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FIXATION

Presented by:

Dr. Manish Jain

Professor & Head

Department of Oral & Maxillofacial Pathology &

Microbiology

Mahatma Gandhi Dental College & Hospital,

M. G. U. M. S. T.

FIXATION

• Fixation is a complex series of chemical

events and differs for the different

groups of substances present in the

tissues.

• The foundation of all good histological

preparations is adequate and complete

fixation.

AIM:

• To preserve tissue in as LIFE-LIKE a

manner as possible

• To Prevent rotting of freshly obtained tissue(by

putrefication & autolysis)

• To preserve original form to carry out future

investigations

Why Fixation is required?

To-

1.Prevent postmortem changes such as

putrefication and autolysis.

2.Preserve various cell constituents in as lifelike

manner as possible.

3.Protect by hardening the soft tissues allowing

easy handling during processing (especially

easy manipulation of naturally soft tissues eg.

Brain).

4.Convert the semi fluid consistency of

cells to an irreversible semi solid

consistency(sol to gel).

5.Optical differentiation:

Fixation alters to varying degrees the

refractive indices of the various cell &

tissue components which enables

unstained components to be more

easily seen than when unfixed.

Classification of fixativesI. Depending on the structures fixed :

A. Micro anatomical fixatives

B. Cytological fixatives

C. Histochemical fixatives

II. A. Simple fixatives

B. Compound fixatives

III. Baker’s classification :

A. Aldehyde containing fixatives

B. Oxidizing agents

C. Protein denaturing agents

D. Other cross linking agents

E. Physical

F. Miscellaneous

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Factors involved in fixation:

-Penetration of fixatives

-Hydrogen ion concentration and buffers

-Temperature

-Osmolality of fixative solution

-Concentration of fixatives

-Duration of fixation

-Other factors

1. Penetration of fixatives

-Thinner the tissue, greater is the fixation.

-Fixatives penetrate the tissues according to a fairly standard form of diffusion.

-The depth of penetration (d) has a direct linear relationship with the square root of the exposure of tissue to fixative (t). For each tissue, there is a constant (k) representing coefficient of diffusion. Thus the general formula

d = k√ t (Medawar 1941)

2.Hydrogen ion concentration

and buffers• P values of different fixatives vary.

• Hydrogen ion concentration is usually adjusted to physiological range by use of suitable buffer.

• Satisfactory fixation occurs between pH

6 and 8.

• Outside this range there are changes which are detrimental to ultra structure.

H

Fixation at specific pH for specific purposes

• Optimal preservation of gastric mucosa is

obtained at pH 5.5

• In the case of chromaffin reaction for

catecholamines, the storage granules for

adrenalin & noradrenalin are most stable

in presence of formalin at pH 6.5

• Perachia & Mittler (1972) introduced the

idea of fixing tissues for EM with a

gradually increasing pH.

• They concluded that glutaraldehyde

polymerizes to different extents & hence

produces different chain lengths with

increasing pH, which may then form

bridges between protein reactive groups

at different distances apart.

• Many buffer systems are available for

use in fixation. The most common ones

are phosphate, s-collidine, veronal

acetate, bicarbonite,Tris & cacodylate.

• Care must be taken that the buffer

chosen does not react with fixative, as

this will reduce both the buffering power

& fixation ability.

eg – barbiturates & Tris will react with

aldehydes.

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• Some buffers may inhibit enzymes or

react with histochemical incubation

media.

eg – Phosphate inhibits glucose -6-

phosphate dihydrogenase & will

combine with lead salts in the metal

precipitation enzyme histochemical

methods for phosphatases.

• The pH chosen for histochemical reaction should be as near the biochemical optimum as possible, although some compromise may be necessary.

• Piperazine N-N’ bis (2 ethanol sulfonic acid) (PIPES) has been found useful in fixation with glutaraldehyde of plant, marine & mammalian tissues for EM. Furthermore, PIPES does not seem to add extraneous ions to the tissues, which in turn will allow accurate element analysis.

3. Temperature

• By tradition, fixation of surgical specimens is carried out at room temperature.

• For electron microscopy & some histochemistry the temperature range chosen is 0-4°C, but some cells such as mast cells are best fixed at room temperature, even for electron microscopy.

Effects of -• Lower temp.

-Autolysis is slowed down

-Diffusion of various cellular components slowed down

-More lifelike picture can be obtained

• Higher temp.

-Chemical reactions involved in fixation are more rapid at higher temp.

-Higher temps (such as those used in drying slides) have a deleterious effect on some antigens such as PCNA (proliferating cell nuclear antigen)

4. Osmolality of fixative solution

• By varying the osmolality of fixative solutions it is possible to alter structure of membrane systems within various cells.

