RECENT CONCEPTSRECENT CONCEPTS

Contents1. Developmental disturbances2. Cysts and tumours of odontogenic origin.3. Benign and malignant tumours4. Salivary gland lesions5. fibro-osseous lesions6. Infections in oral cavity

Recent Concepts in Developmental Disturbances Previous classification: shields classification

DI Type I - Osteogenesis Imperfecta With Opalsent Dentin

DI Type II – Isolated Opalsent Teeth- Herditary Opalsent Teeth

DI Type III - Isolated Opalsent Teeth – Brandywine Isolate

REVISED CLASSIFICATIONREVISED CLASSIFICATION

DENTINOGENESIS TYPE I : OPALESENT DENTIN - DI

WITHOUT OSTEOGENESIS IMPERFECTA. SHIELDS TYPE II.

DENTINOGENESIS IMPERFECTA TYPE II : BRANDYWINE

TYPE, SHIELDS CLASSIFICATION TYPE III Identical pattern of expression was seen in both type 2 and 3 Single mutation in DSPP shows both phenotypes

TYPE I TYPE II

FISSURAL CYSTS Globulomaxillary cyst ?????

The originally described globulomaxillary cyst was acclaimed to be a fissural cyst arising from epithelium entrapped during fusion of the globular portion of the medial nasal process with the maxillary process. ARGUMENTS: 1) Fusion of facial processes does occur and epithelium is entrapped between medial nasal, lateral nasal, and maxilla processes. The term “fusion” is misleading, i.e., On the basis on this view, development of the anterior maxilla occurs by the merging of growth centers rather than fusion of facial processes. So no ectodermal entrapment can occur, and therefore the globulomaxillary cyst cannot ensue.

Histologically, the cyst is lined by ciliated columnar or stratified squamous epithelium, and the supporting fibrous capsule exhibiting an inflammatory cell infiltrate

Cysts in the globulomaxillary area have reportedly been lined by respiratory epithelium. This observation could be explained on basis of the close proximity to the sinonasal cavity and also could be epithelial metaplasia, as respiratory epithelium lining has been reported in inflammatory cysts in the mandible.

3) Globulomaxillary cyst should be considered the intraosseous

counterpart of the nasolabial cyst. There is no any scientific justification of this assumption. On the other hand, there is general consensus among oral pathologists that nasolabial cyst does arise from ectopic epithelium of the lower portion of the nasolacrimal duct.

In conclusion, there is no scientific evidence supporting the existence of globulomaxillary cyst, therefore, this entity should no longer be accepted as a pathologic diagnosis

Galal Omami GLOBULOMAXILLARY CYST: GAME OVER!

Median rhomboid glossitis

Posterior midline atrophic candidiasis

• Smooth , erythematous mucosa , lacking in papilla or taste buds.

Currently the etiology of is no longer thought to be a developmental anomoly but persistent inflammatory process secondary to chronic infection by candida albicans with a location anterior to the circumvallate papillae at the junction between the anterior 2/3 and posterior 1/3 . It is also a degenerative process

What caused this symptomatic change on tounge? Dermatol. Vol 15-issue 8 aug 2007.

Recent Concepts in Odontogenic Cysts and Tumours

• Keratocystic Odontogenic Tumour : Current concepts• Calcifying epithelial odontogenic cyst : cyst or tumour• Current Classification in Odontogenic Tumours • Ameloblastoma Pathogenesis

Keratocystic Odontogenic Tumour

• Keratocystic Odontogenic Tumor (KCOTs) is defined as Keratocystic Odontogenic Tumor (KCOTs) is defined as benign, odontogenic, uni- or multicystic intraosseous tumors, benign, odontogenic, uni- or multicystic intraosseous tumors, with characteristic parakeratinized squamous epithelium lining, with characteristic parakeratinized squamous epithelium lining, having a potential for aggressive and infiltrative growth .having a potential for aggressive and infiltrative growth .

(WHO 2005)(WHO 2005)

• KCOTs also exhibit some cyst-like features, including KCOTs also exhibit some cyst-like features, including response to decompression .response to decompression .

• Tumoural nature of this lesion remains the subject of debate Tumoural nature of this lesion remains the subject of debate among investigatorsamong investigators

IOSR Journal of Dental and Medical Sciences (IOSR-JDMS)Volume 9, Issue 2

Etiology: Remnants of dental lamina, and also proliferations of the

basal cell layer of oral epithelium, are considered as possible sources of epithelial cell proliferation, which proliferate into the deeper tissues and form microcysts, suggesting that KCOTs should be considered as hamartomas.

