect near the inner enamel epithelium.
The dental sac, initially very similar to the dental papilla, becomes more
fibrous near the outer enamel epithelium as the odontogenesis evolves.
In addition, at the right moment, the cells change their initial aspect
at the inner epithelium/dental papilla interface, acquiring columnar characteristics
on both sides of the basal membrane which separates the two tissues. The
cells of the inner enamel epithelium alter the polarity of their nuclei
during the so-called secretory phase.
This group of controlled modifications commands the biological process
of tooth formation. The understanding of these phenomena that occur during
this complex group of successive transformations (and how they may be altered
pathologically) may one day suggest a rational explanation for the existence
of this series of clinically and/or histologically different pathological
conditions, despite being derived from the same original odontogenic organ.
This could explain why the rests of Hertwig's root sheath (epithelial rests
of Malassez) generally lead to periodontal cysts, lacking tumoral characteristics,
while dental lamina remnants (epithelial rests of Serres) may lead to ameloblastomas,
which are extremely aggressive neoplasms. What environmental factors (or
of any other nature) determine these differences? This is a question which
until now does not have a convincing, satisfactory answer, in spite of
the enormous volume of research trying to solve the numerous doubts that
persist. Therefore, only hypotheses remain purely speculative despite being
founded on observations and logical arguments.
Ameloblastoma: benign or malignant tumor?
Ameloblastoma is justly considered the most unexplainable of odontogenic
tumors, because of its clinical and histological features, intriguingly
contradictory, paradoxal and incongruent, if its benign histological aspect
and its invasive and destructive clinical behavior are considered, besides
the reported capacity of establishing pulmonary metastases, a possible,
though infrequent, occurrence.
These characteristics of the ameloblastoma remember the basal-cell carcinoma,
a known malignant neoplasm, although of low malignancy by its slow, invasive
growth and by the fact that it only occasionally produces metastases. Ameloblastoma,
on the contrary; known to be benign by its histological aspect, nevertheless,
presents a highly aggressive behavior and, despite its slow growth, it
is extremely invasive, as are malignant tumors, and produces occasional
metastases. The final result, in both cases, is exactly the same.
Basal-cell carcinoma is a neoplasm which develops exclusively in the
skin, from the epidermal basal layer. or root sheaths of hair follicles,
never occurring in the mucosa (Shafer et al. 1983). As the basal layer
of the epidermis is composed of cells potentially capable of differentiating
into tiny of the skin appendages, aborted attempts to produce these types
of structures arc at times seen in basal-cell carcinomas.
Ameloblastoma is equally a tumor derived indirectly from the epithelial
basal layer, however from the covering of the gingival mucosa, perhaps
from embryonic remnants of that which could be considered grossly as gengivomaxillary
appendages: the teeth.
The histology of a typical basal-cell carcinoma (Figure 18) is very
similar to that of primordial or basaloid type of ameloblastoma (Figure
1C). The follicular aspect observed in many of the cellular islets of the
tumor represents only an aborted attempt of the neoplastic tissue to form
teeth (Figure 1D), in the same manner in which the basal-cell carcinoma
also attempts to form hair follicles.
This analogy of clinical behavior as well as the histological picture
between the two tumors was what led Willis (1948) to categorically affirm
that "attempts to distinguish benign and malignant adamantinomas are futile;
they are all malignant in that they are locally invasive and prone to recur".
Henceforth, the following question remains: May there not be several
cases of ameloblastomas - mainly extra-osseous tumors which develop in
the gingiva - the type of basal-cell carcinoma that is said not to exist,
I.e., the basal-cell carcinoma with its seat in the mucosa?
Why is hard tissue not formed in ameloblastoma?
Another paradox finked to ameloblastomas is the fact that, despite its
name, no calcified dental tissue is formed in the interior of this tumoral
mass. What is the reason? Willis (1948) guarantees that the term "ameloblastoma"
as well as its predecessor "adamantinoma" are misnomers, as the tumor does
not develop from the ameloblasts, nor does it form enamel, and assures
that "it would be better to call them carcinomas of the tooth-germ residues",
reaffirming his opinion of the malignancy of the neoplasm.
