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DENTAL SCIENCE, MATERIALS AND TECHNOLOGY
PATHOPHYSIOLOGY
OF ORAL DISEASES
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DENTAL SCIENCE, MATERIALS
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DENTAL SCIENCE, MATERIALS AND TECHNOLOGY
PATHOPHYSIOLOGY
OF ORAL DISEASES
P. C. ANILA NAMBOODIRIPAD
AND
E. ANURADHA SUNIL
New York
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Library of Congress Cataloging-in-Publication Data

Names: Namboodiripad, P. C. Anila. | Anuradha Sunil, E.
Title: Pathophysiology of oral diseases / editors, P.C. Anila Namboodiripad
and E. Anuradha Sunil (Palissery House, Arimpur, Thrissur District, Kerala
State, India).
Description: Hauppauge, New York : Nova Science Publisher's, Inc., [2016] |
Series: Dental science, materials and technology | Includes index. |
Description based on print version record and CIP data provided by
publisher; resource not viewed.
Identifiers: LCCN 2016017787 (print) | LCCN 2016017080 (ebook) | ISBN
9781634852364 () | ISBN 9781634852203 (hardcover) | ISBN 9781634852364
(ebook)
Subjects: LCSH: Mouth--Diseases. | Teeth--Diseases. | Physiology,
Pathological.
Classification: LCC RC815 (print) | LCC RC815 .P37 2016 (ebook) | DDC
616.3/1--dc23
LC record available at https://lccn.loc.gov/2016017787
Published by Nova Science Publishers, Inc. † New York

Contents
Preface vii
Section 1: Developmental Anomalies
of Oral Tissues 1
Chapter 1 Developmental Anomalies Affecting
Number of Teeth 3
Shape of Teeth 7
Structure of Teeth 17
Tongue 25
Section 2: Benign and Malignant Disorders 29
Chapter 5 Benign and Malignant Epithelial
Tissue Tumors 31
Chapter 6 Benign and Malignant Connective
Tissue Tumors 41
Chapter 7 Benign and Malignant Tumors
of Salivary Glands 57
Chapter 8 Odontogenic Cysts 69
Chapter 9 Odontogenic Tumors 95
vi Contents
Chapter 10 Potentially Malignant Disorders 105

Section 3: Systemic Disorders 109
Chapter 11 Bone Disorders 111
Chapter 12 Disorders of the Skin 129
Section 4: Bacterial, Viral and Fungal Lesions 147
Chapter 13 Bacterial Lesions of Oral Cavity 149
Chapter 14 Viral Infections of the Oral Cavity 157
Chapter 15 Fungal Infections of Oral Cavity 169
Chapter 16 Regressive Alterations of Teeth 175
About the Authors 179
Index 181
Preface
Teaching a large number of ever-inspiring students for the past few years
was the motivation for the authors to compile this book. This book would not
have seen the light of the day if it were not for them.
Knowledge of the pathogenesis of diseases affecting the oral cavity is of
great help in understanding its clinical features, radiographic features,
histological features as well as the finalization of treatment for those diseases.
This knowledge became the reason to compile this book that explains the
various pathophysiological causes of the diseases. Some of the diseases are
still being explained by their old pathogenesis; however, some others are being
attributed to some new causes, following the advent of new and innovative
technologies. This book is a sincere attempt to simplify the subject of Oral
Pathology by elaborating upon the underlying causes of the various diseases.
Apart from students, the author owes her gratitude to Dr. HM Dholakia,
who made the subject of Oral Pathology sound so simple; Dr. Alka Kale,
whose boundless energy and dynamic personality is an inspiration; Dr.
Ramakant Nayak, who harps on the importance of constant updation of
knowledge that is required for one to better the subject of Oral Pathology
and to the management, principals, and staffs of a large number of dental
colleges in India where the idea of the book was concieved. The constant
encouragement and support received is the motivation for the author to
compose this book.
viii
Finally, the author says a million thanks to her family—especially her

parents and daughters—who ungrudgingly bore with her lack of time for them
and finally a special thanks to her ever-encouraging husband, without whose
help this book would not have seen the light of the day.
The author would also like to thank the God Almighty who gave her the
strength to achieve her dream of authoring this book.
Dr PC Anila Namboodiripad, BDS, MDS,

Professor, Oral and Maxillofacial Pathology
Section 1: Developmental
Anomalies of Oral Tissues
Chapter 1
Developmental Anomalies
Affecting Number of Teeth
Introduction
Development of Teeth
Parallel to the lip edge in the late embryonic period (44 days), there is the
formation of the epithelial lamella or the primary epithelial band which plays a
role in the development of the teeth. This epithelial lamella divides into two
parts, one to form the vestibule and the other to give rise to the teeth. The oral
vestibule forms on the labial side, by furrowing of the labio-dental lamina, a
ridge formed from the epithelial lamella. The furrow is called as the labio-
dental sulcus which later forms the oral vestibule. The labio-dental lamina
oriented towards the oral cavity gives rise to the dental lamina, which is a U-
shaped or horseshoe shaped band from which the teeth arises.
The neural crest cells in the form of the ectomesenchyme, and the oral
ectoderm interact with each other to give rise to the 10 roundish teeth buds in
the upper and lower arches and they represent the primordium of the
deciduous teeth. Lingual to these roundish swellings, other swellings form,
and they are the anlagen of the permanent teeth.
The roundish buds give rise to the bud stage of tooth formation. The buds
go through the cap, early bell and advanced bell stages to finally form the
enamel organ that forms enamel, the dental papilla, that is enclosed within the
invaginated portion of the cap, forming dentin and the pulp, and the dental sac
4 P. C. Anila Namboodiripad and E. Anuradha Sunil
which is made up of ectomesenchymal cells derived from the neural crest

cells, surrounding the enamel organ, giving rise to the alveolar bone,
cementum and the periodontal ligament.
Downward extension of the enamel organ determines the morphology of
the root. The epithelium that forms the root is the Epithelial root sheath of
Hertwig which fragments, and disintegrates, to help in the formation of the
outer covering of the root called as the cementum and the formation of root
pulp called as the ‘ root canal ‘and the root dentin.
Initiation Proliferation Morpho Apposition Eruption Attrition

differen-
tiation
Figure 1. Developmental stages in tooth and root formation.
Anodontia
Introduction
When the follicles that needed to grow teeth are completely or partially
absent, it results in a condition called as anodontia or oligodontia. This is a
congenital abnormality affecting the number of the teeth (normal number of
adult teeth- 32, deciduous teeth-20).
When all teeth have been extracted either due to caries or pathology, the
condition is called as pseudoanodotia.
Pathogenesis
The absence or the mutation in the homeobox genes are said to play a role
in anodontia. Homeobox genes are basically genes that play a role in the early
embryonic development of various parts of the body including the teeth. They
are a set of a large family of related genes that control the formation of many
Developmental Anomalies Affecting Number of Teeth 5
structures of the body. They play this role by acting as transcription factors.
They consist of 235 functional genes and about 65 pseudo genes i.e., genes
that are similar in structure, but that which do not provide instructions for
preparation of the proteins. Homeobox genes are normally seen occurring in
clusters and are present on every human chromosome. The genes that play a
role in anodontia include the PAX, MSX, HOX, etc. Any absence or defect in
these genes results in the anodontia. Absence of teeth can also occur in
correlation with other developmental anomalies like the oromandibular limb
dysgenesis, or in case of the hereditary anhidrotic ectodermal dysplasia etc.
Hereditary ectodermal dysplasia has a defective EDA gene and hence is said to
be genetic in nature.
Supernumerary Teeth
Introduction
When more than the normal complement of teeth is present in the oral
cavity, the condition is called as the Supernumerary teeth or hyperdontia. The
extra teeth can be seen at any site in the oral cavity.
Pathogenesis
The etiological role in the formation of supernumerary teeth can be both

genetic and environmental. The various theories put forth include:
1) ‘Atavism theory’: This theory suggests that reversion in the

phylogenetics of extinct primates where there were three incisors in
each quadrant, as against the present day two per quadrant, may be
one of the factors in the favor of occurrence of supernumerary teeth.
This theory has found no takers.
2) Another theory put forth in favor of supernumerary teeth includes the
‘Dichotomy theory.’ This theory states that supernumerary teeth
forms when one tooth bud splits into two, resulting in the formation of
two teeth, which are either of equal or of unequal sizes one of which
may be dysmorphic or of abnormal shape. Excess teeth of equal size

are called as supplementary teeth and if unequal, it is called as
supernumerary teeth.
3) The ‘dental lamina hyperactivity theory’ elaborates that the
supernumerary teeth may arise from the epithelial remnants of the
dental lamina and the supplementary teeth from the lingual extension
of the accessory tooth bud. This is the most accepted theory of
supernumerary tooth formation
4) Genetic theory: According to this theory the occurrence of the
supernumerary teeth is said to run in families. A sex linked
inheritance has been suggested. The condition is found to be more
common in males than in females.
Supernumerary Roots
Introduction and Pathogenesis
Supernumerary roots are excess roots found in teeth and are more than the
number of roots expected. The most common teeth affected are mandibular
canines, premolars, and molars, especially the third molars. Canines and most
premolars, except for maxillary first premolars, usually have one root.
Maxillary first premolars and mandibular molars usually have two roots.
Maxillary molars usually have three roots. When an extra root is found on any
of these teeth, the root is described as a supernumerary root.
These supernumerary roots may occur due to the disturbances in the
Hertwig's epithelial root sheath forming the root. There will be an increased
number of divisions of the epithelial diaphragm (a horizontal extension of the
epithelial root sheath of Hertwig) to form multiple roots instead of the
stipulated number. Cases have been reported wherein both the deciduous and
permanent dentition exhibit supernumerary roots.
Chapter 2
Affecting Shape of Teeth
Figure 2. Developmental stages in tooth formation.
Histophysiological Stages of Tooth

Development
The histophysiological stages of tooth development include
 initiation,
 proliferation,
 histodifferentiation,
 morphodifferentiation,
 apposition
Microdontia
Introduction
Microdontia is a condition of having disproportionately small teeth.

Classified into:
 True generalized microdontia

 Relative generalized microdontia
 Microdontia affecting a single tooth.
Pathogenesis
Development of tooth is a continuous process in which a number of

physiologic growth processes and various morphologic stages interplay to
achieve the tooth's final form and structure.
True generalized microdontia show genetically normal small teeth. All the
teeth in the oral cavity are affected uniformly.
Relative generalized microdontia is a condition wherein a child inherits
the large jaws of one parent and normal sized teeth from the other parent
making the teeth appear relatively small.
Microdontia affecting a single tooth.
It is an autosomal dominant condition with incomplete penetrance.
Prevalence varies from 0.8 to 8.4% of population. When a peg shaped tooth is
present, the remaining permanent teeth often exhibit a slightly smaller
mesiodistal length.
The proliferation and the morphodifferentiation stage of tooth
development are affected in case of the microdontia affecting the maxillary
lateral incisor, and the tooth fails to resemble the normal tooth. Dentin is the
structure that determines the shape of the tooth. Though the odontoblasts and
the dentin histological structure are normal, the morphology of the tooth is
affected and ‘peg laterals’ may be formed.
Developmental Anomalies Affecting Shape of Teeth 9
Macrodontia
Introduction
Macrodontia is a condition of having disproportionately large teeth.

Classified into
 True generalized macrodontia

 Relative generalized macrodontia
 Macrodontia affecting a single tooth.
Pathogenesis
The proliferation and the morphodifferentiation stage of tooth

development are affected in case of macrodontia affecting a single tooth. It is
considered more of a ‘text book’ term than an actual occurrence. It is both a
poorly researched and documented characteristic because very less data is
available for analysis. The published incidence of macrodontia ranges from
0.03% to 1.9% on the one end, while it can be as high as 3.6% on the other
end. Most of the macrodontic tooth is a case of either a germination or fusion.
Although true generalized macrodontia related with hyperpituitarism and
suprarenal hyperfunction is rare, relative generalized macrodontia is more
common but poorly defined.
Fusion and Gemination
Introduction
Gemination is a developmental anomaly in which a developing tooth splits

into two separate teeth. Fusion is a condition where two developing teeth
merge to become a single tooth. Gemination is derived from the latin word
geminus meaning twin.
These teeth have disfigured enamel, separate pulpal space; one pulp
chamber and two canals or they may appear like a large crown with a large
pulpal space. Evolution, trauma, heredity and environmental factors such as
thalidomide embryopathy, hypervitaminosis A and the fetal alcohol exposure

of the pregnant mother are said to play a role in the development of this
condition. Nutritional deficiency, endocrinal disturbances and ionizing
radiation are also said to play a role in the causation of this condition together
with hyperdontia. The condition is also seen to occur in chondroectodermal
dysplasia and achondroplasia. Gemination is seen in both the deciduous and
permanent dentition.
Pathogenesis
When a tooth bud splits into two, the two teeth are said to be ‘twins.’ The
condition is also called as germination.
Thus twinning is defined as an effort to make two teeth from one enamel
organ. The tooth that is formed will have two completely or incompletely
separated crowns having a single root and a root canal. Sometimes the
twinning may be complete, that means, inclusive of both the crown and the
root. The main cause for this condition is said to be trauma but familial
tendency has also been suggested as a factor.
Fusion normally occurs due to joining of the two developing tooth buds
which may be positioned between two simultaneously developing neighboring
teeth whose interdental bone has been resorbed probably due to trauma, or it
may occur due to the joining together of a tooth and its supernumerary
counterpart.
Talon’s Cusp
Introduction
The talon’s cusp is an additional cusp that is composed of enamel, dentin

and the pulp tissue mainly on the lingual surface of the primary or permanent,
anterior teeth. It is called as dens evaginatus when it is seen in relation with the
posterior teeth. It shows a predilection for the maxilla over the mandible and
the maxillary lateral incisors may be the most commonly affected teeth.
Pathogenesis
Both heredity and environmental conditions are said to be responsible for

the formation of the talon’s cusp. It is commonly seen to occur during the
morphodifferentiation stage of the tooth development. There is an outward
folding of the inner enamel epithelial cells and a hyperactivity of the dental
lamina cells early in odontogenesis together with a temporary hyperactivity of
the dental papilla. Endocrinal disturbances may be responsible for initiating
this proliferation. The shape and function of the ameloblasts and odontoblasts
remain unaffected. The condition may coexist with other developmental
anomalies such as mesiodens, odontomes, and unerupted or impacted teeth. It
may also occur in syndromes such as the Mohr syndrome, Sturge Weber
syndrome, Rubinstein Taybi syndrome, Ellis van Crevald syndrome etc.
Taurodontism
Introduction
Taurodontism is a developmental condition found in the molar teeth of

humans whereby the body of the tooth and its pulp chamber is enlarged at the
expense of the roots.
Pathogenesis
A number of pathogenetic factors have been considered in the etiology of

taurodontism. The various theories include
 ‘a primitive pattern’ theory,

 a mutation, and a
 retrograde character,
 an atavistic feature,
 X linked trait or an autosomal dominant trait.
Other factors playing a role include a delay in the aging of the pulp
chamber, odontoblastic deficiency and an alteration in the epithelial root
sheath of Hertwig.
Taurodontism is said to occur in individuals who have heavy masticatory

habits, for example, the Neanderthals and the Inuit or the Eskimos. It has also
been found to be predominant in individuals who use teeth as tools such as for
sharpening, holding etc. Osteomyelitis, developmental homeostasis which is
disturbed, and people who have undergone high dose of chemotherapy or bone
marrow transplantation are also said to manifest this developmental anomaly.
Taurodontism appears most frequently as an isolated anomaly, but it has
also been associated with several developmental syndromes and anomalies
including Down syndrome, amelogenesis imperfecta, ectodermal dysplasia,
Klinefelter syndrome, Mohr syndrome, tricho-dento-osseous syndrome, Wolf-
Hirschhorn syndrome and Lowe syndrome. Other rare syndromes which show
the presence of taurodontism include Smith-Magenis syndrome, Mc Cune
Albright syndrome, William’s syndrome, and Van der Woude syndrome.
Dilaceration
Introduction
Tooth dilacerations is a developmental disturbance which involves the

disfigurement of tooth either at level of the crown or root portion resulting in
the altered morphology or shape of the tooth, commonly seen as extreme
bends or curves in an otherwise straight tooth.
Pathogenesis
The normal growth and remodeling of the maxilla and the mandible
causes a simultaneous fluctuation in the tooth positions relative to the alveolar
and basal bone during the root formation. Therefore a decreased bone
remodeling rate is equal to decreased bone plasticity which is suggested to
increase the resistance to movement of the root growth site relative to the
mineralized root which further results in the stretching of the root sheath and
dilaceration or flexion.
The earlier theory of dilacerations, which considered trauma as an
etiology, could not explain the angulations at the mid root position or the
apical position of the teeth. A new theory stating that these changes took place
due to the plasticity of alveolar bone was introduced. It was also stated that as
the permanent teeth replaced the deciduous teeth some amount of shifting of
the dental follicle would occur, together with the bending of the root of the
tooth.
Figure 3. Showing the process of dilacerations.
Another theory which was proposed in favor of dilaceration was with the
shift of the enamel epithelium and its developing mineralized portion, away
from the dental papilla and the cervical loop. This shift was found to be away
from the central axis of the tooth. No individual structure of the teeth, like the
enamel, dentin, pulp or cementum was affected in this case and the only sign
visible was the bending of the root. The other factors that play a predisposing
role in dilaceration may be
 the rate of eruption of the tooth,

 length of the root,
 length of the eruption path,
 transverse and upward eruption of the teeth especially in the case of
the molars,
 jaw rotation and the
 root resorption.
Damage to the permanent teeth in the form of dilacerations may also occur
following trauma to its deciduous counterpart. This may result in the
displacement of the permanent teeth causing the direction of the root growth to
be altered.
Different parts of the alveolar bone, the apical, the middle, and the coronal
portions all have different turnover time. Thus the movement of the root from
one plane to the other may cause root dilacerations.
There are other relative dento-skeletal alterations occurring during root
formation, such as the mesial drift of the dentition and transverse growth of the
maxilla. So the doubt arises as to why dilacerations do not occur following the
normal mesial drifting of the socket as the growth of the jaws takes place, and
the plasticity gradient of the same after the root apexification is completed.
The question has been answered thus that “dilacerations does not occur in such
conditions due to the presence of the occlusal forces, craniofacial growth type
or due to genetics.”
Dens Invaginatus
Introduction
Dens invaginatus is a rare developmental disturbance of teeth, showing a

set of varied morphological variations. The teeth affected on the radiograph
shows an infolding of enamel and dentine which extends deep into the pulp
cavity and into the body of the root and may sometimes even reach upto the
root apex.
Pathogenesis
Etiology of Dens Invaginatus

The etiology of dens invaginatus malformation is controversial and
remains unclear. Over the last decade several theories have been proposed.
They include:
 The buckling of the enamel organ which may occur due to the growth
pressure may be one of the etiological factors for dens invaginatus.
 Another factor for the occurrence of the dens invaginatus may be in

the case of the inner enamel epithelium failing to grow normally or
remaining stationery, and the remainder of the enamel organ growing
at a normal pace. This may result in the enamel organ engulfing the
inner enamel epithelium resulting in the formation of the dens
invaginatus.
 Or as per Rushton (1937), dens invaginatus arises due to the rapidly
proliferating inner enamel epithelium invaginating into the adjacent
dental papilla. He named this condition as a “benign neoplasma of
limited growth.”
 Ohlers on the other hand made an observation similar to Rushton and
proposed that there was an invagination of the hyperproliferative inner
enamel epithelium but the structure into which it invaginated was not
mentioned by him. That is, there was no mention of the dental papilla.
 Bruszt on the other hand suggested a fusion of two tooth germs- one
inside the other.
 Fischer and Sprawson said that the dens invaginatus occurred due to
infection in the developing tooth germ.
 Trauma was suggested as a cause for occurrence of dens invaginatus
by Gustafson & Sundberg (1950) but why lateral incisors were
commonly affected and not any other teeth, was the big question.
 Foramen caecum was suggested as one of landmark of the enamel
organ and this structure was found infolded into the tooth resulting in
the formation of the dens invaginatus. Hence according to the authors
the invagination may originate starting right at the incisal edge of the
tooth.
 Grahnen, et al. stated the importance of genetic factors in etiology of
dens invaginatus.
Dens Evaginatus
Introduction
The Dens evaginatus (DE) is a developmental anomaly affecting the

premolars and it is seen to commonly occur bilaterally. It may be associated
with any teeth in the arch with a slight predilection for females. The arch
prevalence for the dens evaginatus may vary in relation to the populations
reviewed. Though the DE occurs predominantly in the permanent dentition it

may occur in either the deciduous or the permanent teeth. When associated
with the anterior teeth it is predominantly seen on its lingual surface and is
referred to as the talon’s cusp.
The tubercle on the premolars may be seen to occur either between the
two cusps or on the inclined plane of the buccal cusp of the premolar.
Pathogenesis
Dens evaginatus is said to occur following the invagination of the

hyperproliferative inner enamel epithelium into the stellate reticulum in the
bell stage of tooth development, as opposed to the invagination of the inner
enamel epithelium into the dental papilla that occurs in case of the dens
invaginatus. The result is in the formation of a tubercle or a solid elevation on
the occlusal surface of the posterior teeth.
To understand the mechanism behind this developmental occurrence in
the tooth, the molecular biology of its development has to be understood. The
enamel organ has transient signaling centers located right at its center and
these determine the process of formation of the future cusps. The cells lodging
these signaling centers are known as the enamel knot. The enamel knot is
surrounded by highly proliferative epithelium and an underlying mesenchyme.
This enamel knot is also said to play a role in the induction of the dental
papilla.
The signaling molecules in the enamel knot includes FGF-4and 9, BMP-
2, 4 and 7, and the TGF. These cells of the enamel knot disappear by the early
bell stage of tooth formation that is after the initiation of the hard tissue
formation of the teeth.
Secondary enamel knots arise in the early bell stage of tooth formation,
but this time at the sites of the future cusp tips as opposed to primary enamel
knots located in the center of the enamel organ. The main cusps are formed by
the secondary enamel knot, in the bell stage and any additional cusps are
formed later. This is controlled by signaling molecules in the dental papilla
together with the formation of the Hertwig’s root sheath at the cervical loop.
Chapter 3
Affecting Structure of Teeth
Figure 1. Anomalies affecting enamel.

Amelogenesis Imperfecta
Introduction
Amelogenesis imperfecta (AI) is a disorder which is genetic in origin. It

affects both the structure and morphology of enamel of nearly all the teeth of
the jaws in a similar manner, and may be coexist with the morphological or
biochemical changes that may affect the other parts of the body. The
prevalence rate ranges from 1:700 to 1:14000.
The enamel in case of amelogenesis imperfect may be hypoplastic,
hypomineralised or both and may result in teeth that may be discoloured,
sensitive or prone to disintegration. AI exists in isolation or in association with
other abnormalities in case of numerous syndromes. It may show autosomal
dominant, autosomal recessive, sex-linked and sporadic inheritance patterns.
Pathogenesis
After the initial laying down of the organic matrix of enamel that
comprises of proteins such as amelogenin, and non-amelogenin proteins such
as amelin, tufltin, and enamelin, the matrix is reabsorbed, to make space for
the expanding hydroxyapatite crystals, both in terms of size and volume. This
ameloblast mediated proteolytic destruction, during the maturation stage of
enamel formation, is brought about by a protease called as KLK4. This
degradation continues until almost the entire tissue volume is occluded by the
hydroxyapatite crystals containing minerals such as calcium and magnesium.
Towards the end of the maturation stage the newly formed enamel is rich in its
mineral content by about 95%.
AI may show autosomal dominant, autosomal recessive, sex-linked and
sporadic inheritance patterns. In families with an X-linked form it has been
shown that the disorder may result from mutations in the amelogenin gene,
AMELX. The enamelin gene, ENAM, is implicated in the pathogenesis of the
dominant forms of AI. Autosomal recessive AI has been reported in families
with known consanguinity.
The proposed theory of pathogenesis of amelogenesis imperfecta could be
1) The reduction of the prism density resulting in the hypomineralisation

of enamel. The individual crystals in the enamel fail to grow to its full extent.
Developmental Anomalies Affecting Structure of Teeth 19
The TGF-β is the main gene playing a role in prism formation and is expressed
in the secretory stage of amelogenesis. This TGF-β promotes the MMP20
through the Runx2. This MMP20 plays a role in the development of the
extracellular matrix of enamel comprising of amelogenin, enamelin, tuftelin
and amelin. Thus failure in processing of the enamel matrix leads to retention
of the enamel matrix proteins within ameloblasts and they fail to lie out
completely. The protease KLK4 gene is said to play a role in the matrix
removal. Prism formation is thus disorganized and it is seen irregularly, to
result in pit formation on the tooth crown, the cervical area is normally spared
as the amount of matrix to be deposited here is lesser. The mineralization goes
on normally both in terms of density and appearance.
A) After the normal enamel matrix deposition takes place the ameloblasts
move away from the dentin surface and therefore exposes it for further action.
B) The ameloblasts improve the cell adhesion linkage to bear the ever
mounting deposition of enamel.
As the cuspal volume of enamel grows, the cells of the enamel namely the
ameloblasts, adjusts the cell to cell contact to bear with the force required to
ward off the increasing monolayer of enamel.
Suggestion has been given that most likely the ITGB6 up regulates
MMP20 expression by means of the TGFβ activation. This on the other hand
cleaves through the cadherin, allowing the ameloblasts to reposition them in
relation to one another and thereby resulting in the sinusoidal pattern of the
enamel rods and rod sheaths. MMP20 is also said to play a role in
reabsorbsion of the enamel matrix proteins, predominantly the amelogenin and
also the amelin, tuftlin, enamelin which is a necessity for their final
degradation prior to the completion of mineralization. Hence it has been
suggested that whenever the enamel is affected, the cadherin cleavage and
matrix processing are affected due to the ITGB6 mutation hence resulting in
deep cracks in the ameloblast monolayer in the cuspal portion leading to
pitting, distorted prism architecture and residual matrix proteins that slows
down the final enamel mineralization.
2) MMP20 is also essential for the ameloblast-ameloblast contact or cell

to cell contact. It thus plays a role in cadherin processing. Thus any
compromise in the cell to cell contact would result in an abnormal placement
of the enamel prisms resulting in the disruption in the Hunter Schreger bands
pattern.
Figure 2. Cartoon summarizing the mechanism of the AI subtype.
Hypoplastic Type of Amelogenesis Imperfecta
In case of the hypoplastic type of AI, the enamel organ degenerates too
soon and in some cases there may be a total absence of the differentiation of
the inner enamel epithelium. The above mentioned genes may play a role in
the causation of these alterations.
Figure 3. Depicting the formation of enamel matrix and its degradation to

accommodate the hydroxyapatite crystals.
Hypocalcification Type of Amelogenesis Imperfecta
If the protein matrix does not degrade at the right time there may be a
disturbance in the crystal formation due to either calcium or a phosphorus
deficiency and hence it results in defective calcification, further resulting in
the hypocalcified type of AI. It thus shows a large pooling of amelogenenin
and also the albumin, as the degradation of both these products are extremely
delayed.
Hypomaturation Type of Amelogenesis Imperfecta
Delayed degradation of the matrix and hence delayed growth of enamel

crystals results in the hypomaturation of the enamel. It results in the
hypomaturation type of AI
Developmental Anomalies Affecting

Dentin
Dentinogenesis Imperfecta and Dentin Dysplasia 1 and

2
Introduction
Type 1 Dentinogenesis Imperfecta is a hereditary condition that occurs in
people who also have osteogenesis imperfecta and in those who have brittle
bones which easily break. The Type 2 and Type 3 type of DI do not have
associated inherited disorders. It may show varying signs and may affect both
the primary and permanent dentitions.
Pathogenesis
Dentin formation involves numeorus genes that produce a complex
extracellular matrix that is highly organized, and that eventually mineralizes in
a highly controlled fashion. Type I collagen (product of COL1A1 andCOL1A2
genes) is the most abundant dentin protein. This complex molecule has the
structure of a heterotrimer and forms the foundation for several mineralized
tissues including bone and dentin. The collagen molecules interact with a
variety of non-collagenous proteins such as the bone sialophosphoprotein,
osteopontin, osteonectin, dentin sialoprotein to name a few, to help initiate and

regulate the mineralization process in these tissues. Interestingly, mutations in
either type I collagen or proteins that interact with it can cause the DI.
Dentinogenesis type 1 is normally said to be caused by mutations in the
COL1A1 and the COL1A2 genes.
A deficiency of dentin sialophosphoprotein (DSPP) has also been
suggested as a causative factor in dentinogenesis imperfecta. Mutations in the
DSPP (dentin sialophosphoprotein) gene mapped to chromosome 4q21 and
responsible for the formation of the non-collagenous proteins is said to play a
role in the etiology of the Dentinogenesis imperfecta 2 and 3 and Dentin
Dysplasia type2. The mutations in the genes may cause either a defective or
improper mineralization of dentin. This defective gene would be lodged in the
forming odontoblasts and hence it may affect the odontoblastic cell, or
influence protein processing or transporting of the proteins inside the cell,
during rapid dentin formation. This may result in defective odontoblastic
differentiation and mineralization of the dentin matrix.
The defective gene forms a matrix which is deficient in phosphorus ion,
which is an important mineral during dentin formation. Mutations in the DSPP
gene results in the formation of a very soft dentin, especially the mantle
dentin. This dentin is found to be discolored, weak and more likely to crack.
Probably the hearing loss in the individuals who have Dentinogenesis
imperfecta may also be due to the defective DSPP genes. These patients have
absent enamel prisms in the developing teeth, since the nidus for initiation of
enamel formation is in the dentin and may also be the reason for the defective
mantle dentin.
Abundant insoluble mutant DSPP and its degradation products (dentin
phosphoprotein, bone phosphoprotein, osteopontin, osteocalcin, osteonectin
and dentin sialoprotein, DSP) expressed by odontoblast cells could possibly be
hypothesized to deactivate or indirectly interfere with the metabolism of other
proteins in dentin and result in the phenotypes of DI.
Dentin Dysplasia Type 1
Introduction
Dentin dysplasia (DD) type I is characterized by short or total absence of

roots, obliterated pulp chambers, and peri-apical radiolucencies. It affects both
the primary and secondary dentitions. It is found to be even rarer than DI.DD's
incidence is 1:100,000.
Pathogenesis
 Wesley et al. suggested that the condition is caused by an atypical

contact of odontoblasts with ameloblasts leading to uncharacteristic
differentiation and/or function of these odontoblasts.
 Logan et al. stated that the dental papilla is responsible for the
abnormalities in root development. They proposed that innumerable
degenerative foci within the papilla become calcified, leading to
reduced growth and final obliteration of the pulp space.
Regional Odontodysplasia
The condition is usually identified on routine radiographic examination of
the patient who has visited the dental OP with complaints of failure of eruption
or pulpitis or a necrosis in absence of caries. The radiograph would show
features such as “ghost like appearance of teeth” and a similar radiodensity of
both the enamel and the dentin.
Pathogenesis
The condition is not hereditary and the most common pathogenesis is the
absence of the blood supply which is required to mineralize the teeth. Both the
enamel and dentin matrix will fail to calcify completely.
Somatic mutations affecting the dental lamina, vascular disorders, local or
systemic viral infections, differentiation failures of neural crest cells, local
trauma, nutritional deficiency, and radiation may also result in the occurrence
of the regional odontodysplasia.
Chapter 4
Affecting Tongue
Development of Tongue
The tongue begins to form at almost time as the palate. It is found to arise
from various swellings on the pharyngeal floor. There is the appearance of the
tuberculum impar (median lingual swelling) on the lower edge of the
mandibular arch at the same time of the midline fusion of the first
(mandibular) and the second (hyoid) pharyngeal arches. On either side of it,
two more protuberances are seen called as the lateral lingual prominences.
These lateral lingual swellings grow over the median lingual swelling to
fuse to form the anterior 2/3 of the tongue. It therefore consists of both the
ectodermal and endodermal parts. The primordium of the thyroid arises at the
caudal end of the tuberuculum impar. (Stage 10, ca. 28 days) as an unpaired
ventral endodermic bud. The thyroid then migrates in front of the larynx
leaving behind a foramen caecum on the dorsal surface of the tongue. The 2nd,
3rd pharyngeal arches, the copula and a small portion of the 4th pharyngeal arch
gives rise to the posterior third of the tongue. Hence this part is made up of the
endoderm only. Between the anterior 2/3rd and the posterior 1/3rd the terminal
sulcus forms. The most caudal end of the tongue forms the hypobranchial
eminence that indicates the entrance to the trachea.
Median Rhomboid Glossitis
Introduction
Median rhomboid glossitis occurs on the dorsum of the tongue. It is an

enigmatic inflammatory or infectious condition.
Pathogenesis
This condition is thought to occur due to failure of retraction of the

tuberculum impar during development. In the case of normal development this
tuberculum impar after it descends into thyroid area, is closed over by the two
fused lingual swellings from either side. These lingual swellings are ideally
located on either side of the tuberculum impar prior to the fusion. But since
this condition is rare in childhood, when it must first manifest, this theory has
been rejected.
The present day theory states that median rhomboid glossitis is a type of
distinct type of candidiasis which when occurring on the midline of the
tongue; the name given to it is the ‘median rhomboid glossitis.’ Actinomyces
has also been implicated in the etiology of the median rhomboid glossitis. The
tongue is a favorable site for the candida to lodge since it is a warm and
protected space provided by the lingual papillae. This site is also not a self
cleansing area and this area cannot easily be cleaned by the brush too.
The median rhomboid glossitis may also show the presence of surface
nodules. Excessive pressure on the palate when applied by the involved
tongue, while producing certain sounds such as the ‘g’, ‘k’ and ‘j’, accounts
for the nodularity on the tongue surface.
The presence of the median rhomboid glossitis is also an indication of the
immunocompromised state of the person. It could also be an indication for the
Human immunodeficiency virus infection.
Developmental Anomalies Affecting Tongue 27
Geographic Tongue
Introduction
Geographic tongue is a form of tongue inflammation where red, smooth,

migratory patches covered over by a white border, form on the surface of the
tongue.
Pathogenesis
 Geographic tongue is considered as a psoriasiform tongue. That is, it

is said to occur coincidently with the psoriasis of the skin.
 It is not an infectious condition like HIV. It does not spread between
partners.
 It is not linked to usage of tobacco.
 It is said to be a side effect of consumption of the non metal like
lithium.
 Dental materials may contribute to the initiation of the migratory
glossitis.
 It may occur due to vitamin B deficiencies.
 It may also be seen in relation to allergic conditions such as atopy and
asthma, eczema and contact allergy
 Said to also be associated with hormones since it is predominantly
seen in females on oral contraceptives
 It has even been considered to be a hereditary condition with a
polygenic mode of inheritance. Defective genes are said to be the
HLA-DR5, HLA-DRW6 and HLA-DRCw6.
Section 2: Benign and Malignant
Disorders
Chapter 5
Benign and Malignant Epithelial