• Hypertonic solutions give rise to cell shrinkage.

• Isotonic fixatives produce swollen cells & poor fixation, as do hypotonic fixatives.

• The best results using electron microscopy as the criterion were obtained using slightly hypertonic solutions (400-450 mOsm; isotonic solutions are 340 mOsm )

• The vehicle osmolality of fixative is

more important than total osmolality of

fixative. Ideally it should be more or less

isotonic with tissues in their normal

living environment.

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5. Concentration of fixatives

• The concentration at which fixatives are used appears to be determined by factors of -custom , cost , effectiveness & solubility

• Experiments have been made on effects of different concentrations of fixatives on resulting morphology. (Fox et al. 1985)

• Glutaraldehyde is normally used as 3% solution , but it has been found to be effective down to 0.05% provided the pH of the vehicle is correct in the investigation of the spatial organization of leucocyte surface molecules.

• Presence of buffer causes

polymerization of aldehyde with a

consequent decrease in its effective

concentration.

• The use of low concentrations of

glutaraldehyde (0.25%) has been found

ideal for immuno-electron microscopy

by some workers.

• The staining of tissues has been shown

to alter with concentration of fixative

employed.

6. Duration of fixation

• The common practice in some labs is to

allow primary fixation in buffered

formalin to 2-6 hrs during the day the

specimen is obtained (This may

increase on weekends).

• This may be followed by a period in

formal sublimate.

• For electron microscopy it is

recommended that diced tissues are

fixed for 3 hrs and then placed in a

holding buffer.

• How do these practices square with

chemical knowledge?

- As far as formalin is concerned, if

tissues are fixed for 24 hrs, then most of

the formalin can be washed out.

- Although formaldehyde reacts rapidly

with tissue components, the reaction is

largely reversible.

- Prolonged fixation in formaldehyde is

known to cause shrinkage to hardening

of tissues.

7. Other factors in fixation

These are :

A. Volume changes

B. Substances added to vehicle

C. Use of detergents during fixation

A. Volume changes• During fixation , tissues commonly change in

volume.

• Various factors have been suggested –

inhibition of respiration

changes in membrane permeability

changes in ion transport through membranes

• Some intercellular substances such as collagen swell when they are fixed.

• Besides these volume changes which occur during fixation , the net change in volume of various components of tissue should be considered , through to the section on the slide.

This is of importance when slides are

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• Subsequent dehydration & embedding will also bring about further changes in volume.

Ideally these changes should cancel each other out to give no net change.

• Tissues fixed in formaldehyde & embedded in paraffin wax shrink by some 33% (Baker 1960)

• The nuclei in frozen sections are usually bigger than those of same tissue which have been subjected to conventional preparation ; but these changes are relatively small compared to other organelles.

• Prolonged fixation in formalin can give rise to secondary shrinkage.

Injured cells shrink or swell to a different extent from normal cells in chemical fixatives.

(Rentilla et al. 1975)

B. Substances added to vehicle

• Salts such as ammonium sulphate and potassium dihydrogen phosphate strongly stabilize proteins.

• Sodium chloride increased binding of mercuric chloride to amino group of proteins.

• For some ultra structural investigations of macro substances and intercellular spaces, various substances like alcian blue, ruthenium red and lanthanum are added to fixative.

• Tannic acid has been found to enhance fixation of proteins ,lipid, and complex carbohydrates and improves demonstration of microtubules,filaments especially for EM.

Use of detergents during

fixation

• The intracellular localization of antigens is

limited or prevented by cell membrane in

intact cells.

• Addition of non-ionic detergents or

saponin to the fixative solution allowed the

entry of large molecules without excessive

damage to cell membrane as assessed by

scanning EM.(Laurila et al 1978)

•Agonal changes

•Ideally, tissues should be fixed immediately and completely from the

living state, but this cannot be achieved for human tissues

•As most tissues are removed surgically, the organ or tissue is

relatively anoxic for some period because of anesthesia and the

placement of surgical clamps and ligatures to stop bleeding

•Furthermore, when the tissue is placed in fixative, there is a latent

period before adequate penetration of the tissue.

•Anoxic changes including damage to mitochondria are noticeable ultra

structurally within 10 minutes and enzymes such as those concerned

with oxidative phosphorylation are lost within an hour.

•There is also variation within the tissue as cells in the center

of the block suffer more anoxia due to delays in penetration of

the fixing solution.

•Anoxic changes occur more rapidly at room temperature than

in the cold and thus are exaggerated with post mortem material

as the body remains at room temperature for variable periods

before it is transferred to the mortuary and refrigerated.

•Furthermore, as the autopsy may not be conducted for several

hours or days after death, some degree of autolysis invariably

occurs.