Pathogenesis:• Behaviour : The KCOT is locally destructive and highly

recurrent. • Histopathology: The basal layer of the KCOT budding into

connective tissue in the form of daughter cysts and mitotic figures are frequently found in the supra basal layers.

Keratocystic Odontogenic Tumour : Reclassification of the Odontogenic Keratocyst from Cyst to Tumour J CDA jcda March 2008, Vol. 74, No. 2 .

Daughter cysts in the wall of a KCOT

Genetic factors in pathogenesis

PTCH (“patched”), a tumour suppressor gene involved in both NBCCS and sporadic KCOTs on chromosome 9q22.3-q31, normally forms a receptor complex with oncogene SMO (“smoothened”) for the SHH (“sonic hedgehog”) ligand . PTCH binding to SMO inhibits growth-signal transduction. SHH binding to PTCH releases this inhibition. If normal functioning of PTCH is lost, the proliferation-stimulating effects of SMO are permitted to predominate.

• Loss of heterozygosity (LOH) and frequency of allelic loss for several tumor-suppressor genes p53 and PTCH gene in sporadic KCOTs, associated with the presence of satellite microcysts in KCOT walls.

• Activation of H-ras oncogene in KCOTs was demonstrated .

• Also, recent study indicated that alterations in BIRC5 gene, encoding antiapoptotic protein survivin, may contribute to the pathogenesis of KCOTs.

• Genetic defects in pathogenesis of KCOTs support the opinion of the tumoral nature of these lesions.

• Keratocystic Odontogenic Tumors – Clinical and Molecular Features A Textbook of Advanced Oral and Maxillofacial Surgery

Is a heterogeneous group of lesion existing either as cystic or solid variant.

• In 2005, WHO renamed the lesion as calcifying cystic odontogenic tumor

Calcifying epithelial odontogenic cyst: cyst or tumour ? Gorlin cyst, Calcifying ghost cell odontogenic tumour, Cystic calcifying odontogenic tumor

Calcifying ghost cell odontogenic cyst: A review on terminologies and classifications Journal of Oral and Maxillofacial Pathology Vol. 16 Issue 3 Sep - Dec 2012

PRÆTORIUS 2006, PERSONAL COMMUNICATIONPRÆTORIUS 2006, PERSONAL COMMUNICATIONGroup 1- ‘Simple’ cysts1. Calcifying odontogenic cyst (COC)

Group 2- Cysts associated with odontogenic hamartomas or benign neoplasms: calcifying cystic odontogenic tumours (CCOT). The following combinations have been published:

1. CCOT associated with an odontome2. CCOT associated with adenomatoid odontogenic tumor3. CCOT associated with ameloblastoma4. CCOT associated with ameloblastic fibroma5. CCOT associated with ameloblastic fibro-odontoma6. CCOT associated with odonto-ameloblastoma7. CCOT associated with odontogenic myxofibroma

Group 3 -Solid benign odontogenic neoplasms with similar cell morphology to that in the COC, and with dentinoid formation

1. Dentinogenic ghost cell tumour

Group4 -Malignant odontogenic neoplasms with features similar to those of the dentinogenic ghost cell tumour

1. Ghost cell odontogenic carcinoma

Classification proposed by Toida (1998)Cyst:Cyst: Calcifying ghost cell odontogenic cyst (CGCOC)Neoplasm:Neoplasm:• Benign: Calcifying ghost cell odontogenic tumor

(CGCOT)• Cystic variant: Cystic CGCOT• Solid variant: Solid CGCOT• Malignant: Malignant CGCOTCombined lesionCombined lesion: Each of the categories described

above CGCOC, CGCOT, malignant (CGCOT) associated

with the following lesions:• a. Odontoma• b. Ameloblastoma• c. Other odontogenic lesions

oDONTOGENIC TUMOURS oDONTOGENIC TUMOURS WHO histological classification of odontogenic tumours (WHO

2005)

MALIGNANT TUMOURS Odontogenic carcinomas    Metastasizing (malignant) ameloblastoma   Ameloblastic carcinoma - primary type  Ameloblastic carcinoma - secondary type Intraosseous  