Tissue Tumors
Benign Tumors of Epithelial Tissue Origin
Squamous Papilloma
Introduction
Neoplasia caused by Human papilloma virus (HPV) causes squamous cell
papilloma. Skin papillomas are called as ‘warts’ or ‘verrucas’ and those on the
genital tract are called as the ‘genital warts.’
Pathogenesis
The cause of the squamous papilloma was found to be the virus called as
HPV. There are various known subtypes of HPV, but subtypes 6 and 11 have
been found positive in a large number of squamous papillomas and HPV 16
and 18 positive in another section of the papillomas. Some cases showed a
total absence of HPV in the human papillomas. These viruses have been found
to interfere with the proper functioning of the ‘gate keeper protein,’ the p53.
They play a role in the inactivation of the gene that acts as regulators of the
cell proliferation namely the p53. E6 protein of the HPV-16 is said to be
capable of binding to protein p53, encouraging its degradation and altering the
control of cell growth.
Six early proteins of the HPV play a role in gene regulation and cell
transformation and they include E1,E2,E3,E4,E5,E6 and E7 (E stands for
‘early’ that is before DNA replication starts and are encoded by the HPV
genome) and the 2 late proteins, L1 and L2(‘late’ indicates ‘after DNA
replication’) which forms the shell of the virus. It is the genotypic variations in
the E6 and E7 base proteins that decide the oncogenic potential of the HPV
genes. For example; the E7 protein of HPV 16 is more oncogenic than the E7
protein of HPV 6. The mode of transmission of oral HPV is unclear. What
exactly happens when an HPV enters a cell is that the circular viral genome
breaks at the level of the E1 and E2 regions but never in the E6 and E7 region.
E2 to E5 are lost when the transcription takes place and this causes the loss of
control over the E6 and E7 regions. These then get directly involved in the cell
cycle by inhibiting the normal functions of p53 and pRb (human
retinoblastoma gene). The role of the p53 then, is to arrest the cell cycle by
allowing its repair. If it fails to repair the cell then it induces the programmed
cell death to occur and prevents the error from getting into the next stage. If
there is a p53 mutation, E6 suppresses the properties of p53 gene product, and
acts as a second hit in the ‘two hit hypothesis’ theory of neoplasia. It plays a
role in the degradation by the ubiquitin pathways. The E7 protein on the other
hand acts with retinoblastoma protein (pRb), which is the crucial factor for the
cellular cycle control and causes release of the transcription factor E2F which
will cause the stimulation of the cellular division. E7 also binds and inactivates
the protein kinase inhibitors p21 and p27.
Figure 1. Shows the diagrammatic representation of HPV-induced oral carcinogenesis.
A model for the interaction of HPV E6 and E7 with the DNA damage pathway.
Benign and Malignant Epithelial Tissue Tumors 33
Keratoacanthoma (KA)
Introduction
Keratoacanthoma is a benign tumor that resembles the squamous cell
carcinoma both clinically and histologically. It is also called as a ‘self healing
carcinoma.’ It is found to arise in relation to hair follicle and the associated
sebaceous glands.
Pathogenesis
Various etiological factors have been considered in the formation of
keratoacanthoma:
1) Said to be genetic in nature: genes have been said to play a role in

formation of the keratoacanthoma.
2) Human Papilloma Virus is said to be another etiological factor for the
causation of this lesion
3) Immune factors: since the lesion may be seen in individuals
with malignant disorders or in immunosuppressed individuals’
immunology is said to an etiological factor for the keratoacanthoma.
4) Envoirnmental factors like sunlight, chemicals carcinogen, and trauma
have also been implicated in the etiology of the keratoacanthoma.
5) It is also said to occur in persons who are on medications that target
the Ras/Raf/MAP kinase pathways.
6) Keratoacanthoma is commonly seen to occur in cigarette smokers and
hence is said to be another etiological factor for KA.
7) This lesion is also seen in case of patients with psoriasis being treated
with psoralen
8) Said to occur at sites of burns.
No details about the pathogenesis for any of the above etiological factors
are available.
Nevus
Introduction
Nevus cells are melanocytes that do not have cytoplasmic extensions or

processes called as dendrites. They do have an abundant cytoplasm and coarse
granules and they are commonly seen at the dermoepidermal junction or in the
dermis of the skin. These nevus cells are epitheloid in shape when located at
the dermoepidermal junction, transform into the lymphocytoid cells as they
reach the dermis and further into the neuroid morphology when they enter the
dermis. They are hence classified into the Type A, Type B and the Type C
cells respectively. Nevus cells occur in the form of clusters and the
melanocytes may also be evenly dispersed as single units. Nevus cells are the
primary components of a melanocytic nevus.
Pathogenesis
The main pathogenesis for the nevus is the point mutation in the BRAF
gene (a part of the Ras-Raf-Mek-Erk-MAPK (mitogen-activated protein
kinase) signaling cascade): a serine/threonine protein kinase gene or the
Neuroblastoma ras viral oncogene. No details are elaborated in case of the role
of the above genes in the pathogenesis of nevus.
Malignant Epithelial Tissue Tumors
Basal Cell Carcinoma
Introduction
Basal cell carcinomas are malignant neoplasias arising from the basal
layer of the skin. They appear in the form of open sores, red patches, pink
growths or scars. They usually occur due to intense UV exposure, and may
result in a disfiguring mass if allowed to grow, but never seems to metastasize.
Pathogenesis
Mutation in the gene MC1R or the melonocortin gene is said to cause
basal cell carcinoma and the malignant melanoma. The UV radiation causes
damage to a lot of proteins of the skin when it is exposed to it. The MC1R is
said to provide protection against this damage. There are also genes that
produce proteins which help in removing the damaged proteins such as the
lipid peroxide and the DNA hydro peroxides. These genes if defective may
also cause the occurrence of the basal cell carcinoma as these proteins are
toxic to the body. The genes that play a role in damaged protein removal
include the CYP2D6 and the GST genes.
HPV is also said to play a role in the basal cell carcinoma but HPV plays a
major role in Squamous Cell Carcinoma than Basal cell carcinoma.
The cell membrane receptor of the epidermal cells form a complex with
the sonic hedgehog protein(SHH) which is a component of the hedgehog
protein, which is an extracellular protein of the hedgehog pathway (HH). The
combined protein complex initiates a cascade of cellular events that leads to
cell proliferation.
The cell receptor complex comprises of the
1) Patched (PTCH) 1 protein that is the ligand binding component of the

Horse Hedgehog (HH) receptor complex in the cell membrane
2) Smoothened (SMO) protein which plays a role in transducing the
hedgehog signaling to the downstream genes.
When active:
SHH binds to PTCH1

↓
PTCH1 inhibition of SHH is released
↓
HH pathway is activated
↓
Activation of transcription factors
↓
Expression of cell cycle regulator genes
So improper HH pathway and any of the genes playing a role in the

pathway like the PTCH1, PTCH2, and SMO genes may cause human
malignancies including the basal cell carcinoma.
PTCH 1 may also prevent the binding of the protein to the SMO. This
unbound SMO permits uncontrolled proliferation of the cells through
activation of the following:
a. GLI1 (glioma-associated oncogene 1; also called zinc finger protein)

and GLI2, the transcription factor genes.
b. Genes helping in cell proliferation like the cyclin D, cyclin E, myc,
and
c. Proteins playing a role in the angiogenesis.
d. Numerous other genes that may play a role in Basal Cell Carcinoma
and they include:
1. XRCC 3, a DNA repair gene
2. CDKN2A and CDKN2B both cyclin-dependent kinase inhibitor
genes
3. K5 gene a basal keratinocyte gene and the
4. BRM gene
Mutations in the p53 genes have been found to play a role in formation of
Basal cell carcinoma. Genes such as the CD95, BCL-2, PDGFRα, or cFLIP,
are presently under study as also the FOX gene. Hence it was proposed that
these genes may be the ‘drivers’ and not ‘passengers’ in the cause for BCC.
Gremilin 1 has been identified in the stroma of patients with BCC and is
said to be a gene that antagonizes the genes that play a role in tumor growth
such as the BMP2 and the BMP 4. Hence this gene sustains the growth of the
tumor.
Verrucous Carcinoma
Introduction
Verrucous carcinoma (VC) was first described by Ackerman in 1948 and

is described as a low-grade, well-differentiated variant of squamous cell
carcinoma (SCC).
Pathogenesis
Surprisingly no pathogenesis of the verrucous carcinoma has been

described in literature. Etiological factors for the carcinoma include the
tobacco chewing, HPV 6 and 11. Verrucous carcinoma has been associated
with smoking but not drinking.
Malignant Melanoma
Introduction
It is a type of cancer arising from the melanocytic cells of the skin.
Pathogenesis
The role of melanin is not only producing pigmentation but also protecting
the skin against the UV rays. This protection is brought about by genes that
break down the protein formed, following UV exposure. So melanin is an
antioxidant protecting the skin against various malignancies. Melanin takes on
the property of a chelator by converting from an antioxidant to a prooxidant. It
also produces a large amount of superoxide anion. Melanin is converted from
an antioxidant to a pro-oxidant, takes on properties of a metal chelator,
becomes a redox generator, and produces large amounts of superoxide anion.
Thus the oxidative stress that is increased, produces transcriptional factor
activation namely AP-1and Ref-1 and this whole process lead to drug
resistance.
This activity if defective would result in malignancy of melanocytes and is
called as the melanoma. The uptake of metals into the cells is controlled by an
enzyme the metallothioneins. Non metals would also bind melanin. The non
metals include pesticides, dyes, organic amines, polychlorinated biphenyls and
herbicides.
Figure 2. A model for chemoprevention of early melanoma progression. Oxidation of

melanin leads progressively to generation of a redox-active tautomer (quinone-imine),
intracellular redox cycling (enhanced by metals or other substances bound by melanin)
with melanosomal and DNA damage, transcription factor activation and enhancement,
and activation of the natural antiapoptotic (drug-resistant) phenotype of the
melanocyte. Antioxidants include a number of cellular antioxidants (ascorbic acid, α-
tocopherol, and glutathione) whereas upstream inhibitors of oxidation might include
such drugs as inhibitors of cholesterol synthesis or inhibitors of mitochondrial activity.
Metal uptake into cells is regulated by metallothioneins, and polymorphisms should
contribute to differential uptake and risk. ROS, reactive oxygen species and predict that
the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia.
Activation of the human telomerase reverse transcriptase (Htrt) and a

deficiency in the p16INK4a-Rb pathway results in the occurrence of the
immortalization of the melanocyte. This thus results in the Radial Growth
Phase (RGP) of melanoma and it also indicates the role of keratinocytes in the
survival of the melanocytes and its growth, only near or in the epidermis.
In the RGP melanoma there is a high apoptotic rate of these melanocytes.
Once the melanoma enters the Vertical Growth Phase, there is the repressed
apoptosis which allows the cells to survive in the absence of the keratinocytes.
This is brought about by the PTEN loss, which inhibits apoptosis mainly
through the AKT activation and also the over-expression of a number of
protein kinases or RAS activation, and β-catenin activation. There is also a
loss of the E cadherin and an altered expression of the N-cadherin and αVβ3
integrin as the RGP melanoma transforms into the VGP melanoma. For the
tumor growth, migration and the angiogenesis, a close relationship must also
exist between the melanocytes and the fibroblasts in the connective tissue.
For the melanocyte development, survival, migration and differentiation in
the KIT-SCF signaling is essential. This KIT expression is highly expressed in
all the benign variants of the melanoma and also it is highly suppressed in the
invasive and metastatic melanomas.
Figure 3. The disruption of the p16ink and p16ARF by the inactivation of the CDKN2A
gene results in the melanocytic nevus transforming into a dysplastic nevus. The
retinoblastoma pathway may be affected resulting in the occurrence of the malignant
melanoma.
The role of CCND1 gene is also found to be important in the occurrence

of the melanoma. It has already been implicated in previous tumors like the
centrocytic lymphomas and parathyroid cancers.
CRAF is the primary mediator that initiates cell proliferation and it is not
certain whether it is the BRAF or the CRAF that transmits signals from
mutated Neuropeptide RAS to MEK. The activated RAS triggers the MAPK
pathway through interactions with the RAF oncoproteins (BRAF and CRAF).
The MEK phosphorylation leads to the activating phosphorylation of the MEK
(MAPK/ERK kinase) which in turn activates the phosphorylation of the ERK.
Cell proliferation is the primary step in the initiation of malignancies.
Mutations in this BRAF contribute to the melanoma formation. Increased
MAPK activity prevents the apoptosis and initiates the cell proliferation
through increased cell cycle progression. PTEN deletion results in Akt
activation which further results in phosphorylation and inactivation of Raf.
The Altered State of Melanin during Melanogenesis

Melanin is normally in a reduced antioxidant state. Exposure to ROS leads
to an oxidized condition which facilitates binding of transition metals (and
other compounds such as polyphenol chlorinated biphenyls). Metal uptake into
the cell is closely regulated by a family of metallothioneins. This situation sets
up the oxidized melanin as a redox generator, which leads to increasing

intracellular oxidative stress, a widespread adaptive response including TGF
up regulation, cell death, a high rate of cellular turnover and secondary
intrinsic drug resistance. Studies have also shown that the melanoma cells
have an augmented ROS as compared to the normal melanocytes which may
be shown by the increased superoxide anion.
Oral Squamous Cell Carcinoma
Introduction
Squamous cell carcinoma (SCC) is an uncontrolled growth of abnormal

cells arising within the spinous cells of the squamous epithelium. SCCs often
look like scaly red patches, open sores, elevated growths with a central
depression, or warts; they may crust or bleed.
Pathogenesis
Oncogenes and tumor suppressor genes are said to play a role in the
pathogenesis of oral squamous cell carcinoma. The primary among them being
the K-ras and the p53. Cytogenetic alterations can occur due to defect or the
mutation in the genes namely the bcl-1, int-2, n-ras and hst-1 have been
mapped to chromosome 11q13 and also the check point genes namely the
cyclins and the CDKs. Cyclin D1, Cyclin A, Cyclin B, Cyclin B1are all said to
play a role in oral carcinogenesis. The action takes place at various levels of
the cell cycle G1, S, G2 and M phase.
TGF-α and TGF-β mutations are said to occur early in occurrence of
squamous cell carcinoma. The p53 protein activates the production of the p21
protein. There is also a mutation in the Rb gene and the APC gene. The p16ink4
inhibits phosphorylation of Rb gene when apoptosis is induced. P-cadherin, E-
cadherin, β1 integrins and the α6 β4 are commonly affected in the poorly
differentiated squamous cell carcinoma. HPV types 2, 6, 11, 16, 18, 31, 33 and
35 have also been implicated in the initiation of the squamous cell carcinoma.
Apart from the various pathogenesis of oral squamous cell carcinoma
mentioned above there is large number of other pathogenesis mentioned in
literature and to elaborate on all of them would be beyond the scope of this
book.
Chapter 6
Benign and Malignant

Connective Tissue Tumors
Benign Tumors of Connective Tissue

Origin
Giant Cell Granuloma
Introduction
Reparative giant cell granuloma (RGCG) is a non odontogenic lesion
which is not a true neoplasm but may occur in reaction to trauma or
inflammation. It is a rare lesion in the head and neck region.
Pathogenesis
The etiopathogenesis of the giant cells in the giant cell granuloma may be:
1) Derived from the multinucleated osteoclasts, or

2) It may be the result of fusion of the endothelial cells or
3) The fusion of the background spindle shaped cells.
4) The nuclei of these giant cells are found positive for Cyclin D1 and
the surrounding macrophages are found positive for Cyclin B1 and the
MI B-1. But their roles in the giant cell granuloma remain unknown.
Oral Lipoma
Introduction
Lipoma is a benign, rubbery, soft, encapsulated tumor of adipose tissue
usually made up of mature fat cells.
Pathogenesis
There were the following theories proposed for the development of the
lipoma
1) ‘Hypertrophy theory.’ In this theory the adipose tissue was found to
be increased in size in some areas of the body. But this theory did not
have many takers as the lipoma was found in areas where fat tissue
was negligent; and secondly during starvation the fat was found lost
from the body but not from the fat deposits of the lipoma lesions.
2) Another theory to explain the lipoma included the ‘metaplasia theory.’
According to this theory it was thought that the mesenchymal cells
underwent metaplasia into lipoblasts which laid down the adipose
tissue. It also supported the theory of lipoma occurring anywhere in
the body. These mesenchymal cells were the multipotential embryonic
cells that differentiated into the fat cells under hormonal influence
especially during adolescence.
3) The third theory stated that lipoma was formed due to the trauma and
the chronic irritation of the soft tissues.
Since the theories 1 and 3 did not explain many features of the theory of
the lipoma formation the metaplastic theory was found to be most acceptable.
Neurofibroma, Schwannoma and Malignant Peripheral

Nerve Sheath Tumor
Introduction
Neurofibromas are the benign peripheral nerve sheath tumors.
A neurilemmoma is the other benign peripheral nerve sheath tumor apart
from the neurofibroma. It is benign and usually encapsulated neoplasm made
up of Schwann cells.
Benign and Malignant Connective Tissue Tumors 43
Pathogenesis
Somatostatin receptors (SST) have been said to play a role in the
formation of the schwannoma, neurofibroma and malignant peripheral nerve
sheath tumor. Among the SST receptors, the SST2A was found positive in
schwannomas but not in the neurofibromas and the malignant peripheral nerve
sheath tumors. These receptors have been found predominantly within the
Schwann cells. But the exact role they play in the formation of these
neoplasias is unknown.
VEGF an endothelial cell marker was found lesser in the neurofibroma
than the schwannoma and the bFGF (β Fibroblastic growth factor) was found
increased in the schwannoma.
Malignant Connective Tissue Tumors
Osteosarcoma
Introduction
Malignant tumor of bone comprising of malignant osteoblasts play a role
in formation of the osteosarcomas.
Intramedullary and surface osteosarcomas are the two types of
osteosarcomas.
In case of the intramedullary type it has been further subdivided into the
three; namely the typical type, the telangiectatic type and the highly
differentiated variant.
Surface osteosarcomas have been divided into periosteal, paraosteal and a
high grade type.
Histologically the osteosarcoma has been divided into the osteoblastic,
chondroblastic and the fibroblastic types. Other types include giant cell, small
cell and the mixed types of osteosarcomas.
Pathogenesis
Osteosarcoma is seen predominantly in the growing bones especially
during puberty. It is also seen in patients affected by the Paget’s disease,
fibrous dysplasia and other bone disorders. People constantly exposed to
radiation, for e.g., women who fix the radium dials in watches to make them
luminescent, may also suffer from osteosarcoma. People exposed to the
chemical agents, like methlycholanthrene, chromium salts; beryllium oxide

etc. may also succumb to osteosarcoma.
Figure 1. W. Michael Kuehl,P. Leif Bergsagel. Molecular pathogenesis of multiple

myeloma and its premalignant precursor. Clin Invest. 2012; 122(10):3456-3463.
A simian virus SV40 has been stated as another one of the etiological
factors for osteosarcoma.
Exaggerations of the chromosome 6p21, 8q24 and 12q14 and the loss of
heterozygosity of chromosome 10q21.1have been implicated as the etiological
factors for osteosarcomas. Also the loss of the chromosome 9, 10, 13 and 17
and gain of chromosome 1 are other chromosomes suggested as a causative
factor for the osteosarcoma.
P53 mutations seen commonly in other malignancies may be seen in some
osteosarcomas
The Rb tumor gene which is important in the cell cycle control is also said
to play a role in the osteosarcoma. Myc in the bone marrow stromal cells may
be increased in the osteosarcoma.
Another transcription factor involved in cell proliferation is c-Myc, whose
amplification has been implicated in osteosarcoma pathogenesis and resistance
to chemotherapeutic drugs. Overexpression of Myc in bone marrow stromal
cells leads to osteosarcoma development and loss of adipogenesis (Shimizu et
al., 2010). Overexpression of MET (Ferracini et al., 1995; Rong et al., 1993)
and c-Fos (Wu et al., 1990) has been reported in more than 50% of
osteosarcoma cases, whereas c-Myc is overexpressed in less than 15% of cases

(Barrios et al., 1993; Ladanyi et al., 1993). c-Myc, c-Fos, and cathepsin L have
been shown to be overexpressed in a high proportion of relapsed tumors
and metastases (Gamberi et al., 1998; Park et al., 1996). Transforming
growth factor beta (TGF-β) family proteins are also implicated in
osteosarcomagenesis through impairment of osteoblast proliferation,
differentiation and cell death. High-grade osteosarcomas are found to express
(TGF-β) in significantly higher amounts than low-grade osteosarcomas
(Franchi et al., 1998). IGF (insulin-like growth factor)-I and IGF-II are growth
factors that are often overexpressed by osteosarcomas (Rikkof et al., 2009).
Runx2 has a very low expression in osteosarcoma cell lines. Runx2 also
associates with BMPs, Rb, and p27KIP1 playing a crucial role in cell cycle
and bone differentiation regulatory pathways.
Bone morphogenetic proteins (BMPs) such as bone morphogenetic
protein-6 and bone morphogenetic protein receptor 2 are expressed in more
than 50% of osteosarcomas and related to poor prognosis (Gobbi et al., 2002;
Guo et al., 1999; Yoshikawa et al., 2004).
Rhabdomyosarcoma
Introduction
Based on histopathologic features, two subtypes, embryonal (ERMS) and
alveolar (ARMS) were identified. They are found to be associated with distinct
clinical characteristics and genetic alterations.
Pathogenesis
The tumor is said to arise from primitive mesenchyme with a propensity
for muscle formation rather than a malignancy arising from the skeletal muscle
cells. Hence the tumor may be located even in bones even though the bone is
not a site for occurrence of muscle cells.
1) The condensation of the mesenchyme is said to form a muscle tumor.

The loose primitive mesenchyme condenses to form an embryonic
muscle.
2) Embryonal tissue that was trapped during the early phase of tissue
formation may also be the cause for this tumor. It may also arise from
embryonal muscle tissue that was trapped during the early phases of
tissue development.
3) Though the exact pathogenesis for the RMS is unknown, studies have
shown that the cause for the occurrence for this tumor may be the
mutations that overturn the balance between the differentiation and
the proliferation of the primitive mesenchymal tissue during
myogenesis and hence the development of the rhabdomyosarcoma
4) The chromosomal translocations in the t(2;13)(q35;q14) or
t(1;13)(p36;q14) or 1;13ARMS is said to result in the generation of
the PAX3-FKHR and the PAX7-FKHR fusion products. This
contributes to the oncogenic behavior of the tumor by altering the
growth, differentiation and apoptosis pathways.
On the other hand the ERMS have allelic loss in chromosome 11p15.5.
This allele on the other hand is said to suppress the tumor suppressor gene. It
causes the loss of maternal genetic information and the duplication of the
paternal genetic information. The gene matched to this chromosome is the IGF
II gene and in case of RMS (rhabdomyosarcoma) it stimulates tumor growth.
Both of them are found to target the p53 and the Rb pathways through
amplification of the genes MDM2 and the CDK4. The amplifications are
frequent in ARMS but rare in the ERMS. Embryonal RMS (eRMS) is
characterized by loss of heterozygosity on the short arm of chromosome 11
(11p15.5), suggesting inactivation of a tumour-suppressor gene. In contrast,
the majority (80-85%) of the alveolar RMS (aRMS) have the reciprocal
chromosomal translocations.
The cell motility and invasion in epithelial cells is brought about by the
aberrant expression of the MET oncogenes in both the ERMS and the ARMS.
The MET is found to code the receptor for the HGF/scatter factor which is said
to play a role in the cell motility and invasion. The overexpression of MET is
said to create the same role in the myoblasts like embryonal myoblasts where
they migrate into the surrounding connective tissue.
PAX is another gene which is said to play an inhibitory role in the
myogenic differentiation of the cultured myoblasts. PAX3/7-FOXO1 can
suppress MyoD expression and also induce the NFκB signaling and this
inhibits the myogenesis through the Cyclin D1/CDK4 complexes. They may
sequester the MyoD which could hinder the cell cycle and the differentiation
of the myoblasts.
The GLI1 is said to play a role when primitive myoblasts are present. But
the association of the GLI1 is found to be associated with an undifferentiated
muscle tumor rather than with the ERMS or ARMS.
Lymphomas
Non Hodgkin’s Lymphoma
Introduction
Non Hodgkin’s lymphomas are malignancies of the lymphocytes that are
diverse in nature and include all tumors of the lymphocytic lineage excepting
the Hodgkin’s lymphoma.
Pathogenesis
Based on the classification of lymphomas numerous types have been
stated.
B-Cell Lymphoma
Abnormal lymphocyte production, maturation or action may cause a
malignant phenotype of the lymphocytes and this is seen due to mutation of
the gene responsible for the lymphocyte production. These mutations are
responsible for the expansion of the monoclonal population of the malignant
lymphocytes. The type of lymphomas depends on the stage of lymphocyte
production or maturation of the lymphocytes resulting in tumors related to the
immature B cells, naïve B cells, activated B cells and hence they produce
tumors such as Burkett’s lymphoma, diffuse large B cell lymphoma and
mantle cell lymphoma.
T-Cell Lymphoma
T cells arise from the CD34 stem cell and give rise to both T and B cells.
The T cells migrate early into the thymus where they transform into mature T
cells. The T cells form a complex with its receptor α, forming a mature TCR
complex and then decide to develop into either a CD4+ or the CD8+ cell. They
identify suitable MHC and subsequently leave the thymus. In the thymus, the
process starts from thymic lymphoid cells developing into T-cell receptor
(TCR) alpha, forming the mature TCR complex, and then developing into
CD4+/CD8+ cells. Interaction between TCR and peptide/MHC leads to a
commitment to be either CD4+ or CD8+ cells. Subsequently, T cells undergo
a positive selection (to recognize host MHC, self-MHC restriction) and
negative selection (to not bind MHC too strongly, which would lead to
autoreactive clone, self-MHC tolerance) and are ready to leave the thymus.
Those that were unable to perform its function of CD4+ or CD8+ production,
die in the thymus through apoptosis. Mutations can occur at any of the above
mentioned stages and result in the formation of the lymphomas.
Figure 2.
Source: Courtesy: Front. Pediatr.24 August 2015. MicroRNAs and potentialtargets in

osteosarcoma: review. Valerie B. Sampson, Soonmoon Yoo,Asmita Kumar,
Nancy S. Vetter and E. Anders Kolb
Figure 3. Network of miRNAs and target genes in OS. The figure depicts altered
miRNA genes that play a critical role in the development and progression of OS. The
majority of miRNAs are downregulated (tumor suppressors) and target genes are
overexpressed (oncogenes). Upregulated miRNAs (oncogenes) are depicted by
upward arrows and target genes are repressed (tumor suppressors). Abbreviations:
MDR1, multi-drug resistance 1; FasL, Fas ligand;IGF-1R, insulin-like growth factor
1receptor; EGFR, epidermal growth factor receptor; ROCK1, Rho-associated coiled-
coilkinase 1; Bcl2, B-celllymphoma-2;Bcl-xL, B-cell lymphoma-extralarge;Mcl-1,
myeloid leukemia cell differentiation protein;PTEN, phosphatase and tensin
homolog;MMP-13, matrix metalloprotease-13;N-Cad, N-Cadherin; SATB2, special
AT-rich sequence-binding protein 2; RUNX2, runt-related transcription factor2; DTL,
denticleless protein homolog). Solid gray arrows represent activated signaling
pathway;solid blunt lines represent inhibition of signals; dotted gray lines represent
indirect signaling pathways.
Information about the activation of the proto-oncogenes, e.g., bcl-1, 2, 6

and c-myc or the disruption of the p53 tumor suppressor gene is an important
knowledge for the clinician so that the proper treatment can be implemented.
The NHL is divided into the mantle cell, follicular, diffuse large cell and
Burkett’s lymphoma.
The ‘first hit’ leading to the Follicular Lymphoma is probably the
translocation of the t (14; 18). This is based on the genetic aberration. Naïve B
cells carrying the translocation, exit the bone marrow and lodge in secondary
lymphoid tissues where they undergo the germinal center reaction, but
survives it due to the presence of the bcl-2 which occurs in the germinal
centers during such malignancies, unless it is otherwise absent. These cells
may also be rescued from apoptosis due to its weak B cell affinity. But it has
been found that there must be another mechanism playing a role together with
t (14; 18) which may help in the occurrence of the HL.
Hodgkins Lymphoma
Introduction
Hodgkin’s lymphoma is another type of lymphoma which does not fit into
the category of the Non Hodgkin’s lymphoma. Mixed cellular infiltrate is a
feature of the Hodgkin lymphoma (HL) together with the presence of the
Hodgkin’s and the Reed Sternberg cells (HRS) which comprises a minor
component.
Pathogenesis
EBV infected B cells express latent membrane protein that
↓
Upregulates NF-kB (Transcription factor for activating lymphocytes)
Mutation in ↓
Negative regulators of NF-Kb
Leads to excessive B cell proliferation/protection of B cell from proapoptotic signals
↓
Increased number of B cells
↓
Mutation in Immunoglobulin gene of B cell
↓
Production of RSCs
EBV, NF, RSCs
Figure 4.
Evidence states that HRS cells are from the B cell clone that has lost their
B cell characteristics. In normal circumstances these B cells undergo
apoptosis. But there is said to be some mechanism that prevents the B cells
from undergoing the apoptosis and hence they survive, and the mechanism is
said to be a ‘virus.’ The virus said to play a role in inhibition of apoptosis has
been identified as the EBV.
The EBV alters the cell to such an extent that it replaces the survival
signals that are normally provided by the B-cell receptor (BCR) during
germinal center reaction that the B cell receptors on the cell surface are also
altered and they now appear as the HRS cells. The survival of the B cells from
apoptosis is brought about by the LMP2A expression. Constitutive activation
of Notch1(that plays a role in development) by LMP2A, and subsequent
inhibition of E2A and downregulation of EBF, two transcription factors that
regulate B-cell development, appears to be involved in both survival signaling
and transcriptional regulation. Thus, LMP2A is likely to play a key role in
both the survival and reprogramming of EBV-positive HRS cells. The cells are
modified to resemble an activated B cell receptor due to this expression. The
cells showing absence of the EBV may have had the latent infection during
childhood resulting in the appearance of episomes i.e., showing the absence of
disintegration of the viral particles.
There is compelling evidence that HRS cells are clonal B cells that have
lost their B cell phenotype. EBV is said to play a role in reprogramming and
survival through dysregulation of several signalling networks and transcription
factors, including nuclear factor (NF)-κB. Activation of NF-κB, AP-1,
members of the JAK/STAT signaling and the NOTCH-1 signalling pathway,
are features of all HRS cells and the gene mutations affecting this pathway
appear common in EBV-negative HL. The HRS also attracts cells supportive
to its microenvironment like the immune and the stromal cells. Also there is a
coincident production of the cytokines and the chemokines by the HRS,
thereby circumventing the normal apoptotic pathway and allowing the survival
of BCR (B cell receptor)-deficient B cells.
LMP1 mimics a constitutively active CD40 molecule, which is a receptor
for activating the B cells of the germinal center, although providing a more
potent and sustained signal. Activation of the NF-kB pathway, which is a
feature of HRS cells, leads to upregulation of antiapoptotic genes, including c-
FLIP and XIAP, which are likely to contribute to HRS cell survival.
Figure 5.
EBV produces a gene rearrangement and gene mutation in the B cell and hence it
escapes apoptosis and shows the presence of receptors that are different from
other B cells. LMP2A is the factor that protects Bcells from undergoing apoptosis.
The concept of the same cells in negative EBV cases suggest that EBV is negative
at present but may have been EBV positive earlier and the cell has lost its viral
episome’ hit and run hypothesis’
Burkitt’s Lymphoma
Introduction
This is a very rare and fast growing form of a Non Hodgkin’s lymphoma.
It is a high grade B cell lymphoma that is very aggressive. It is commonly seen
in the sub Saharan Africa and is said to be caused by EBV.
Pathogenesis
Figure 6. Depicting the pathogenesis of Burkitt’s lymphoma.
The BL cells show a characteristic germinal center derivation. It

comprises the CD10+ CD77+ Bcl2.
High levels of the bcl-6, c-myc are seen in the germinal centers due to the
translocation of the chromosome t (8:14), t (2:8), or t(8:22) is considered the
hallmark for the development of the BL. It places the c-myc allele into the
heavy or light chain locus of the Ig. The presence of c-myc not only allows
cells to enter cell cycle but also plays a role in apoptosis in the absence of the
inhibiting signals such as the ras, bcl-2 or the EBNA 1. Though they exhibit
high levels of HLA class II it fails to stimulate the CD4+T cells. The EBV has
the property to convert the normal B lymphocytes into both the BL and the B-
lymphoblastoid cells. Even though translocation of MYC is generally
considered a hallmark for BL and this characteristic has been uniformly
observed across the different BL subtypes, c-myc does not act alone. Further,
in order for c-myc to initiate its transcriptional activities, it must first form a
heterodimer with the constitutively expressed max. If the formation of c-
myc/max heterodimers is prevented, cells do not undergo c-myc-induced
transformation and alternately may even prevent its deregulation. The mistakes
in the repair of the mutated c-myc results in translocation between
chromosomes t (8; 14). But deregulated oncogene is unable to transform
normal cells into cancer cells. This role is performed by the p13 k, which is a
key element in the Burkitt lymphoma development.
Another enzyme the AID (Activation-induced cytidine deaminase) has

been implicated in the development of the BL and the deregulated expression
of the AID causes a c-myc translocation in a cell latently infected with the
EBV.
A transcription factor found active in the BL is the TCF-3. Not much
detail is known about this agent.
It has been observed that malaria occurs together with the BL. The reason
is the inverse proliferation of the B and the T cells: ↑ of the B cells and the ↓
of the T cells cause a reactivation of the EBV in the infected T cells.
HIV represents another infection that may aggravate the pathogenesis of
BL. Reduced CD4+ count may play a role in an EBV infection of the B cells.
There are 5 viral glycoproteins that help the EBV to enter the B cell
namely the viral gp 350 and the viral gp 42. The other viral proteins include
gB, gH, and gL.
Multiple Myeloma
Introduction
Multiple myeloma, also called as plasma cell myeloma is an uncommon
cancer of the plasma cells.
Pathogenesis
The underlying pathophysiologic phenomena of the clinical features
include suppression of humoral- and cell-mediated immunity, elevation of IL-
6, abnormalities of the bone marrow microenvironment, and increased
osteoclastic activity.
Translocations in the chromosome 14q32 and other chromosomes such as
11, 4, 6, 16 results in the occurrence of the multiple myeloma. Deletion of
whole or parts of chromosome 13 are also said to play a role in the malignant
melanoma.
The overproduction of the plasma cells results in secretion of the IL-6
which is also called as the osteoclast activating factor (OAF) and this is said to
play a role in bone destruction. It causes the lysis of the long bones resulting in
fractures.
Light chains of the plasma cells may be excessively deposited in the
kidneys (light chain deposition disease) resulting in the renal failure, in the
nerves (neuropathy) and also leading to immunologic deficiencies that result in
infections.
It also results in production of the single clone of antibody or the

monoclonal antibody (M protein) which is detected in the urine and is known
as the Bence Jones proteins.
Hemangioendothelioma
Introduction
Hemangioendothelioma are those vascular neoplasms that exhibit a
borderline biological behavior that is intermediate between totally benign
hemangiomas and highly malignant angiosarcomas.
Pathogenesis
The pathogenesis is said to occur following the reciprocal translocation
between the t (1; 3) (p36; q25). The genes involved in the translocation are the
WWTR1 or the TAZ gene to the CAMTA1 gene. Gene fusion between two
other genes YAP with TFE3 is also said to play a role in the formation of the
hemangioendotheliomas.
The above mentioned WWTR1 (WW domain-containing transcription
regulator 1) and the CAMTA1 are both transcription factors. An evolutionary
conserved signal transduction pathway playing a role in the regulation of the
organ size and anoikis (a type of programmed cell death) was said to play a
role in this tumor formation and they form the end effectors of the Hippo
pathway. So basically the fusion occurs between an oncogene and a tumor
suppressor gene. The CAMTA1 in mammals helps in formation of the cardiac
muscle and also plays a role in the neural development and acts as a
suppressor in formation of the neuroblastoma, glioblastoma multiforme and
glial tumors.
Congenital Epulis
Introduction
Congenital epulis, also known as granular cell tumor of the newborn or
Neumann's tumor is a rare tumor of the newborn. It commonly arises from the
anterior part of the maxillary gingiva and is seen as a mass protruding from a
newborn’s mouth. It may hinder the child’s respiration or the feeding.
Pathogenesis
The occurrence of the tumor in neonates and in females suggested that this
tumor may be hormonally affected. However neither high estrogen nor
progesterone has been detected in these individuals.
The absence of markers for the primary tumors indicates an origin from an
uncommitted mesenchymal cell. The similarity of this tumor with the
Schwann cell granular cell tumor indicates that the lesion could arise from the
Schwann cells. But the Schwann cell marker, S100 was found negative in the
CGCE.
Granular Cell Tumor
Introduction
Granular cell tumor is an uncommon poorly understood tumor.
Pathogenesis
 Earlier thought to arise from the myoblasts but the markers for muscle
cells was found negative.
 The theory that it arises from the Schwann cells has been proved
correct since it is found to be S100 positive.
 Said to arise from fibroblasts or mesenchymal cells but authors have
proven that it is not a neoplastic condition and it probably arose due to
trauma.
Chapter 7
Benign and Malignant Tumors of