•These can be reduced by immediate fixation and use of needle

technique to obtain tissue from solid organs soon after patient

dies.

Fixation artefacts⚫ While one of the major aims of fixation is preservation of

tissues in as life-like state as possible, it is important to

appreciate that fixation itself may cause certain artefacts.

⚫ Expansion and shrinkage of tissues during fixation have been

previously discussed.

⚫ Another important artefact relates to the movement of unfixed

material so that organelles and other subcellular structures may

be falsely localized at sites where they do not belong.

⚫ For example, the vesicles which are commonly seen fused

with the fibroblast cell membrane are not seen with freeze

fracture techniques, and it is felt that the vesicles exist in the

subjacent cytoplasm and are induced to fuse with the cell

membrane by glutaraldehyde fixation.

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•Not only may large molecules move within a block but materials

may diffuse from the tissue altogether.

•During fixation this occurs with both large and small molecules

including inorganic ions and cofactors for enzymes.

•Biogenic amines, for example, are stored in membrane-bound

granules in the cells Fixation denatures chromogranin, an

associated protein, with the release of the biogenic amines and

ATP.

•Unless the amines can be fixed in some way such as by

precipitation, they may be lost from the tissue.

•The opposite situation may also occur with false fixation of

extraneous material within the tissue.

•This is particularly so when employing radioactive labeled amino

acids, sugars, thymidine and uridine.

•Chemical changes caused by fixation may give false histochemical

reactions in the tissue. For example, glutaraldehyde will add

carbonyl groups to tissues and these will react with Schiff's reagent.

•In removing excess mercuric chloride after fixation, substances

such as histidine, tyrosine and mercaptides may also be removed.

•Crust effect-is an artefact associated with intense eosinophilia at

the center of tissue in H&E stained sections. Suggested mechanisms

include protein coagulation by ethanol of partially fixed protein in

subsequent histological processing. Incomplete wax impregnation

has also been blamed

Fixation for special substancesGlycogen

Removal, by dehydration, of bound water molecules from

normal forms of tissue glycogen decreases solubility, amounting

to denaturation.

The use of alcohols especially 100% ethanol has, therefore, been

the main method of fixing glycogen in tissues.

Bouin's fixative is also a useful fixative for glycogen.

• LipidsTwo reagents osmium tetroxide and chromic acid fix lipids by

altering the chemical reactivity of the lipid considerably.

•Lipids can be demonstrated in cryostat sections fixed with

reagents containing mercuric chloride and potassium dichromate

such as Elftman's fluid, with fixation for unsaturated lipids

completed over 3 days at room temperature.

•Proteins

The fixation of tissue proteins by aldehydes is largely through

production of cross-linkages between various reactive groups in

proteins. Most fixatives preserve proteins adequately in 1 to 2

days.

•Mucosubstances

•Four per cent basic lead acetate was introduced as a fixative for

acid heteroglycans and 1% lead nitrate in place of acetate has also

been used. Alcoholic 8% lead nitrate, with or without 10%

formalin, has been employed for connective tissue

glycosaminoglucoronoglycans.

•Formalin-alcohol mixtures have also been used and calcium

acetate has been added to formalin as a cationic precipitate for

acidic mucins

•Nucleic acids and nucleoproteins

Precipitant fixatives like alcohol, acetic acid, and Carnoy's

fluid precipitate nuclear proteins and at the same time

progressively break the bonds between nucleic acids and

proteins, thereby increasing the number of acid groups

available for staining

•Biogenic amines

The chromaffin reaction may be demonstrated by fixing the

tissue in a solution of formalin with sodium acetate and

potassium dichromate. The Biogenic amines can also be

demonstrated by formaldehyde-induced fluorescence.

•Enzymes

Enzyme activity is best demonstrated histochemically in

fresh frozen sections. The most common methods of

preserving enzymes for paraffin embedding are fixation in

alcohol or acetone usually at 4°.

Microwave fixation⚫ Microwave irradiation for tissue fixation was first

introduced by Mayers.and well developed by Ehrlich

⚫ Preservation of various tissues depended upon

generation of an optimal temperature for each tissue,

which ranged between 70°C and 85°C. Heating

above or below these temperatures produced various

artefacts such as vacuolation and changes in

chromatin pattern.

⚫ Microwaves of 2.5 GHz penetrate several

centimeters into biological material and the heat

produced can be controlled by adjustment of the

energy levels and the duration of exposure.

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•MW fixation does not have any deleterious effect on special

stains. It has also been shown that tissue antigens are often better

preserved in MW irradiated tissue than those fixed routinely in

10% formalin and processed in the usual manner

•2 mm thick blocks are placed in cassettes, completely immersed

in normal saline, irradiated to a temperature of 62°C and held at

this temperature for 30 seconds (this can be easily set in ovens

which have temperature probes).