(dedifferentiated)    Ameloblastic carcinoma - secondary type Peripheral (dedifferentiated)    Primary intraosseous squamous cell carcinoma - solid  type    Primary intraosseous squamous cell carcinoma derived from keratocystic

odontogenic tumour    Primary intraosseous squamous cell carcinoma derived from odontogenic

cysts    Clear cell odontogenic carcinoma    Ghost cell odontogenic carcinoma   John M. Wright • Edward W. Odell. Odontogenic Tumors, WHO 2005:Head and Neck Pathol

(2014) 8:373–382

Odontogenic sarcomas   • Ameloblastoma fibrosarcoma•   Ameloblastic fibrodentino-and fibro-odontosarcomaBENIGN TUMOURSOdontogenic epithelium with mature, fibrous stroma without

Odontogenic ectomesenchyme    Ameloblastoma, solid/multicystic type  Ameloblastoma, extraosseous/peripheral type   Ameloblastoma, desmoplastic type    Ameloblastoma, unicystic type    Squamous odontogenic tumour  Calcifying epithelial odontogenic tumour    Adenomatoid odontogenic tumour    Keratocystic odontogenic tumour 

Odontogenic epithelium with odontogenic ectomesenchyme, with or without hard tissue formation

•   Ameloblastic fibroma  •  Ameloblastic fibrodentinoma   • Ameloblastic fibroodontoma    Odontoma      I .Odontoma, complex type       II. Odontoma, compound type  •  Odontoameloblastoma   • Calcifying cystic odontogenic tumour  • Dentinogenic ghost cell tumour 

Odontogenic ectomesenchyme with or without included odontogenic epithelium

• Odontogenic fibroma epithelium poor or ‘‘simple type epithelium rich or ‘‘WHO type’’.• Myxoma( myxofibroma)• Cementoblastoma( benign cementoblastoma,true cementoma)

Bone related lesionsBone related lesions• Osseous dysplasias• Fibrous dysplasias• cherubism• Ossifying fibromas• Central giant cell granulomas • Aneurysmal bone cysts• Simple bone cyst

Other tumoursOther tumours• Melanotic neuroectodermal tumour

AMELOBLASTOMA PATHOGENESISmolecular mechanisms

The overexpression and under expression of signaling molecules may

play an important role in tumorogenesis and oncogenesis Locally invasive behaviour and recurrence CLONALITY:CLONALITY: The pathogenesis of tumours is the determination of its clonal

pattern. Recently, has been demonstrated that solid ⁄ multicystic ameloblastoma as monoclonal in origin.

TUMOR SUPPERSSOR GENESTUMOR SUPPERSSOR GENES• Increased reactivity for p53 has been detected in ameloblastomas• Overexpression of MDM2 and p14ARF has been detected in

ameloblastomas

GROWTH FACTORSGROWTH FACTORS

EGFR and TGF -β expression in ameloblastomas, are involved in tumorgenesis of ameloblastomas

CELL CYCLE REGULATORSCELL CYCLE REGULATORS Expression of cyclin D1, p16, p21, and p27is well preserved when

compared with tooth germs, suggesting that the proliferation of odontogenic epithelial cells is strictly controlled by these cell cycle regulators

J Oral Pathol Med (2010) 39: 585–591

HARD TISSUE RELATED PROTIENSHARD TISSUE RELATED PROTIENS• Mutations of ameloblastin gene have been detected in

ameloblastomas.• Ameloblastomas have shown expression of several integrins

and CD44 predominantly at epithelial–mesenchymal interfaces, suggesting that these cell adhesion molecules might mediate parenchymal–stromal interactions in the odontogenic tumors

J Oral Pathol Med (2010) 39: 585–591

MATRIX DEGRADING PROTEINASESMATRIX DEGRADING PROTEINASES

Ameloblastomas express MMPs-1, 2, and 9Degrade extracellular matrix and basement membrane components

Their inhibitors, tissue inhibitors of metalloproteinases (TIMPs)-1 and -2, have also been recognized in ameloblastomas.

These features suggest that matrix-degrading enzymes may contribute to the local invasiveness of odontogenic tumors.

OSTEOLYTIC CYTOKINESOSTEOLYTIC CYTOKINES• Inflammatory cytokines with osteolytic

activity, such as IL-1, IL-6, and TNF-α, are synthesized in ameloblastomas

• Benign and malignant ameloblastomas express RANKL and OPG predominantly in stromal cells rather than tumor cells

• These observations suggest that osteolytic cytokines have a role in local bone resorption during the progression of odontogenic tumors.