Salivary Glands
Benign Salivary Gland Tumors
Pleomorphic Adenoma
Introduction
This tumor is also called as the benign mixed tumor. It is one of the most
common tumors of the salivary glands. The tumor is painless, slow growing,
and composed of biphasic population of epithelial and mesenchymal cells.
Pathogenesis
A large number of theories have been put forth to describe the origin of
the Pleomorphic Adenoma (PA).
It is proposed that the tumor is of monoclonal origin i.e., single source
giving rise to both the epithelial and mesenchymal components for e.g.,
pluripotent intercalated duct cells. The tumor could be derived from the
epithelial basal duct cells which undergo neoplastic differentiation to form
1) An epithelial component and the other

2) A mesenchymal component.
A gene PLAG1 mapped to chromosome 8q12.1 may play a role in

Pleomorphic Adenoma pathogenesis. This gene probably induces the growth
factor production, mainly the IGF 2 and cytokine like growth factor 1, and
which therefore results in cell proliferation. This has been studied by both the
Western blot and immunohistochemical analysis. It was found that the PLAG1
expression has been identified in the epithelial, myoepithelial, and also the
mesenchymal components of the Pleomorphic Adenoma.
PLAG1 and HMGA2 genes are said to play a role in cell cycle regulation
and growth factor signaling.
Fusion of the PLAG1 gene and the FGFR1 gene was stated as another
mechanism for the development of the Pleomorphic Adenoma. The PLAG1
gene was mapped to chromosome 8q12.1 and FGFR1 mapped to chromosome
8q12. The breakpoints for the fusion occurred in the 5' non coding regions of
both genes, leading to activation and the promoter substitution of PLAG1
expression.
Another partner gene identified in Pleomorphic Adenoma is the WIF1
(wnt inhibitory factor 1). Wnt proteins are extracellular signaling molecules
that play a role in the control of embryonic development. Wnt proteins play a
role in stem cell biology, in angiogenesis and even in carcinogenesis.
Figure 1. Normal cell has a multi looping transmembrane receptor, one end of which is
in the cytosol and the other end attached to the wnt ligand. Through cytosolic factor
like disheveled (dsl) they are attached to the beta catenin, a cadherin which plays a role
in cell to cell adhesion and cytosol to nucleus signaling.
Benign and Malignant Tumors of Salivary Glands 59
WIF1is expressed at a high level in normal salivary glands but on the

other hand HMGA2 is not expressed. These 2 genes are fusion partners and
the WIF1 is the suppressor of this wnt molecule. And a rearrangement in the
WIF1 gene is said to play a role in development of the pleomorphic adenoma.
A combination effect between upregulation of HMGA2 and a downregulation
of WIF1 gene is the main cause for pleomorphic adenoma.
Translocations involving chromosome 8q12 and 12q14-15 are also
observed in the pleomorphic adenoma of salivary glands. Another
translocation observed is the t (3; 8) (p21; q21) translocation seen in nearly
half of pleomorphic adenomas. This results in promoter swapping between the
gene (CTNNB1) for Il-catenin or β catenin and PLAG i, a novel zinc finger
gene at 8q12 (1). This finding indicates that PLAGi activation due to promoter
swapping is very likely to be a crucial event in salivary gland tumorigenesis.
High amplification of the HMGA2 gene, either in its intact or disrupted
form or in the form of fusion with the WIF1 gene indicates a malignant
transformation of the tumor. Other authors try to play down its role and
suggest that the real role of these genes is to provide elements for proper
translation of the fusion transcripts.
The highest expression levels of HMGA2 gene are detected in fetal tissues
whereas gene expression is undetectable in normal adult tissues. The HMGA2
genes are also said to partner 2 other genes to play a role in occurrence of
pleomorphic adenoma and they include the NFIB (nuclear factor I B gene) and
HMGA2-FHIT (fragile histidine triad gene). These have been identified in
pleomorphic adenomas with translocation t (9; 12) (p23; q12-15) and t(3;12)
(p14.2;q14) respectively. There is a rearrangement of the HMGA2 gene and
such changes are said to result in an increased expression of that gene. Thus,
HMGA2 gene rearrangements may promote tumorigenesis in pleomorphic
adenoma.
Histologically, the pleomorphic adenoma is said to consist of features that
indicate its origin from the myoepithelial cells. Those features include
perinuclear tonofilaments, actin microfilaments, and remnants of basement
membrane. Epithelial markers showed that benign pleomorphic adenomas of
the major salivary glands are pure epithelial cell tumors. Pleomorphic
adenoma was also said to arise from neoplastically transformed intercalated
ducts cells.
Viruses have been implicated in the pathogenesis of pleomorphic
adenoma and predominant among them was the SV40 virus, as SV40 DNA
sequences and associated T antigen were said to be identified in these tumors.
Basal Cell Adenoma
Introduction
Basal cell adenomas are rare salivary gland tumors comprising of basaloid
cells arranged in a solid and trabecular pattern and nuclei of peripheral cells
are said to show palisading. They lack the chondromyxoid matrix material
characteristic of pleomorphic adenomas.
Pathogenesis
Trisomy 8(three copies of the same chromosome) (genes on chromosome
8 are involved in brain development and function, and about 16% are involved
in cancer) has been identified in the basal cell adenoma. In some cases
alterations in chromosome 13 and 16 q has also been found. On the
chromosome 16q12-13 there is alteration in the CYLD1gene. Translocations
in the chromosome 8 and 16 results in acute myeloid leukemia. The CYLD1 is
a deubiquinating enzyme and the loss of its activity shows an opposite and
exaggerated activity of the NF-kappa B indicating tumorigenesis.
Canalicular Adenoma
Introduction
It is a rare tumor that comprises less than 1% of all the salivary gland
tumors. If present, it is commonly observed in the minor salivary glands of the
upper lip in nearly 80% cases. The tumor is multifocal in nature and may be
mistaken for metastasis.
Pathogenesis
The multifocality suggests a field effect. It is thought to arise from the
terminal ducts or the striated ducts of the salivary gland.
Oncocytoma
Introduction
It is a benign tumor that is composed of cells that contain granular
eosinophillic cytoplasm, called as oncocytes. It has also been called as an
oxyphillic adenoma.
Pathogenesis
There have been various theories that have been proposed for the
oncocytic change in the acinar cells
1) Oncocytic change seen in the acinar cells due to metaplasia is said to

be one of the theories put forth with regard to oncocytic change.
2) The second theory states that oncocytoma may be composed of acinar
cells that have aged and those that have lost their capacity to perform
their specific tasks. They are considered as burnt out. This theory was
proposed by Hamperl
3) Another theory states the importance of mitochondria and this being
the reason for transformation of the acinar cells. According to these
authors, as the acinar cells age, the number of mitochondria in them
increases in number due to the damage or the burning out of the
mitochondrial enzymes.
4) Mitochondrial DNA damage was said to be another factor responsible
for the oncocytic change and this was said to result in the disturbance
of the respiration of the cells together with it a multi organ failure.
This theory was proposed by Linnane et al. in 1989.
5) Sunmunn et al. stated that a previously hyperplastic or hypertrophic
duct that was undergoing regressive alteration resulted in
mitochondriopathy which could be a reason for the oncocytic change.
Oncocytoma in its early stages shows the presence of oncocytes having an

increased number of mitochondria which undergoes pleomorphism hence
resulting in biochemical changes and altered cell metabolism.
Warthin’s Tumor
Introduction
Warthin’s tumor of the salivary glands is a benign tumor which is
considered more of a hamartoma or a reactive proliferation of ductal salivary
gland cells and lymphoid elements, than a neoplasia. Hamartoma is the
abnormal proliferation of tissue native to its part.
Pathogenesis
Authors have identified three main observations that are unique to the
pathogenesis of Warthin’s tumor and they have been described as:
1. One set of patients whose Karyotype is normal and the other where
the karyotype was affected.
2. The next set of them wherein the changes occurred only in number of
the chromosome for e.g., loss of Y chromosome or trisomy or
monosomy 5, and
3. The third type of cases in whom the entire chromosome had
undergone structural changes with one or two reciprocal
translocations at (11; 19) (q21; p13). This probably suggests a link to
mucoepidermoid carcinoma. This karyotyping was an individual
event or may be a part of a complex karyotyping.
1. The complex karyotype carried a MECT1-MAML2 fusion
transcript. But this transcript cannot be considered as a hallmark
in the diagnosis of the Warthin’s tumor.
2. A theory put forth by another group of authors with regard to the
pathogenesis of Warthin’s tumor stated that the heterotropic
intercalated and striated duct cells got entrapped in the
intraparotid or paraparotid lymph nodes.
According to this theory the parotid gland was among the first
salivary glands to develop during embryogenesis and the last one
to get encapsulated. Lymph nodes get entrapped within them and
they are found to lie on the inside of the capsule. Heterotropic
salivary gland ducts may get entrapped in this lymphoid tissue to
become neoplastic and result in the formation of the Warthin’s
tumor.
3. The lymphoid tissue was considered by some authors, as a
defensive reaction to the metaplastic epithelial change or
Warthin’s tumor. These authors do not consider the Warthin’s
tumor to be a neoplasia.
4. Because of its coexistence with autoimmune diseases like
Hashimoto’s thyroiditis etc., and the presence of lymphoid
element, this tumor is considered to be an autoimmune lesion.
5. So what is the factor that causes the epithelial portion of the
Warthin’s tumor to become metaplastic? The authors who have
propositioned this theory believe that
 EBV could be an inciting factor for Warthin’s tumor and
 Type 2 Nitrous Oxide is said to another stimulating
factor for the tumor.
Another gene suggested as the cause for the tumor is the
WAMTPI gene (Warthin and mucoepidermoid tumour
translocation partner gene) and this gene has been implicated in

the histogenesis of the Warthin’s tumor.
A theory for pathogenesis of Warthin’s tumor states that the
striated duct cells undergo oxyphilic metaplasia and produce an
apocrine secretory activity. The duct epithelium proliferated due
to the metaplasia which then incited a stromal reaction with
proliferation of the immune cells together with the epithelial cells.
The causative factor(s) that caused this metaplasia was unknown.
Cigarette smoke could be one of the predisposing factors causing
the metaplastic change. This has been speculated, because of the
close relationship between smoking and Warthin’s.
6. Some authors have identified the presence of the class II HLA on
the epithelial cells in the Warthin’s tumor. Similar HLA has also
been identified on the epithelial cells of the some autoimmune
salivary gland conditions like for e.g., The Sjogren’s syndrome
involving the salivary and lacrimal glands. Thus according to
these authors the epithelial cells acted as an antigen presenting
cell (APC) that could stimulate the lymphoid stroma. Thus, these
authors suggested that the expression of HLA-DR antigens and
interleukin-1 production by the epithelial component of WT could
especially excite the lymphoid cells within the salivary gland.
Malignant Salivary Gland Tumors
Mucoepidermoid Tumor
Introduction
Mucoepidermoid carcinomas were first described by Masson and Berger
in 1924. It represents a distinct type of tumor. It comprises of three cellular
elements in varying proportions: mucus-secreting cells, the squamous cells,
and the “intermediate” cells.
Pathogenesis
Mucoepidermoid carcinoma may originate from excretory duct reserve
cells, but the issue remains non-explanatory.
Cytogenetics: Even though MEC is the most common type of malignant
salivary gland tumors’ its pathogenesis and the key molecular events leading
to its development are yet to unravel. At least two partially overlapping

cytogenetic subgroups have been identified, i.e., MECs with t (11; 19) (q21;
p13) or variants thereof, and MECs with single or multiple trisomies, either
observed as the sole abnormality or in combination with structural
rearrangements. A recurrent t (11; 19) (q21; p13) translocation has been
identified in Mucoepidermoid carcinomas of both the salivary glands and of
the bronchopulmonary tissues. Such a translocation leads to the fusion of exon
1 from a gene of unknown function at 19p13, termed mucoepidermoid
carcinoma translocated 1 (MECT1, also known as CTRC1, TORC1, or
WAMTP1), with exons 2-5 of a member of mastermind-like gene family,
MAML2, at 11q21. It has been demonstrated that the resultant fusion
transcript MECT1-MAML2 activated the transcription of the Notch target
gene HES1, independent of ligand stimulation.
The translocation t (11; 19) (q21; p13) and the MECT1-MAML2 fusion
transcript have been detected in 38-81% of mucoepidermoid carcinoma cases.
This same translocation is also seen in case of acute leukemia, and an
apparently identical rearrangement has been identified in Warthin’s tumor.
Apart from Warthin’s tumor, it has not been demonstrated in any other
salivary gland tumor. Immunohistochemistry using an MECT1-MAML2
antibody in fusion-positive mucoepidermoid carcinomas resulted in nuclear
staining of all three major cell types, i.e., mucus-producing, epidermoid, and
intermediate cells. However, stromal cells did not express the fusion protein.
Expression of the hybrid gene in all cell types suggests that it may play an
early role in tumor initiation. Such a distinct translocation and resulting fusion
transcript may be a useful tool in diagnosing morphologically ambiguous
MEC. In addition, there is an association between transcript expression and
tumor stage, with fusion-positive tumors behaving in a less aggressive fashion.
Fusion-positive patients had a significantly lowered risk of local
recurrence, metastases, or tumor-related death compared to fusion-negative
ones (median survival of more than 10 years compared to 1.6 years). In
addition, there was a preponderance of highly differentiated low-grade tumors
in fusion-positive patients compared to the fusion-negative group.
Not all fusion-positive tumors carried the translocation t (11; 19), meaning
that other cryptic translocations may contribute to the disease in such cases.
Fusions may thus be found in MECs with complex 11; 19 rearrangements and
also with variant translocations such as t (11; 17) and t (11; 13), as well as in
tumors with apparently normal karyotypes and trisomies.
The other common chromosomal abnormality was single or multiple
trisomies, observed in 7 of 21 MECs in one series. Trisomies were mostly
observed in cases not harboring a t (11; 19). The most frequently encountered
trisomies were +7, +8, and +X. Other recurrent abnormalities found were
deletions of the terminal part of 6q. Apart from these abnormalities, the t (11;
19)-negative MECs showed a heterogeneous pattern of rearrangements with
no obvious recurrent aberrations.
Very recently, deletions of CDKN2A gene have been shown to be
associated with poor prognosis in MECT1-MAML2 fusion-positive MECs. In
the same study, neither activating EGFR mutations nor copy number gains at
the EGFR locus was detected in fusion-positive and fusion-negative cases.
Finally, the detection of HER-2 overexpression by immunohistochemistry
has been correlated to adverse clinicopathologic features in the
Mucoepidermoid carcinoma.
Acinic Cell Carcinoma
Introduction
Acinous cell carcinoma makes up approximately 6-10% of the salivary
gland cancers. It is one among the rare salivary gland cancers. Acinic cell
carcinomas commonly arise in the parotid gland (86.3% in largest study) but
submandibular and sublingual glands have also been seen to be affected.
Pathogenesis
Histogenesis: Acinic cell carcinomas may arise from neoplastic
transformation of the terminal duct cells (intercalated duct cells) with
differentiation towards serous acinar cells. Another theory put forth suggests
that the tumor could arise from transformation of terminally differentiated
serous acinar cells.
Cytogenetics: Multiple structural and numerical aberrations have been
described in acinic cell carcinoma but no specific alteration has been
identified. Loss of Y and trisomy 7, 8, and 21 has been reported. In one of the
largest study to date, acinic cell carcinomas showed LOH (loss of
heterozygosity) in at least one of the 20 loci tested on chromosomes 1, 4, 5, 6,
and 17. Chromosomal arms 4p, 5q, 6p, and 17p were the most frequently
altered, with 4p15-16, 6p25-q, and 17p11 regions showing the highest rate of
abnormalities. In another study, analysis of different samples from a single
case found evidence of polyclonality.
Adenoid Cystic Carcinoma
Introduction
Adenoid cystic carcinoma (ACC) is a rare form of malignant neoplasm
that arises within secretory glands, especially the major and minor salivary
glands of the head and neck. Glands of the trachea, lacrimal glands, breast,
skin, and vulva may also be affected by the adenoid cystic carcinoma. This
malignancy has a distinctive histologic appearance.
Pathogenesis
Adenoid cystic carcinoma is characterized by a t (6; 9) (q22-23; p23-24)
translocation. The translocation fuses exon 14 of MYB gene, on chromosome
6q22-23, to the last coding exons of NFIB gene, on chromosome 9p23-24.
Most breakpoints occur in intron 14 of MYB and intron 8 of NFIB. The
minimal common part of MYB that is deleted is exon 15 including the 3'-UTR
which contains several highly conserved target sites for miR15a/16 and miR-
150 micro RNAs. These micro RNAs are known to negatively regulate MYB
expression. Deletion of these target sites may lead to overexpression of MYB-
NFIB transcript and activation of MYB targets, including genes associated
with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion.
Deregulation of expression of MYB and its target genes may be a key
oncogenic event in the pathogenesis of adenoid cystic carcinoma.
Mutations in the c-kit gene have recently been described in adenoid cystic
carcinoma, but their occurrence is rare, and they most probably do not
represent ‘driver’ mutations in this entity.
The tumors were composed of four major cell types; intercalated duct,
myoepithelial, secretory, and pluripotential reserve/stem cells. The cellular
composition of adenoid cystic carcinoma is similar to that in the “terminal
tubule” complex stage of a developing salivary gland except that in the tumor
the pluripotential reserve/stem cells differentiate predominantly along the
intercalated duct cell line rather than secretory cells as in the acinic cell
carcinoma. Furthermore, adenoid cystic carcinoma appears to contain a far
greater number of myoepithelial cells than acinic cell carcinomas.
Pathogenesis Regarding the Perineural Invasion

The exact mechanism behind the perineural invasion is still a mystery yet
a number of theories have been put forth; a recent theory states that reciprocal
signaling interactions between the tumor and the peripheral nerve plays a role
in the perineural invasion. The tumor cells acquire the capacity to respond to
signals in the peripheral nerves and hence promote the invasion.
Neutotropic agents (cytokines within nerves) have been identified in other
malignancies such as the prostrate and the pancreas and they include the NGF
and other factors, such as neural cell adhesion molecule (NCAM), have been
shown to have increased expression in Head and Neck squamous cell
carcinoma. Older theory included the spread of the tumor along any path
which showed the least resistance and this happens to be the peripheral nerves,
and another theory stating the presence of lymphatic channels within nerves
has been discounted. Lymphatic channels have been found unable to penetrate
the epineurium, around a single nerve, hence this theory has been discarded
Carcinoma Ex Pleomorphic Adenoma
Introduction
Carcinoma ex pleomorphic adenoma (CXPA) is a poorly understood
malignancy that are rare and that develops from either a long-standing primary
or a recurrent pleomorphic adenoma (PA).
Pathogenesis
Genomic alterations in carcinoma ex- pleomorphic adenoma are identical
to those found in pleomorphic adenomas. Alterations at 12q13-15 with
amplification of HMGA2 and MDM2 genes have been reported. MDM2 (at
12q14-15) is one of the most frequently co-amplified genes together with
HMGA2, suggesting a pathogenetic role for MDM2 in carcinoma ex-
pleomorphic adenoma. The genes were co-amplified in the same
homogeneously staining regions and double minute chromosomes (MDM2)
in a case of carcinoma ex- pleomorphic adenoma with a del (5)(q22-23q32-33)
and t(10;12)(p15;q15). However, there was little MDM2 protein expression,
when assessed by immunohistochemistry, compared to high HMGA2
expression levels in the carcinomatous parts of the tumor.
Cerb-B2 expression has been detected in one third of carcinoma ex-
pleomorphic adenomas and could help distinguish it from atypical
pleomorphic adenoma. Mutation and overexpression of TP53 are also frequent
events in carcinoma ex pleomorphic adenoma.
Chapter 8
Odontogenic Cysts
Odontogenic Keratocyst or Keratocystic

Odontogenic Tumor
Introduction
Odontogenic keratocyst is an uncommon, benign cystic tumor derived

from the odontogenic apparatus.
Pathogenesis
The cyst is said to arise from the odontogenic apparatus namely the
 Dental lamina or its remnants

 Basal cells extension from the overlying epithelium.
 In case of the Nevoid Basal cell carcinoma syndrome the cyst is more
likely to arise from the dental lamina and the satellite cysts have been
considered to be the
 Primordial cyst on the other hand was said to arise in place of a tooth,
from the enamel organ, more specifically from the degeneration of the
stellate reticulum within the enamel organ.
The proliferative activity of the OKC was studied by various authors due
to its highly aggressive nature. It was found that there was an increased
proliferation of the markers such as the Ki 67 and PCNA in OKC compared to
other odontogenic lesions. But the proliferative markers are not an indication
for the neoplastic nature of this lesion. In some cases though the lesion is
neoplastic there is no much exaggeration of the markers seen.
Another theory in favor of the neoplasticity of the lesion is its
heterozygosity. Allelic loss in tumour suppressor genes such as p16, p53,
PCTH, MCC, TSLC1, LTAS2 and FHIT, have been found in case of the OKC
indicating their aggressiveness as these marker have already been used to
identify some of the common human neoplasias. Also the lesion showing the
presence of larger number of daughter cysts show a more tendency for allelic
loss.
P53 has been found low expressed in OKC.
Growth characteristics of the OKC have been co-related to the
overexpression and underexpression as well as the deletions in the 3q13.1,
5p14.3, 7q31.3 genes and also the overexpression and amplification of the
12q13, EGFR3, glioma associated oncogene (GLI1). Faults in the cell
adhesion molecule is said to play a role in detachment of the epithelium from
the connective tissue.
The most important genetic alteration is said to be in the Drosophilia
Patched gene (PTCH1). Germline mutation in this gene is said to play a role in
the NBCCS. The Ki-67 showed a higher labeling index in the cases that
showed a PTCH1 mutation.
The ‘two hit’ or the haploinsufficiency theory is another factor in favor of
the development of the OKC. The first hit is a mutation in one allele, which,
although it can be dominantly inherited, has no phenotypic effect. The second
hit refers to loss of the other allele and is known as “loss of heterozygosity.”
Precursor cells to be hit by the loss of an allele namely 9q22.3-q31, which
leads to loss of gene dosage, have already been affected by the ‘first hit’ in
case of the NBCCS, whereas the sporadic OKC occur in cells in which there is
already ‘two somatic hits.’ The 9q22.3-q31 is already a targeted site in case of
carcinomas such as basal cell carcinoma, squamous cell carcinoma etc.
Another important event in tumorigenesis where there is no exact change
in the gene sequence is the epigenetic alterations which occur in case of
benign and malignant tumors of the head and neck. DNA methylation is one
such event where there is an addition of the methyl group in cytosines and in
case of the OKC the PTCH1 methylation may occur in place of a true
mutation.
Odontogenic Cysts 71
Methylation is the process rather than mutation, seen to occur in the

P21gene and the absence of methylation in the Rb1 gene in OKC samples as
opposed to normal dental follicles.
Figure 1. Possible molecular mechanisms related to PTCH1 inactivation. One or more

of these genetic or epigenetic alterations may act in cooperation causing PTCH
inactivation, leading to Sonic Hedgehog pathway activation.
Y. Kubota et al. showed that Interleukin-1α (IL-1α) is strongly expressed

in odontogenic keratocysts. IL-1α may up-regulate matrix metalloproteinase-2
activation by increasing the expression of membrane-type 1 matrix
metalloproteinase in the fibroblasts isolated from odontogenic keratocysts
synergistically with type I collagen. Ogata et al. showed that in keratocystic
odontogenic tumour fibroblasts, IL-1α may stimulate COX-2 expression.
Andric et. al. investigated the expression of survivin, an inhibitor of apoptosis,
in odontogenic keratocysts and compared it to the findings in non-neoplastic
jaw cysts - periapical cysts they also studied a possible relationship between
survivin expression and human cytomegalovirus presence within these cysts. It
was found that survivin may contribute to the aggressive behavior of
odontogenic keratocysts, and thus support the emerging opinion of their
neoplastic nature. Gli2-mediated reactivation of quiescent epithelial rests
to form keratocysts indicates that these cells retain the capacity to function
as progenitor cells on activation by an appropriate developmental signal.

Furthermore, markers known to be rapidly induced in response to growth
factors, tumor promoters, cytokines, bacterial endotoxins, oncogenes,
hormones and shear stress, such as COX-2, may also shed a new light on
biological mechanisms involved in the development of these benign but
sometimes aggressive neoplasms of the jaws.
Dentigerous Cyst
Introduction
Dentigerous cysts are benign non-inflammatory odontogenic cysts thought
to be developmental in nature.
Pathogenesis
The dentigerous cyst may be either extrafollicular or intrafollicular. The
extrafollicular dentigerous cyst arises mostly as an envelopmental OKC.
Intrafollicular dentigerous cyst is said to arise due to accumulation of fluid
between the tooth crown and the follicle. The tooth in this case would not be
hypoplastic. But if the cyst has arisen due to degeneration of stellate reticulum
of an enamel organ the tooth is most likely to be hypoplastic. The fluid that
accumulates, most probably arises from the capsular vessels either between the
layers of the reduced enamel epithelium or between the crown of the tooth and
the reduced enamel epithelium. Capsular ground substance based
glycosaminosglycans (GAG) causes the expansion of the cyst either in
response to normal metabolic turnover of the tissue or in response to
inflammation. The GAGs further enter the lumen through channels in the
epithelial lining. This may also result in the further cyst expansion.
A permanent tooth counterpart entering into the radicular cyst of a
deciduous tooth may be another reason for the formation of the dentigerous
cyst. But is has been noticed that the radicular cysts in association with the
deciduous teeth are rare. And the permanent teeth are more likely to invaginate
into the radicular cyst of the deciduous tooth rather than cover over it, is the
explanation given by other authors. But in the histology of these cysts it has
been found that there is a presence of inflammatory cells apart from the cyst
lining. It may be mistaken for the radicular cyst.
A new theory states the role of a structure of primary cilia that are said to
be involved in the pathogenesis of dentigerous cyst and the OKC. These cilias
have been identified in the lining of both the aforementioned cysts. The cilias
have already been proved to be involved in the pathogenesis of cysts in the

kidneys. They have been found to be normal inhabitant of the oral epithelium
so it is not unusual for them to play a role in the pathogenesis of the cysts. The
study is still underway for confirmation of this theory.
Figure 2. Diagram of ciliary structure.
The motile cilia have a central core of microtubules and an inner and outer
dynerin structures required for motility. The organelle is covered over by a
membrane which contains the multiple microtubules.
From ‘The Nature Publishing group.’

These primary cilia have been presenting a variety of receptor functions
and hence it is not unusual for them to play a role in signaling. Apart from
simple signal transduction function the cilia is also said to play a role in a large
number of developmental activities and also plays a role in memory.
Lateral Periodontal Cyst
Introduction
Lateral periodontal cyst (LPC) is an uncommon but well recognized type
of a developmental odontogenic cyst.
Pathogenesis
There is no clear information about the pathogenesis of the lateral
periodontal cysts but they have been postulated to arise from these three
sources:
 Reduced enamel epithelium, of a developing adjacent tooth.

 Remnants of dental lamina were suggested due to the presence of the
glycogen rich islands of the lateral periodontal cysts. It is said that
cyst LPC differs from that of the Dentigerous Cyst in that the LPC
arises from the postfunctional (quiescent) cells of the dental lamina
and the DC from the active cells of the dental lamina.
 Cell rests of Malassez: But the cyst normally occurs on the facial
aspect of the jaws and not the lingual aspect hence the probability of
the cyst arising from the dental lamina and not the rests of Malassez is
considered.
 Also a possible origin from a primordial cyst of supernumerary tooth
germs has also been considered. This theory has been suggested, due
to the presence of a large number of supernumerary teeth in this
region.
 A pulpal infection opening on the lateral aspect of the root or a
periodontal ligament infection, stimulating the rests of Malassez is
also considered another possibility.
 Clear cells’ presence in the cyst lining points to their resemblance to
the clear cells in the dental lamina rests and not to the rests of
Malassez or reduced enamel epithelium and neither can they arise
from the radicular or the dentigerous cysts as both these cysts arise
from the above two mentioned sources.
 The final and the most recent theory states that the origin of the LPC
is based on genetics. The reduced enamel epithelium covering the
crown of the developing adjacent teeth was said to be the cause for the
formation of this cyst. The replantation of the epithelial plaques which
may give rise to a cyst, by canalisation within it shows the active
nature of the epithelial lining. But why does the cyst take so many
years for formation is the next question, since LPC is predominant in
the middle ages and the implantation must occur in childhood. Also if
the lining was said to be so active how it can it not erupt into the oral
cavity and how come it does resorb the bone and not the roots, are all
questions for which there are no concrete answers. Also why the LPC
is seen in the specific premolar areas and not in others cannot be
explained by this theory.
Figure 3. The above sketches show the hypothetical pathogenesis of the lateral
periodontal cyst. The eruption of a tooth through the lateral dentigerous cyst may result
in the formation of the lateral periodontal cyst.
Figure 4. Figures illustrate the different origins of the lateral periodontal (left) and
gingival cysts (right). Both cysts are said to originate from the epithelia comprising a
part of the dental follicle.
In view of this varied etiology, the authors suggested that the term should
be qualified to indicate whether the cyst’s origin was pulp infection, infection
through the gingival crevice or idiopathic stimulation of cell rests. It is now
widely accepted that the term ‘lateral periodontal cyst’ should be confined to
cysts in the lateral periodontal position in which an inflammatory etiology and
a diagnosis of gingival cyst of the adult and collateral keratocyst have been
excluded on clinical and histological grounds.
Gingival Cyst of the Adult and New Born
Introduction
Gingival cyst of the adult and new born arises on the gingiva of the new
born and the adult.
Pathogenesis
Derived from the reduced enamel epithelium and the remnants of the
dental lamina i.e., the cell rests of Serre after 4th month in-utero. It is also said
to arise from the invagination of the rete peg of the overlying epithelium, or
the traumatic implantation of the surface epithelium and from the degeneration
from the aberrant mucous glands.
It was postulated that the gingival cyst of adults and the lateral periodontal
cyst have a common histogenesis and represent the intra-osseous and extra-
osseous manifestations of the same lesion. Buchner and Hanssen considered
that they probably were of the same epithelial origin.
Glandular Odontogenic Cyst
Introduction
Glandular Odontogenic Cyst (GOC) is a rare odontogenic cyst that is
unique with respect to its histopathologic features and its unclear histogenesis.
Pathogenesis
Origin from dental lamina rests:
Disintegration of the Dental Lamina:
Shortly after the laying down of the hard tissues of the teeth, such as
enamel and dentin, the complex pattern of dental laminae begins to section or
disintegrate due to ectomesenchymal invasion and/or programmed cell death.
From the zone where the dental lamina joins with the oral epithelium,
disorganization or fragmentation of the From the zone where the dental lamina
joins with the oral epithelium, disorganization or fragmentation of the dental
lamina progresses towards the developing enamel organ. Some cells of the
laminae persist and tend to aggregate through proliferation into nests, known
traditionally as epithelial pearls (Serres pearls or glands of Serres). The
successional laminae (for formation of permanent teeth enamel organ) as well
as the accessional laminae (for formation of supernumerary teeth or salivary
gland) also disintegrate and give rise to epithelial cell remnants. Cells
deactivate epithelial markers (E-cadherin, cytokeratin), up-regulate Slug and
MMP2 (matrix metalloproteinase-2), and activate mesenchymal markers
(vimentin), while residual lamina cells are removed by apoptosis. 3 Sometimes
the dental lamina cells persist as rests (rests of Serre) which may later become
active to form odontogenic cysts and tumors.
The histological features of GOC strongly suggest an origin from the
remnants of dental lamina because of the below mentioned features.
A. Rests of dental lamina:
1. Because of its histological features comprising of:
a. Nonkeratinised epithelial lining

b. Mucus metaplasia of rest cells
c. Aggressive nature of the cyst may indicate that it arises from the dental
lamina rests.
2. High recurrence rate.