•Advantages-High speed of fixation of both large and small

biopsy specimens is a major asset.

• Can also accelerate the fixing action (cross-linking)

of aldehydes or alcohols.

• Allows investigation of cellular processes which

proceed very rapidly e.g. exocytosis

• Less tissue volume changes.

Advantage of microwave

decalcification

Secondary fixation

(Post fixation)• Tissues may be fixed with 2 fixatives used in

succession.

• In some labs, after fixation of tissues in buffered formaldehyde they are subjected to secondary fixation with mercuric chloride-formaldehyde solution for period of hours.

• Sections are more easily cut and also stain more brilliantly after sublimate post fixation and flatten better than after buffered formaldehyde fixation alone.

Micro anatomical fixatives

• A.Routine formalin fixatives

Buffered formalin,formol calcium and formol

saline are probably most useful and widely

used fixatives.

Incorporation of calcium chloride(Baker

1944)-to preserve phospholipids.

Calcium acetate-buffers the solution

a..formol calcium(Lillie,1965)

⚫Formula

⚫Formalin 10ml

⚫Calcium acetate 2gm

⚫Water to 100 ml

b.formol calcium(Baker,1944)

⚫Formula

⚫Formalin 10ml

⚫Calcium chloride 2gm

⚫Water to 100 ml

⚫c.buffered formalin

⚫Formula

⚫Formalin 10ml

⚫Acid sodium phosphate monohydrate 0.4gm

⚫Anhydrous disodium phosphate 0.65gm

⚫Water to 100ml

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⚫d.buffered formol sucrose(Holt & Hicks,1961)

⚫Formula

⚫Formalin 10ml

⚫Sucrose 7.5 gm

⚫M/15 phosphate buffer(ph7.4) to 100ml

⚫This fixative gives excellent preservation of fine

structure,phospholipids and some enzymes. It is

recommended for combined cytochemistry and electron

microscopy

⚫To get best results it should be used refrigerator

cold(4degree Celsius)on fresh tissue.EM pictures show well

preserved mitochondria,EM after fixation by this fixative.

⚫e. alcoholic formalin

⚫Formula

⚫Formalin 10ml

⚫70-95%alcohol 90ml

⚫If desired calcium acetate may be added to ensure

neutrality.

⚫f. acetic-alcoholic-formalin(Tellyeniczky’s)

⚫Formula

⚫Formalin 5ml

⚫Glacial acetic acid 5ml

⚫70%alcohol 90ml

B. Buffered glutaraldehyde

Formula

• Glutaraldehyde stock25%solution 16ml

((charcoal treated)

phosphate buffer ph7.5 84ml

It is obtained commercially as 25%solution in

which form it contains various impurities.

Hopwood(1967)noted that glutaraldehyde could

be fractionalized from these impurities.

Chambers and his colleagues used activated

charcoal for this purpose.

C. Heidenhain’s susaFormula

• Mercuric chloride 4.5gm

• Sodium chloride 0.5gm

• Trichloroacetic acid 2.0gm

• Acetic acid 4ml

• Formalin 20ml

• Distilled water to 100 ml

• This is an excellent fixative allowing brilliant cytoplasmic staining with good cytoplasmic detail.

• It is well balanced,gives rapid and even penetration if fixed for less than 24 hours.small pieces not exceeding 3mm are fixed in 2-3 hours.

D. Zenker’s fluidFormula

• Mercuric chloride 5gm

• Potassium dichromate 2.5 gm

• Sodium sulphate 1 gm

• Distilled water to 100 ml

• glacial acetic acid immediately before use 5ml

• Following its use tissues must be washed overnight to remove excess dichromate& mercuric chloride pigment must be removed with iodine.

E. Zenker’s formol (Helly’s

fluid)Formula

• Mercuric chloride 5gm

• Potassium dichromate 2.5 gm

• Sodium sulphate 1 gm

• Distilled water to 100 ml

• Formalin immediately before use 5ml

• This is stock Zenker mixture.

• It is an excellent fixative for bone marrow and

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F. Bouin’s fluidFormula

• Picric acid,saturated aqueous solution75ml

• Formalin 20ml

• Glacial acetic acid 5ml

• This fixative keeps well,penetrates rapidly

and evenly with little shrinkage.

• Tissues fixed in it give brilliant staining by

trichrome methods.

• Tissues not more than 3mm will be fixed in 2-

3 hours.

G.Gendre’s fluid

Formula

• Picric acid,saturated aqueous solution

in 95% alcohol 80ml

• Formalin 15ml

• Glacial acetic acid 5ml

• This fixative is said to give good fixation of

glycogen.