J Oral Pathol Med (2010) 39: 585–591 Odontogenic tumors & allied lesions- Reichart

Odontogenic Carcinomas:

• Odontogenic carcinomas are the malignant epithelial odontogenic neoplasms. These tumours are believed to take origin from the epithelial components of the odontogenic apparatus.

• The cell rests of Malassez, reduced enamel epithelium, the rests of Serres in the gingiva, and the linings of odontogenic cysts represent the precursor cells for odontogenic carcinoma.

• Pathogenesis and Nomenclature of Odontogenic Carcinomas: Revisited . journal of oncology march 2014

Classification of odontogenic carcinomas ( L J Slater) Classification of odontogenic carcinomas ( L J Slater) • Odontogenic carcinomas1. metastasizing ameloblastoma2. Ameloblastic carcinoma a. carcinoma ex ameloblastoma b. De novo 3. Primary intraosseous carcinomaa. Solidb. Cystic c. central mucoepidermoid carcinoma 4. ghost cell odontogenic carcinoma 5. Clear cell odontogenic carcinoma

Malignant Ameloblastoma

• Described as “ benign neoplasm in which the features of an

ameloblastoma are shown by the primary growth in the jaws and

by any metastatic growth

• Clinical behaviour justifies the diagnosis of this lesion

Ameloblastic carcinoma Ameloblastic carcinoma combines the

histological features of Ameloblastoma with

cytological atypia.

• The tumour may arise de novo, in which

case it is called a primary type, or from a

preexisting benign odontogenic tumour it is

called secondary.

•Cortical expansion and spread into adjacent

soft tissues is seen

Molecular markers of cell adhesion in ameloblastomas. An update Molecular markers of cell adhesion in ameloblastomas. An update

• Cellular adhesion potentially plays an important role in the manifestation

of characteristics and in the tumor biology of ameloblastomas.

• Med Oral Patol Oral Cir Bucal. 2014 Jan 1;19 (1):e8-14.

E-cadherin

Modulator during development tooth, participate in morphodifferentation of the

odontogenic epithelium of ameloblastomas. Promotes the adhesion between

distant cells

catenins- alpha,beta,gamma catenins- alpha,beta,gamma

Participates in cell-cell adhesion and in Wnt signaling pathway during

odontogenesis, especially at the bell stage.

SDC-1 SDC-1

Plays an important role in the maintenance of proliferation and movement in

dental follicle cells.

CD56 CD56

Maybe have an important role morphoregulatory during tooth molar development

.

CD147 CD147

Possible This protein participates in perivascular cells, may

promote the capability to differentiation in odontoblast Integrin ntegrin

Important component in organization and tension of the

cytoskeleton and that in turn strongly influence in intracellular

phenomena that possibly are implicated in growth, adhesion,

migration, proliferation, apoptosis and cellular morphology Claudins Claudins

• May particpate in activation of various MMPs leading to

controlled enamel matrix formation.

Odontogenic Tumor Markers - An OverviewOdontogenic Tumor Markers - An Overview

Tumor markers are molecules that help the pathologists for

confirmatory diagnosis of histopathologically confounding

lesions

Journal of International Oral Health. Mar-Apr 2013; 5(2):59-69

Markers clinical significance

• CK 14,19 ------ Differentiates odontogenic epithelial

tumors from other epithelial tumors

• Amelogenin ------ Expressed in odontogenic tumors with

odontogenic epithelial component

• Ameloblastin ------ Mutated in odontogenic tumors with

odontogenic epithelial component

• Nestin ---- Marker for odontogenic ectomesenchyme

• Calretinin ---- Differentiates ameloblastoma from other tumors

• Bone Morphogenic Protein ----- Expressed in odontogenic tumors with dental hard tissue formation

• Tenascin ----- Expressed in tumors forming calcified masses

• HMGA2 ---- Over expression in odontogenic mesenchymal tumors

• Basement membrane proteins : Laminin 1 ---- Marker for odontogenic epithelium

Current Concepts in Benign and Malignant Current Concepts in Benign and Malignant TumoursTumours

ORAL POTENTIALLY MALIGNANT DISORDERS (OPMDS)

Precancerous potentially malignant disordersPrecancerous potentially malignant disorders

• In 1978, working group of WHO classified ‘precancer’ into

‘lesions’ and ‘conditions’ with following definitions

• A precancerous lesion precancerous lesion is ‘a morphologically altered tissue in

which oral cancer is more likely to occur than in its apparently

normal counterpart’

• A precancerous condition precancerous condition is ‘a generalized state associated with

a significantly increased risk of cancer’.