This detail of embryonic cellular remnants from the tooth germ evoked
by Willis appears interesting, and perhaps explains much in respect to
the question. In fact, embryonic development involves spacial as well as
temporal details which cannot be upset - i.e., things ought to always occur
at an established place and at an established moment, all in a pre-established
order, as if it was previously programmed by a computer. If there is any
change, be it ambiental conditions, be it the time in which the phenomenon
ought to occur, there is always a detour in programming, with results and
consequences quite different. from those foreseen by the biological determinism.
In relation to ameloblastoma, it is necessary to analyze step by step
the circumstances and the moments in the odontogenic process in which it
is possible for local or temporal errors to occur which could determine
the biological impossibility of the ameloblastomatous tissues to produce
calcified dental tissues in the tumoral mass. For this, it is necessary
to invoke each evolutive step of odontogenesis, trying to associate the
observed histological details common in ameloblastomas, in order to detect
eventual space-time errors capable of impairing the elaboration of dental
tissues in a neoplasm which theoretically is composed of forming cells
of these tissues.
I. Epithelium/mesenchyme interaction. Odontogenesis begins about
the 6th week of intrauterine life, with a thickening of the epithelium
of the embryonic oral mucosa resultant from the multiplication of the cells
of the basal layer of this epithelium, forming the dental lamina and the
tooth buds. The local changes occurring in the epithelium induce a condensation
of mesenchymal cells around the tooth buds, principally joined to its distal
extremity, giving origin to the dental papilla and an outline of the dental
sac. What determines these alterations in cellular behavior, epithelial
as well as mesenchymal, at exactly that instant in embryonic development?
To explain the phenomena which occur at predetermined moments of tissue
development, and others which appear to occur in the interaction of different
tissues at their interfaces, Slavkin (1988) suggests the existence of chemical
mediators produced by the cells, autocrine and paracrine factors. The autocrine
factors are those which, elaborated by the cell at a determined time of
its development, act on the actual cell, modifying its behavior from then
on. The paracrine factors, formed by some cells, are liberated into the
tissue space, acting on other nearby cells altering the behavior of those
and not the behavior of the secreting cells, as is the case with autocrine
These autocrine factors, in the specific case of the odontogenesis,
act at the time of proliferation of the cells of the basal layer orienting
them to form the dental lamina and the dental buds. Paracrine factors are
responsible for mesenchyme condensation near this epithelial tissue in
The important factor to consider at this point of tooth germ development
is the moment when the phenomenon occurs, i.e., the embryonic period, in
which the epithelial cells are prone to proliferate, and the connective
cells still have a mesenchymal character, appearing only slightly differentiated.
In ameloblastoma: Exactly in what are the environmental conditions different
in ameloblastomas? In everything. In general, due to the fact that the
moment of its installation is another, the connective stroma present in
the tumor is dense fibrous and already perfectly differentiated. The histological
aspect of the neoplasm makes one believe that probably the inductive power
of the proliferating epithelium, which acts effectively on mesenchymal
cells, perhaps does not act as appropriately on differentiated fibrous
connective tissue. In consequence, instead of activating cell proliferation
in the sense of causing cellular condensation dud dental papilla formation,
the result of the epithelial influence on the connective tissue is rather
a degenerative process of present collagenous fibers. This fact explains
the clear area of less dense tissue often seen around the epithelial islands
and cords of the neoplastic parenchyma (Figure 2A,B). It gives the impression
that the paracrine factors, in the presence of a differentiated tissue,
try to revert this differentiation process and return the surrounding connective
tissue again to the mesenchymal state.
This degeneration of the fibrous stroma is responsible for the formation
of cystic cavities in the interior of connective tissue, found principally
in the type of ameloblastoma known as plexiform (Figure 2C). It has already
been suggested that this degeneration may be caused by a nutritional deficiency,
as a result of the complicated path of the blood vessels through the existing
connective tissue labyrinth within the mesh of the neoplastic epithelial
network (Spouge, 1973). However, the actual aspect of the tissue seems
to contradict this hypothesis, since the blood vessels, which are directly
responsible for the tissue nourishment, are exactly the last structures
to disappear in the degenerating tissue (Figure 2D).