H. Rossman’s fluid(1940)

Formula

• Formalin (neutralized) 10ml

• Absolute ethyl alcohol saturated with

picric acid(approximately8.5-9%) 90ml

This is recommended for carbohydrate

fixation.

Cytological fixatives

• A. Nuclear fixatives

• a.Carnoy’s fluid

• Formula

• Absolute alcohol 60ml

• Chloroform 30ml

• Glacial acetic acid 10ml

• It penetrates very well and gives excellent nuclear fixation with preservation of Nissl substance and glycogen.

• Tissue < 3mm fixed in 15 mins.

b.Clarke’s fluid

Formula

• Absolute alcohol 75ml

• Glacial acetic acid 25ml

• It penetrates rapidly and gives good nuclear fixation.

• It is excellent for smears or cover slip preparations of cell cultures for general fixation or chromosome analysis.

c.Newcomer’s fluidFormula

• Isopropanol 60ml

• Propionic acid 30ml

• Petroleum ether 10ml

• Acetone 10ml

• Dioxane 10ml

• It was devised for fixation of chromosomes

and gives better chromatin demonstration

than Carnoy’s fluid.

• Tissue < 3mm fixed in 2-3 hours

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d. Flemming’s fluid

Formula

• 1% aqueous chromic acid 15ml

• 2% aqueous osmium tetroxide 4ml

• Glacial acetic acid 1ml

• Good fat fixative , rarely used with advent

of cryostats and freezing micro tomes.

• Tissue < 2mm fixed in 12 hours.

B. Cytoplasmic fixatives• a. Champy’s fluid

Formula:

3% potassium dichromate 7 ml

1% chromic acid 7 ml

2% osmium tetroxide 4 ml

- Good cytoplasmic fixative.

- Requires fresh preparation from stock solutions.

- Poor & uneven penetration, hence only thin pieces of tissue should be treated.

- Preserves mitochondria , fat , yolk & lipids.

- Tissue < 2mm fixed in 12 hours.

• b. Regaud’s fluid

Formula:

3% potassium dichromate 80 ml

Formalin (40% formaldehyde) 20 ml

- Regaud’s solution does not keep & needs to be mixed immediately before use.

- Penetrates evenly & fairly rapidly, but has a tendency to over harden the tissue.

- It is particularly good for mitochondria.

- Tissue < 3-4mm fixed in 4-6 hours.

• c. Muller’s fluid

Formula:

Potassium dichromate 2.5 gm

Sodium sulphate 1 gm

Distilled water to 100 ml

- This is rarely used as a fixative except

for bone specimens.

- It may be substituted for 3% potassium

dichromate for post chroming.

• d. Formol saline & formol calcium

- Fixation in formol saline followed by

post chromatization gives good

cytoplasmic fixation in most instances,

with improved preservation of micro-

anatomical features of tissue.

- Good cytoplasmic fixative.

- Fixes loose cells in smears well with

less likelihood of becoming detached.

• e. Zenker formol (Helly’s fluid)

- Like formol saline it can be used with

good results both as a cytoplasmic

fixative & a micro anatomical fixative,

particularly for bone marrow & blood

forming organs.

- When used for mitochondria , it is

advisable to transfer tissues to 3%

potassium dichromate for 6-8 days, or

treat sections before staining in

dichromate solution for 24 hrs.

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• f. Schauddin’s fluid

- Mercuric chloride,

- Saturated aqueous solution 2 parts

- Absolute alcohol 1 part

- Popular as a cytoplasmic fixative for wet

smears.

- It is not recommended for tissue, being harsh

in action & causing excessive shrinkage

probably due to time of exposure needed for

penetration.

- Tissue or smears need T/t with iodine-

alcohol& sodium thiosulphate to remove

mercury deposit.

- Wet smears are well fixed in 10-20 mins.

Histochemical fixatives• A good histochemical fixative should

• -Preserve the constituent to be demonstrated,particularly preserving its morphological relationships.

• -Bind or otherwise preserve the specific tissue constituent, without affecting the reactive groups to be used in its visualization

• Not affect the reagent to be used in the process of visualization e.g.glutaraldehyde fixation leaves the tissue proteins so fixed with a coating of free reactive aldehyde group which give a positive Schiff or PAS reaction

• 1. Formol saline

• As formalin is the most common

fixative, it is likely that much of the

material on which the histochemical

methods are to be applied with have

been fixed.

• Provided it is buffered to prevent the

formation of formalin pigment and the

tissue is well washed to remove the

excess fixative, majority of

histochemical techniques are available.

⚫2. Cold acetone

⚫Immersion in acetone at 0-4degree Celsius

⚫Widely used for fixation of tissues in which it

is intended to study enzymes, particularly the

phosphatases.