3. Cytokeratin (CK), 7,13,14,19 is positive on immunological testing and
negative for CK 8 and 18 indicating an origin from odontogenic epithelium,
rather than the salivary gland.
4. Wysocki et al. (1980) have pointed out that the characteristic glycogen-
rich clear cells so commonly seen in dental lamina- derived cysts and remnants
are never found in cysts derived from reduced enamel epithelium or rests of
Malassez. Similarly, the epithelial linings of radicular and dentigerous cysts
which are derived from the latter do not contain such clear cells.
B. Salivary gland origin:

It was thought by the earlier authors that GOC was derived from salivary
gland tissue because of the following factors.
a) Histological features similar to low grade central mucoepidermoid

carcinoma (LGMEC).
b) First named as sialo-odontogenic cyst.
c) Contains mucus cells.
d) Is aggressive in nature like a malignant neoplastic salivary gland
lesion.
e) The distinguishing feature in GOC is found to be the typical thin
epithelial lining without any solid epithelial proliferation as normally
seen in MEC.
f) Swirling spherical/epithelial plaque that is often seen in GOC is not
observed in MEC.
g) In cases where diagnosis of GOC or LGMEC cannot be made based
on the morphological features alone, especially in small incisional
biopsy samples, mammary serine protease inhibitor (maspin)
immunolocalization can be used to distinguish these two lesions. The
high levels of maspin in the epithelial-mucous cells (in both
cytoplasm and nuclei) in LGMEC may serve as a tool to differentiate
it from GOC. It has been suggested that many cases formerly
diagnosed as central MEC can be the examples of GOC, and also
some LGMECs would have originated from GOCs.
h) CK expression has been demonstrated in GOC and central MEC.
They found differences in CK18 and 19. CK18 is expressed by all
MECs (mucoepidermoid carcinoma), but it is only expressed by 30%
of the GOCs, whereas CK19 is expressed by all GOCs and only 50%
of the central MECs. They suggested that GOC and central MEC
are distinct entities that and expression of CKs 18 and 19 can be
useful adjunctive tools in differentiating these two lesions.
Immunohistochemical studies using cytokeratin 7, 13, 14, and 19 and
their positivity strongly support the odontogenic nature.
i) The detection of osteodentin and negative reaction for EMA
(epithelial membrane antigen) in the glandular structure show that
these features are not of glandular origin and support the concept of
odontogenic differentiation in GOC.
j) Platelet Derived Growth Factor (PDGF) signaling is a possible
mechanism involved in the interaction between epithelial and neural
crest-derived mesenchyme in development of salivary glands. These
results suggest that the FGF/FGFR, ShhPtc, and Eda/Edar signaling
cascades are critical for salivary gland organogenesis namely
the submandibular gland. Similarly multiple signaling molecules,
including BMPs, FGFs, Shh, and Wnt proteins, have been implicated
in tooth development.
Features distinguishing GOC from other odontogenic cysts:
a) The immunohistochemical expression of the apoptosis- inhibiting

protein bcl-2, the cell cycle-related antigen ki-67 and the P53 which is
involved both in cell cycle and apoptosis regulation was lower in
GOC as compared to dentigerous cyst. They suggested that the
biological behavior of GOCs may be associated with deregulation of
cell death in the lining epithelium, indicated by increased expression
of bcl2, while cell proliferation and P53 do not play a significant role.
b) The aggressive biologic behavior of the GOC and its propensity for
recurrence might be associated with, cell kinetics in the lining
epithelium, as has been demonstrated in Odontogenic Keratocyst. It
has been also demonstrated that the rate of recurrence increases with
the radiographic complexity of the cyst.
c) Botyroid odontogenic cysts, lateral periodontal cyst are slow growing
as compared to GOC though they show histological features similar to
the GOC.
Origin from epithelial rests of malassez (ERM):

The formation of the ERM occurs during the development of the root,
which begins before eruption. They break up to remain lodged in the
surrounding dental follicle or may disintegrate. These rests are called the rests
of Malassez. It was first identified by Serres as ‘restes de l’organe de l’email’
(Rests from the enamel organ). However, Malassez, in 1885, presented the
first description of the cells and their distribution. Proliferation of the ERM
has been implicated in developmental cyst formation, such as the gingival or
lateral periodontal cyst. Inflammatory cysts, such as the paradental and peri-
apical cysts, also arise commonly from the ERM (epithelial cell rests of
Malassez). A number of odontogenic tumors may also arise from the ERM.
Growth factors are important mediators of intercellular communication
between connective tissues and epithelium; several growth factors have
stimulatory effects on epithelial rests of Malassez, proliferation and
differentiation. The recently described keratinocyte growth factor (KGF)
appears to be of particular interest. It is possible that quiescence of the rests of
Malassez is normally associated with low local levels of KGF or related
growth factors in the PDL but that inflammation enhances the expression of
growth factors necessary for their activation. KGF production is markedly up-
regulated during epithelial wound healing.
Absence of inflammation and hence reduced expression of KGF indicates
that GOC does not arise from the rests of Malassez.
Outer Enamel Epithelium

Eriguchi (1959) has produced evidence for the existence of yet another
source of odontogenic epithelial remnants not previously recognized. In
embryos of 230-260 mm CRL (Crown of the foetus Rump length) the author
demonstrated thin epithelial strands of polyhedric cells radiating from the
outer enamel epithelium. The strands tend to proliferate and may reach 1.5-1.8
mm in length and thus, almost contacting the ridges of the overlying oral
epithelium. They are often accompanied by or intermingle with minute blood
vessels. The strands later show fragmentation with the formation of several
spherical epithelial pearls that will blend with remnants from the dental
laminae. The outer enamel epithelium-derived residues often show
keratinisation similar to that found in the dental lamina-induced micro-
keratocysts mentioned above. The residues are thought to act as source for the
development of odontogenic lesions later in life, similar to those originating
from dental lamina remnants. These findings have never been confirmed and
convincing evidence is thus lacking.
Radicular Cyst
Introduction
The radicular cyst or periapical cyst or apical periodontal cyst is among
the most common cystic lesions in the oral cavity. It is an odontogenic cyst of
inflammatory origin. Since the cyst is the sequelae of dental caries and the
periodontal infection, which are the most predominant diseases of the oral
cavity, radicular cysts are the commonest among all the cysts affecting the oral
cavity.
Pathogenesis
Pathogenesis of Radicular Cyst is considered in 3 Phases, which are as
follows
 Phase of Initiation,
 Phase of Cyst Formation,

 Phase of Cyst Enlargement
Phase of Initiation: The lining of the radicular cyst is said to arise from
the proliferation of the cell rests of Malassez, and on the other hand in some
cases, epithelial lining is also said to stem from:
a) Maxillary sinus wall lined respiratory epithelium, where the periapical

lesion is in connection with the sinus wall.
b) Oral epithelium from fistulous tract.
c) Oral epithelium that proliferates apically from the periodontal pocket.
The mechanism responsible for stimulation of epithelial cells is not clear.

It may be due to inflammation in periapical granuloma or some products of the
dead necrotic pulp that may initiate the process & at the same time evoke an
inflammatory reaction.
Local changes in the connective tissue may also activate these cells. The
cells of central portion of mass after proliferation of the epithelial cells become
distanced further & further from nutrition in comparison with basal layer due
to which they fail to obtain sufficient nutrition, they eventually degenerate,
become necrotic & liquefy. This creates an epithelium lined cavity filled with
fluid.
There is another theory which suggests that the cyst may form through
proliferation of epithelium which lines a pre-existing cavity formed through
focal necrosis & degeneration of connective tissue in periapical granuloma.
But such an area of necrosis near the epithelium or epithelial proliferation is
not common.
Epithelial Proliferation
The endotoxin from the necrotic tooth is the most important cause for the
epithelial cells to proliferate. This endotoxin has mitogenic effect on epithelial
cells. They were reported to stimulate keratinocyte proliferation directly, and
the infection is also said to release a large number of inflammatory mediators,
proinflammatory cytokines, and growth factors through innate and adaptive
immune responses. Inflammatory mediators and proinflammatory cytokines
produced by host cells that can be identified in radicular cysts include the
prostaglandins (PGs), interleukin-1 (IL-1), Il-3, IL-4, IL-6, interferon (IFN),
tumor necrosis factor-alpha (TNF-α), and transforming growth factor-alpha
(TGF-α). These mediators in turn stimulates the EGF(epidermal growth factor)
and causes it to act on the epithelial cell rests. Epithelial rests are also
stimulated by the action of the keratinocyte growth factor (KGF) in the stromal
fibroblasts. The chemokine and cytokines are found to be in much larger
proportion than that in the granuloma.
The epithelial cell rests of Malassez are quiescent or stable cells, which
are generally in standby in the G0 phase of the cell cycle. For the cells to
divide they need to pass through the G1, S and M phases. Proliferation
markers are found in large quantities in the cyst, like the PCNA and the Ki-67
indicating an increased mitotic activity.
Growth factors which are also found in large quantities in the cyst linings
induce the proliferation of the epithelial cells which were earlier resting and
quiescent cells.
Causes for Cyst Enlargement Include

1) Directly releasing of heparin into the luminal fluid,
2) Release of hydrolytic enzymes which could degrade capsular
extracellular matrix components, and hence facilitating their passage
into the fluid, and
3) The action of histamine on vascular permeability, thus leading to the
transudation of serum proteins.
Mechanism of bone resorption in radicular cyst may also result in cyst

expansion. The bone resorption is brought about by the osteoclasts whose
presence is indicated by the presence of the RANKL and the OPG proteins in
the radicular cyst wall.
The mucinous or viscid consistency of the cyst fluid is mainly due to the
mucous secretions from the goblet cells.
At the sites of inflammation in the wall of the cyst, there are repeated
small hemorrhages. Foamy macrophages play an important role here. They
engulf extravasated RBCs. The cholesterol esters from the cell membranes of
the RBC are engulfed by the macrophages. The acid lipase in the lysosomes
breaks down this cholesterol into the cholesterol and fatty acids. Off-loading
of cholesterol occurs when suitable acceptors are found in the external
environment.
 Toller showed that radicular cyst exhibited a 5-11g/100 ml (mean

7.1g/100 ml) of protein due to various inflammatory factors playing a
role.
Types of Radicular Cysts Based on Its Pathogenesis
Simon (1980) pointed out that there are two distinct types of radicular
cysts namely,
 Those containing cavities completely enclosed in epithelial lining, and

 Those containing epithelium-lined cavities that is open to the root
canals.
Simon (1980) designated the latter as ‘bay cysts.’

The presence of necrotic tissue in the cyst lumen attracts neutrophilic
granulocytes, which extravasate and transmigrate through the epithelial lining
into the cyst cavity where they perish. The lytic products of the dying cells in
the cyst-lumen release a greater number of molecules. As a result the osmotic
pressure of the cyst fluid rises to a level higher than that of the tissue fluid.
The latter diffuses into the cyst cavity so as to raise the intraluminal
hydrostatic pressure well above the capillary pressure. The increased
intracystic pressure may lead to bone resorption and expansion of the cyst.
However, the fact that an apical pocket cyst with lumen opening to the
necrotic root canal, that becomes larger, would eliminate osmotic pressure was
a factor that worked in favor of development of radicular cysts by the above
mechanism.
Periapical Pocket Cyst

The periapical pocket cyst is a radicular cyst containing an epithelium-
lined pathological cavity which is open to the root canal of the affected tooth
apex. As has been mentioned previously such lesions were originally
described as ‘bay cysts’ and has been recently investigated in detail and
renamed as the ‘periapical pocket cysts.’ It is postulated that a pocket cyst is
initiated by a small bubble-like extension of the infected root canal space into
the periapex. The microluminal space is enclosed in a stratified squamous
epithelium which grows and forms an epithelial collar around the root tip. The
epithelial collar forms an ‘epithelial attachment’ to the root surface so as to
seal off the infected root canal and the microcystic lumen from the periapical
setting. The presence of micro-organisms in the apical root canal attracts
neutrophilic granulocytes by chemotaxis into the microlumen. But, the pouch-
like lumen – biologically outside the body environment– acts as a ‘death trap’
and ‘garbage bag’ to the externalized and dying neutrophils. As the necrotic
tissue and microbial products accumulate, the sac-like lumen enlarges to
accommodate the debris to form a huge bag of the root canal space into the
periapical area. Thus these extensions of the root canal space of such lesions is
found to be similar to the marginal periodontal pockets and hence the name
‘periapical pocket cyst’ as against a pointless nomenclature of ‘bay cyst.’
Calcifying Odontogenic Cyst
Introduction
Calcifying cystic odontogenic tumour (CCOT) is a benign cystic
neoplasm of odontogenic origin, characterized by an ameloblastoma-like
epithelium with ghost cells that may calcify. COC is a controversial
odontogenic cyst/tumor. It is a developmental cyst said to arise from the
stratum intermedium part of the tooth germ. Due to the controversy regarding
its histology a new terminology was coined for it namely “Calcifying cystic
odontogenic tumor.” And another variant of the same was the COC or the
calcifying odontogenic cyst.
 Peripheral COC: in gingival tissues, ie: extra-osseous

 Central COC: within bone of jaws, ie: intra-osseous.
The following discussion pertains only to central COC
 a huge range of histopathologic patterns exists, ranging from a benign

lesion that is primarily cystic, a benign lesion with a solid pattern of
growth to a rare tumor with features of carcinoma.
 Simple cystic, non-proliferative: single-chambered cyst lined by
squamous or stellate reticulum–like cells with a varying degree of
palisading of the basal cells; ghost cells present, eosinophilic
dentinoid is mostly present and often juxtaepithelial in position, but
no other hard tissues seen
 Cystic, proliferative/ameloblastomatous: apart from simple cystic
features, there is proliferation of ameloblastoma-like cords, islands,
and sheets of epithelium with palisading of basal cell nuclei with
reverse polarization within the wall; odontogenic epithelial
proliferations that can superficially resemble ameloblastoma extend
into the lumen as well as the connective tissue wall of the lesion
 Odontoma-associated: Odontoma-like tissues are seen in the wall of

the lesion; when associated with an odontoma, patient’s age tends to
be younger, with mean age 17 years
 Solid lesions may be more aptly designated “Dentinogenic Ghost cell
tumors”
Dentinogenic Ghost Cell Tumor
 Also called epithelial odontogenic ghost cell tumor, odontogenic

ghost cell
 Similar components to COC, but without a cystic structure, and with a
neoplastic growth pattern.
 It is controversial whether this is a developmental cyst or a true
neoplasm
 In 1992, WHO classified this lesion as odontogenic tumor but
continued to use the term calcifying odontogenic cyst
 In 2005, WHO redesignated the lesion as calcifying cystic
odontogenic tumor
 Although the condition is often described as being cystic in majority
of cases the calcifying odontogenic cysts grow as more solid,
seemingly neoplastic proliferations, and the term dentinogenic ghost
cell tumor has been used to describe these lesions
 Even the cystic lesion has an apparent neoplastic potential but most of
them appear to be non-neoplastic
Pathogenesis
Controversy exists as to whether tumor arises from the wall of the cyst or
whether the cyst arose from the transformation of the solid tumor mass. The
cyst was said to arise from the reduced enamel epithelium.
Ghost Cells
The ghost cells were found in the thickened part of the lining epithelium.
The ghost cells represent abnormal keratinisation that undergoes calcification
in the future. The spinous cells in such situations may be widely separated by
intercellular edema and the epithelium around the ghost cells is often
convoluted.
Atubular dentinoid was found in relation to the ghost cells. Foreign body
giant cells were also found in relation to these ghost cells.
Ultrastructurally the keratin was absent in these cells.
There were a large number of theories regarding pathogenesis of the Ghost
cells:
1) The ghost cells were thought to be normal or abnormal keratinisation.

2) The ghost cells were thought to be a squamous metaplasia undergoing
calcification due to ischaemia. Praterois thought that the ghost cells
indicated different stages of normal and altered keratinisation and
were derived from metaplastic transformation of odontogenic
epithelium.
3) Ghost cells were considered by some authors to be abortive enamel
matrix in odontogenic epithelium.
4) Dentinoid was considered by Gorlin et al. as an inflammatory
response to ghost cells. Some authors stated that it was not dentinoid
but the osteoid which is laid down as a response of granulation tissue
to ghost cells.
5) Sauk et al. on the other hand stated that the osteiod and dentinoid
were seen in areas devoid of granulation tissue and that it was just an
inductive phenomenon.
6) Sam Pyo Hong, et al. stated that ghost cells were probably the result
of coagulative necrosis occurring at the same time when CCOT is
undergoing liquefaction necrosis. This was suggested because of their
negative reaction to cytokeratin antibody as opposed to the adjacent
odontogenic epithelium indicating an altered keratin antigen. CK19
was positive in CCOT lining and all odontogenic epithelium and
odontogenic tumors but ghost cells were negative for the CK19
staining and this proved the antigenic alterations.
CK13 immunoreactivity was weak in ghost cells as compared to its
positivity in CP and CCOT further indicating the degenerative nature
of the ghost cells. Moreover, ghost cells do not express reactivity for
cytokeratins[1,3,5,7] but express for AE1/AE3 and 34bE12. All these
reactivities indicate a coagulative necrosis pathogenecity in the
odontogenic epithelium of the CCOT.
7) Yamamoto et al. found high molecular weight keratins and lowered
involucrin staining as compared to the oral epithelium. Thus,
they deciphered that these cells go through an abnormal terminal
differentiation by making altered homogenous acellular materials and
ghost cells which may be formed into probably different subclasses of

keratins which has strong propensity to degenerate.
Till date the pathogenesis of ghost cells is not completely known.
Fissural or Non Odontogenic Cysts
Nasopalatine Duct Cyst
Introduction
These are the most common of the epithelial and non odontogenic cyst of
the maxilla. It has also been called as the incisive canal cyst.
Pathogenesis
The nasopalatine duct cyst is said to arise from the nasopalatine duct in
the incisive canal.
In the lower animals these glands of the nasopalatine duct played a role in
perception of smell. In man vestigial remnants of the cord, canal or even ducts
are found as epithelial islands that proliferate and undergo cystification
resulting in the formation of the nasopalatine duct cyst. The epithelial lining
was varied depending upon the site within the duct where the epithelial islands
were found either towards its oral end or towards its nasal end. If near the
nasal end the epithelial islands were ciliated columnar, if in the center the cells
were pseudostratified and if towards the oral end it was stratified squamous in
nature. Accordingly the epithelial lining of the cyst also varied.
The vomeronasal organ of Jacobsson, a vestigial olfactory organ in man,
placed just above the nasal end of the nasopalatine duct, was said to be another
source for the formation of the nasopalatine duct cyst. Trauma or infection of
these islands would cause the epithelial cells of this organ to proliferate and
then degenerate resulting in the formation of the cyst. In such a case there
must be the presence of inflammatory cells either in the stroma or the
epithelial lining of the cyst. But was no inflammatory infiltrate within the cyst
lining in any of the specimen. Hence this theory was disapproved.
Mucous gland cells make up the third theory in the formation of the
nasopalatine duct cyst. But the content of the cystic fluid was found to be more
transudate like than exudates and was found to contain no mucin. Hence this
cyst theory was also rejected.
The final mechanism that is responsible for playing a role in the

etiopathogenesis is thus still under speculation as none of the theories hold
credence.
Globulomaxillary Cyst
Introduction
Globulomaxillary cyst was named as such as it was considered as a non
odontogenic cyst thought to arise at the line of fusion between the globular
process and the maxillary process.
Pathogenesis
Fissural cysts were said to occur at the sites of fusion of the
developmental processes. In case of the globulomaxillary cyst, it was said to
originate at the junction of the fusion between the globular, medial nasal and
maxillary process. A slight variation was proposed in the above theory and it
was considered that these cysts formed at the junction of the premaxilla and
maxilla rather than the above mentioned sites, and that they should be called
premaxillary- maxillary cysts. Embryologists have disproved this theory and
stated that, in fact, at these junctions there is no actual ectodermal to
ectodermal contact but contact takes place between the mesoderms which are
covered over by the folded epithelium, and when fusion occurs there is a
mesoderm to mesoderm fusion and the ectoderm grows over the underlying
fused mesoderm.
The theory of there being no globulomaxillary cyst but that these are
actually just OKC or lateral periodontal cysts or radicular cysts present
adjacent to the teeth has found favor with the embryologists.
Nasolabial Cyst
Introduction
The nasolabial cyst occurs outside the bone in the nasolabial folds below
the alae nasi. It is traditionally regarded as a jaw cyst although strictly
speaking it should be classified as a soft tissue cyst.
Pathogenesis
This neoplasm is said to arise from the nasolacrimal duct which forms at
the line of fusion between the lateral nasal and the maxillary process,
ensconced in the nasolacrimal ridge extending between the inner canthus of
the eye, where its cranial end is situated and the lateral wall of the nose where
its caudal end is seen. The duct is lined by pseudostratified lining and the same
cells are found to line the nasolabial cyst.
The proliferation and the cystic degeneration of the epithelial islands is
said to be the reason for the formation of the cyst.
Cysts of the Salivary Gland
Mucous Retention Cyst and Ranulas
Introduction
A mucus cyst is a benign, common, mucus-containing cystic lesion of the
minor salivary glands in the oral cavity. Mucoceles in the floor of the mouth
are called as ranulas. They usually involve the major salivary glands. More
precisely the ranula begins in the body of the sublingual gland.
Pathogenesis
Mucus retention cysts results from the obstruction of salivary flow within
a salivary gland duct, because of a sialolith, periductal scar, or impinging
tumor. The retained mucin is surrounded by ductal epithelium, giving the
lesion a cyst-like appearance microscopically. A sialolith represents the
precipitation of calcium salts (predominantly calcium carbonate and calcium
phosphate) around a central nidus of cellular debris or scattered mucin.
The trauma causes destruction of large amount of the glandular acini and
continuous secretion of mucin from the remainder of the acini. The above
factors cause pooling of saliva distal to the obstruction resulting in a swelling,
which histologically has an epithelium lined cavity filled with mucin, because
the majority of salivary glands affected by the mucoceles or the salivary duct
cyst are the minor mucous salivary glands.
Ranula is said to have a similar pathogenesis as that of a mucus retention
cyst but in this case the obstruction is in the duct (ducts of Rivinus) of the
small major salivary gland namely the sublingual gland.
Mucous Extravasation Cyst
Introduction
Another cyst of the salivary gland is the mucous extravasation cyst and
this is not a true cyst in the true sense; i.e., it is not lined by an epithelium.
Pathogenesis
The mucus from the disintegrated cells, following trauma to the salivary
gland, pools up and is then surrounded by the surrounding connective tissue
that undergoes walling off to protect the spillage of the mucin to the
neighboring areas. The epithelial structure, whether they are the duct or the
acini, may persist after trauma, finally distintegrates resulting in the mucus
extravasation cyst. Mucous extravasation type of cyst is basically a false cyst.
It occurs due to extravasation of mucus from a severed duct into the
surrounding connective tissue. The severance of the duct mostly follows a
crush type injury. This type of cyst is not normally lined by an epithelium.
The spreading of the mucus in the connective tissue stroma may be due to
the assistance obtained by the additional invasive proteins namely the MMPs,
TNF-α and the plasminogen activators.
False Cysts or Pseudocysts
Aneurysmal Bone Cyst
Introduction
Aneurysmal bone cyst (ABC) is a solitary, expansile and erosive lesion of
bone. The cause of this non-neoplastic lesion is unknown.
Pathogenesis
Aneurysmal bone cyst is said to be located commonly at two predominant
sites in the body as stated by Jaffe.
 The juxtacortical and

 subperiosteal.
 And the etiology for the former was considered as trauma and for the
latter as occurring secondarily within a primary lesion. Another theory
for its occurrence may be due to a sudden vascular disturbance or

following the development of an arteriovenous shunt.
The theory about the cyst arising in a primary lesion has received support.
The primary lesion in question is said to be a benign giant cell tumor that has
regained communication, during its course of formation, with a large blood
vessel which has been damaged by the tumor. Fibrous dysplasia was another
lesion in which the ABC was found to arise. Chondromyxoid fibroma may
show aneurysmal cystic changes.
Non-ossifying fibroma, chondroblastoma, giant cell tumor of bone,
osteoblastoma, giant cell granuloma, fibrous dysplasia, myxofibroma and
solitary bone cyst was also seen to undergo cystic changes. One case of
Paget’s disease of bone showed the presence of large blood-filled spaces, as
did several of the malignant lesions. These ABC occurs following the fusion
of a large number of microcysts within the primary lesion. In the case of the
giant cell lesions, the multinucleate giant cells may form a part of their
margins.
The central giant cell granuloma has a propensity to form microcysts
because of its loose, oedematous, fibrillar connective tissue stroma in which
lie many thin-walled blood vessels and extravasated erythrocytes. Microcyst
formation is facilitated by localised areas of necrosis in the stroma brought
about by stagnation and ischemia. The resulting microcysts are lined by
stromal connective tissue. They enlarge by further stromal breakdown and
coalesce with each other. Loss of stromal support leads to dilatation and
rupture of the thin-walled vessels resulting in the haemorrhage into the stroma
and the further formation of the microcysts. An association between the dilated
blood vessels and microcysts has frequently been observed. Once a vascular
connection is established between a larger vessel and a microcyst,
haemodynamic pressure participates in its enlargement and little supportive
resistance is offered if the surrounding stroma is loose and edematous. The
spaces now assumes the dimensions of macrocysts which are surrounded by a
layer of compressed stroma and these multiple expanding blood-filled cysts
produce the pressure resorption of bone. Endosteal resorption of the cortical
plates occurs ultimately and once these are breached, a ‘blow out’ of the lesion
covered with periosteum, is seen. A layer of periosteal new bone may be
deposited to form a thin shell covering the aneurysmal bone cyst.
The rare development of aneurysmal bone cyst that occurs in malignant
lesions probably explains the so-called malignant form of the cyst,
occasionally reported in the literature. Some authors believe that the latter
represented the telangiectatic form of osteosarcoma which several authors

have described, as resembling the aneurysmal bone cyst.
To conclude no concrete evidence exists till date to explain the validity of
the above claims.
Solitary Bone Cyst
Introduction
A solitary bone cyst of the mandible or the traumatic bone cyst of jaw,
(extravasation cyst, haemorrhagic cyst of the mandible, unicameral bone cyst,
extravasation cyst and progressive bone cavity) is said to be an uncommon
nonepithelial lined, radiolucent, mandibular lesion. The main etiological factor
for the same, is said to be trauma together with other theories described later.
Pathogenesis
The pathogenesis is based upon a traumatic etiology.
Olech et al. introduced their hypothesis which stated that following the
trauma to the bone there may be an intramedullary haemarrohage. There is a
failure in the organization of the clot and its subsequent liquefaction. This is
similar mechanism as seen in case of the “dry socket” following extraction of
teeth. That bone in which the spongy bone is enclosed within the compact
cortical bone has more propensities for undergoing the cystic changes. This
would explain the most frequent sites of occurrence of this cyst, such as in the
mandible and the metaphysis of long bones. It would also explain the fact that
most solitary bone cysts develop in young individuals. The failure in the
organization of the clot is especially seen in cases where the bone together
with the endosteum has undergone necrosis, following trauma. The trabaculae
of the bone is removed by osteoclastic activity, till viable connective tissue
gains contact with the hematoma, but since the wound is large, the time taken
for this action would be too long and subsequently, by that time, the clot
liquefies.
On surgically venturing into the cystic lesion it was either found to be
empty or containing air, or containing blood and serosanguinous fluid. The
latter two discoveries support the theory of the breakdown of the hematoma.
This breakdown causes a rise in the osmotic pressure which results in further
pressure resorption of the bone, or sometimes the occurrence of a swelling due
to constructive periosteal deposition. Fluid gets diluted as the process repeats
and finally the osmotic pressure drops. As transudartion into the cyst occurs,
the fluid is diluted so that intracystic pressure drops, but further bleeds may be
responsible for progression of the lesion. After the bleeding stops there will
the absorption of this fluid and the cyst becomes empty. Hence this explains
the various types of cystic fluids encountered by the surgeons.
Surgical intervention results in fresh bleeding but since the pathological
area is now in contact with a healthy flap, the cyst finally heals though the
mechanism responsible for the initiation of the cyst and the treatment
mentioned above appears to be the same. This theory though it has many flaws
is now considered as the pathogenesis of the solitary bone cyst.
No other theories regarding the pathogenesis of the solitary bone cyst
other than the one described above has been proposed till date.
Chapter 9
Odontogenic Tumors
Ameloblastoma
Introduction
Ameloblastomas are benign and locally aggressive tumors affecting

predominantly the posterior aspect of the jaws especially the molar ramus area
of the mandible and sometimes the maxilla.
Pathogenesis
The enamel organ plays a role in the formation of the only ectodermal
structure of the tooth called as the ‘enamel.’ The neural crest derived dental
papilla and the dental sac play a role in the formation of the other remaining
structures of the teeth. The enamel organ is made up of four layers namely the
outer enamel epithelium, the stellate reticulum, the stratum intermedium and
the inner enamel epithelium. The absence of the stratum intermedium in the
tumor indicates that probably the absence of this structure may be the reason
for the lack of formation of the enamel and hence resulting in an
ameloblastoma.
Parathyroid hormone-related proteins, the fibroblast growth factor, and the
matrix metalloproteinases (MMP-2, TIMP-2, and MMP- 14.) have been found
in many tumors including the ameloblastoma, and they have been linked, to
the bone or tissue destruction and tumor growth. These proteins probably play
a role in the aggressiveness of the ameloblastoma. These patients are also

found to have hypercalcemia which is found to revert back to normal after the
removal of the tumor.
The tumor is thought to originate from sources that include residual
epithelium of the tooth germ; and the cell rests of the enamel organ (cell rests
of Malassez and cell rests of Serre), epithelial odontogenic cysts namely the
dentigerous cysts), basal cells of the surface epithelium of the jaws and
heterotrophic epithelium in other parts of the body. The peripheral ameloblast
like cells are found to be rich in the Ki-67 in both the plexiform and follicular
ameloblastomas. In the case of the unicystic ameloblastoma Ki-67 was found
predominantly in the basal cells. The stellate reticulum cells are found to be
negative for the Ki-67. In case of the desmoplastic ameloblastoma, though it is
said to be an aggressive tumor there was a lowered proliferation of the cells
than the peripheral ameloblastoma. Ki-67 is said to be a marker for increased
cell proliferation.
Caspase3, an indicator for apoptosis was positive in the central stellate
reticulum cells. Bcl-2 an antiapoptotic protein was found positive in the
peripheral ameloblast like cells of the ameloblastomas and negative in the
stellate reticulum like central cells. But there was no difference in values of
mediators like cytochrome oxidase c, AFAP-1, caspase 9 and AIF between
normal enamel organ and ameloblastoma and between the primary and
secondary ameloblastomas; hence they could not be used as markers for the
identification of these tumors.
Genes such as ameloblastin were found absent in ameloblastoma: amelin,
tuftelin and enamelin were found positive. Hence it is said that the
ameloblastin gene may be playing a role in the protection against the
development of the ameloblastoma. The development of ameloblastoma is also
dependent on the heparin binding domain deficient ameloblastin, p27 and the
p21. Mutations of the ameloblastin gene is also said to play a role in the
formation of other odontogenic tumors hence cannot be used as a tumor
marker for ameloblastoma.
The epithelial lining of cysts, especially dentigerous cysts, is another
source for the formation of the ameloblastoma.
Ameloblastoma may also undergo malignant change. But the cause or
stimulus for the malignant change of these remnants is unknown.
P53, ‘the gate keeper genes’ is found to play no role in the formation or
the enlargement of the ameloblastoma.
Osteoclastogenesis is said to be caused by genes such as RANKL and
MMP-9. They cause a rapid destruction of the bone and bone marrow and
Odontogenic Tumors 97
hence when present in tumors they help in its enlargement. Ameloblastoma is

positive for these markers. IL-1α and IL-6 plays a role in the tumor size of the
ameloblastoma and they may also play a role in bone resorption and causing
the expansion of the ameloblastoma.
A growth factor seen commonly in human malignancies is positive in both
ameloblastoma and ameloblastic carcinoma. The protein involved is the
Midkine growth factor which is a heparin-binding growth factor. The midkine
is said to play a role in the tumor development and its progression.
The Transforming growth factor protein β/SMAD, a transcription factor,
is found to be reduced in ameloblastomas indicating a more aggressive
behavior of this tumor. This protein plays a role in cell proliferation,
differentiation and reduced apoptosis.
WNT proteins, a set of signaling proteins, excepting the WNT-10 b are
found present in ameloblastomas and are found heterogeneously expressed in
different types of ameloblastomas, thus indicating a role in the invasion and
differentiation of the tumor cells. The level of the E-cadherin or β-catenin
remains the same in case of the normal tooth germ and the unicystic
ameloblastomas. They play a role in cell differentiation.
Rho GTPases are said to play a role in the phenotypic expression of the
ameloblastoma that is solid or cystic, peripheral or central. And these Rho
GTPases play a role in the cell cycle regulation, its polarization, invasion etc.
The presence of the apoptosis inducing ligand (TRAIL) and its receptor
and FAS (CD95), FAS ligand are all responsible for the slow growth and the
failure of the tumor to metastasize in case of the ameloblastoma.
Peripheral ameloblastomas, not overlying bone are said to arise from the
pluripotent basal layer cells of the surface epithelium. Some authors suggest
that such tumors may be representing just a variant of the salivary gland tumor
or the adamantoid pattern of the squamous cell carcinoma.
AOT
Introduction
This tumor is aggressive since it has a short life span i.e., seen in the 2nd
and 3rd decades of life and quite localized in its appearance in the canine
premolar area.
Pathogenesis
Though there is a controversy to the exact cell playing a role in AOT, the
stratum intermedium, the reduced enamel epithelium, dental lamina and its
remnants have been said to play a role. Hemidesmosomes have been identified
by electron microscope in the luminal membrane of the duct-like and the
adenomatoid structures that is connected to the basal lamina like structures on
the surface. Enamelysin, amelogenin, sheathilin were observed in the luminal
surface of the columnar cells. Thus all features point to a histogenesis from the
reduced enamel epithelium because of the similarity of this basal lamina like
structure which is found adjacent to the reduced enamel epithelium in normal
enamel development of the human tooth.
There was variable positivity in the epithelial cells of the AOT. Laminin
was positive in luminal surface of AOT indicating its origin from the reduced
enamel epithelium, seen during the protective stage of reduced enamel
epithelium. Type IV collagen was seen at the interface between tumor
epithelium and the stroma. Some epithelial cells resemble the dental lamina
while others were found to be mature odontogenic cells due to α4 (IV) chain
expression that had occurred on the cribriform areas and hyaline materials.
The cells in the spindled areas showed high PCNA content indicating the sites
for tumoral growth.
Other authors suggest a pathogenesis arising from the gubernacular dentis.
The gubernacular cord running along the gubercular canal is the gubernacular
dentis. This gubernacular cord was also found to contain the dental lamina
which played a significant role in the formation of the ameloblastoma and the
OKC. The cord was found to be directly connected with the dental follicle.
Hence the occurrence of AOT was seen more in the permanent dentition than
the deciduous dentition. But the existence in the permanent molar could not be
explained by this hypothesis since it has no deciduous predecessor. It was later
found that permanent molar also has the gubernacular cord that has been found
in teeth which have no predecessors.
The AOT is said to arise from the enamel organ, dental lamina, cell rests
of dental lamina and Hertwig’s epithelial root sheath but none of the factors
have found favors with the various authors. Earlier theory stated the origin of
the tumor from both the epithelial and salivary gland tissue. The duct like
structures showed presence of amelogenin and the non ductal structures
showed absence of this protein. The spindle shaped cells between the epithelial
islands resembled the stellate reticulum and the area adjacent to the islands
resembled the stratum intermedium. The eosinophillic, luminar material

resembled basement membrane material, laminin.
Though the AOT is found in relation to an impacted tooth it does not
envelope the crown like in case of a dentigerous cyst. It has a fibrous tissue
separating the crown and the tumor, which may be a fibrous capsule of the
tumor too. Since the tumor forms at 6 months of age it probably shows the
presence of a tooth erupting through a lesion. It is normally found attached to
the tooth at different levels that is the neck, the root and finally may enclose
the entire crown.
Calcifying Epithelial Odontogenic Tumor
Introduction
Calcifying epithelial odontogenic tumor is a rare tumor first described by