2. Morphodifferentiation: The condensation of mesodermic cells
around the free end of the epithelial buds induces this epithelium to differentiate
morphologically, adopting the specific form of the determined dental type
that this bud would form in the future. This mutual induction in the epithelium/connective
tissue interface was studied extensively by Kollar (1972), Koch (1972)
and Slavkin (1972). According to Kollar (1972), for example, the basal
membrane which separates these two tissues of different embryological origin
ought to fulfil a very important role in this interface, as does the quality
of the adjacent connective tissue. In case the environmental conditions
are altered in relation to the normal embryological situation, the epithelium
of the enamel organ also changes its behavior. Experimental research in
animals, involving the transplantation of maxillary dental germs to diverse
areas shows that if, for example, these germs are transferred to the plantar
tissues of the animal paw, where the stroma is the dense fibrous connective
type, the epithelium of the enamel organ begins to irregularly proliferate,
adopting the pattern of growth histologically similar to that of the ameloblastoma.
This detail possibly explains the irregular proliferation of ameloblastomatous
neoplastic tissue since the stroma in this tumor usually is also the differentiated
fibrous type (Figure 2A,B).
3. Odontoblastic differentiation: In odontogenesis, once the
dental papilla is formed, the induction by this part, besides the general
dental form, also transforms the inner epithelial cells of the enamel organ
into pre-ameloblasts. These induce the cells of the adjacent dental papilla
to differentiate into odontoblasts, forming two layers of different embryonic
origin, which face vis-a-vis, separated by-the basal membrane.
In ameloblastoma: This induction does not occur in ameloblastoma because
a mesenchyme capable of responding to this inductive action of the pre-ameloblasts
does not exist; rather, there is a dense fibrous connective tissue (Figure
2A,B). This detail explains the lack of odontoblasts in the neoplastic
tissue and consequently the lack of formation of dentinary matrix and calcified
4. Ameloblastic differentiation: Once the odontoblastic layer
is complete, the formation of the dentin matrix begins with a thickening
of the basal membrane which separates the two tissues. This initial thickening
progressively increases and, as the odontoblasts are pushed apart, initiates
the depositing of calcium salts on the matrix so formed. With the formation
of the dentin matrix there is an interruption of the source of nourishment
for the cells of the inner epithelium of the enamel organ which obliges
these cells to acquire their nutrients at another source, I.e., from the
stellate reticulum. This leads to an internal recomposition of the intracellular
organelles of the pre-ameloblasts: the nucleus polarizes at the opposite
end to the basal membrane, adjacent to the stellate reticulum, while the
other structures, such as the Gold complex and the endoplasmic reticulum,
position between the nucleus and the basal membrane, preparing for the
depositing of organic enamel matrix and posterior calcification. In short,
the pre-ameloblasts differentiate into actual ameloblasts (Figure 3A).
In ameloblastoma: In spite of the fact that in ameloblastoma the differentiation
of connective cells in odontoblasts does not occur, and consequently dentin
matrix is not formed or calcified, in the peripheral layer of the epithelial
islands and cords which compose the neoplastic tissue, cells very similar
to ameloblasts are present. There is evidence that in these cells there
exists a clear polarization of the nuclei in the cellular extremity opposite
the connective cells and thus adjacent to that which would be the stellate
reticulum. This leads to conjecture if the simple presence of a thickening
of the basal membrane would not be sufficient to determine the migration
and polarization of the nuclei in the opposite cellular extemity, giving
the tumoral cells a histological aspect similar to those of ameloblasts,
since this type of thickening is commonly encountered around the epithelial
islands and cords of the tumoral tissue (Figure 3B).
However, if these neoplastic cells are similar to differentiated ameloblasts,
why are they unable to form a recognizable enamel matrix? Perhaps because
they lack some detail which transforms them in biologically active ameloblasts.
This functional detail is probably the absence of a stratum intermedium
adjacent to the ameloblastic layer. In fact, the stratum intermedium cells
are looked upon as the suppliers of elements adequate for posterior metabolism
of the ameloblasts, these elements that the ameloblasts are not able to
mobilize from the stellate reticulum. For some reason, there is no stratum
intermedium in the ameloblastoma (Figure 3C).
5. Stratum intermedium: In normal odontogenesis, when polarization
of the nuclei occurs and the epithelium passes from the inductive to the
secretory phase, differentiating into active ameloblasts, profound modifications
in the stellate reticulum and in the outer epithelium of the enamel organ
occur. The stellate reticulum atrophies driving the outer epithelium to
approximate the stratum intermedium, forming the reduced epithelium of
the enamel organ. At the same time, the outer epithelium acquires a meshed
aspect, becoming permeable to nutritive elements from the blood capillaries
of the dental sac, which are then more conspicuous close to the reduced
epithelium, protruding to the stellate reticulum (Figure 3A). This all
facilitates the arrival of nutritional elements to the stratum intermedium
where they will be pre-metabolized, passing later to the ameloblasts.