⚫3. Absolute alcohol

⚫Fixation of sections cut from freeze dried

material may be effected by immersion in

absolute alcohol for 24 hours.s

⚫Post chromatisation

⚫Treatment of tissues with 3% potassium dichromate

following normal fixation

⚫either before processing-tissue is left in dichromate solution

for 6-8 days

⚫after processing-just before staining leave in dichromate

solution for 12-24 hours followed by thorough washing

⚫advantages-to mordant tissues particularly mitochondria

⚫improves preservation

⚫improves staining.

.⚫Vapour fixatives•Vapour as opposed to liquid fixation was originally

used to retain soluble materials in situ by converting

them to insoluble products before contacting with water

or non-aqueous solvents.

• Various chemicals which act as vapour fixatives most

commonly include formaldehyde, osmium tetroxide,

and perhaps alcohol.

•Osmium tetroxide at 37°C produces a vapour pressure

which is sufficient to allow very rapid penetration into

freeze-dried blocks of tissue and exposure for 1 hour or

less is usually adequate

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•The most important application of vapour fixation

has been the use of formaldehyde at elevated

temperatures for the conversion of catecholamines

and 5-hydroxy-tryptamine in freeze-dried tissue to

produce fluorescent condensation products.

•This method highlights the ability of highly

reactive fixative vapour to capture and render

insoluble otherwise highly soluble, low molecular

weight compounds.

• The usual source of monomeric formaldehyde is

heated paraformaldehyde and the technique can also

be applied to frozen sections.

•The most important application of vapour fixation

has been the use of formaldehyde at elevated

temperatures for the conversion of catecholamines

and 5-hydroxy-tryptamine in freeze-dried tissue to

produce fluorescent condensation products.

•This method highlights the ability of highly

reactive fixative vapour to capture and render

insoluble otherwise highly soluble, low molecular

weight compounds.

• The usual source of monomeric formaldehyde is

heated paraformaldehyde and the technique can also

be applied to frozen sections.

PELCO BioWave® DFR-10 Laboratory

Tissue Processing System

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HEALING

OF

ORAL WOUNDS

Presented by: Dr. Manish JainProfessor & HeadDepartment of Oral & Maxillofacial Pathology & MicrobiologyMahatma Gandhi Dental College & Hospital, M. G. U. M. S. T.

General factors affecting the

healing of oral wounds◼ Location of wound◼ Wounds in the area on which there is a good

vascular bed heal considerably more rapidly thanwounds in an area which s relatively avascular.

◼ Immobilization of the wound

◼ It also important in healing reaction. If the areasubjected to constant movement so thatformation of the new connective tissue isconstantly disrupted (e.g. in the corner ofmouth), delayed healing will take place.Immobilization is particularly important in thehealing of fractures, without it bony union maybe delayed or even completely inhibited.

◼ Physical factors

◼ Severe trauma to tissue obviously adeterrent to rapid wound healing. Undercertain situations, however, mild traumaticinjury may actually favor the healingprocess. For example, it is well recognizedthat a second wound inflicted in the site ofa healing initial wound heals more rapidlythan the initial or single wound.

◼ The local temperature in the area of awound influence the rate of healing,probably through the effect on localcirculation and cell multiplication. Thus inenvironmental hyperthermia woundhealing is accelerated , while inhypothermia healing is delayed.

◼ The effect of x-ray radiation on thehealing of wound has been ratherextensively studied, and the data indicategenerally that low doses of radiation tendto stimulate healing while large focaldoses of radiation or total body radiationepithelium tend to suppress healing.

◼ Circulatory factors

◼ Anemia has been reported to delaywound healing, although not all studieshave confirmed this observation. Similarly,dehydration has been found to affectadversely a healing wound

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◼ Nutritional factors

◼ Poorly nourished patients whose lowprotein intake result in a protein deficiencymanifested by a hypoproteinemia exhibit adelay in the appearance of new fibroblastsas well as a decreased rate ofmultiplication of fibroblasts in wounds.

◼ Vitamin C, or ascorbic acid. It has beenshown that the mechanism by which it acts isthrough regulation of collagen formation andformation of normal intercellular ground

substance of the connective tissue. It appearsthat in scurvy or ascorbic acid deficiency, thisinhibitory effect on wound healing is specificallyrelated to interference with the production ofmucopolysaccharides which make up the groundsubstance.

◼ Vitamin A. deficiency retards healing andthat vitamin A and D, as in cod liver oil,may be factors in promoting tissue repair.The available studies indicate that theriboflavin and pyridoxine deficienciesresult in a delay in the healing process.

◼ Age of patient

◼ Wound in younger persons heal considerablymore rapidly than wounds in elderly persons andthe rate of healing appears to be in inverseproportion to the age of the patient. The causefor this is unknown, but probably relates to thegeneral reduction in the rate of tissuemetabolism as the person ages, which itself may

be a manifestation of decreased circulatoryefficiency.