Pindborg in 1955. It comprises less than 1% of all odontogenic neoplasms.
The tumor is histologically made of polygonal epithelial cells, eosinophilic
deposits resembling amyloid and calcifications.
Pathogenesis
This tumor is said to arise from the dental lamina residue. Another theory
states its origin from the stratum intermedium cells of the enamel organ. The
polyhedral cells of the CEOT express laminins 1 and 5, fibronectin, vimentin
and are negative for amyloid. Tumor epithelium is slightly positive for
vimentin but negative for desmin. The epithelial cells are also strongly positive
for alkaline phosphatase and shows ATPase localization in their cell
membranes. The amyloid like material is found to arise from the lamina densa
material degradation.
A large number of dendritic cells may also be seen between epithelial cells
and they are found to be similar to the Langerhans cells. Ameloblastin gene is
found in the CEOT and also shows Amelogenesis Imperfecta like features.
The epithelial cells slowly transforms from an odontogenic to squamous
epithelium in the case of this tumor. Thus it is positive for keratin -14, keratin
10/13. The proteins that affect the progression and invasion of the tumor
include the NF-KB, Ki-67 and MMP-9. The marker for the lymphatic
endothelial cells is seen in both the CCOT basal and the polyhedral cells and
these cells are said to be associated with the extracellular matrix signaling and
the cell proliferation in the CCOT.
Squamous Odontogenic Tumor
Introduction
Squamous odontogenic tumor is a rare benign odontogenic tumor.
Pathogenesis
The histogenesis is said to be from the epithelial rests of Malassez but

there is no substantiating evidence available, to support this theory. Another
source of origin of this tumor has been identified and that is from the basal
layer of the oral mucosa. Some other authors state that the origin of the tumor
may be from more than one source i.e., surface epithelium, Malassez rests, and
dental lamina rests. Hence the variation in the behavior of the tumor is seen
when it arises at different locations.
Clear Cell Odontogenic Carcinoma
Introduction
The clear cell odontogenic tumor is a benign but locally invasive

odontogenic tumor and it has been included in the revised World Health
Organization classification for odontogenic tumors. Clear cell odontogenic
tumour (CCOT) was classified as a benign tumor in the earlier classification,
but has been found to be a more menacing lesion and currently it has been
designated as a carcinoma. These tumors show an aggressive growth,
recurrences, and metastasize to distant sites.
Pathogenesis
Although the origin is unknown, the tumor cells has been found to
resemble clear cell rests of primitive dental lamina that are frequently
observed in the same locations.
The clear cells stain positively with PAS stain and undergo diastase
digestion. The positivity is due to reduced number of organelles rather than
due to the presence of glycogen granules. These granules are also
mucicaramine negative. They show positivity to cytokeratins and EMA. The
tumor cells may rarely act positive to antibodies against vimentin, S100 and
actin.
Primary Intraosseous Carcinoma
Introduction
Type 1 PIOC ex odontogenic cyst

1. Malignancies in ameloblastoma
Type II 1. Malignant ameloblastoma
2. Ameloblastic carcinoma
Type III Clear cell odontogenic carcinoma
Type IV Primary de novo Intraosseous squamous cell carcinoma
Type V Intraosseous Mucoepidermoid Carcinoma
Pathogenesis
The PIOC is said to arise from within the jaws and found to have no
connection with the surface epithelium. It is said to form from the entrapped
odontogenic epithelium which may be the rests of the dental lamina, or from
the linings of odontogenic cysts or previously present odontogenic tumor. The
squamous cells of the tumor may also arise from other sources and to diagnose
it as the PIOC, the exact source of origin of the tumor has to be identified.
Ameloblastic Fibroma/Fibrosarcoma
Introduction
Ameloblastic fibroma (AF) was first described by Krause in 1891. It is an
extremely rare, mixed benign tumor that may occur predominantly in the
posterior region of either the mandible or maxilla and often associated with an
unerupted tooth. It has a slight female predilection and is commonly seen in
the first two decades of life, altering the tooth eruption sequence and causing a
delay in tooth eruption pattern.
Pathogenesis
Immunomarkers for dental lamina namely the CK 7, 13, 14 were found
positive in case of the ameloblastic fibroma. The connective tissue determines
the etiology for the ameloblastic fibroma. The proportion of the proliferation
of the epithelium and connective tissue was under question. It has been found
that the Ki-67 was found in higher proportion in the epithelial tissue part of the
tumor as compared to the mesenchmal tissue part, indicating a higher
proliferative index. This Ki-67 may also be used as a marker for indication of
transformation of the ameloblastic fibroma to the ameloblastic fibrosarcoma.
The apoptotic activity is also said to be an important factor in regulation
of the tumor growth. An inhibitor of apoptosis calrectin was not
immunodetected in AF. This calrectin was also negative in the mesenchymal
portion of the normal tooth germs. Bcl-2 was found negative in the
mesenchymal portion of the AF while it was positive in the epithelial portion.
The latter marker was positive in the sarcomatous portion of the Ameloblastic
fibrosarcoma and epithelial strands were negative for the Bcl-2. Thus these
markers could be used to distinguish the benign tumor from its malignant
counterpart.
Vimentin was positive in the immature dental papilla cells and also in case
of the AF. Nestin is another marker found in both the developing mesenchyme
and the mesenchyme of the AF. The role of this protein is found to be unclear.
Among the ameloblastic proteins only amelogenin was found positive in
the AF. All the other proteins like amelotin, ameloblastin and enamelin were
negative. This positivity shows that the tumor arises from the dental lamina
cells.
Odontoma
Introduction
Odontoma is a developmental anomaly of odontogenic origin, resembling
a hard tumor and composed of enamel, dentin, cementum, and pulp tissue.
Pathogenesis
Trauma during the deciduous tooth formation and the inflammatory and
infectious process, heredity, odontoblastic hyperactivity are said to be the
etiologic factors for odontomas. A mutant gene which causes the odontogenic
cells to intermix, would result in the formation of the odontome. There may
also be a defect in the morphodifferentiation or histodifferentiation stages of
tooth development resulting in the formation of this hamartoma. Hard keratin
is present in the ghost cells of the odontoma and the CCOT and the Wnt
signaling pathway plays a role in the pathogenesis of the ghost cells during
metaplasia.
Cementoma
Introduction
Cementomas have been classified by the WHO in 1971 into 4 groups:
1) Cementifying fibroma.
2) Benign cementoblastoma (true cementoma).
3) Periapical cemental dysplasia.
4) Gigantiform cementoma.
Pathogenesis
No available material is available with regard to the pathogenesis of this
tumor. The tumor was thought to arise from cells of Malassez that has
transformed into the cementoblasts which later form the cementoma.
Dentinoma
Introduction
Dentinoma is a rare tumor of odontogenic origin, comprising of immature
connective tissue, odontogenic epithelium and dentin which is dysplastic.
Pathogenesis
Not much data is available regarding the pathogenesis of the dentinoma.
The origin of such a growth is discussed, and the possibility of its development
as a result of proliferation of connective tissue and of cells of Hertwig's
epithelial root sheath is taken into consideration. The epithelial remnants
induce the undifferentiated cells of the connective tissue to transform into
odontoblasts to produce dentine.
Chapter 10
Potentially Malignant Disorders
Leucoplakia
Introduction
Leukoplakia is a clinical term used to describe a white patch on the oral

mucosa which cannot be given another diagnostic name, i.e., it is a diagnosis
of exclusion. Leukoplakia, is a clinical diagnosis which has the unusual feature
of being reliant not so much on definable appearances as on the exclusion of
other lesions which present as oral white plaques such as lichen planus,
chronic cheek bite, frictional keratosis, tobacco pouch keratosis, nicotine
palatinus, leukoedema, white sponge nevus, etc. These lesions must be ruled
out before a diagnosis of leukoplakia can be made.
Pathogenesis
Smoking and Leucoplakia

The white patch mistaken as leucoplakia may more likely be a reactive
lesion to local tissue irritation rather than a lesion induced by carcinogens in
cigarette smoke, and hence smoker’s keratosis could be a better term than
leucoplakia. The mechanism of the white appearance in actual leucoplakia is
said to be due to the thickening of the keratin layer, called hyperkeratosis. This
atypical keratin appears white when it becomes hydrated by saliva, and it
reflects light off the surface evenly. Therefore it hides the normal pink-red
color of mucosae (the result of underlying vasculature showing through the

epithelium).A similar state is seen on areas of thick skin such as the soles of
the feet or the fingers after extended dipping in water. Another possible
mechanism is increased thickening of the stratum spinosum, called acanthosis.
The proliferative activity of the oral mucosa by the tobacco smoke, causes
a tendency in the leucoplakia to undergo malignant transformation, and this it
does through the stimulation of epidermal growth factor receptor (EGFR) that
later activates the cyclin D1. But apart from the above pathogenesis the
prolonged exposure to the tobacco smoke may also cause localized genomic
instability and lack of resolution of the lesion even after the etiology has been
withdrawn.
HPV 16 infection that causes leucoplakia has a high propensity of
converting to malignancy and this occurs even in the case of non smokers and
non alcoholics.
Other studies state that the HPV infected patients have the HPV infection
as a ‘second hit’ and the ‘first hit’ being the genetic probability of malignancy
in such patients. The E6 and E7 proteins of low-risk HPV types established in
oral leukoplakia may kindle the suprabasal post mitotic infected basal cells to
reenter the S-phase of the cell cycle, further resulting in epithelial proliferation
and altered maturation, without causing a genomic instability associated with
consequent cell transformation. This mechanism may be a co-factor for the
development of the leukoplakia, but there is no tangible evidence to support
this.
p53 plays a major role in DNA repair and cell-cycle regulation after
carcinogen-induced damage (tobacco, alcohol, etc) to the DNA of the oral
epithelium. The carcinogen induces a stress which results in the protein
production by activation of the phosphorylation of its serine residues of the
p53 such that the level of the active p53 protein is determined based on this
carcinogen induced damage. If the damage is negligent the cell cycle progress,
would be detained to allow DNA repair. If on the other hand the level of p53 is
high the cells enter apoptosis. So when there is a mutation of the p53 protein
this protective pathway is lost and the epithelium undergoes malignant
transformation. The p53 mutation is also found to occur in case of the UV-B
irradiation. But if the p53 has already undergone 2-3 mutations there is a direct
transformation to malignancy. Only the mutant p53 can be detected
immunohistochemically not the normal p53.
The overexpression of the telomerase in leucoplakic patients is an
indication for a malignancy.
Potentially Malignant Disorders 107
Oral Submucous Fibrosis
Introduction
Oral submucous fibrosis (OSF) was first described in the early 1950s, as a
potentially malignant disease largely seen in people of Asian descent. It is a
slow chronic progressive disorder and its clinical manifestation depends on the
stage of the disease at the time of detection. The majority of patients will have
intolerance to spicy food, stiffness of lip, tongue and palate leading to
limitation of mouth opening and tongue movement.
Pathogenesis
The possible etiological factors to date are capsaicin in chilies, areca nut,
micronutrient deficiencies of zinc, iron, and essential vitamins. Apart from
these factors there is a possible demonstration of various auto-antibodies and
an association with specific HLA antigens has been suggested. It is
hypothesized that there is either an increased collagen synthesis or reduced
collagen degradation following areca nut usage.
There is a high content of copper in the areca nut and the probable role of
copper as an arbitrator of fibrosis is supported by the demonstration of the up
regulation of lysyl oxidase in OSMF biopsies. Lysyl oxidase is required for
stabilizing the collagen fibres.
Due to the effect of the slaked lime (Ca (OH) 2); the arecoline gets
hydrolyzed to arecadine, which has an immense effect on fibroblasts. As per
the study by Harvey et al., exposures to 0.1-10 μg/ml arecoline will stimulate
fibroblasts and concentrations greater than 25 μg/ml, slows the fibroblast
growth and collagen synthesis. According to Jeng et al. the depletion of
cellular glutathione (GTH) levels by arecoline, predisposes the fibroblasts of
the oral mucosa to various genotoxic and cytotoxic stimulation.
Stablization of Collagen Structure by Tanins and Catechins

Flavonoids in areca like the tannins and catechins, causes an increased
fibrosis by forming a more stable and non soluble collagen structure by
inhibiting the collagenase enzyme activity. As the disease progresses the type
III collagen is completely replaced by type 1 collagen which is more likely to
resist degradation. There is also an excess of alpha 1 (1) chains as compared to
alpha 2(1) chains, that suggests an alteration of collagen molecule during the
disease progression.
Inhibition of Collagen Phagocytosis

In fibrotic connective tissue lesion such as OSMF, that do not exhibit
gross inflammation, the main route of collagen removal is by phagocytosis and
not by the process of extracellular digestion and the phagocytic activity in
OSMF is inversely dose dependent to levels of arecoline, nicotine and safrole
in saliva.
Copper and OSMF

Copper is a component of the enzyme lysyl oxidase which, as mentioned
earlier, plays a major role in cross linking of collagen and elastin molecules.
Copper also affects specific growth and development of fibroblasts. The cell
doubling time of OSMF fibroblast was increased to 3.2 days as compared to
3.6 days in case of the normal fibroblasts.
Lack of iron is said to cause improper vascular channel formation and
associated decrease in vascularity. This makes diffusion of esters of arecoline
easier. Also the iron also plays a role in normal epithelium maturation as it is a
component of the enzyme cytochrome oxidase. In iron deficiency, there is a
lowered level of this enzyme and subsequent atrophy of epithelium results,
which may lead to the burning sensation and ulcerations of oral cavity in the
areca chewers. This causes a decreased appetite in these patients leading to
further anemia and results in a never ending vicious cycle.
Lichen Planus
Discussed in Chapter 15 -Skin disorders.
Section 3: Systemic Disorders
Chapter 11
Bone Disorders
Osteogenesis Imperfecta
Introduction
Osteogenesis imperfecta (OI) exhibits varied clinical features ranging

from the bone problems, blue sclerae, short stature, hearing loss, respiratory
problems, and a disorder of tooth development called dentinogenesis
imperfecta. OI Type1 is characterized clinically by increased bone fragility
often leading to fractures, ranging from few to 100, without secondary
deformities; in combination with blue sclera, conductive or mixed hearing loss
in late adolescence, short or sometimes normal height, and dentinogenesis
imperfecta. Radio logically, in OI type I, bone fragility in combination with
generalized demineralization, slender shafts of tubular bones with thin cortex
and poorly trabeculated spongiosa are evident. Also the ossification of the
cranial vault is often retarded, leading to a mosaic pattern of wormian bones.
Several kinds of mutations in the COL1A1 gene cause the more severe forms
of osteogenesis imperfecta, including types II, III, and IV.
Pathogenesis
Collagen is a protein that strengthens and supports many tissues in the

body, including cartilage, bone, tendon, skin and the sclera.
Role of Type I Collagen in Osteogenesis
Type I collagen creates layers of fibrils in the extracellular matrix of bone,

giving bone it’s tensile strength and forming a template for the deposition of
inorganic minerals. Type I collagen owes its ability to form fibrils to its very
specific amino acid sequence. Collagen begins as procollagen molecules,
which must be processed by enzymes outside the cell, to remove extra protein
segments from their ends. Each rope-like procollagen molecule is made up of
three chains: two pro-α1 (I) chains, which are produced from the COL1A1
gene, and one pro-α2 (I) chain, which is produced from the COL1A2 gene.
Both are built from 338 uninterrupted repeats of the amino acid sequence.
Glycine-X-Y, where X is often proline and Y is often hydroxyproline. Due to
the regular pattern of prolines and hydroxyprolines, the alpha chains assume a
left-handed helical conformation. Two alpha1 helices and one alpha2 helix
then wind around each other to form a right-handed triple helix. Presence of a
glycine in every third position is critical for triple helix formation, since only
glycine, the smallest of all amino acids, fits into the confined space in the
center of the triple helix. Triple helix formation starts at the C-termini of the
alpha chains and proceeds toward the N-termini in a zipper-like fashion. Prior
to and simultaneously with triple helix formation, prolines and lysines in the
alpha chains are chemically modified by addition of hydroxyl or sugar groups.
These modifications are believed to play a role in triple helix stabilization.
Completed triple helices are secreted from the cells and spontaneously
assemble into collagen fibrils. Fibril-forming collagens such as type I collagen
are synthesized into larger precursors, known as procollagens, which contain
globular N-terminal and C-terminal propeptides. After procollagens are
processed, the resulting mature collagen molecules arrange themselves into
long, thin fibrils. Individual collagen molecules are cross-linked to one another
within these fibrils. The formation of cross-links results in very strong type I
collagen fibrils, which are found in the spaces around cells.
The association is then stabilized by the formation of interchain disulphide
bonds. From the carboxyl end, helix formation proceeds towards the amino
terminal end in a zipper-like fashion. Simultaneously, proline and lysine
residues are hydroxylated by specific hydroxylases and hydroxylysine residues
are glycosylated by sugar transferases. These modifications occur only in
chains that are in nonhelical configuration and cease as soon as the protein
folds into a triple helix. In the extracellular space, specific N- and C-peptidases
cleave the terminal extensions. The mature helical molecules self-aggregate
into highly ordered fibrils stabilized by intermolecular cross-links formed by
Bone Disorders 113
oxidative deamination of lysine and hydroxylysine residues. Mechanical

strength of connective tissue is due mainly to fibrils which form a template for
matrix deposition. In bone, the fibrils are the template for mineralization, i.e.,
in this case, for incorporation of hydroxyapatite crystals. The mechanical
properties of bone are dependent on an intimate association between the
collagen fibrils and crystals of hydroxyapatite.
Most cases of osteogenesis imperfecta have an autosomal dominant
pattern of inheritance, which means one copy of the altered gene in each cell is
sufficient to cause the condition. Many people with type I or type IV
osteogenesis imperfecta inherit a mutation from a parent who has the disorder.
Most infants with more severe forms of osteogenesis imperfecta (such as type
II and type III) have no history of the condition in their family. In these
infants, the condition is caused by new (sporadic) mutations in the COL1A1 or
COL1A2 gene.
Osteogenesis imperfecta is the most common disorder caused by
mutations in the COL1A1 gene. More than 400 COL1A1 gene mutations that
cause osteogenesis imperfecta have been identified. Most of the mutations that
are responsible for osteogenesis imperfecta type I, the mildest form of this
disorder, reduce the production of pro-α1 (I) chains. With fewer pro-α1 (I)
chains available, cells can make only half the normal amount of type I
collagen. A shortage of this critical protein underlies the bone fragility and
other characteristic features of osteogenesis imperfecta type I.
Some of the mutations that cause severe forms of osteogenesis imperfecta
delete segments of DNA from the COL1A1 gene, resulting in an abnormally
shortened, often nonfunctional pro-α1 (I) chain. Other genetic changes alter
the sequence of amino acids in the pro-α1 (I) chain, usually replacing the
amino acid glycine with a different amino acid. In some cases, amino acid
substitutions alter one end of the protein chain (called the C-terminus), which
interferes with the assembly of collagen molecules. These COL1A1gene
mutations lead to the production of abnormal versions of type I collagen.
When this abnormal collagen is incorporated into developing bones and other
connective tissues, it causes the serious health problems associated with severe
forms of osteogenesis imperfecta.
The COL1A1 gene is located on the long (q) arm of chromosome 17 at
position 21.33.
More precisely, the COL1A1 gene is located from base pair 50,184,095 to
base pair 50,201,641 on chromosome 17. Less commonly, osteogenesis
imperfecta has an autosomal recessive pattern of inheritance. Autosomal
recessive inheritance means two copies of the gene in each cell are altered.
The parents of a child with an autosomal recessive disorder typically are not
affected, but each carry one copy of the altered gene. Some cases of
osteogenesis imperfecta type III are autosomal recessive; these cases usually
result from mutations in genes other than COL1A1 and COL1A2. When
osteogenesis imperfecta is caused by mutations in the CRTAP or LEPRE1
gene, this condition also has an autosomal recessive pattern of inheritance. The
COL1A1 gene provides instructions for making part of a large molecule called
type I collagen.
Many people with type I or type IV osteogenesis imperfecta inherit a
mutation from a parent who has the disorder. Most infants with more severe
forms of osteogenesis imperfecta (such as type II and type III) have no history
of the condition in their family. In these infants, the condition is caused by
new (sporadic) mutations in the COL1A1 or COL1A2 gene.
Mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes cause
osteogenesis imperfect in 90 percent of all cases Most of the mutations that
cause osteogenesis imperfecta type I occur in the COL1A1 gene. These genetic
changes reduce the amount of type I collagen produced in the body, which
causes bones to be brittle and to fracture easily. The mutations responsible for
most cases of osteogenesis imperfecta types II, III, and IV occur in either the
COL1A1 or COL1A2 gene. These mutations typically alter the structure of
type I collagen molecules. A defect in the structure of type I collagen weakens
connective tissues, particularly bone, resulting in the characteristic features of
osteogenesis imperfecta.
Mutations in the CRTAP and LEPRE1 genes are responsible for rare, often
severe cases of osteogenesis imperfecta. In cases of osteogenesis imperfecta
without identified mutations in the COL1A1, COL1A2, CRTAP, or LEPRE1
gene, the cause of the disorder is unknown. These cases include osteogenesis
imperfecta types V and VI. Researchers are working to identify additional
genes that may be responsible for these conditions. Most collagen mutations
arise de novo, that is, they are new mutations that occur in one sperm or one
egg as a random event and the couple has no increase in their risk of having a
second child with OI. However, a small proportion of couples who have had
one child with OI are at increased risk of having a second child with OI
because one partner is a mosaic carrier. Collagen mutation in some cells of the
body but not in others is called as mosaic carriers and hence has been called as
‘mosaic.’ The collagen mutation occurs during the fetal development of the
mosaic carrier and all cells that arise from the first cell with a mutation will
also carry the mutation. This includes germ cells (eggs or sperm) and some
body cells. The mosaic carrier does not have symptoms of OI or may have
Bone Disorders 115
very mild symptoms (blue sclerae, shorter stature, dentinogenesis imperfecta).

OI is dominantly inherited and caused by a heterozygous mutation in either of
the two genes, COL1A1 and COL1A2, encoding the chains of type I collagen.
Fibrous Dysplasia
Introduction
Fibrous dysplasia is an uncommon bone disorder in which scar-like

(fibrous) tissue develops in place of normal bone. This can weaken the
affected bone and cause it to deform or fracture.
Fibrous dysplasia is a developmental abnormality characterized by a
disorganized mixture of fibrous and osseous elements in the medullary region
of affected bones.
Fibrous dysplasia can affect any bone, and can divide into four sub types:
 monoostotic - single bone

 polyostotic - multiple bones
 craniofacial fibrous dysplasia - skull and facial bones alone
 cherubism - mandible and maxilla alone (not true fibrous dysplasia)
Pathogenesis
Fibrous dysplasia is stated to occur as a result of a developmental failure

in the transformation of primitive bone into mature lamellar bone and its
inability to respond to mechanical stress. This failure of maturation results in a
mass of immature secluded trabeculae intertwined in dysplastic fibrous tissue
that are remodeling constantly but never or very nearly never completing the
process of bone maturation and mineralization.
This lack of remodeling and combination of deficient mineralization
results in great loss of mechanical strength, leading to the pain, pathological
fractures and deformity.
The mutation in the GNAS gene, located at chromosome 20q13.2-13.3,
which occurs after fertilization in somatic cells is said to be the cause of this
condition which encodes the alpha subunit of the stimulatory G protein, G s α.
The general function of Gs

↓
is to activate adenylate cyclase,
which, in turn,
↓
produces cAMP,
which, in turn
↓
activates cAMP-dependent protein kinase.
Further effects of Gs are therefore found in function of cAMP-dependent

protein kinase.
It hence provides a step in signal transduction. Amplification of the signal
occurs because the receptor activates multiple Gs. But, each Gs activates only
one adenylate cyclase.
As a consequence of this mutation, amino acid arginine, in position 201 of
the genomic DNA in the osteoblastic cells, is substituted by cysteine or
histidine. The abnormal G1 protein stimulates cyclic adenosine
monophosphate (AMP), and the osteoblastic cells expressing this mutation
have a higher rate of DNA synthesis than normal cells.
The dysplastic features are seen in all cells derived from these mutated
cells and this may also result in varied clinical presentation. The Gnas
mutation was first acknowledged in patients with McCune-Albright syndrome
(MAS), a rare disorder presenting features such as polyostotic fibrous
dysplasia, skin pigmentation, and one of several endocrinopathies.
The G-proteins begin a cascade that ultimately leads to activation of the
enzyme adenylyl cyclase that produces cAMP. Normally, there is an almost
immediate deactivation of adenylyl cyclase and a breakdown of the cAMP. In
MAS, that does not occur. Overproduction of cAMP leads to increased
amounts of activity that affects each tissue differently, based on its designated
function. Café-au-lait spots occur due to overproduction of the enzyme
tyrosinase, which plays a role in melanin production. In Fibrous dysplasia, this
mutation causes hyperproliferation and incomplete differentiation of marrow
stromal cells to abnormal osteoblasts. cAMP also activates Fos, which inhibits
osteoblastic-specific genes as well as stimulates cytokines that promote bone
resorption by osteoclasts. Hypophosphatemia/ phosphaturia, sometimes found
in FD and MAS, is caused by excess secretion of a phosphatonin fibroblast
growth factor. Similarly, most of the endocrine problems associated with MAS
Bone Disorders 117
can be related to Gs-activation. In addition, activating Gs-α mutation have

been shown to potentiate WNT/β-catenin signaling, and removal of Gs-α leads
to reduced WNT/β-catenin signaling and decreased bone formation. Activation
of WNT/β-catenin signaling in osteoblast progenitors causes an FD-like
phenotype and reduction of β-catenin levels, rescued differentiation defects of
stromal cells derived from patients with FD. This suggests that activated G
proteins have significant roles during both skeletal development and disease
by modulating the WNT/β-catenin signaling strength. This abnormal growth
leads to the formation of a disorganized fibrotic bone matrix with primitive
bone formation, and lack of maturation to lamellar bone. Mineralization is also
abnormal. There is a failure of the bone to align in response to mechanical
stress. This defect is seen in the monostotic as well as the polyostotic forms of
fibrous dysplasia. The extent of disease is related to the stage at which the
postzygotic mutation in Gs α has occurred, whether during embryonic
development or postnatally.
Osteoblastic Abnormalities in Fibrous Dysplasia
The histological analysis of fibrous dysplasia suggests abnormalities in the

formation of osteoprogenitor cells. The number of immature osteoblasts was
found to be low. The cells located along the bone surface were not inclined
and elongated, and were different from the normal cuboidal mature
osteoblasts. The marrow cavity was filled with elongated, immature, alkaline
phosphatase-positive cells, and this cellular invasion does not allow the normal
development of the resident blood cells and the fat cells. These histological
features indicate that the preosteoblastic population is increased in these
patients, whereas the count of mature cells was decreased. Osteoblast
differentiation was also found to be defective and it is visible in the abnormal
collagen organization in the immature bone. The collagen fibers show features
of immature bone in that they are not parallelly oriented and they sometimes
appear perpendicular to the bone surface, showing a comb-like structure.
These abnormalities found are seen in both monostotic and polyostotic lesions
reflecting a disorganization of collagen fibers synthesized by dysplastic cells.
Together with the abnormal formation and direction of collagen, the non-
collagenous protein formation is also affected. Osteopontin and the bone
sialoprotein are decreased and the osteonectin level is increased, projecting the
immature composition of the matrix of the dysplastic bone. These dysplastic
osteoblasts give rise to more than the normal number of osteocytes which are
also lodged in larger than normal lacunaes.’ Their intercellular canaliculis

which form a network are also found to be disorganized in the bone matrix. In
this dysplastic bone, the osteoclasts, which are multiple, are also found to be
dysfunctional and they show local lytic areas. These dysplastic cells exhibited
an elevated intracellular cAMP associated with an increased proliferation rate.
The less differentiated osteoblast phenotype was found to be associated with
an increased cell proliferation in these dysplastic lesions and this was
evidenced by the alteration of osteocalcin mRNA expression and protein
synthesis. Osteocalcin expression was enhanced in osteoblasts of dysplastic
bone when they were made to respond to 1, 25, dihydroxyvitamin D. The
concomittant decrease in cell differentiation and increased proliferation of pre-
osteoblastic cells in dysplastic lesions lead to a rapid deposition of an
immature, poorly organized woven bone characteristic of the bone lesion at the
histological level.
Other important factors regulating bone formation include the members of
the AP-1 family.
It seems therefore possible that the increased osteoblastic cell proliferation
and the abnormal osteoblast differentiation observed in fibrous dysplasia
results in part from the increased expression of c-fos and other members of the
in vitro, AP-1 control genes that are involved in osteoblast differentiation, and
the c-fos expression that modulates the expression of osteoblast genes such as
osteocalcin and osteopontin whose promoter contains AP-1 sites.
The increased c-fos protein by cAMP may induce cells to enter into the
G1 phase of the cellular cycle.
This is consistent with the finding that c-fos is expressed by immature
osteoblasts and controls osteoblast proliferation and differentiation.
There may be other mechanisms playing a role in the cellular alterations
observed in fibrous dysplasia. Studies have reported an increased level for
estrogen expression in osteoblasts in both monostotic fibrous dysplasia and
McCune-Albright syndrome. Endocrine receptors were found to be defective
here. Estrogens have been said to play a role in proliferation of osteoblastic
cells by increasing the expression of local growth factors such as TGF-β and
IGF-1 which play an important role in controlling osteogenesis. McCune
Albright syndrome patients have also reported a rise in the expression of the
parathyroid hormone related peptide (PTHrP) in their osteoblastic cells.
Bone Disorders 119
Cleidocranial Dysostosis
Introduction
Cleidocranial dysplasia (CCD) is a skeletal dysplasia characterized by

delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and
multiple dental abnormalities. CCD was initially thought to engage only the
bones of membranous origin but more current and comprehensive clinical
investigations have shown that CCD is a widespread skeletal dysplasia
affecting not only the clavicles and the skull but the complete skeleton. CCD
was as a result considered to be a dysplasia instead of a dysostosis.
Pathogenesis
Mutations in the CBFA1 gene that presumably lead to synthesis of an

inactive gene product were identified in patients with CCD. The function of
CBFA1 during skeletal development was further elucidated by the generation
of mutated mice in which the Cbfa1 gene locus was targeted. Main cause of
CCD is the mutation in the RunX2 gene on Chromosome 6p21 and whose
main role is to give instructions for making a protein that is involved in the
development and maintenance of cartilage and bone. The formed protein is a
transcription factor, and hence it binds to specific regions of DNA that helps to
control the activity of a particular gene. According to various researchers the
RUNX2 is a protein that acts as a “master switch,” controlling a number of
other genes implicated in the development of osteoblasts.
Mutations in this gene may include either a change in one amino acid in
the RUNX2 protein or the introduction of a premature stop signal which may
result in an abnormally short protein or sometimes the entire gene is missing.
These mutations result in shortage of functional RUNX2 protein which may
result in abnormal bone and cartilage development hence giving rise to signs
and symptoms of CCD. Loss of genes in the neighborhood of RUNX2 may
result in other disturbances in these individuals.
In a third of CCD individuals, no mutation in the RUNX2 gene is seen.
The etiology in such individuals is unknown. Mutations may be missense and
they gather at arginine 225 (Arg225) of the RUNX2 protein. Nuclear
accumulation of RUNX2 protein is affected.
The different steps of endochondral bone formation are listed. Patterning

genes regulate the shape and number of the individual skeletal elements.
Precursor cells aggregate and subsequently differentiate into chondrocytes.
Chondrocytes proliferate, hypertrophy, and calcify before they are replaced by
bone. Some of the factors that are known to regulate this process are shown on
the right. Cbfa1 controls the differentiation of precursor cells into osteoblasts,
regulates chondrocyte differentiation towards hypertrophy, and is necessary
for the invasion of calcified cartilage. Cbfa1 controls differentiation of
aggregated precursor cells of the clavicular anlage.
Figure 1. Role of Cbfa1 in bone formation.
Cherubism
Introduction
Cherubism is a rare, self-limiting, fibro-osseous, genetic disease of

childhood and adolescence characterized by varying degrees of progressive
bilateral enlargement of the mandible and/or maxilla, with clinical
repercussions in severe cases.
Pathogenesis
The main etiological factor for Cherubism is said to be the mutations in

the SH3BP2 gene linked to chromosome 4p16.3and has been recognized in
about 80%of patients. In the remaining 20% the genetic cause is unidentified.
Bone Disorders 121
This gene is important because it is found to provide instructions for

manufacturing a protein whose exact function is unknown. This protein is
thought to play a role in the transmission of the chemical signals within cells
of those predominantly playing a role in bone remodeling and certain immune
system cells. So large scale active version of this protein is produced following
mutations in the SH3BP2 gene. The mutations of SH3BP2 are still under
study. The hyperactive protein may cause jaw bone inflammation and
stimulates the production of osteoclasts that causes destruction of bone in the
upper and lower jaws. Bone loss and inflammation may be the likely cause for
the cyst-like growths which is a trait of cherubism.
The second theory in pathogenesis as stated by Caballero and Vinals
includes mesenchymal changes during jaw development, an odontogenic
origin or even hormonal and traumatic factors.
The third theory as stated by Silva et al. that includes the breaking down
of Msx-1 gene, involved in the regulation of mesenchymal interaction during
craniofacial development.
Hyckel et al. proposed the molecular model of cherubism pathogenesis
which is based on interaction between a disturbed parathyroid hormone related
proteins (PTHrP) receptor with the Hox gene Msx-1 activity occurring
following mutation in SH3BP2. This causes interference with jaw
morphogenesis which further leads to the dysregulation of mesenchymal bone
formation, and to the presence of osteoclasts in the developing giant cell
granulomas.
Cherubism is caused by mutations in SH3BP2. Studies of cherubism mice
showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a
major cause of the disorder but failed to explain why human cherubism lesions
are restricted to jaws and regress after puberty. It has been demonstrated that
the inflammation in cherubism mice is MYD88 dependent and is rescued in
the absence of TLR2 and TLR4. However, germ-free cherubism mice also
develop inflammation. Mutant macrophages are hyper responsive to PAMPs
(pathogen-associated molecular patterns) and DAMPs (damage-associated
molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-
α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-
α production. Finally, SYK depletion in macrophages prevents the
inflammation. These data suggest that the presence of a large amount of TLR
ligands, presumably oral bacteria and DAMPs during jawbone remodeling,
may cause the jaw-specific development of human cherubism lesions.
Reduced levels of DAMPs after stabilization of jaw remodeling may
contribute to the age-dependent regression.
Figure 2. Showing the mutation of SH3BP2 gene and its action on bone to cause
cherubism.
Paget’s Disease
Introduction
Paget’s disease occurs when there is a disturbance in the bone remodeling

that characteristically begins with unwarranted bone resorption followed by an
increase in bone formation. This osteoclastic hyper activity followed by
substituted osteoblastic activity leads to the formation of a structurally
disordered mosaic of bone which is still a woven bone, and which is
mechanically larger, weaker, more vascular, less compact, and more prone to
fracture than normal adult lamellar bone.
Pathogenesis
1. Viruses. Slow virus infection (intra-nuclear nucleocapsid-like

structure) in [osteoclasts and osteoclast precursors].
a. Paramyxovirus
Human bone marrow cells shows increased numbers of large,

highly nucleated osteoclasts and they express measles nucleocapsid
protein, due to which IL-6 levels are increased. But these nuclear and
Bone Disorders 123
cytoplasmic inclusions, which are a feature of pagetic osteoclasts, are

not specific to this disease. Osteopetrosis shows the presence of
similar inclusions in osteoclasts or macrophages and hence might
represent a nonspecific stress response in osteoclasts. Similar nuclear
inclusions are also seen in brain cells of patients with subacute
sclerosing panencephalitis which is a fatal condition caused by a long-
term measles virus infection of the brain. These inclusions are similar
in size to those in Paget's disease, but their arrangement may appear
different. Recent work has suggested that the inclusion bodies contain
SQSTM1, VCP (valocin containing protein) and ubiquitin. These
facts suggest that, rather than being viral particles, they may be
protein degradation products, which may be exaggerated by aging.
b. Infection of human osteoclast precursors with canine

distemper virus stimulates expression of NF-κB.
c. Respiratory syncytial virus.
But no virus has been identified till date.
2. SQSTM1 gene is said to play a role in Paget’s disease of bone and

is said to be caused by more than 20 mutations in the gene. The
mutations in the SQSTM1gene are brought about by replacement
of the amino acid proline with the amino acid leucine at protein
position 392. Mutations result in hyperactivation of the chemical
signaling pathway which encourages osteoclast formation. Paget’s
disease of bone results when affected bone is broken down and
replaced much sooner than normal and the new bone is weaker and
less regular than normal bone. This altered bone remodeling causes
certain bones to become unusually large, malformed, and easily
fractured. It is unclear why the disease affects some bones but not
others.
a. Mutations in an unknown gene results in sporadic and familial