In ameloblastoma: Although forming an ameloblastic layer in ameloblastoma,
it is not able to elaborate enamel matrix, probably because it lacks the
stratum intermedium. Perhaps, the explanation for the lack of stratum intermedium
is in the absence of outer epithelium in the neoplastic islands, which
could hinder the formation of reduced epithelium. In fact, it is only necessary
to histologically examine an ameloblastoma to verify that the neoplastic
epithelial islands are surrounded by a peripheral cellular layer resembling
the inner epithelium of the enamel organ, either in the pre-ameloblastic
or the ameloblastic phase (Figure 3C,D). There is no simultaneous occurrence
of the cellular layers which could recall the inner and outer epithelia
occurring at the same neoplastic island, or the formation of the reduced
epithelium of the enamel organ.
Lucas and Thackray (1952) attribute the formation of intrafollicular
cystic cavities to a deficiency in absorption and diffusion of nutritive
elements (coming from the perifollicular blood capillaries) to the center
of the cellular islands, causing their degeneration by nutritive insufficiency,
since the neoplastic growth causes extremely large follicles.
However, this same central degeneration could have been caused by the
polarization of the nuclei at the cellular end facing the stellate reticulum.
This probably causes the cells of the peripheral layer of the follicles
to remove nutritive elements from the interior of these cellular islands
and not from the connective tissue facing the other cellular extremity.
This nutritive competition can cause metabolic deficiencies for the cells
of the stellate reticulum, which can explain the degeneration of the central
cells of the islands and the consequent formation of cystic cavities in
its interior (Figure 3D).
6, The role of connective stroma: The influence of dense fibrous
connective tissue around the epithelial islands, as well as the possible
morphological and functional changes occurring in the cells of the peripheral
layer of the follicles, could be responsible for the squamous metaplasia
often observed in the ameloblastoma (Figure 3D). These alterations are
able to impart characteristics of the basal cell layer to the peripheral
cells of the follicle (Figure 3E). In fact, according to Kollar (1972),
the epithelium of the enamel organ, when transplanted to regions which
are normally covered by stratified squamous epithelium and have their own
densely fibrous lamina propria or dermic layer - for example, the oral
diastema and the plantar region of the rat paw - tends to grow as squamous
stratified epithelium, loosing its ability to form dental tissues.
In conclusion, it can be said that ameloblastoma is probably no more
than epithelial cells remaining from the embryonic phase, reactivated from
their latent state and engaged in vain attempts to resume their original
functions - an obligation that they, having been awakened in a different
world and in another time, are not able to conclude.
Koch WE: Tissue interaction during in vitro odontogenesis. In: Developmental
aspects of oral biology. Slav-kin HC & Bavetta LA ed. Chapter 8: 151-164.
Academic Press, New York 1972
Kollar EJ: Histogenetic aspects of dermal-epidermal interactions. In:
Developmental aspects of oral biology. Slavkin HC & Bavetta LA ed.
Chapter 7: 125-149. Academic Press, New York 1972
Lucas RB, Thackray AC: Cyst formation in adamantinomata. British Dent
J 93: 62-65, 1952
Shafer WG, Hine MK Levy BM: A textbook of oral pathology. 4th ed. Saunders,
Slavkin HC: Intercellular communication during odontogenesis. In: Developmental
aspects of oral biology. Slavkin HC & Bavetta LA ed. Chapter 9: 165-199.
Academic Press, New York 1972
Slavkin HC: Molecular biology of dental development: a review. In: Biological
mechanisms of tooth eruption (An international conference). Davidovitch
Z ed. EBSCO Media, Birmingham 1988
Spouge JD: Oral pathology. Mosby, Saint Louis 1973
Willis RA: Pathology of tumours. Butterworth, London 1948
Correspondence: Dr. Geraldo Maia Campos, Departamento de Estomatologia,
Faculdade de Odontologia de Ribeirão Preto, Universidade de São
Paulo, 14050 Ribeirão Preto, SP, Brasil.