◼ Infections◼ It has been demonstrated that wounds

which are completely protected frombacterial irritation heal considerably moreslowly than wounds which are exposed tobacteria or other mild physical irritation. Itis obvious, however, that severe bacterialinfection slows the healing of wounds. Inview of the vast bacterial flora of the oralcavity, one might question whether allwounds of the oral cavity are not heavilyinfected.

◼ Since the antibody titter of a personagainst his own microorganisms isusually extremely high, there isseldom cause to worry aboutinfection from autoinoculation.Occasionally, however, the resistanceof the tissue is decreased, eitherlocally or on a systemic basis, and anoral wound becomes massivelyinfected and heals slowly , if at all.

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◼ Hormonal factors◼ Adrenocorticotropic hormone (ACTH) and

cortisone are substance that has beenrepeatedly shown to interfere with the healing ofwounds. Not long after ACTH and cortisone wereused clinically, it was noted that wounds inrecipients of these compounds exhibited delayedhealing. since this observation a number ofcareful experimental studies were carried out inwhich it was shown that in patients receivingACTH or cortisone the growth of granulationtissue was inhibited apparently because ofinhibition of proliferation of new fibroblasts andnew endothelial sprouts and because of adepression of the inflammatory reaction.

◼ Wound in diabetic patients arenotoriously slow to heal and frequentlyshow complications in the repair process.The exact mechanism of this phenomenonis not known, but is probably related tothe disturbance in carbohydratemetabolism at the cellular level in the localarea of the wound.

◼ Miscellaneous factors

◼ These factors include enzymes, such astrypsin, streptokinase, alkalinephosphatese, and coenzyme adenosine 5– monophosphate, mucopolysaccharides,N-acetyl –D glucosamine, tissue extractsand pantothenyl alcohol; hydroxyproline;hydrogen-ion concentration; electrolytebalance..

◼ Therapeutic agents such as dilantinsodium,sulfonamides and antibiotics;anticoagulants such as heparin anddicumarol; emollients; sclerosing agents;cancericidal alkylating agents;carcinogenic agents; metals, particularlytrace elements such as zinc as andcopper; deuterium oxide; antigen-antibodyreactions; and lathyrism

Healing of biopsy wound

◼ The healing of biopsy wound of a oralcavity is identical with the healing ofsimilar wound in any other part of thebody and thus may be classified as eitherprimary healing or secondary healing. Thenature of the healing process dependsupon whether the edges of the wound canbe brought into the apposition, often bysuturing, or whether the lesion must fill ingradually with granulation tissue.

◼ Primary healing or healing by primaryintention or healing by first intention istype of healing which occurs after theexcision of the edges of the wound. This isthe form of healing one might expect afterthe excision of a lesion in an area of theoral cavity where the pliability of thetissue is such that wound may be drawntogether sutured.

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4

◼ When the edges of the wound are brought intocontact and held in place by sutures, the bloodclots, and in a matter of hours numerousleukocytes are mobilized to the area. Connectivetissue cells in the immediate vicinity undergotransformation into fibroblasts which in turnundergo an mitotic division, and the newfibroblast begin to migrate into and across theline of incision . In time, these cells form thin,delicate collagen fibrils which intertwine andcoalesce in a general direction parallel to thesurface of the wound. At the same time,endothelial cells of the capillaries begin toproliferate and small capillary buds eventuallyform new capillaries which fill with blood, and arich network of young capillaries and capillaryloops is formed.

◼ When there is a close apposition of the edges ofthe wound, the surface epithelium proliferatesrapidly across the line of incision andreestablishes the integrity of the surface. Thedelicate connective tissue fibrils eventuallycoalesce into denser bundles and usuallycontract, so that in time all that is left to indicatethe biopsy area is a small linear scar which maybe depressed below the surface. Because thereis no defect which must be filled with new tissue, this type of wound heals rapidly

◼ Secondary healing.

◼ Secondary healing or healing by secondintention, healing by granulation or healing of anwound occurs when there is of loss of tissue andthe edges of the wound cannot beapproximated. Healing of this type is oftenspoken of as a process in which the wound“granulates in “, since the material which fills the

defect during the healing process is calledgranulation tissue.

◼ This type of wound is a result of biopsy ofa lesion in an area of the oral cavity inwhich the tissue are not pliable and inwhich the edges cannot be approximated.For example, removal of a lesion of thepalate or a large lesion of the alveolarridge is usually followed by healing bysecondary intention,

◼ After the removal of the lesion, the blood fillingthe defect clots and the repair process begins. Itis basically identical with healing by primaryintention expect that the fibroblasts and

capillaries have a greater distance to migrate;more granulation tissue must form, and ofnecessity the healing is slower. Cellularproliferation begins around the periphery of thewound, and the fibroblasts and endothelial cellsgrow into the clot along fibrin strands.