Paget’s disease of bone. This gene binds to a multifunctional
protein that binds ubiquitin and controls activation of the nuclear
factor kappa-B (NF-kB) signaling pathway. The protein
functions as a scaffolding/adaptor protein with TNF receptor-
associated factor 6 to arbitrate activation of NF-kB in response to

upstream signals. On the other hand spliced transcript types
programming either the same or different isoforms have been
identified for this gene.
b. The p62 is encoded by the SQSTM1 gene (sequestome 1);
which may do the function of a scaffold protein in the RANK
signaling pathway. This mutated protein can cause accelerated
osteoclast activity but how it influences it, is unknown. The
significance of the p62 in osteoclast function was identified
during the inactivation of SQSTM1 which caused defects in
RANKL-induced osteoclastogenesis. Overall, Paget’s disease is
characterized by localized increases in osteoclast formation that
lead to bone resorption and associated osteoblastic activity.
c. p62 is also said to perform other functions in addition to bone
remodeling, such as recycling worn-out cell parts, autophagy,
apoptosis, and the body's immune responses and inflammatory
reactions
The role of SQSTM1 as a scaffold in NF-κB signaling is certainly relevant

to osteoclastogenesis and bone biology. SQSTM1 forms a complex with
TRAF6 or receptor interacting protein and an atypical protein kinase C to
facilitate NF-κB signaling stimulated by factors such as RANKL, TNF-α and
IL-1. This complex allows optimal and sustained activation of NF-κB, but the
effects of SQSTM1 on NF-κB signaling are complex.
Apert’s Syndrome
Introduction
Apert’s syndrome is an unusual autosomal dominant disorder featured by

craniofacial anomalies, craniosynostosis, and severe symmetrical syndactyly
(affecting the skin and the bone) of the hands and feet.
Bone Disorders 125
Pathogenesis
Apert’s syndrome is an autosomal dominant disorder, and a single copy of

the altered gene in the cell is enough to cause the disorder. A mutation in the
FGFR2 gene located on chromosome 10q causes Apert’s syndrome. The
function of this gene is to signal the undifferentiated mesenchymal cells to
become bone cells during embryonic development. Mutation in a specific part
of FGFR2 gene which alters the protein that plays a role in signaling, results in
prolonged signaling and the consequence of this would be the premature
fusion of bones of hands and feet and the skull.
Down’s Syndrome
Introduction
Down syndrome is a lifelong condition in which a person is born with

distinct physical features and some degree of cognitive disability.
Pathogenesis
The chromosomal karyotype for standard trisomy 21 is indicated as 47,

XY, +21 in males and 47, XX, +21 in females. A large number of errors can
happen during cell division. Disjunction occurs when the pairs of
chromosomes in a cell undergoing division, are supposed to split up and go to
different points during meiosis. But in rare cases this doesn’t occur and that
defective pair completely goes to only one point without splitting. So the
finally formed cell will have 24 chromosomes and the other cell will have 22
chromosomes only. This error is called “nondisjunction.” This may affect
either the sperm or the egg and when one of them fuses with a normal set of
chromosome the offspring chromosome would have 47 chromosomes instead
of the normal 46 i.e., an additional 21st chromosome. Therefore the technical
name, trisomy 21. In most of the cases the extra chromosome is from the egg
and the reason may be due to increased maternal age and research is on to
identify the exact cause for this disjunction.
Molecular and cytogenetic studies indicated that duplicate21 (q22.1-22.2)
is sufficient to cause Down syndrome. It contains genes that code for enzymes,
such as cystathionine beta-synthase (CBS), superoxide dismutase 1 (SOD1),

glycinamide ribonucleotide synthase-aminoimidazole ribonucleotide synthase-
glycinamide formyl transferase. GARS-AIRS-GART.
Down’s syndrome is also seen to occur when part of chromosome 21q22.3
becomes translocated to another chromosome during embryogenesis and the
affected individuals with this genetic change are said to have translocation
Down syndrome.
Another scenario is when a patient with Down’s syndrome has an extra
copy of chromosome 21 in only some of the body's cells and the condition is
called mosaic Down syndrome. Having these extra copies of genes on
chromosome 21 causes disturbance in embryogenesis and causing the
distinguishing features of Down syndrome and the amplified risk of health
problems associated with this condition. This mosaic Down’s syndrome is not
inherited similar to the Trisomy 21.
Achondroplasia
Introduction
One of the most common types of short-limb uneven dwarfism is called as

Achondroplasia. Parrot in 1878 was the first to coin the term achondroplasia,
suggesting absent cartilage formation. Histologically the name seems
inappropriate but it has been used universally and has also been accepted by
the International Working Group on Constitutional Diseases of the Bone.
Pathogenesis
Achondroplasia is a bone disorder commonly affecting the long bones and

the base of the skull and is characterized by large head, short extremities, and
trident-shaped hands. It is an autosomal dominant disorder that primarily
affects the FGFR3 due to mutations affecting it. About 80% of parents are
unaffected.
Research suggests that the disease occurs due to increased signal
transduction from the mutant receptors in the FGFR-3 genes and it has been
proved by introducing drugs that reduce signal transduction such as the kinase
inhibitors and neutralizing antibodies. It has hence been proved that functional
Bone Disorders 127
impact of the mutations of the FGFR3 gene may be the key negative regulator
of endochondral ossification and may play a role in targeting the chondrocyte
growth plate. However, it was mapped to the p axis of chromosome 4. It has
been seen that all patients with the typical features of achondroplasia have the
same glycine to arginine substitution at position 380, which maps to the
transmembrane domain of the FGFR. Signaling pathways seen downstream of
FGFR-3, include the mitogen activated protein kinase (MAPK), signal
transducer and activator of transcription (STAT), and phospholipase Cg
pathways. The STAT signals are thought to inhibit the proliferation of the
chondrocytes, but MAPK signals not only influence proliferation negatively,
but also disrupt terminal differentiation and postmitotic matrix synthesis.
Multiple pathways of the FGFR3 signal downregulate growth-promoting
molecules, resulting in the inhibitory proliferation and differentiation of
chondrocytes in growing bones. The transmembrane domain of the FGFR3 is
affected in the achondroplasia.
Marfan Syndrome
Introduction
Marfan syndrome is an autosomal dominant inherited disorder that affects

the body's connective tissues, which provides the strength, support, and
elasticity to tendons, cartilage, heart valves, blood vessels, and other vital parts
of the body.
Pathogenesis
Mutations in the fibrillin-1 (FBN1) gene on chromosome 15, which

encodes for the glycoprotein fibrillin is said to be the cause of Marfan
syndrome. Recent works have stressed the role of proteases and disturbances in
tissue homeostasis as other causes for occurrence of MFS.
Fibrillin, a 350 kDa glycoprotein, was discovered in 1986 and
characterized as the main component of the extracellular microfibrils. The
major element of microfibrils is fibrillin, which makes up the structural
components of the suspensory ligament of the lens and serves as a matrix for
elastin in the aorta and other connective tissues. Hence a deficient fibrillin
deposition leads to reduced structural integrity of the aorta of the heart, spinal
dura, ligaments, lens zonules, and lung airways.
TGF-β signaling pathway which may ultimately lead to incorporation of
fibrillin into the connective tissue matrix may also be playing a role in the
pathogenesis of Marfan syndrome. Fibrillin-1 is translated from an mRNA
encoded by the FBN1 gene on chromosome 15. The protein is processed and
secreted and then forms microfibrils in the matrix in association with other
extracellular molecules. Microfibrils may function alone or form the basis of
elastic fibers following deposition of elastin. Among molecules that are
associated with fibrillin-1 is LTBP-1, a binding protein for the latent form of
TGF-β. TGF-β is expressed as a precursor, which is cleaved to make the active
form, but the two peptides remain associated and are then bound by a protein,
LTBP-1.
Elastic Fibers, Micro Fibrils, and Fibrillin

The elastic fiber which is laid down over the fibrillin matrix in the sites
mentioned above is a complex structure, which contains lysyl oxidase, elastin,
10-12 nm microfibrils, and perhaps proteoglycans. By electron microscopy,
elastic fibres can be seen to be composed of two morphologically distinct
components: an amorphous fraction lacking any regular structure and
constituting about 90% of the mature fiber, which consists exclusively of
elastin, and a microfibrillar component consisting of 10-12 nm microfibrils.
Specific and effective treatment can be brought about by understanding
the molecular basis of human genetic disease and that is the mantra of human
molecular genetics. Till date this optimism has often been more of a buildup
than realization. The genetic story of the Marfan syndrome has only recently
been unraveled and this pathway to treatment may be both multifaceted and
full of discoveries into unexpected areas of biology. It is quite likely that in a
short time we may observe the usage of TGF-β blockade in place of β-
(adrenergic) blockade as a more effectual treatment of many aspects of Marfan
syndrome — and this treatment is the penultimate goal of understanding this
intricate phenotype.
Chapter 12
Disorders of the Skin
Pemphigus Vulgaris
Introduction
Pemphigus vulgaris is an uncommon, grave autoimmune disease in which

vesicles and bullae erupt on the skin, the lining of the oral cavity, the genitals,
and other mucous membranes.
Pathogenesis
Theories of the Pathogenesis of Pemphigus Vulgaris
1. The Desmoglein Compensation Theory

Based on the position of Dsg 1 and Dsg in the skin and mucosa, two
authors Amagai and Stanley projected the desmoglein reparation theory. This
landmark theory stated that the survival of any one Dsg type is adequate to
preserve the integrity of the epidermis and mucosa.
2. ‘Multiple Hits’ Hypotheses

New advances in the study of pathogenesis of Pemphigus vulgaris states
that patients develop antibodies against desmocollins, and plakins and
nondesmosomal proteins, other than Dsg 1 and 3which function as cell-
membrane receptors and they include pemphaxin, thyroperoxidase, nicotinic

acetylcholine receptor and some annexins.. The desmocollin 3 is detected
throughout the basal, spinous and lower granular layer and the blocking of
Dsg3 function with a monoclonal antibody results in the formation of vesicles
and bullae.
Apart from that, some patients also developed antimitochondrial
antibodies, which could pierce keratinocytes and react with mitochondrial
proteins.
Hence at least 3 autoantibodies are said to play a role for e.g.,
autoantibodies directed against keratinocyte, desmosomal autoantigens and
mitochondrial autoantigens. The ‘multiple hits’ theory which was recently
published, explained the occurrence of acantholysis. But the Dsgs’ were said
to play a major role. Autoantibodies against other antigens are also found but
were nonpathogenic and their contributions remain disputable.
Figure 1. Showing the pathogenesis of pemphigus. Acantholysis of the spinous cell

layer due to the autoantibody acting against the Dsg1 and Dsg.
Disorders of the Skin 131
3. The Antibody-Induced Apoptosis Theory

Researchers are considering the mechanism of keratinocyte detachment, as
the underlying mechanism for acantholysis in pemphigus vulgaris. Apoptosis
signaling is said to be induced by pemphighus IgG and the anti-Fas receptors
under experimental conditions and the pathway involved include an increase in
intracellular Fas R, Fas L, Bax and p53 and also a reduction in the level of
Bcl-2; increased caspase 8, activation of caspase 1 and 3. It was found that
the inhibitors of caspases 1 or 3 were effective in suppressing apoptosis and
stopping acantholysis, and hence favoring the concept that apoptosis
contributes to cell separation.
4. The Basal-Cell Shrinkage Hypothesis and the Apoptolysis

Theory
A new hypothesis of pemphigus pathogenesis was introduced in 2006,
suggesting that after the binding of the keratinocyte receptor by the pathogenic
pemphigus vulgaris autoantibody there was an involvement of a chain of
signal transduction pathways that initiated the rupture of the cytoskeleton,
resulting in the collapse and shrinkage of the keratinocytes. Desmosomal
cadherin disruption caused by the autoantibodies may be the reason for the
acantholysis. The cadherin may be a part of the signaling pathway involved in
the PV pathogenesis and they include the p38 MAPK, RhoA, PKC, c-myc, and
plakoglobin. The internalization and reduction of Dsg 3 in PV has been linked
to the p38 MAPK activity. However, the p38 MAPK may also regulate
desmosomal adhesion independent of intermediate filaments. For example, the
alteration in the organization of the actin cytoskeleton and the actin filament
dynamics via the heat shock protein 27, especially within the marginal
junction-associated actin belt were shown to influence the autoantibody-
induced loss of cell adhesion.
A novel term, ‘apoptolysis’ was introduced in 2009 which stated that
suprabasal acantholysis and cell death pathways occurred, following the basal
cell shrinkage. The predominant difference between apoptosis and apoptolysis
in PV was that of basal cell shrinkage and that no actual death of keratinocytes
occurred. Experiments conducted have shown that the acantholysis and
apoptosis can be prevented by the anti- Fas L antibody. This new concept of
apoptolysis is critical for the description of PV development. However,
whether apoptosis occurs prior to acantholysis or whether it is just an
intermediate step in acantholysis is still under debate.
Figure 2. Model for PV pathogenicity.
The mitochondrial antigens have been shown to be attacked by the

autoantibodies that have been identified in the sera of PV patients and this
theory can be used to explain the acantholysis in patients lacking desmoglein
antibodies.
Pemphigus vulgaris IgGs go through keratinocytes (KCs) and exclusively
bind to mitochondrial proteins, which is linked to the mitochondrial injury
stimulating apoptosis and acantholysis. The mitochondrial proteins most
commonly attacked in pemphigus vulgaris include those involved in O2
respiration, oxidative phosphorylation, tricarboxylic acid cycle and the
assembly/inactivation of reactive oxygen species (ROS). The increased ROS
production by the PV IgGs, following proton leakage from KCs, PV sera

reduced the ability of KCs to respond to stress.
An increase in lipid peroxidation shown by increased production of ROS
is an indicator of the mitochondrial dysfunction in PV and the oxidative stress
indicated by altered peroxidant-antioxidant balance and the intrinsic apoptotic
pathway dependant on the mitochondria indicate an important role for
mitochondria in keratinocytes to indirectly play a role in acantholysis. But how
the PV anibodies enter the mitochondria is controversial and it has been
suggested that a cell surface protein showing features of a mitochondria may
play a role. Mitochondrial antibodies enter the keratinocytes which present
with annexins, and the annexins can reposition to the cytosol to reach the
mitochondria. Or an antibody in a complex with the Fc receptor present on the
keratinocytes, may show the path for it to enter the mitochondria.
Another theory for pathogenesis of PV as suggested by Lanza et al.
includes the role of CDK2. Exposure of PV serum to synchronized human
keratinocytes increased the quantity of cells in S phase, which resulted in the
rounding of the cell, cell-cell disconnection, increased CDK2 expression in a
dose-dependent manner, and also changed the expression of over 500 genes.
The most significantly enriched genes were those involved in cell
communication and cell- cell junction formation. Small interfering RNA
against CDK2 reversed PV serum-induced CDK2 overexpression and reduced
cell-cell detachment. Lanza et al. (2008) concluded that activation of CDK2-
mediated signaling is a crucial event in the development of PV lesions.
Pemphigus Vegetans, Pemphigus

Foliaceous, Paraneoplastic Pemphigus
Introduction
Pemphigus Vegetans was (PV) initially considered a variant of pemphigus

vulgaris in 1876, by Neumann and in 1889, Hallopeau described a patient with
pustules and vegetating plaques, suggestive of a variant of PV of Neumann.
Both types of pemphigus vegetans show the expansion of vegetating plaques,
especially in skin folds (perianal, axilla and inguinal). They majorly affect
younger patients.
Pemphigus foliaceus (PF) is a persistant autoimmune blistering disease

mainly involving the skin of the face and upper part of the body, such as chest
regions, rather than the lower part or the scalp.
Paraneoplastic pemphigus (PNP) is a predominantly fatal paraneoplastic
mucocutaneous blistering disease most likely caused by lymphoproliferative
disorders.
Pathogenesis
Pemphigus is an autoimmune disease with the IgG found directed against

desmoglein 1 in pemphigus vegetans and pemphigus foliaceous and
desmoglein 3 in case of paraneoplastic pemphigus.
Cicatricial Pemphigoid
Introduction
Cicatricial pemphigoid is a rare, chronic, blistering and scarring disease

that affects the oral and ocular mucosa.
Pathogenesis
The parts of the basement membrane zone i.e., the dermal-epidermal

junction is made up of four compartments: sublamina densa, the basal cell
plasma membrane, the lamina lucida, and the lamina densa.
Hemidesmososmes are located in the dermal surface of the plasma
membrane of the keratinocytes. They anchor the epidermis, through the lamina
lucida and connecting (anchoring) filaments to the lamina densa and
eventually to the underlying dermis. The basal set of intermediate filaments
namely the keratins 5 and 14, also form a part of the hemidesmosome apart
from the other four protein components, namely the Bullous pemphigoid
antigen 1 (230 kD) and plectin that are the intracellular components and the
Bullous pemphigoid antigen 2 (180 kD, type XVII collagen) and alpha 6 beta
4 integrin which are the transmembrane components.
The lamina lucida contains the anchoring filaments, laminins 5, 6, and 7

which originate in the hemidesmosomes of the plasma membrane and insert
into the lamina densa. The lamina densa is composed predominantly of type
IV collagen. However, laminin, nidogen/entactin, and heparin sulfate
proteoglycans are also found in this region.
The sublamina densa zone which is located beneath the lamina densa
contains anchoring fibrils (collagen VII), anchoring plaques (type 4 collagen
and laminin), collagen fibers, and elastic fibers. Anchoring fibrils in addition
to connecting anchoring plaques, bind to laminin 5 in the lamina lucida and to
anchoring plaques and type IV collagen in the lamina densa. So it is the
anchoring fibrils that connect all of these structures, in due course anchoring
the epidermis and its basic basement membrane zone to the papillary dermis.
In the cicatricial pemphigoid affecting the oral cavity, IgG and C3 may be
confined to a small area to the lower lamina lucida and lamina densa or else to
the recognized overlying the hemidesmosome. The sublamina densa remains
uninvolved because of the involvement of the β4 integrin, BP180 or laminin
332. This anti-laminin Ab interferes with the adhesion of laminin-5 causing
separation of the keratinocytes from the underlying basement membrane.
BP180 forms a complex with laminin-5 and it spans the lamina lucida and
interacts with the lamina densa-which may explain the scarring in this disease.
Bullous Pemphigoid
Introduction
Bullous pemphigoid (BP) is a chronic blistering of the skin. It ranges from

mildly itchy welts to severe blisters and infection, and may affect a small area
of the body or be widespread. The vast majority of those affected are elderly,
but it has been seen at all ages.
Pathogenesis
Cell Junctions
The hemidesmosomal junction comprises of a plaque which may be
electron dense, disc shaped structure. Keratin intermediate filaments may be
attached to the α6β4 integrins and BP180 which are the hemidesmosomal
proteins. Hemidesmosomal plaque components BP 230 and plectin are

attached to the intracellular portions of α6β4 and BP180 whereas their
extracellular domains contact the anchoring fibrils via filamentous proteins
such as laminin 5 after they lengthen into the basement membrane zone.
Anchoring fibrils originate in the lamina densa of the basement membrane,
and they widen into the adjacent connective tissue and end in a structure
known as anchoring plaques. Type VII collagen forms the major component of
anchoring fibrils. BP230 gene is found to be mapped to 6p11–12, and the
BP180 gene to the 10q24.3. BP230 is a plakin protein family member that
associates the hemidesmosomes with keratin intermediate filaments. This
intracellular protein has significant similarity in origin with plectin and
desmoplakins I and II. BP230 is said to contain a central coiled domain region
supported by two globular end domains whereas BP180 is a transmembrane
protein with a type II orientation. It has an amino-terminal region located in
the intracellular hemidesmosomal plaque, and a carboxyl terminal portion
projecting into the extracellular portion of the BMZ.
This sequence pattern is prognostic of a protein domain that forms into a
collagen triple helix.
The exact role of bullous pemphigoid antigens in the etiopathogenesis of
bullous pemphigoid is not completely clear. BPAg1 (BP230) is an intracellular
component of the hemidesmosome; BPAg2 (BP180, type XVII collagen) is a
transmembranous protein with a collagenous extracellular domain. The
binding of antibodies at the basement membrane activates complement and
inflammatory mediators. Activation of the complement system is thought to
play a critical role in attracting inflammatory cells to the basement membrane.
These inflammatory cells are postulated to release proteases, which degrade
hemidesmosomal proteins and lead to blister formation. Eosinophils are
characteristically present in human patients' blisters as demonstrated by
histopathologic analysis, although their presence is not an absolute diagnostic
criterion.
Interleukin 16, a major chemotactic factor responsible for recruiting CD4+
helper T cells to the skin and for inducing functional interleukin 2 receptors
for cellular activation and proliferation, was found to be expressed strongly by
epidermal cells and infiltrating CD4+ T cells in lesional bullous pemphigoid
skin.
The binding of autoantibodies to antigens initiates a series of immune
inflammatory events, including neutrophillic infiltration; complement
activation, macrophage activation, and mast cell degranulation, which lead to
the development of clinical blisters or bullae.
Figure 3. The diagrammatic representation of the dermal-epidermal anchoring

complex.
1. Mast Cells
The mast cell released during inflammation degranulates and plays an
essential role in getting neutrophils to the target tissue and once the
complement is activated it plays a key role in the inflammatory cascade
leading to the blister formation.
2. Neutrophils
Inflammation at the site of Bullous pemphigoid further aggravates due to
recruitment of the neutrophils. Neutrophils release proteases which results in
the local tissue damage of BM. Thus; the disease severity is directly correlated
to the number of infiltrating neutrophils.
3. Eosinophils
Eosinophils are also found in the BP lesions and are often found scattered
throughout the upper dermis or collected at the edge of the dermal–epidermal
junction. Eosinophil count in the circulating blood is elevated too. Blister fluid
is found to contain a large amount of IL-5, eotaxin, and eosinophilic cationic
protein (ECP). IL-5 encourages expansion and activation of eosinophils.
Eotaxin is eosinophil-specific chemokine, regulating eosinophil migration

produced by fibroblasts and probably keratinocytes. CCR3, the specific
eotaxin receptor, has been stated to be strongly seen on eosinophils, basophils,
and Th2 cells in BP. IL-5 and eotaxin probably increases the inflammatory
reaction and adds to the invasion of granulocytes, which, by release of
proteinases or cytotoxic agents such as eosinophil major basic protein (MBP)
and ECP, finally causes the separation of epidermis and dermis at the position
of the lamina lucida in the basement membrane zone.
4. Role of Proteolytic Enzymes

Elevated levels of proteolytic enzymes, such as collagenase, neutrophil
elastase (NE), plasminogen activators, cathepsin G, plasmin, matrix
metalloproteinase-2 (MMP-2, gelatinase A), MMP-9 (gelatinase B), and
MMP-13 have been isolated from blister fluid and lesional biopsies of BP
patients. These enzymes are released into the ECM upon cell activation, by
neutrophils and eosinophils, and are also believed to proteolytically degrade
various extracellular matrix proteins including the extracellular domain of
BP180. Other than plasmin, the MC-specific serine protease MCP-4
(chymase) is also able to activate MMP-9. The physiological inhibitor of NE
namely α1-proteinase inhibitor is inactivated when the MMP-9 is
proteolytically activated and this allows unrestrained activity of NE. These
observations show that proteolytic enzymes released from inflammatory cells
harm the BMZ directly, causing the separation of the dermoepidermal
junction.
Mechanisms of Tissue Injury and Blister Formation
The mechanisms by which BP autoantibodies are thought to be

pathogenic, include complement activation, recruitment of inflammatory cells,
liberation of proteolytic enzymes and direct interference with the adhesion
function of the autoantigens.
1. Role of Direct Mechanisms

The blister formation in the BP usually requires cellular and humoral
immunity as compared to that in pemphigus and anti-laminin 5 mucous
membrane pemphigoid. There is news that apart from the mechanisms
mentioned above, the disruption of the junction may also occur due to direct
binding of the autoantibody independent of their Fc portions.
There is competition with the natural ligand, in blocking the key binding
sites of the antibody to the BP180antigen which may result in the impairing
the functions of these molecules. The autoantibodies from BP patients largely
belong to the non-complement fixing IgG4 subclass; lower concentrations of
the IG1 subclass are also present. Hemidesmosomal disassembly or the
inducing of the proinflammatory cytokines may also be caused by the
activation of the intracellular signaling pathways which results in formation of
blisters by autoantibodies. IL-6 and IL-8 is modulated due to autoantibody
action but its pathogenic relevance is not known.
2. Role of Complement System

Several early studies have already shown that BP autoantibodies fix
complement in vitro and that C3 is detected by direct immunofluorescence
along the basement membrane zone of perilesional skin in almost all cases of
BP. Both BP autoantibodies and C3 are detected by immunoelectron
microscopy at the site of immunological injury, i.e., the lamina lucida of the
skin. Lesional skin of patients with BP shows components of both the
alternative and the classical pathways of complement (including C4, C5, C1q
and C5-9), factor B, properidin and B1H globulin.
T cells giving rise to matrix metalloproteinase (MMP)–2, MMP-9, and
MMP-13 were significantly increased in lesional bullous pemphigoid skin
compared with that of healthy skin. Hence a role for MMP is suggested in the
blistering of bullous pemphigoid.
A cytokine named BAFF (B-cell activating factor –From the TNF family)
that plays a role in survival and regulation of B-cell was found to be
considerably higher in sera of bullous pemphigoid patients compared with
healthy subjects, even though no major association was detected between
serum BAFF levels and titers of anti-BPAg2 antibodies. In 2008, a
responsibility for IgE class of autoantibodies, in relation to BP180, was
established and a higher level of the IgE correlated with an even more severe
clinical state.
The coagulation cascade was found to be involved in the bullous
pemphigoid patients, and hence is said to play a role in its severity. There was
also an increase in eosinophils which was also said to play a role in the
coagulation, hence increasing the potential thrombotic risk, blister formation,
tissue damage, as well as inflammation.
Reports in 2009, of bullous pemphigoid developing after adalimumab
treatment for psoriasis brought forward the idea whether drugs can play a role
in inducing the disease or it may simply be the coincident association of

bullous pemphigoid with psoriasis.
The initiating factor for BP includes the binding of the pathogenic
autoantibody to a specific antigen but the cause and the method of
autoantibody production remains uncertain. These facts mentioned above may
enable further studies to be conducted, to determine the source of the
autoantibody concerned and the pathogenesis, as well as more useful therapy
of BP.
Lichen Planus
Introduction
Lichen planus (OLP) is a pruritic, papular eruption characterized by its

violaceous color and polygonal shape, sometimes with a fine scale. It is most
often found on the flexor surfaces of the upper extremities, genitalia and on the
mucous membranes.
Pathogenesis
Recent data has suggested that both antigen-specific and non-specific

mechanisms are involved in the pathogenesis of OLP and it has been
suggested that both factors play a role in lesion development. The primary
event in OLP lesion formation and the factors that establish OLP vulnerability
are unknown. Unspecified agents like altered protein, autoreactive peptide,
contact allergen, hapten, drug reaction, and viral or infectious agents on a class
I major histocompatibility complex molecule on the keratinocyte is believed to
activate a CTL-inciting disease (chronic T lymphocytic lesion). Precipitating
factors for the same may include trauma, stress, and infectious agents (i.e.,
hepatitis C virus (HCV).
Most T cells in the epithelium and adjacent to the damaged basal
keratinocytes are activated CD8+ lymphocytes. This could be in combination
with increased Th1 cytokine production (IL-1, IL-8, IL-10, IL-12, TNF-a) and
an increase in the expression of intercellular adhesion molecule-1 on
Langerhans cells and macrophages, and major histocompatibility complex
antigens by keratinocytes.
The perivascular localization of CD4+ T cells is a pointer to the possible

support offered to the cytotoxic CD8+ cells by secretion of Th1 cytokines.
Keratinocyte damage by CD8+ T cells which releases cytokines would lead to
basement membrane disturbance such as apoptosis through the
perforin/granzyme or Fas/Fas ligand pathways, making way for the entry of
more CD8+ T cells and further basal cell damage which causes a vicious cycle
leading to chronicity of the disease. Both the cutaneous lichen planus and oral
LP are found to have similar pathogenesis. The preponderance of T cells in the
inflammatory infiltrate, also suggests a major role for humoral immune
mechanism in the pathogenesis of cutaneous LP. The CD8+ T lymphocytes are
attracted to the antigen presentation by the basal keratinocytes which presents
with the major histocompatibility complex (MHC) class I on it. The lichen
planus antigen is unknown, though it may be a self-peptide or a protein similar
to the self-peptide, in which case lichen planus would be a true autoimmune
disease.
Keratinocyte apoptosis results in Civatte bodies. And this keratinocyte
apoptosis caused by the immune system occurs through many mechanisms
namely:
a. The caspase cascade, that requires the tie up between the

ligand/protein found on the surface CD95L (FasL) of the cytotoxic T
lymphocytes (CTL) to the keratinocyte CD95 (Fas) to trigger
apoptosis;
b. CTL and natural killer cell secretion of granzyme B, that forays into
keratinocytes via the cell membrane pores from perforin, resulting in
apoptosis; and
c. The lymphocyte secreting the cytokines such as tumor necrosis factor
thereby inducing matrix metalloproteinase 9, which can interfere with
the basement membrane zone integrity and promote keratinocyte
apoptosis through deprivation of basement membrane zone–derived
cell survival signals.
Other authors have suggested the vacuolar degeneration of basal

keratinocyte during apoptosis. But this phenomenon would cause severe and
extensive oral erosions. Erosive LP is rare and the reticular variant is
predominant, so it can be assumed that there is a reciprocal action by the oral
mucosa that controls these erosions and it maybe by the increased cellular
proliferation. Hence a mixed pattern of both apoptosis and increased cell
turnover is seen occurring in LP. Another author also suggested that the cells
may undergo senescence rather than apoptosis as shown by the presence of

positive p21waf1 expression in OLP, which indicates cell cycle arrest and
senescence.
This cell cycle arrest maintains the tissue structure and helps in the DNA
repair mechanisms but senescence would point towards malignant change. The
level of p21WAFK was found to vary in different research studies.
As p53 expression has been identified as a response to DNA damage, the
identification of p53 in OLP tissue is interpreted as an indication of
precancerous potential by some researchers.
The expression of NF-kappa B has been found higher in OLP than in
cutaneous lichen planus (CLP), a fact that is considered consistent with the
more persistent inflammation observed in OLP in comparison to CLP. IL-6
expression in serum and saliva of OLP patients is considered indicative of a
Th2 cellular involvement in OLP, a fact that was underestimated initially in
the pathogenesis of OLP.
Other mechanisms which may be non-specific like the MMP activation
and the mast cell degranulation are also said to play a role in the OLP
pathogenesis. The expression or unmasking of the lichen planus antigen may
be induced by drugs (lichenoid drug reaction), contact allergens in dental
restorative materials or toothpastes (contact hypersensitivity reaction),
mechanical trauma (Koebner phenomenon), viral infection, or other
unidentified agents.
There is also found to be a correlation between LP and LP variants to
hepatitis C virus, syphilis, HIV, human herpesvirus 2, chronic bladder
infections, human papilloma virus or the Helicobacter pylori. However,
screening for hepatitis C virus infection is advisable, as case-control studies
have shown an association of hepatitis C virus and LP.
Carcinogenesis in OLP may be dictated by the incorporated signal from
various tumor promoters and inhibitors such as MIF, MMP-9 and TNF-alpha,
TGF-beta 1, IFN-gamma and IFN C gamma-12.
Lupus Erythematosus
Introduction
A collection of autoimmune diseases which shows a hyperactive human

immune system and which attacks the normal healthy tissues is named as
Lupus erythematosus. The different body systems affected by this disease

includes the skin, joints, kidneys, blood cells, heart, and lungs.
Pathogenesis
Systemic lupus erythematosus (SLE, lupus) shows the presence of a

uniform loss of the self tolerance with the stimulation of the autoreactive T
and B cells leading to pathogenic autoantibodies and tissue injury. The
etiopathogenesis is said to be multifactorial with various genetic and
envoirnmental factors playing a role. Sex hormones and the hypothalomo-
pituitary adrenal axis are also found to be contributory factors to the
pathogenesis of SLE.
Defective immune regulatory mechanisms, such as the clearance of
apoptotic cells and immune complexes, are important contributors to the
development of SLE. The loss of immune tolerance, increased antigenic load,
excess T cell help, defective B cell suppression, and the shifting of T helper 1
(Th1) to Th2 immune responses leads to B cell hyperactivity and the
production of pathogenic autoantibodies. Finally, certain environmental
factors are probably required to trigger the disease.
The predominant disturbance in the patients with the SLE is the
autoantibody production. These antibodies are found to attach to the nucleus,
cytoplasm and the cell surface. This antinuclear antibody is characteristic for
the pathogenesis for the SLE. Also the anti-double stranded DNA (ds-DNA)
and anti-Sm antibodies are exclusive to patients with SLE. The Sm antigen is a
small nuclear ribonucleoprotein (snRNP) composed of a distinctive set of
uridine rich RNA molecules attached to a common group of proteins
associated with the RNA molecules.
Anti-DNA antibody titers frequently vary over time and disease activity
but anti-Sm antibody titers are usually constant.
Their association with the glomerulonephritis is the most remarkable
feature of anti-DNA antibodies. Anti-DNA antibodies can be identified from
patients with active lupus nephritis and anti-DNA antibodies can induce
nephritis.
Immune mediated cells like the B cells, T cells, monocytic cells resulting
in the polyclonal B cell activation also play a role in the pathogenesis of the
SLE.
Figure 4. Depicting the causative factors for Lupus Erythematosus.
Figure 5. Showing the etiological factors responsible for formation of systemic lupus
erythematosus.
Irritating chemicals such as cell wall phospholipids, viral antigens and

bacterial DNA can induce anti-DNA antibodies in mice. Self antigens and the
environmental antigens are taken up by professional antigen presenting cells
(APCs) to induce antibodies on the surface of B cells. They then present them
to the T cells after processing into peptides through surface HLA molecules.
The activated T cells on the other hand stimulate the B cells to produce
pathogenic autoantibodies. Several cytokines may play a role together with the
B and T cells and it includes the IL-10. Accessory molecules such as those of
the CD40/CD40L and B7/CD28/CTLA-4 systems help the IL-10 cytokines.
The B cells produced in these patients are abnormal. They are found to
exhibit increased intracytoplasmic calcium responses than controls. They are
more prone to the polyclonal activation by various agents. Abnormalities in T
cell and its reduced number is also observed in patients with SLE probably
because of the effects of antilymphocytic antibodies.
Apoptosis is also found defective in these individuals and this may lead to
a prolonged existence of the diseased lymphocytes in SLE.
Infectious agents, diet, toxins/drugs may affect the production of
inflammatory mediators and enhance the immunogenicity of the self antigens.
Agents, such as ultraviolet (UV) light, causing photosensitivity, may also play
a role in SLE. Protection against this UV radiation is brought by the Nitrous
oxide which is found increased in these individuals.
The consumption of meat and milk products of livestock fed with
synthetic estrogens and synthetic estrogens used by postmenopausal women
for contraception may also initiate apoptosis.
Drugs such as procainamide and hydralazine, which are aromatic amines
or hydrazines, can induce a lupus-like syndrome, predominantly in persons
who are genetically slow acetylators. These chemicals and their derivatives are
commonly used in the agriculture, industry, and in the various commercial
applications.
Section 4: Bacterial, Viral
and Fungal Lesions
Chapter 13
Bacterial Lesions of Oral Cavity
Tuberculosis
Introduction
Tuberculosis (TB) is an infectious disease, primarily affecting the lungs (a