• WHO monograph of Head and Neck Tumors (2005) uses the term ‘epithelial ‘epithelial

precursor lesions’. precursor lesions’.

• It defined it as ‘altered epithelium with an increased likelihood for progression

to squamous cell carcinoma’.

• It is also mentioned that word ‘altered’ in the definition means epithelial

dysplasia.

• Development of second primary tumor at clinically normal mucosa supports

the contention.

LeukoplakiaLeukoplakia is purely a clinical terminology and histopathologically

it is reported as epithelial dysplasia.

• WHO in 2005 proposed five grades of epithelial dysplasia

1. Squamous Hyperplasia – benign lesion.

2. Mild Dysplasia – better prognosis.

3. Moderate Dysplasia.

4. Severe Dysplasia.

5. Carcinoma In-situ – poor prognosis.

• It has been recently proposed to modify the above 5- tier system

into a binary system of ‘high risk’ and ‘low risk’ binary system of ‘high risk’ and ‘low risk’ lesions to

improve clinical management of these lesions

Oral squamous cell carcinoma

• Staging: It is the extent of spread of tumor within patients

• Grading : It is defined as macroscopic and microscopic degree of differentiation of tumor.

• TNM staging system has been used clinically estimating response to therapy and survival.

• TNM system does not provide any information on the biologic characteristics- and thus an aggressive clinical behaviour of the tumor.

Broder system Broder system • Does not provide any correlation between

degree of differentiation and prognosis Jacobsson et al system includes :

Morphologic parameters Tumor-host relationship as estimated by

parameters Fisher (1975):Fisher (1975): Slight modification of JAKOBSSON et al. Lund et al (1975) Modified grading system of Jakobsson et al. by presenting a more

exact definition of each parameter and grade and by introducing a histologic score, defined a total sum of points divided by the number of parameters evaluated.

Bryne’s (1989, 1992) (ITF) Invasive Tumor Front Bryne’s (1989, 1992) (ITF) Invasive Tumor Front Grading System: Grading System:

• Parameters were measured in the deepest invasive margins.• Did not measure the entire thickness of the tumor

Histologic grading of malignancy of tumor cell population

Morphologic Parameters

1 2 3 4

Degree of keratinization

Highly keratinized (>50% of the cells)

Moderately keratinized (5-20% of the cells)

Minimal keratinization (5-20% of the cells)

No keratinization (0-5%)

Nuclear polymorphism

Little nuclear polymorphism (>75% mature cells)

Moderately abundant nuclear polymorphism (50-75% mature cells)

Abundant nuclear polymorphism (25-50% mature cells)

Extreme nuclear polymorphism (0-25% mature cells)

Number of mitoses/HPF

0-1 2-3 4-5 >5

Morphologic parameters

1 2 3 4

Pattern of invasion

Pushing, well delineated infiltrating borders

Infiltrating, solid cords, bands and or strands

Small groups or cords of infiltrating cells (n > 15)

Marked and widespread Cellular dissociation in small groups of cells(n<15) and or in single cells

Grade I: 4-8 Grade II: 9-12

Grade III: 13-16

Oral cavity squamous cell carcinoma classification using the (TNM) classification system.

Primary Tumor Regional Lymph Nodes Distant Metastasis• TX cannot be assessed NX cannot be assessed M0 absent

• T0 no evidence of tumors N0 none M1 present

• Tis carcinoma in situ N1 single, ipsilateral, < 3 cm

• T1 < 2cm N2a single, ipsilateral, 3-6 cm

• T2 2-4 cm N2b multiple, ipsilateral, < 6 cm

• T3 > 4 cm N2c bilateral or contralateral, < 6 cm

• T4a invades adjacent structure N3 > 6 cm• T4b invades distant structures

Staging system of oral cavity squamous cell carcinoma

Stage T N M 0 Tis N0 M0 I T1 N0 M0 II T2 N0 M0 III T1-3 N1 M0

T3 N0 M0 IV T1-3 N2 M0

T4 N1-2 M0 T1-3 N0-3 M0 T1-3 N0-3 M1

Oral Cavity Squamous Cell Carcinoma – An Overview