pneumonia), and is caused by the bacteria called as Mycobacterium
tuberculosis. It normally spreads from person to person through aerosol or by
droplet infection.
Pathogenesis
Primary Tuberculosis
The immediate reaction following the entry of the organism through the
routes such as the respiratory tract, oral mucosa etc. is the onslaught by the
neutrophils. The glycolipid capped mannose on the organism acts as
an antigen and initiates the procedure to engulf it. But the organism resists
this digestion by interfering with the fusion between the lysosome and
phagolysosome, multiplies in the phagosome, and causes macrophage
necrosis. It thus makes the macrophage ineffective though the lysosome has
initiated the maturation arrest of the organism. This macrophage would be
engulfed by another macrophage. This is brought about under the control of
genes called as the Natural Resistance-Associated Macrophage protein
1(NRAMP-1). On the other hand some macrophages are able to complete the
digestive action and destroy the microorganism. The macrophage that has
engulfed the processed antigen will then present the MHC on its surface and it
now becomes an antigen presenting cell (APC). This APC then releases the
IL-12 which would attract the T cells, namely the helper T cell. In two weeks
time the delayed hypersensitivity reaction would be initiated causing antibody
production against the mycobacteria. Mantoux test is positive at this stage.
The next in the defense line, against the microorganism would be, in the
manufacture of the interferon gamma by the Th 1 cells which transforms the
macrophages into the epitheloid cells. These epitheloid cells produce TNF
which would recruit more monocytes from the circulation. The monocytes will
again coalesce to form larger phagocytic cells which are then called as the
‘Langerhans giant cells.’ These cells are unique in that they have the cell
which is large and they exhibit multiple nuclei that are arranged in a ‘horse
shoe shaped’ manner adjacent to the cell membrane of the giant cell. Finally
there is the collection of the inflammatory cells and the fibroblasts with the
collagen fibers which walls of the above mentioned cells, to be now known as
a ‘granuloma.’ This granuloma prevents the spread of the organism and its
toxins into the neighboring areas. In the lung this granuloma is known as the
‘Ghon focus’ and if it accumulates in the lymph nodes it is called as the ‘Ghon
complex.’ Upon fibrosis calcification and healing this complex is known by
the name ‘Ranke’s complex.’
The Mycobacterium tuberculosis and the Mycobacterium bovis strains,
but not the vaccine strain BCG Mycobacterium bovis was found to have a
region of difference 1(RD 1) that was important site for indication of the
virulence of the organism.
Secondary Tuberculosis
Secondary tuberculosis occurs some time after exposure to the organism
as compared to the primary which occurs immediately on being infected with
the organism. When organism has remained latent in the individual without
causing any symptoms, and when it has become active due to a lowered
immunity it is called as secondary tuberculosis. The presentation is then
similar to that of the primary tuberculosis except that it can become extensive
as compared to the primary TB which is more localized.
Miliary Tuberculosis
When the organism spreads through the blood stream or hematogenous
spread of the organism to the different parts of the body or becomes
disseminated it is called as the miliary tuberculosis. The name has come about
Bacterial Lesions of Oral Cavity 151
because of the ‘millet seed’ like appearance on a chest radiograph of a patient

with miliary tuberculosis. The clinical manifestation of this condition may be
acute or is most commonly sub-acute or chronic.
Syphilis
Introduction
It is a highly contagious disease that mainly spreads through sexual

contact. It is said to be caused by a spirochetal organism called as the
Treponema pallidum.
Pathogenesis
The entry of the organism into the body is followed by the invasion of the
epithelial cell and the fibroblast like and endothelial cells. Endothelial cells are
traversed by the corkscrew type motility of the organism. This is followed by
the production of the matrix metalloproteinase-1 in the connective tissue thus
breaking down collagen which causes organism to enter the lymphatics and
the bloodstream to disseminate following nutrient gradients (chemotaxis) and
causing its varied clinical manifestations.
Actinomycosis
Introduction
It is rare type of bacterial infection caused by a dormant bacterial

organism called as actinomyces. Most of the infections caused by bacteria are
localized as they are unable to penetrate the body’s tissues. But in the case of
the actinomycosis the infection is able to move slowly and steadily through the
body tissues. The actinomycosis is not a contagious disease since the organism
needs an anaerobic environment to thrive, which is available within the body,
but absent once t is exposed to the environment.
Pathogenesis
The disease is caused by the actinomyces organism which is a gram +ve

bacilli and not a fungus as the name suggests. The organism is neither a
parasite nor a saprophytic organism. In most cases, the bacteria live without
causing any harm mainly on the throat, lining of the mouth, vagina and the
digestive system. The virulence of the actinomyces organism is low and it
normally produces infection in the humans following a breach in the tissue or
through a necrotic tissue. It also has the characteristics of producing infection
that has varying manifestations and varying clinical features. But once the
infection is established it mounts an intense inflammatory response by
producing pus and a granuloma formation. The inflammatory response is
found to conclude by fibrosis. Prior to that, the infection spreads and invades
surrounding tissues or organs. Draining sinuses from these swellings that spout
‘sulfur granules’ are seen, or called so because of it’s ‘sulfur yellow’ color,
which is the hallmark of the infection. The sulphur granules are found teeming
with the actinomyces organisms when viewed under the microscope.
Sarcoidosis
Introduction
Sarcoidosis is an inflammatory disease that mainly affects numerous

organs in the body, but most commonly affected includes the lungs and lymph
glands.
Pathogenesis
The main pathogenesis in sarcoidosis is the formation of the non caseating

granuloma. The centre of this granuloma is said to show the presence of the
antigen which is surrounded by the epitheloid cells and the multinucleated
giant cells. Both CD4+and CD8+T cells, B cells and fibroblasts are found
lining the periphery of the granuloma.
Figure 1. Immunopathogenesis of sarcoidosis (a proposed model).
The so called sarcoid antigen is engulfed by circulating dendritic cells.

Dendritic cells stimulate the T cells. Activated T cells are highly polarized and
they produce IL-2 which causes monoclonal proliferation of T cells. Also,
upon TCR activation, T-bet production increases. T-bet upregulates and
enhances the production of IFNγ which enables the granuloma formation. The
future antigen clearance and increased IL-10 levels bring about disease
clearance. Disease chronicity results in a predominance of TH2 cytokines
which leads to lung remodelling by fibrosis.
Recurrent Aphthous Stomatitis
Introduction
Recurrent aphthous stomatitis is a disorder characterized by recurring

ulcers in the oral mucosa in patients with no other signs of the disease.
Pathogenesis
A large number of etiological factors have been suggested as the cause for
the recurrent aphthous stomatitis. The etiological factors other than ones
mentioned below cannot be pathogenetically explained as etiopathogenetic
factors, since no substantiating evidence has been found between the etiology
and the disease.
 Stress has been emphasized as a causative factor in RAU.

 Stress as an etiological factor in RAS patients induces parafunctional
habits in them such as lip or cheek biting that may result in trauma to
the site and the patient acquiring ulceration. But correlating stress
with RAU in experimental studies the relationship has been found
negative, thus implying that stress may only be a contributory factor
in RAS and plays no role in its etiology.
 Oral organisms have been found at the site of the ulcer, suggesting
that probably the bacteria such as oral streptococci, helicobacter
pylori etc may play a role in the causation of RAS and though the role
of virus has been suggested, it is still said to be under speculation.
Viruses that have been suggested include the viruses from the herpes
family like the EBV, CMV, HSV, HSV6, etc. These organisms may
act as an antigenic stimuli initiating an immunologic reaction and
damaging the oral mucosa in the bargain.
 TNF-alpha is said to play a major role in formation of the RAU. The
inciting factor may be any of the above mentioned antigens that
stimulate the production of IL-2 and TNF-alpha, following its attack
on the oral mucosal keratinocytes. This TNF-alpha causes expression
of MHC 1 which further attracts the CD 8+ cells resulting in the ulcer
formation of the oral mucosa.
 Both types of immune responses humoral and acquired is said to play
a role in RAS. It is said to result in neutrophil reactivation,
complement addition, role of NK cells, B cells altered CD4+/CD 8+
ratio and T cell receptors in the peripheral blood. The Th1 is said to
play a major role in RAS formation.
 There was found to be an increase in the production of the IL-2, IFN-c
and the TNF- alpha in the acute cases of RAS and also a simultaneous
reduced secretion of the TGF- beta and the IL-10. This imbalance in
the pro and the anti-inflammatory cytokines may be the reason for the
ulcer formation in the RAS.
 Also the increased Th1 as compared to the Th2 may also be the cause
for the RAS. The heat shock proteins are a component of the anti-
inflammatory cytokine and this is said to inhibit the differentiation of
the monocytes into the dendritic cells. This may further aggravate the
inflammatory process. The heat shock proteins are found at elevated
levels in smokers thus explaining the reduced occurrence of aphthae
in the smokers.
 Autoimmunity is suggested as another etiological factor for RAS.
Here the structures of the epithelium such as the desmosomes,
hemidesmosomes get disrupted due to an auto-antibody antigen
reaction at that site.
Chapter 14
Viral Infections of the Oral

Cavity
Herpes Simplex Infection
Introduction
Herpes simplex is a common viral infection that presents with localized

blistering and it affects mostly all people on one or more occasions during
their lives.
There are two main types of herpes simplex virus (HSV), although there
may be an overlap.
 Type 1, which is mainly affects the face (cold sores or fever blisters)
 Type 2, mainly affecting the genitalia (genital herpes)
Figure 1. Showing the structure of HSV-1.
Pathogenesis
The virus enters the host through disrupted skin or mucous membrane and
the source of spread of the herpes simplex infection is normally from the
bodily fluids such as the saliva, semen or the vaginal fluid or from herpes sore.
After the organism enters the host cell, it multiplies without causing any
symptoms. But if the immunity of the host is low, the virus destroys the cell.
This results in the formation of a vesicle or bullae, due to the seeping in of the
transudate from the surrounding blood vessels into the empty space left behind
by the destroyed cells. The blister lasts for duration of only about 7 to 14 days
and then disappears without scarring. The virus would have reached the site of
manifestation from the skin along the nerve fibers. They cluster at the dorsal
root ganglias where they remain latent and do not multiply. Whenever the host
Viral Infections of the Oral Cavity 159
immunity is lowered they travel again to the surface skin to produce the
manifestations of the disease. The virus may also pass through the bodily
fluids and infect other persons.
The main pathogenesis occurs in the epithelial cells of the oral mucosa. It
enters the nucleus of the cell to alter its structure. The nucleus is enlarged, and
is called a ‘giant cell,’ and this giant cell is a diagnostic feature for this
disease. The involved cell undergoes apoptosis and releases the liquid material
into the intraepithelial space and these results in the formation of the vesicles
and the bullas which is later released into the surrounding tissues after a period
of 7 to 14 days. The reactivation of this virus is normally triggered by stress,
UV light, trauma or immunosuppression. The virus now moves along the
nerve gradient to the peripheral epithelium to manifest the disease.
In what way does HSV interact with and enter Dendritic Cell (DC)?
The virus entry into the host cell passes through various barriers. The viral
envelope is made up of 11membrane glycoproteins such as gD, gH, gL and
gB. The first target is the heparin sulfate, a surface glycosaminoglycans to
which the glycoprotein C (gC) and/or gB binds to. For the virus to penetrate
the cell, the fusion needs to take place between the cell membrane and the
glycoproteins B, D, H, and L.
HSV represents a flexible and clever pathogen, which has developed a
high number of immune evasion strategies to defend itself effectively against
the attacks of the host cells. HSV takes advantage of the crucial position of DC
in antigen presentation and T cell stimulation processes. The knowledge about
the sophisticated interplay of HSV with DC enables us to introduce effective
prevention strategies such as the development of effective HSV vaccines or
new methods using the wide variety of HSV functions, as promising targets
for immunization strategies.
The defense strategy of the host consists of the dendrite mediated T helper
cell response and antibody production. But in counteraction to this there is a
down regulation of the CD4+ response which interrupts the MHC 2 antigen
processing of the host. It thus prevents it from responding to the HLA DR and
HLA DM polypeptides.
Another defense strategy by the virus includes a biphasic mechanism
where apoptosis of the host dendritic cell is inhibited. This is the early phase.
In the late phase the pro-apoptotic mechanisms are said to play a role. The
early inhibition of apoptosis enables sufficient time for the virus to multiply
within the host dendritic cell and the delayed phase helps in efficient
incapacitation and elimination of dendritic cell by HSV.
Herpes Zoster
Introduction
Shingles, also known as zoster or herpes zoster, is a painful skin rash and
is caused by the varicella zoster virus (VZV), which is the same virus that
causes chickenpox.
Figure 2. HSV remains latent along a peripheral nerve fibre.
Pathogenesis
The virus spreads by airborne viral particles discarded from the skin of an
infected person. The organism spreads without its envelope from cell to cell
producing a characteristic vesicle on an erythematous base on the epithelium,
replicates in the epithelium and then acquires a period of latency after
traveling to the dorsal root ganglia and ascending the sensory nerves. During
the period of reactivation following lowered immunity, the virus spreads
distally from the ganglion to start new cutaneous and/or mucosal lesions. The
virus invades T-cells of the blood and those T-cells carry the virus to the skin.
There, the virus can regenerate itself as the glycoproteins of the virus which is
required to form its envelope is unaffected. The superficial layers of the
epithelium or the skin lack the endosomal pathway that removes the
glycoprotein from the envelope. The mannose 6 phosphate in its glycoprotein
envelope helps it to get attracted to the sensory nerves which have the suitable
receptors where it would travel through, and then remain latent. It causes no
damage to the sensory nerves but reactivates whenever the immunity of the
individual is lowered.
Whenever there is a lowered immunity the virus travels through the nerve
pathway to reach the skin and rekindle the infection.
As the enveloped virus builds up, it creates the characteristic chickenpox
rash. Hence once the virus enters the aerosol form it can become infective
again.
The multiplication of the genes of the virus during its replication phase
occurs in installments.
1) Initially the immediate early genes are produced. These genes encode
regulatory proteins.
2) The next are the early genes which encodes enzymes necessary for
replicating the viral DNA and
3) The late genes which encode the structural proteins
4) The envelope and other structures are developed as the virus buds out
from the nuclear membrane or may arise from the endoplasmic
reticulum. They are then transported to the cell membrane via the
Golgi complex thus putting an end to the host cells.
How the virion gets reactivated and the genetic mechanism of the same is
unknown.
HIV
Introduction
It is the disease or an infection caused by the human immunodeficiency

virus. It alters and weakens the immune system and makes the person immune
to other infections and diseases.
Pathogenesis
Figure 3. Multiplication of the HIV has been studied by numerous scientists. And there
is now a consensus in the method of the action of the virus. It is a known fact that
viruses require a host to multiply. The host in this case is said to be the lymphocyte
especially the T lymphocyte, and also sometimes the macrophage.
Viral Attachment
Once HIV comes into contact with a cell, the T-cell, it must at first
connect itself to the cell so that it can fuse and inject its genetic material into
it. Attachment is a specific binding that occurs between the surface proteins of
the cell and proteins that serve as receptors. Usually, these receptors help the
cell communicate with other cells. Two receptors, namely the CD4 and a beta-
chemokine receptor (either CCR5 or CXCR4), are used by HIV to attach onto
the cell. On the surface of the viral envelope, two sets of proteins, gp120 and
gp41 attaches to CD4 and CCR5/CXCR4.
Viral Penetration/Fusion
After the completion of the attachment, viral penetration occurs.
Penetration allows the nucleocapsid or the genetic core of the virus to be
inserted directly into the cell's cytoplasm. gp120 majorly contains three sugar-
coated glycoproteins and, once gp120 attaches itself to CD4, these three
proteins spread apart. The gp41 which is normally hidden is then exposed and
this then binds to the chemokine receptor. Once this occurs, the viral envelope
and the cell membrane are brought into close contact and melt into each other.
Drugs called fusion inhibitors prevent the binding of gp41 and the
chemokine receptor.
Figure 4.
Uncoating
Once HIV has penetrated the cell membrane, it is ready to release its RNA
into the cell. The viral RNA is completely protected in the nucleocapsid. This
nucleocapsid needs to melt to allow the conversion of the viral RNA into
DNA, which is required if the virus has to enter a human T cell’s genetic core.
Figure 5.
Figure 6.
Reverse Transcription
The process whereby the single stranded viral RNA is converted to double
stranded DNA is called as reverse transcription and the enzyme necessary to
perform this action is called as reverse transcriptase. This action is necessary
for the virus to seize a T-cell's genetic machinery in order to reproduce itself.
The transcription is a normal action in all human cells, but here the DNA
converts into RNA. Reverse transcriptase uses nucleotides – which are the
building blocks of DNA -- from the cell cytoplasm to make this process
possible.
Drugs called reverse transcriptase inhibitors block HIV's reverse
transcriptase from using these nucleotides.
Integration
Figure 7.
HIV must then put in its DNA (the preintegration complex) into the host
cell's DNA, if HIV was successful in translating its instructions from RNA to
DNA. This process is called integration and in order for integration to occur,
the newly translated DNA must be transported across the nuclear membrane
into the nucleus.
HIV may carry this preintegration complex with the help of a viral
protein, to the nucleus. Once the viral RNA has successfully crossed the
nuclear membrane and been helped to the nucleus, HIV uses an enzyme
integrase to insert HIV's double-stranded DNA into the T cell's existing DNA.
Figure 8.
Drugs that inhibit the HIV preintegration complex from traveling to the
nucleus -- integrase inhibitors -- are currently in early clinical trials.
Viral Latency and Protein Synthesis
The host cell is now latently infected with HIV after the successful
integration of the viral DNA. This viral DNA is addressed as provirus. This
HIV provirus now awaits activation. When the immune cell becomes
activated, this latent provirus awakens and instructs the T cell’s cellular
machinery to produce the necessary components of HIV. From the viral DNA,
two strands of RNA are constructed and transported out of the nucleus. One
strand becomes the HIV protease, reverse transcriptase, integrase, and
structural proteins and the other strand becomes the genetic material for the
new viruses. Compounds that inhibit or alter the viral RNA have been
identified as potential antiviral agents.
Cleavage and Viral Assembly
The viral protease enzyme cleaves the various viral subunits after they
have been produced and processed, as they are now ready to convert into new
viruses.
Drugs called protease inhibitors bind to the protease enzyme and prevent
it from separating, or cleaving, the subunits.
The new HIV virions are created, if the cleavage is successfully
completed. To form the membrane of the virus the cell’s membrane begins to
undergo deformation. The viral RNA is wound tightly within the nucleocaspid
formed from this membrane. Researchers are looking at drugs called zinc
finger inhibitors, which interfere with the packaging of the viral RNA into the
nucleocapsid.
Figure 9.
Figure 10.
Budding
The conclusive step of the viral life cycle is called budding. Here, the
genetic material enclosed in the nucleocapsid fuses with the distorted cell
membrane to form the new viral envelope. Once the virus is completely
protected from the host environment, it pinches off from the cell and enters
into the circulation and it is ready to start the whole multiplication process
again.
The host T cell is killed but how exactly it dies is not known and scientists
have come up with many theories. First, is the process of apoptosis where the
host cell tries to protect itself and tries to destroy the virus within it. The next
theory is about the damage to the cell membrane which occurs due to the HIV
particles budding off from the cell. The third theory is that of the killer cell,
that recognizes that the cell is infected and injects it with chemicals and
destroys it. Due to all these mechanisms the T cells begin to decline in number
and there are not enough T cells to defend the body. At this stage, a person is
said to have AIDS, and becomes prey to infections that a healthy immune
system could have very well dealt with.
There is still much that is not yet known about HIV's life cycle. More
research will help the scientists to persuade HIV into giving up more secrets of
how it survives and spreads in the body. In turn, this will initiate the design
and development of new drugs and vaccines that could be produced to help
stop the infection.
Chapter 15
Fungal Infections of Oral Cavity
Candidiasis
Introduction
C. albicans resides normally as a lifelong, harmless commensal. C

albicans is one of the many eukaryotic species which is said to comprise about
8.7 million organisms in the world and of which only 7% of it is the fungi. Of
the 7% fungi only 600 species are said to be pathogenic to human. Among the
pathogenic fungi life threatening infections are said to be caused by
Cryptococcus neoformans, Aspergillus fumigatus, Histoplasma capsulatum,
and Candida albicans. Candida organism is responsible for most of the hospital
related infections. Superficial candidiasis and the life threatening systemic
candidiasis are the two manifestations of the candidial infections.
HIV is one of the major risk factors for developing oral candidiasis.
Further risk factors for developing oral candidiasis include the wearing of
dentures and the extremes of age.
The various predisposing factors for candidiasis are less well defined than
for oral candidiasis and include the use of antibiotics, oral contraceptives,
diabetes mellitus, pregnancy and hormone therapy. Though superficial
candidiasis is predominant and despite their frequency and associated
morbidity, they are non-lethal. But in stark contrast, in case of the systemic
candidiasis there is an associated high crude mortality rate, even with first line
antifungal therapy.
Other risk factors may play role too, namely venous catheters, trauma, and
any GI surgeries that penetrate the mucosal barrier.
Pathogenesis
A large number of factors called as virulence factors, are found to play a

role in the pathogenecity of the yeast organisms, namely the morphological
transition from the yeast to the hyphael forms, the adhesins and invasins on the
cell surface, thigmotropism, secretion of the hydrolytic enzymes and the
formation of biofilms. There is a great interplay between the candidial
organism and the host defense in the candida infections. Like any other
infections that affect the human body, the lymphocytes and the other
nonspecific inhibitors play a role. The organism undergoes multiple steps, like
an induced endocytosis and an active penetration for it to reach the internal
surfaces of the body. In case of the induced endocytosis, the host ligands such
as the E cadherin on the epithelial cells and the N-cadherin on the endothelial
cells act as the receptors, to the specialized proteins on the cell surface of the
organism, and these have been called as the ‘invasins.’
Several factors and activities have been identified which contribute to the
pathogenic potential of this fungus. Among them are molecules which mediate
adhesion to and invasion into host cells, the secretion of hydrolases, the yeast-
to-hypha transition, contact sensing and thigmotropism, biofilm formation,
phenotypic switching and a range of fitness attributes.
The candida organism is found to have three surface adhesion molecules
and an aspartyl proteinase enzyme to enable the initial penetration into the
keratinized surfaces. Fungal adhesion and physical forces are believed to be
crucial for the penetration. The deeper penetration is facilitated by hypha and
this is guided for by a mechanism of contact sensing, called the
‘thigmotropism.’ Once contact sensing occurs the organism switches to its
hyphael form and that may be enabled by the aspartic protease (Saps) which is
another factor that has been proposed to contribute to active penetration.
Whereas on the other hand lipases and phospholipases, have not been shown
to contribute majorly to this process.
The invasins have been found to be two in number:
i. Als3 (agglutinin like sequence) (an adhesin) and

Fungal Infections of Oral Cavity 171
ii. Ssa1. They bind to the host receptors by a clathrin dependent

mechanism and results in the endocytosis. Macropinocytosis is found
to be another mechanism that helps in the endocytosis.
The Als family gene is made up of 8 members, Als1-7to Als9. It encodes

the glycosylphosphatidylinositol (GPI)-linked cell surface glycoproteins. The
Als 3 is important for the adhesion. It is upregulated during the candidial
infections, whether they are the mucosal or vaginal.
Ssa1 is a cell-surface expressed member of the heat shock protein 70
(Hsp70) family.
Another important adhesin of C. albicans is the Hwp1, which is a hypha-
associated GPI-linked protein. The link between Hwp1 and C albicans is said
to be by covalent bonds.
Once the fungus enters the various phagocytic cells either the neutrophils
or the macrophages, it switches conveniently from one form to the other. Like
for e.g., in the PML, the cells produce the reactive oxygen species,
antimicrobial peptides etc. The organism is now nutritionally starved. The
organism then switches to the hyphae form and resists the unfavorable
environment. In case of the macrophages the organisms switches from
glycolysis to gluconeogenesis and later it makes use of the lipids and the
amino acids as the food source.
Schematic diagram illustrating the contribution of the various virulence
factors contributes to C. albicans pathogenicity. C. albicans commonly
colonizes the epithelial surface (stage 1) and causes superficial infections
(stage 2), but under conditions when the host is compromised, the fungus
establishes deep-seated infections (stage 3) by penetrating further into the
epithelial tissue. Occasionally, C. albicans causes disseminated infections
(stage 4), which allow the fungus to colonize and infect other host tissues and
can be fatal. This infective process involves numerous virulence attributes
including adhesins, hydrolytic enzyme production (Sap proteins,
phospholipases, and lipases), hypha formation, and phenotypic switching.
Sap2 (and possibly other Sap proteins) is known to degrade many human
proteins, including mucin, extracellular matrix proteins, numerous immune
system molecules, endothelial cell proteins, and coagulation and clotting
factors. Therefore, the action of Sap proteins could be involved in all four
stages of infection and probably greatly enhance the pathogenic ability of C.
albicans.
Figure 1. An overview of selected C. albicans pathogenicity mechanisms. Yeast cells

adhere to host cell surfaces by the expression of adhesins. Contact to host cells triggers
the yeast-to-hypha transition and directed growth via thigmotropism.
Figure 2.
Fungal Infections of Oral Cavity 173
Mucormycosis
Introduction
Mucormycosis (also called zygomycosis) is a rare infection caused by

organisms that belong to a group of fungi called Mucoromycotina in the order
Mucorales. These fungi are classically found in the soil and in involvement
with decaying organic matter, such as compost piles, leaves, or rotten wood.
Pathogenesis
The mucorales are common organisms to which a human is constantly

exposed. They predominantly play a role in the patients with diabetes due to
the ketoacidosis occurring in them, which has a property of removing iron
from sequestering proteins in serum and this serves as a nutritional source for
the fungus and in patients having defects in the phagocytic functions. The
infection is also commonly seen in persons having increased free iron, which
is a nutritional bed for the fungi. The presence of a glucose regulated protein
GRP 78 is said to protect the patients from being infected by mucormycosis.
But it provides no immunity against the other fungi, candida and aspergillus
fumigatus.
Chapter 16
Regressive Alterations of Teeth
Internal Resorption
Introduction
The classification for internal resorption includes internal inflammatory

resorption and internal replacement resorption.
External resorption is classified into external replacement resorption,
external inflammatory resorption, external surface resorption, external cervical
resorption and the transient apical breakdown.
Pathogenesis
Internal resorption occurs following caries, pulpotomy, following the heat

generated during cutting of dentin, trauma to the teeth or a cracked tooth and
also sometimes in relation to the orthodontic treatment. In the root canal
replacement type the dentin is severely damaged and the tissue is replaced by a
hard tissue that resembles bone or cementum.
Herpes zoster has been said to play a role in the degeneration of the
odontoblasts during its systemic infectious state. It has been speculated that
such a state occurs due to the attraction of the virus to the nerve endings in the
pulp and is commonly seen during the involvement of the maxillary branch of
the trigeminal nerve.
Genes such as the IL-1 gene polymorphism has been suggested to play a
role in the development of the internal resorption.
The inflammation in the pulp attracts a large number of the inflammatory
cells, predominantly the macrophages and together with it the odontoclasts.
These clast cells initiate the resorption from the inside. The intensity of the
inflammation primarily determines the internal resorption. The resorption is
followed by formation of granulation tissue and this, walls of the infection and
prevents its further spread into the surrounding tissue. The collateral blood
supply from periodontal tissue helps in continuing with the resorptive process.
In the case of the internal resorption, the inflammatory type, there is no
associated hard tissue formation and the resorption ends with the formation of
the granulation tissue.
In the replacement type the resorbed area is replaced by tissue resembling
bone or cementum. This may result in enlargement of pulp space with partially
or fully obliterated pulp chamber.
Figure 1. Depicting the etiopathogenesis of internal resorption.

Regressive Alterations of Teeth 177
Pulp stones
Introduction
Pulp stones (denticles) are nodular, calcified masses of substance

appearing in either or both in coronal and radicular portion pulp organ in teeth.
Pathogenesis
The focus or the loci for formation of the pulp stones are the degenerating
neural sheath and blood vessels. Hence this may result in reduction in both
these structures in the pulp chamber. The pulp also becomes fibrotic, together
with the appearance of the pulp stones.
True pulp stones show the presence of odontoblasts lining a focal area of
pulp tissue.
Epithelial cell nests, considered as the epithelial cell rests of Malassez,
which had become entrapped during development, become surrounded by
concentrically arranged fibers – an organic phase that is impregnated with
mineral salts.
True pulp stones were formed following an inductive interaction between
the epithelium and the pulp tissue. The false pulp stones formed around a
nidus. It has been suggested that the fibroblasts themselves have the property
of inducing the formation of the apatite crystals. Unidentified mesenchymal
stem cells and pericytes are cell lines that differentiate into odontoblast like
cells when suitable conditions are prevalent. Experiments have shown that the
mineral formed may be bone like or dentin like. Minor circulatory
disturbances in the pulp vessels could result in the initiation of the said
mineralization in the mitochondrial matrix when viewed through an electron
microscope. Different forms of calcium phosphate may play a role in
formation of these stones. Small stones may show just a single layer of the
collagen fibers that has undergone mineralization. But the larger stones are
formed by multiple layers of these collagen fibers wound one around the
other and then undergoing mineralization. It has been found that the
chemical constituent of the pulp stones are similar to that of the hydroxyapatite
crystals, in terms of the presence of zinc, calcium and phosphorus.
Immunohistochemical antibodies to the pulp stones such as against Type 1
collagen and non collagenous proteins like osteopontin, osteonectin and
osteocalcin, showed that type 1 collagen was evenly distributed in the stone,
osteonectin and osteocalcin were not detected and osteopontin was found
positive in the peripheral area of the pulp stone and played a major role in the
calcification and it has come from the less differentiated pulp cells. The
osteopontin presence in the pulp stone indicated its similarity to the
atherosclerotic plaques in the heart tissue and the urinary stones in the kidneys.
In the deciduous dentition the pulp stones were smaller in size and very low in
proportion indicating that pulp stones increased in size and number as the
tooth aged. Also the diffuse calcifications were more predominant in adult
teeth as opposed to the deciduous teeth.
A possibility of dental procedures conducted on the pathological tooth
prior to the stone formation suggested that this factor may play a role in stone
formation. But the correlation was said to be very weak. Another factor
playing a role in initiating stone formation was the occurrence of caries in the
involved teeth.
Though the property of the pulp stone was found similar to the kidney
stone but they never occurred simultaneously.
But on the other hand patients having atherosclerotic plaques did show an
increased occurrence of the pulp stones.
Occurrence of pulp stones was also found to be higher in persons with
developmental anomalies of teeth such as dilacerations, impactions,
taurodontism and enamel pearls.
Further studies have stated that the stones are formed due to the
nanobacteria which produce the apatite crystals.
About the Authors
Dr PC Anila Namboodiripad, is an alumini of the prestigious KLE

Society’s Dental College, Belgaum, Karnataka, India. She is currently working
as a Professor in the Department of Oral and Maxillofacial Pathology at the
Royal Dental College, Kerala. She has about 23years of teaching experience,
guiding both the undergraduate and post graduate dental students. She is a life
member of the Indian Association of Oral and Maxillofacial Pathologists. She
has attended numerous National Conferences and has also had the privilege to
chair scientific sessions. She has a number of Pubmed indexed articles in
International journals to her credit. She is currently the Associate Editor of the
prestigious Oral and Maxillofacial Journal, a Journal of the Kairali Society of
Oral and Maxillofacial Pathologists.
E-mail: anilla93@yahoo.co.in
Dr. E. Anuradha Sunil did her graduation and Post graduation in Oral
Pathology from Govt. Dental College, Patna, India.
Currently she is the Principal and also heads the Department of Oral
Pathology in Royal Dental College, Kerala, India. She is a guide of Post-
graduate students and also the editor of the Oral and Maxillofacial Pathology
Journal of the local Kairali Society of Oral and Maxillofacial Pathologists. She
is a member of the Indian Association of Oral and Maxillofacial Pathologists.
She has attended National Level Conferences and also chaired scientific
sessions.
Index
alkaline phosphatase, 99, 117

# allele, 46, 52, 70
allelic loss, 46, 70
10q24, 136
allergens, 142
allergy, 27
A alters, 50, 125, 161
Ameloblastoma, 95, 96, 97
acetylcholine, 130 Amelogenesis imperfecta, 18
achondroplasia, 10, 126 amelogenin, 18, 19, 98, 102
acid, 82, 112, 113, 123 amines, 37, 145
Acinic cell carcinoma, 65 amino acid, 112, 113, 116, 119, 123, 171
Actinomycosis, 151 anchoring, 134, 135, 136, 137
acute leukemia, 64 anemia, 108
acute myeloid leukemia, 60 Aneurysmal bone cyst, 90
adalimumab, 139 angiogenesis, 36, 38, 58, 66
adaptive immune responses, 81 anhidrotic ectodermal dysplasia, 5
Adenoid cystic carcinoma, 66 anodontia, 4
adenoma, 59, 60, 67 antibody, 54, 64, 86, 131, 133, 139, 143,
adenosine, 116 150, 155, 159
adhesion, 19, 58, 66, 67, 70, 131, 135, 138, antigen, 59, 63, 78, 79, 86, 134, 140, 141,
140, 170, 171 142, 143, 145, 149, 152, 153, 155, 159
adipose tissue, 42 antioxidant, 37, 39, 133
Africa, 51 antiviral agents, 167
aggressive behavior, 70, 71, 96, 97 aorta, 127
agriculture, 145 APC, 40, 63, 145, 150
AIDS, 168 apex, 14, 83
airways, 127 apoptosis, 38, 39, 40, 46, 48, 49, 50, 51, 52,
albumin, 21 66, 71, 77, 79, 96, 97, 102, 106, 124,
alcoholics, 106 131, 132, 141, 145, 159, 168
182 Index
apoptosis pathways, 46 blood, 23, 80, 91, 92, 117, 127, 137, 143,
apoptotic mechanisms, 159 150, 158, 161, 176, 177
appetite, 108 blood stream, 150
arginine, 116, 119, 126 blood supply, 23, 176
arteriovenous shunt, 91 blood vessels, 80, 91, 127, 158, 177
ascorbic acid, 38 bloodstream, 151
asthma, 27 BMP, 16, 36
atherosclerotic plaque, 178 bonds, 112
atopy, 27 bone, 4, 10, 12, 14, 21, 22, 43, 44, 45, 49,
atrophy, 108 53, 75, 82, 83, 84, 88, 90, 91, 92, 93, 95,
attachment, 83, 162 96, 97, 111, 112, 113, 114, 115, 116,
autoantibodies, 130, 131, 132, 136, 138, 117, 118, 119, 120, 121, 122, 123, 124,
139, 143, 145 125, 126, 175, 176, 177
autoantigens, 130, 138 bone biology, 124
autoimmune disease, 62, 129, 134, 141, 142 bone cells, 125
autosomal dominant, 8, 11, 18, 113, 124, bone form, 117, 118, 120, 121, 122
126, 127 bone marrow, 12, 44, 49, 53, 96, 123
autosomal recessive, 18, 113 bone resorption, 82, 83, 97, 116, 122, 124
axilla, 133 BRAF gene, 34
brain, 60, 123
breakdown, 91, 92, 116, 175
B BRM gene, 36
budding, 168
bacteria, 121, 149, 151, 152, 154
building blocks, 165
bacterial infection, 151
Bullous Pemphigoid, 135, 136, 139
barriers, 159
Basal cell adenoma, 60
Basal cell carcinoma, 34, 35, 36, 69, 70 C
basal lamina, 98
basal layer, 34, 81, 97, 100 caecum, 15, 25
base, 32, 113, 126, 160 calcification, 21, 85, 86, 99, 150, 178
basement membrane, 59, 99, 134, 135, 136, Calcifying epithelial odontogenic tumor, 99
138, 139, 141 calcium, 18, 21, 89, 145, 177
basophils, 138 CAMTA1, 54
BCL-2, 36 canals, 9, 83
bending, 13 cancer, 37, 52, 53, 60
benign, 15, 33, 39, 42, 44, 54, 57, 59, 60, candida, 26, 169, 170, 173
61, 69, 70, 72, 84, 89, 91, 95, 100, 102 capillary, 83
beryllium, 44 capsule, 62
bilateral, 120 carboxyl, 112, 136
biological behavior, 54, 79 carcinogenesis, 32, 33, 40, 58, 106
biopsy, 78 carcinoma, 33, 35, 36, 37, 40, 62, 63, 64,
bleeding, 93 65, 66, 67, 69, 78, 84, 97, 100, 101
cardiac muscle, 54
Index 183
caries, 4, 23, 175, 178 circulation, 150, 168

cartilage, 111, 119, 120, 126, 127 classification, 47, 100, 175
cascades, 78 Clear cell odontogenic carcinoma, 101
caspases, 131 cleavage, 19, 167
cathepsin G, 138 clinical diagnosis, 105
causation, 10, 20, 33, 154 clinical presentation, 116
CBS, 125 clinical trials, 166
CCND1, 39 clone, 48, 50, 54
CD8+, 47, 140, 141, 152 closure, 119
CD95, 36, 97, 141 clusters, 5, 34
CDKN2A, 36, 39, 65 coding, 58, 66
CDKN2A and CDKN2B both cyclin- cold sore, 157
dependent kinase inhibitor genes, 36 collagen, 21, 71, 98, 107, 108, 112, 113,
cell biology, 58 114, 117, 134, 135, 136, 150, 151, 177
cell cycle, 32, 35, 39, 40, 44, 45, 46, 52, 58, collateral, 76, 176
66, 79, 82, 97, 106, 142 color, 106, 140, 152
cell death, 32, 40, 45, 54, 76, 79, 131 commercial, 145
cell differentiation, 97, 118 communication, 79, 133
cell division, 125 competition, 139
cell line, 45, 66, 177 complement, 5, 136, 137, 138, 139, 154
cell membranes, 82, 99 complexity, 79
cell metabolism, 61 composition, 66, 117
cell surface, 50, 133, 143, 170, 171, 172 compost, 173
Cementoma, 103 compounds, 39
Cerb-B2, 67 condensation, 45
chemical, 33, 44, 121, 123, 145, 168, 177 configuration, 112
chemokine receptor, 50, 162, 163 Congenital epulis, 54
chemoprevention, 38 connective tissue, 38, 46, 70, 79, 81, 84, 90,
chemotaxis, 83, 151 91, 92, 102, 104, 108, 113, 114, 127,
chemotherapy, 12 136, 151
Cherubism, 120, 121 consanguinity, 18
childhood, 26, 50, 75, 120 consensus, 162
cholesterol, 38, 82 consumption, 27, 145
chondroblastoma, 91 contraceptives, 27, 169
chondrocyte, 120, 126 controversial, 14, 84, 85, 133
chromium, 44 cooperation, 71
chromosome, 5, 22, 40, 44, 46, 52, 53, 57, copper, 107
58, 59, 60, 62, 66, 113, 115, 120, 124, correlation, 5, 142, 178
125, 126, 127, 128 cortex, 111
chronic irritation, 42 cortical bone, 92
Cicatricial Pemphigoid, 134 covalent bond, 171
cigarette smoke, 33, 105 covering, 4, 74, 91
cilia, 72, 73 cracks, 19
184 Index
crown, 9, 10, 12, 19, 72, 74, 99 deprivation, 141

crust, 40 deregulation, 52, 79
crystals, 18, 20, 21, 113, 177, 178 derivatives, 145
Cyclin, 40, 41, 46 dermis, 34, 134, 135, 137
cycling, 38 destruction, 18, 53, 89, 95, 96, 121
cyclins, 40 detachment, 70, 131, 133
CYP2D6, 35 detection, 65, 78, 107
cyst, 69, 72, 74, 75, 76, 77, 78, 79, 80, 81, developmental process, 88
82, 83, 84, 85, 87, 88, 89, 90, 91, 92, 93, diabetes, 169, 173
99, 101, 121 diaphragm, 6
cystathionine, 125 diet, 145
cysteine, 116 diffusion, 108
cytochrome, 96, 108 digestion, 101, 108, 149
cytokines, 50, 67, 72, 81, 116, 139, 141, dilacerations, 12, 13, 14, 178
145, 153, 155 disability, 125
cytomegalovirus, 71 disease activity, 143
cytoplasm, 34, 60, 78, 143, 162, 165 disease progression, 108
cytoskeleton, 131 diseases, 80, 161
cytotoxic agents, 138 disorder, 18, 107, 111, 113, 114, 115, 116,
121, 124, 126, 153
displacement, 14
D distribution, 79
DNA, 32, 35, 36, 38, 59, 61, 70, 106, 113,
defects, 117, 124, 173
116, 119, 142, 143, 145, 161, 163, 165,
deficiency, 10, 11, 21, 22, 23, 27, 38, 54,
166
107, 108
dosage, 70
deformation, 167
Down syndrome, 12, 125, 126
degenerate, 81, 87
drug resistance, 37, 40
degradation, 18, 19, 20, 21, 22, 31, 32, 107,
drugs, 38, 44, 126, 139, 142, 145, 167, 168
123
dwarfism, 126
dendrites, 34
dyes, 37
dendritic cell, 99, 153, 155, 159
dysplasia, 10, 22, 91, 103, 115, 116, 118,
dens invaginatus, 14, 15, 16
119
dental caries, 80
Dentigerous cyst, 72
dentin, 3, 4, 8, 10, 13, 19, 21, 22, 23, 76, E
103, 104, 175, 177
dentin formation, 22 EBNA, 52
Dentinogenesis Imperfecta, 21, 22, 111, 115 EBV infection, 53
Dentinoma, 104 E-cadherin, 40, 77, 97
dentures, 169 ECM, 138
deposition, 19, 42, 53, 92, 99, 112, 113, ectoderm, 3, 88
118, 127, 128 ectodermal dysplasia, 5, 12
depression, 40 ectomesenchymal cells, 4
Index 185
eczema, 27 external environment, 82

edema, 85 extracellular matrix, 19, 21, 82, 100, 112,
egg, 114, 125 138, 171
elastin, 108, 127, 128 extraction, 92
electron microscopy, 128 extravasation, 90, 92
embryogenesis, 62, 125, 126
ENAM, 18
enamel, 3, 4, 9, 10, 11, 13, 14, 15, 16, 17,
F
18, 19, 20, 21, 22, 23, 69, 72, 74, 76, 77,
families, 6, 18
79, 80, 85, 86, 95, 96, 98, 99, 103, 178
FAS, 97
encoding, 115
fat, 42, 117
endocrine, 116
fatty acids, 82
endoderm, 25
fertilization, 115
endothelial cells, 41, 100, 151, 170
fetal development, 114
endotoxins, 72
fever blisters, 157
enlargement, 91, 96, 97, 120, 176
fibers, 117, 128, 135, 150, 177
environmental conditions, 11
fibroblast growth factor, 95, 116
environmental factors, 9, 143
fibroblasts, 38, 55, 71, 82, 107, 108, 138,
enzyme, 37, 53, 60, 61, 82, 107, 108, 112,
150, 152, 177
116, 125, 138, 161, 165, 166, 167, 170,
fibrosarcoma, 102
171
fibrosis, 107, 150, 152, 153
eosinophils, 137, 138, 139
fibrous cap, 99
epidermis, 38, 129, 134, 135, 138
Fibrous dysplasia, 43, 91, 115, 116, 117,
epigenetic alterations, 70, 71
118
epithelial cells, 11, 46, 63, 81, 82, 87, 98,
fibrous tissue, 99, 115
99, 159, 170
filament, 131
epithelium, 4, 13, 15, 16, 20, 40, 63, 69, 70,
fitness, 170
72, 73, 74, 75, 76, 77, 79, 80, 81, 83, 84,
flaws, 93
85, 86, 88, 89, 90, 95, 96, 97, 98, 99,
flexor, 140
100, 101, 102, 104, 106, 108, 140, 155,
fluid, 72, 81, 82, 83, 87, 92, 137, 138, 158
159, 160, 177
follicle, 13, 72, 75, 79, 98
epulis, 54
follicles, 4, 71
ERMS, 45, 46, 47
food, 107, 171
erythrocytes, 91
foramen, 25
estrogen, 55, 118
force, 19
etiology, 11, 12, 14, 15, 22, 26, 33, 76, 90,
formation, 3, 4, 5, 6, 7, 11, 12, 14, 15, 16,
92, 102, 106, 119, 154
18, 19, 20, 21, 22, 33, 36, 39, 42, 43, 45,
eukaryotic, 169
46, 48, 52, 54, 62, 72, 74, 75, 77, 79, 80,
evidence, 50, 65, 80, 92, 100, 106, 154
87, 89, 91, 95, 96, 98, 103, 108, 112,
exaggeration, 70
117, 122, 123, 124, 126, 130, 133, 136,
exclusion, 105
137, 138, 139, 140, 144, 152, 153, 154,
exons, 64, 66
155, 158, 159, 170, 171, 176, 177, 178
exposure, 10, 34, 37, 106, 150
fractures, 53, 111, 115
186 Index
fragility, 111, 113 glycosaminoglycans, 159

fragments, 4 goblet cells, 82
fungus, 152, 169, 170, 171, 173 Granular cell tumor, 55
fusion, 9, 15, 25, 26, 41, 46, 54, 58, 59, 62, granules, 34, 101, 152
64, 65, 88, 89, 91, 125, 149, 159, 163 granulomas, 121
Gremilin, 36
growth factor, 43, 45, 58, 72, 79, 81, 97,
G 106, 118
growth pressure, 14
ganglion, 160
GST, 35
gelatinase A, 138
GTPases, 97
gene expression, 59
gene regulation, 31
genes, 4, 14, 20, 21, 22, 27, 32, 33, 34, 35, H
36, 37, 40, 46, 50, 54, 58, 59, 60, 66, 67,
70, 74, 96, 114, 116, 118, 119, 120, 125, hard tissues, 76, 84
126, 128, 133, 149, 161 healing, 33, 150
genetic alteration, 45, 70 health problems, 113, 126
genetic disease, 120, 128 hearing loss, 22, 111
genetic factors, 15 heart valves, 127
genetic information, 46 heat shock protein, 131, 155, 171
genital herpes, 157 height, 111
genital warts, 31 helical conformation, 112
genomic instability, 106 Helicobacter pylori, 142, 154
Geographic tongue, 27 Hemangioendothelioma, 54
germ cells, 114 hematoma, 92
germination, 9, 10 hemidesmosome, 134, 135, 136
Giant cell granuloma, 41 hepatitis, 140, 142
gingival, 75, 76, 79, 84 HER-2, 65
gland, 59, 61, 62, 63, 65, 77, 78, 87, 89 heredity, 9, 11, 103
GLI1, 36, 47, 70 herpes, 154, 157, 158, 160
glioblastoma, 54 histamine, 82
glioblastoma multiforme, 54 histidine, 59, 116
glioma, 36, 70 histogenesis, 63, 76, 98, 100
Globulomaxillary cyst, 88 histological features, 77, 79, 117
glomerulonephritis, 143 histology, 72, 84
glossitis, 26, 27 history, 113, 114
gluconeogenesis, 171 HLA, 27, 52, 63, 107, 145, 159
glucose, 173 HLA antigens, 107
glutathione, 38, 107 HMGA2, 58, 59, 67
glycine, 112, 113, 126 homeostasis, 12
glycogen, 74, 77, 101 hormones, 27, 72, 95, 143, 169
glycolysis, 171 host, 48, 81, 158, 159, 161, 162, 166, 168,
glycoproteins, 53, 159, 161, 162, 171 170, 171, 172
Index 187
HPV, 31, 32, 35, 37, 40, 106 individuals, 12, 22, 33, 55, 92, 119, 126,
human, 5, 31, 32, 35, 38, 70, 71, 97, 98, 145
121, 123, 128, 133, 136, 142, 161, 163, induction, 16
165, 169, 170, 171, 173 industry, 145
human body, 170 infants, 113, 114
human immunodeficiency virus (HIV), 27, infection, 15, 50, 53, 74, 76, 80, 81, 87, 106,
53, 142, 161, 162, 163, 165, 166, 167, 135, 149, 151, 152, 158, 161, 168, 171,
168, 169 173, 176
human papilloma virus, 142 infectious agents, 140
humoral immunity, 138 inflammation, 27, 41, 72, 80, 81, 82, 108,
Hunter, 19 121, 137, 139, 142, 176
hyaline, 98 inflammatory cells, 72, 87, 136, 138, 150,
hybrid, 64 176
hydroxyapatite, 18, 20, 113, 177 inflammatory disease, 152
hydroxyl, 112 inflammatory mediators, 81, 136, 145
hyoid, 25 inguinal, 133
hyperactivity, 6, 11, 103, 143 inherited disorder, 21, 127
hypercalcemia, 96 inhibition, 35, 36, 50, 71, 78, 102, 138, 159
hyperpituitarism, 9 initiation, 7, 16, 22, 27, 39, 40, 64, 93, 177
hypersensitivity, 142, 150 injury, 90, 132, 139, 143
hypertrophy, 120 insulin, 45
hypothesis, 32, 51, 92, 98, 131 integration, 166
integrin, 38, 40, 134, 135
integrity, 127, 129, 141
I intercellular adhesion molecule, 140
interface, 98
identification, 96, 142
interference, 121, 138
idiopathic, 76
interferon, 81, 150
IL-8, 139, 140
interferon (IFN), 81 142, 154
immune response, 124, 143, 154
interferon γ (IFNγ), 153
immune system, 121, 141, 142, 161, 168,
interferon gamma, 150
171
Internal resorption, 175
immunity, 53, 150, 158, 159, 160, 161, 173
internalization, 131
immunodeficiency, 26
intervention, 93
immunofluorescence, 139
intron, 66
immunogenicity, 145
invaginate, 72
immunohistochemistry, 65, 67
ionizing radiation, 10
immunolocalization, 78
iron, 107, 108, 173
immunoreactivity, 86
irradiation, 106
immunosuppression, 159
ischemia, 91
impacted teeth, 11, 99
islands, 74, 84, 87, 89, 98
in vitro, 118, 139
isolation, 18
incidence, 9, 23
incisors, 5, 8, 10, 15
188 Index
lipid peroxidation, 133

J lipids, 171
lipoma, 42
joints, 143
lithium, 27
LMP1, 50
K localization, 99, 141
locus, 52, 65, 119, 177
K5 gene a basal keratinocyte gene and the, lumen, 72, 83, 84
36 lupus erythematosus, 143, 145
karyotype, 62, 125 lymph gland, 152
keratin, 86, 99, 103, 105, 136 lymph node, 62, 150
keratinocytes, 36, 38, 79, 81, 130, 131, 132, lymphocytes, 47, 49, 52, 140, 145, 170
133, 134, 135, 138, 140, 141, 154 lymphoid, 47, 49, 61, 62, 63
Keratoacanthoma, 33 lymphoma, 47, 49, 51, 52
keratosis, 105 lysine, 112
ketoacidosis, 173 lysis, 53
kidneys, 53, 73, 143, 178
kinetics, 79
KIT-SCF, 38 M
KLK4 gene, 19
macrodontia, 9
macrophages, 41, 82, 121, 123, 140, 149,
L 150, 171, 176
magnesium, 18
labio-dental lamina, 3 major histocompatibility complex (MHC),
labio-dental sulcus, 3 47, 140, 141, 150, 154, 159
lamella, 3 malaria, 53
laminin-5, 135 malignant melanoma, 34, 39, 53
Langerhans cells, 99, 140 malignant tumors, 70
larynx, 25 mandible, 10, 12, 92, 95, 102, 115, 120
latency, 160 mantle, 22, 47, 49
Lateral periodontal cyst, 74 manufacturing, 121
leakage, 133 MAPK/ERK, 39
lens, 127 Marfan syndrome, 127, 128
lesions, 42, 44, 70, 78, 80, 83, 85, 91, 105, marrow, 116, 117
117, 118, 121, 133, 137, 160 MAS, 116
leucine, 123 material degradation, 99
leukoplakia, 105, 106 materials, 27, 86, 98
liberation, 138 matrix metalloproteinase, 71, 77, 95, 138,
Lichen Planus, 105, 108, 140, 141, 142 139, 141, 151
life cycle, 168 maxilla, 10, 12, 14, 87, 88, 95, 102, 115,
ligament, 4, 74, 127 120
ligand, 35, 58, 64, 97, 139, 141 MBP, 138
lipases, 170, 171 MC1R, 34
Index 189
MCP, 138 morbidity, 169

MDM2, 46, 67 morphogenesis, 121
measles, 123 morphology, 4, 8, 12, 14, 18, 34
mechanical properties, 113 mortality, 169
mechanical stress, 115, 117 mortality rate, 169
MECT1-MAML2, 62, 64, 65 mosaic, 111, 114, 122, 126
median, 25, 26, 64 motivation, vii
Median rhomboid glossitis, 26 mRNA, 118, 127
meiosis, 125 mucin, 87, 89, 90, 171
MEK, 39 mucormycosis, 173
melanin, 37, 38, 40, 116 Mucormycosis, 173
Melanogenesis, 39 mucosa, 100, 105, 106, 107, 129, 134, 141,
melanoma, 37, 38, 39, 40 149, 153, 154, 159
mellitus, 169 mucous membrane, 129, 138, 140, 158
melt, 162, 163 mucus, 63, 64, 78, 89, 90
mesenchymal stem cells, 177 multiple myeloma, 53
mesenchyme, 16, 45, 78, 102 mutation, 4, 11, 18, 19, 22, 23, 32, 38, 40,
mesoderm, 88 44, 46, 47, 50, 51, 65, 66, 70, 71, 103,
MET, 45, 46 106, 111, 113, 114, 115, 116, 119, 121,
metabolism, 22 120, 122, 123, 124, 126
metalloproteinase, 71 mycobacteria, 150
metastasis, 60 myoblasts, 46, 47, 55
methyl group, 70 myogenesis, 46
methylation, 70, 71
microdontia, 8
microorganism, 150
N
microscope, 98, 139, 152, 177
natural killer cell, 141
migration, 38, 138
necrosis, 23, 81, 86, 91, 92, 149
miliary tuberculosis, 150
neonates, 55
mineralization, 19, 22, 113, 115, 177
neoplasm, 41, 42, 66, 84, 85, 89
mitochondria, 61, 133
nephritis, 143
mitogen, 34, 127
nerve, 42, 43, 66, 67, 158, 159, 160, 161,
MMP, 90, 95, 96, 99, 138, 139, 142
175
MMP-2, 95, 138
nerve fibers, 158
MMP-9, 96, 99, 138, 139, 142
neural crest cells, 3, 4, 23
modifications, 112
neural development, 54
molecular biology, 16
neuroblastoma, 54
molecular weight, 86
neurofibroma, 42, 43
molecules, 16, 21, 58, 79, 83, 108, 112, 113,
neuropathy, 54
114, 127, 128, 139, 143, 145, 170, 171
neutrophils, 83, 137, 138, 149, 171
monoclonal antibody, 54, 130
nevus, 34, 39, 105
monolayer, 19
nicotine, 105, 108
monosomy, 62
NK cells, 154
190 Index
nodes, 62
nodules, 26
P
non-amelogenin, 18
translocations at (11; 19) (q21), 62
nondisjunction, 125
p53, 31, 32, 36, 40, 46, 49, 70, 106, 131,
normal development, 26, 117
142
NOTCH-1, 50
palate, 25, 26, 107
nuclear membrane, 161, 166
pancreas, 67
nuclei, 41, 58, 60, 78, 84, 143, 150, 159,
parasite, 152
166, 167
parathyroid, 39, 118, 121
nucleotides, 165
parents, 114, 126
nutrient, 151
parotid, 62, 65
nutrition, 81
pathogenesis, 18, 23, 33, 34, 37, 40, 44, 46,
52, 53, 54, 57, 59, 61, 62, 63, 66, 72, 74,
O 75, 83, 86, 87, 89, 92, 93, 98, 103, 104,
106, 121, 127, 129, 130, 131, 133, 140,
obstruction, 89 141, 142, 143, 152, 159
odontoblastic cell, 22 pathology, 4
odontodysplasia, 23 pathway, 32, 35, 38, 39, 45, 46, 50, 54, 71,
Odontoma, 85, 103 103, 106, 127, 128, 131, 133, 139, 141,
oligodontia, 4 161
Oncocytoma, 60, 61 PDGF, 78
oncogenes, 46, 72 PDL, 80
oncoproteins, 39 pemphigus, 130, 131, 132, 133, 134, 138
oral cavity, 3, 5, 8, 75, 80, 89, 108, 129, 135 penetrance, 8
Oral submucous fibrosis, 107 peptide, 47, 118, 128, 140, 141, 145, 171
oral vestibule, 3 pericytes, 177
organ, 3, 4, 10, 14, 15, 16, 20, 54, 61, 69, periodontal, 4, 74, 75, 76, 79, 80, 81, 84, 88,
72, 77, 79, 87, 95, 96, 98, 99, 152, 177 176
organelles, 73, 101 periosteum, 91
organic matter, 173 peripheral blood, 154
organism, 149, 150, 151, 152, 158, 160, permeability, 82
169, 170, 171 peroxide, 35
orthodontic treatment, 175 phagocytic cells, 150, 171
osmotic pressure, 83, 92 phagocytosis, 108
ossification, 111, 126 phenotypes, 22, 38, 47, 50, 117, 118, 128
osteoclastogenesis, 124 phosphate, 89, 161, 177
Osteogenesis, 111, 113 phospholipids, 145
osteogenesis imperfecta, 21, 111, 113, 114 phosphorus, 21, 22, 177
osteonectin, 22, 117, 177 phosphorylation, 39, 40, 106, 132
Osteosarcoma, 43 photosensitivity, 145
overproduction, 53, 116, 121 physical features, 125
oxidation, 38 pigmentation, 37, 116
oxidative stress, 37, 40, 133 plaque, 78, 135
Index 191
plasma cells, 53 proteins, 5, 18, 19, 21, 22, 31, 35, 45, 53,
plasma membrane, 134, 135 54, 58, 79, 82, 90, 95, 97, 99, 102, 106,
plasminogen, 90, 138 116, 121, 129, 130, 132, 136, 138, 143,
plasticity, 12, 14 155, 161, 162, 170, 171, 173, 177
playing, 11, 19, 35, 36, 45, 49, 54, 82, 88, proteoglycans, 128, 135
96, 98, 118, 121, 127, 143, 178 proteolytic enzyme, 138
Pleomorphic adenoma, 59 proto-oncogene, 49
pneumonia, 149 Pseudocysts, 90
point mutation, 34 psoriasis, 27, 33, 139
polarization, 84, 97 PTEN, 38, 39
polychlorinated biphenyl, 37 puberty, 43, 121
polymorphisms, 38, 176 pulp, 3, 4, 9, 10, 11, 13, 14, 22, 23, 76, 81,
polyostotic fibrous dysplasia, 116 103, 175, 176, 177, 178
polypeptides, 159 pus, 152
population, 8, 47, 57, 117
precipitation, 89
precursor cells, 120
Q
pregnancy, 169
quinone, 38
premolars, 6, 15, 16, 75, 97
preparation, 5
prevalence rate, 18 R
prevention, 159
primary epithelial band, 3 radiation, 23, 43
primary tumor, 55 radiodensity, 23
probability, 74, 106 radium, 43
progenitor cells, 72 RAS, 38, 39, 154, 155
progesterone, 55 rash, 160, 161
prognosis, 45, 65 Rb, 38, 40, 44, 45, 46
programming, 124 RBC, 82
proliferation, 7, 8, 9, 11, 31, 35, 36, 39, 44, reactions, 124
46, 49, 53, 58, 61, 63, 70, 77, 78, 79, 81, reactive oxygen, 38, 132, 171
82, 84, 89, 96, 97, 100, 102, 104, 106, reactivity, 86
118, 127, 136, 141, 153 receptor, 35, 43, 45, 46, 47, 50, 51, 58, 73,
proline, 112, 123 97, 106, 116, 118, 121, 123, 124, 126,
promoter, 58, 59, 118 130, 131, 133, 136, 138, 161, 162, 170,
prostaglandins, 81 171
protease inhibitors, 167 reciprocal translocation, 54, 62
protection, 35, 37, 49, 96 recruiting, 136
protein components, 134 recurrence, 64, 77, 79
protein family, 136 Recurrent aphthous stomatitis, 153
protein kinase C, 124 regenerate, 161
protein synthesis, 118 regression, 121
proteinase, 138, 170 regulator gene, 35
remodelling, 153
192 Index
renal failure, 53 sexual contact, 151

repair, 32, 52, 106 shape, 6, 8, 11, 12, 34, 120, 140
reparation, 129 shear, 72
replication, 32, 161 shock, 155
researchers, 119, 142 shortage, 113, 119
residual matrix, 19 showing, 14, 50, 65, 70, 106, 117, 133
residues, 80, 99, 106, 112 sialophosphoprotein, 21, 22
resistance, 12, 44, 67, 91 signal transduction, 54, 73, 116, 126, 131
resolution, 106 signaling pathway, 123, 124, 127, 131, 139
respiration, 55, 61, 132 signals, 39, 49, 50, 52, 67, 121, 123, 127,
respiratory problems, 111 141
response, 40, 72, 86, 117, 123, 142, 152, sinuses, 152
159 skeletal muscle, 45
restorative materials, 142 skin, 27, 34, 35, 37, 66, 106, 111, 116, 124,
reticulum, 16, 69, 72, 84, 95, 96, 98, 161 129, 133, 134, 135, 136, 139, 143, 158,
retinoblastoma, 32, 39 160, 161
reverse transcriptase, 38, 165, 167 SLE, 143, 145
Rhabdomyosarcoma, 45 smoking, 37, 63
risk, 38, 64, 106, 114, 126, 139, 169, 170 somatic cell, 115
RMS, 46 Somatostatin, 43
RNAs, 66, 133, 143, 163, 165, 166, 167 species, 38, 132, 169, 171
root, 4, 6, 10, 11, 12, 13, 14, 16, 22, 23, 74, speculation, 88, 154
75, 79, 83, 98, 99, 104, 158, 160, 175 spindle, 41, 98
root growth, 12, 14 spongy bone, 92
squamous cell carcinoma, 33, 36, 40, 67, 70,
97, 101
S stabilization, 112, 121
starvation, 42
S100, 55, 101
stem cells, 66
saliva, 89, 105, 108, 142, 158
stimulation, 32, 64, 76, 81, 106, 107, 143,
salivary gland, 57, 59, 60, 61, 62, 63, 64,
159
65, 66, 77, 78, 89, 90, 97, 98
stimulus, 96
salts, 44, 89, 177
stomatitis, 153, 154
sarcoidosis, 152, 153
streptococci, 154
scatter, 46
stress, 72, 106, 123, 133, 140, 154, 159
Schwannoma, 42
stretching, 12
sclera, 111
stromal cells, 44, 45, 50, 64, 116
scope, 40
structural changes, 62
secretion, 53, 89, 116, 141, 154, 170
structural protein, 161, 167
senescence, 142
structure, 5, 8, 13, 15, 18, 21, 72, 73, 78, 85,
sensation, 108
90, 95, 98, 107, 114, 117, 122, 128, 135,
sensing, 170
142, 158, 159
serine, 34, 78, 106, 138
subacute, 123
serum, 82, 133, 139, 142, 173
Index 193
subgroups, 64 TP53, 67
substitution, 58, 113, 126 trachea, 25, 66
sulfate, 135, 159 transcription, 5, 32, 35, 36, 38, 44, 50, 53,
sulfur, 152 54, 64, 97, 119, 127, 165
supernumerary teeth, 5, 6, 74, 77 transducer, 127
suppression, 53, 143 transduction, 126
survival, 38, 50, 64, 129, 139, 141 transformation, 31, 52, 59, 61, 65, 85, 86,
SV40, 44, 59 102, 106, 115
swelling, 25, 89, 92 transforming growth factor (TGF), 16, 19,
symptoms, 114, 119, 150, 158 40, 45, 81, 118, 127, 128, 142, 154
syndrome, 11, 12, 63, 69, 116, 118, 124, transition metal, 39
125, 126, 128, 145 translation, 59
synthesis, 38, 107, 116, 119, 127 translocation, 49, 52, 53, 54, 59, 63, 64, 66,
syphilis, 142, 151 126
systemic lupus erythematosus, 144 transmission, 32, 121
trauma, 9, 10, 12, 14, 23, 33, 41, 42, 55, 89,
90, 92, 140, 142, 154, 159, 170, 175
T treatment, 49, 93, 128, 139
tricarboxylic acid cycle, 132
T cell, 47, 52, 53, 136, 139, 140, 141, 143,
trigeminal nerve, 175
145, 150, 152, 153, 154, 159, 163, 166,
trisomy 21, 125
168
tuberculosis, 149, 150, 151
tannins, 107
tumor cells, 67, 97, 101
taurodontism, 11, 12, 178
tumor development, 97
tendon, 111, 127
tumor growth, 36, 38, 46, 95, 102
tensile strength, 112
tumor necrosis factor, 81, 121, 141
therapy, 140, 169
tumorigenesis, 59, 60, 70
thigmotropism, 170, 172
tumour suppressor genes, 70
third molar, 6
turnover, 14, 40, 72, 141
threonine, 34
type 1 collagen, 107, 178
thymus, 47
thyroid, 25, 26
thyroiditis, 62 U
TIMP-2, 95
tissue homeostasis, 127 ubiquitin, 32, 123
TLR, 121 ulcer, 154, 155
TLR2, 121 undifferentiated mesenchymal cells, 125
TLR4, 121 unmasking, 142
TNF-α, 81, 90, 121, 124, 142, 154 urine, 54
tobacco, 27, 37, 105, 106 UV light, 159
tooth, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, UV radiation, 34, 145
15, 16, 18, 19, 22, 23, 69, 72, 74, 75, 76,
79, 81, 83, 84, 88, 92, 95, 96, 97, 98, 99,
102, 103, 111, 175, 177, 178
194 Index
Wnt signaling, 103

V World Health Organization (WHO), 85,
100, 103
vaccine, 150
wound healing, 80
vagina, 152
WWTR1, 54
variations, 32
vasculature, 106
VEGF, 43 X
Verrucous carcinoma, 36, 37
vesicle, 158, 160 XRCC 3, a DNA repair gene, 36
vessels, 72, 91, 177
viral infection, 23, 26, 122, 123, 142, 157
viruses, 31, 154, 162, 167
Y
vitamins, 107
Y chromosome, 62
vulnerability, 140
yeast, 170, 172
vulva, 66
Z
W
zinc, 36, 59, 107, 167, 177
warts, 31, 40
zygomycosis, 173
Western blot, 58

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DENTAL SCIENCE, MATERIALS AND TECHNOLOGY

Additional books in this series can be found on Nova’s website

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NOTICE TO THE READER

Library of Congress Cataloging-in-Publication Data

Published by Nova Science Publishers, Inc. † New York

Chapter 10 Potentially Malignant Disorders 105

Finally, the author says a million thanks to her family—especially her

Dr PC Anila Namboodiripad, BDS, MDS,

which is made up of ectomesenchymal cells derived from the neural crest

Initiation Proliferation Morpho Apposition Eruption Attrition

Figure 1. Developmental stages in tooth and root formation.

The etiological role in the formation of supernumerary teeth can be both

1) ‘Atavism theory’: This theory suggests that reversion in the

may be dysmorphic or of abnormal shape. Excess teeth of equal size

Introduction and Pathogenesis

Figure 2. Developmental stages in tooth formation.

Histophysiological Stages of Tooth

Microdontia is a condition of having disproportionately small teeth.

 True generalized microdontia

Development of tooth is a continuous process in which a number of

Macrodontia is a condition of having disproportionately large teeth.

 True generalized macrodontia

The proliferation and the morphodifferentiation stage of tooth

Fusion and Gemination

Gemination is a developmental anomaly in which a developing tooth splits

thalidomide embryopathy, hypervitaminosis A and the fetal alcohol exposure

The talon’s cusp is an additional cusp that is composed of enamel, dentin

Both heredity and environmental conditions are said to be responsible for

Taurodontism is a developmental condition found in the molar teeth of

A number of pathogenetic factors have been considered in the etiology of

 ‘a primitive pattern’ theory,

Taurodontism is said to occur in individuals who have heavy masticatory

Tooth dilacerations is a developmental disturbance which involves the

Figure 3. Showing the process of dilacerations.

 the rate of eruption of the tooth,

Dens invaginatus is a rare developmental disturbance of teeth, showing a

Etiology of Dens Invaginatus

 Another factor for the occurrence of the dens invaginatus may be in

The Dens evaginatus (DE) is a developmental anomaly affecting the

reviewed. Though the DE occurs predominantly in the permanent dentition it

Dens evaginatus is said to occur following the invagination of the

Figure 1. Anomalies affecting enamel.

Amelogenesis imperfecta (AI) is a disorder which is genetic in origin. It

1) The reduction of the prism density resulting in the hypomineralisation

2) MMP20 is also essential for the ameloblast-ameloblast contact or cell

Figure 2. Cartoon summarizing the mechanism of the AI subtype.

Hypoplastic Type of Amelogenesis Imperfecta

Figure 3. Depicting the formation of enamel matrix and its degradation to

Hypocalcification Type of Amelogenesis Imperfecta

Hypomaturation Type of Amelogenesis Imperfecta

Delayed degradation of the matrix and hence delayed growth of enamel

Developmental Anomalies Affecting

Dentinogenesis Imperfecta and Dentin Dysplasia 1 and

osteopontin, osteonectin, dentin sialoprotein to name a few, to help initiate and

Dentin Dysplasia Type 1

Dentin dysplasia (DD) type I is characterized by short or total absence of

 Wesley et al. suggested that the condition is caused by an atypical

Median Rhomboid Glossitis

Median rhomboid glossitis occurs on the dorsum of the tongue. It is an

This condition is thought to occur due to failure of retraction of the

Geographic tongue is a form of tongue inflammation where red, smooth,

 Geographic tongue is considered as a psoriasiform tongue. That is, it