◼ In addition, polymorphonuclear leukocytes andlater, lymphocytes and mononuclear phagocytesmigrate into the granulation tissue from theadjacent vessels and tissues. Large numbers ofleukocytes also accumulate on the surface of thewound. As the granulation tissue matures, itbecomes more fibrous through condensation ofcollagen bundles and the surface of thegranulation tissue becomes epithelized. As inhealing by primary intention, the collagen fibrilscoalesce; the lesion becomes somewhat lessvascular; and eventually the only evidence ofthe wound may be a small depressed area of themucosa.

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5

Healing of an excisional wound of the palatal epithelium at 3 days after

wounding. The epithelium already has migrated almost 1 mm from the

original wound margin (dotted line). The tip of the epithelial outgrowth

(arrow) is migrating under a slough of inflammatory cells and necrotic

tissue debris. The underlying connective tissue is highly cellular and

contains fibroblasts, endothelial cells, and inflammatory cells.

Healing of an excisional wound of the palatal epithelium at 20 days after

wounding. The epithelium forms a continuous covering over the wound,

but the differences between the normal fibrous connective tissue at the

wound margin and the healing connective tissue in the wound are

obvious (dotted line). The wound connective tissue contains numerous

fibroblasts, capillaries, and immature collagen fibers

Schematic summary of tissue repair. The epithelial response is achieved

by proliferation and migration of cells to cover the defect. The connective

tissue response involves successively (1) a polymorph response (12 to

24 hours), (2) a macrophage response (2 to 5 days), and (3) a fibroblast

response (2 days and on) from undifferentiated perivascular cells and

undamaged fibroblasts. The new fibroblasts (4) form collagen that may

result in scar tissue in skin but not in oral mucosa

HEALING OF THE

GINGVECTOMY WOUND

◼ The elimination of the periodontal pocket bygingivectomy has become a routine clinicalprocedure principally because of the excellentresults which are generally attained. numeroustechniques are in use for the removal of thetissue, and different types of postoperativepacking material are applied to control bleeding,maintain tissue position, relieve pain and keepthe fresh wounds free of debris .Despite thesevariation, the general features of the healingprocess are similar and must be under stoodbefore attempting to carry out such a surgicalprocedure.

◼ Orban and archer studied the wound healing following gingivectomy without the application of a surgical packing or dressing while Bernier and Kaplan carried out a similar investigation, but used a zinc oxide-eugenol packing.

◼ EARLY HEALING PHASE

◼ Healing of the gingivectomy wound takes placerapidly regardless of whether a postoperativepack is used. There is some evidence, howeverthat healing may be slightly facilitated by thedressing .

◼ Two days after the gingivectomy the surface ofthe tissue is covered by a grayish blood clot, andbeneath this clot there is histological evidence ofdelicate connective tissue proliferation. Even atthis early stage there is also considerable activityof the epithelial cells bordering the woundpreparatory to beginning of actual epithelization.

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6

◼ Four days after the operation the deeper portionof the blood clot demonstrates considerableorganization, while the more superficial portionexhibits dense numbers of polymorphonuclearleukocytes entrapped of in the fibrinousmeshwork. There is proliferation of youngcapillaries and young connective tissue cells intothe base of the blood clot. Infiltration ofpolymorphonuclear leukocytes in the deeperconnective tissue is present in varying degrees.The epithelium has extended over a portion ofthe wound below the necrotic surface layer ofthe clot, but above the proliferating andorganizing connective tissue

◼ LATE HEALING PHASE◼ Continuation of the healing process is

manifested by a condensation of the youngconnective tissue with nearly completeorganization of the clot after eight to ten days.Clinically, at this period the wound has a red,granular appearance and bleeds readily.Epithelization is usually complete within ten tofourteen days after gingivectomy. Theepithelium remains thin, however and begins tomature and form rete pegs only after the twoweek interval. At this time the inflammatory cellshave largely disappeared, except for those in thesubepithelial zone.

◼ Healing of the interproximal tissue appears tolag behind that adjacent to the labial or buccalsurface. This may be partly because theepithelium which covers the interproximal tissuemust grow in form the labial and lingual areas, arelatively great distance.

◼ The surface epithelium grows downward alongthe surface cementum within a month aftergingivectomy , This is a rather shallowproliferation which ,nevertheless, is in closephysical apposition to the tooth.

◼ Healing of the gingivectomy wound isbasically similar to the healing of woundselsewhere in the body, but is somewhatmodified by the special anatomy of theinvolved region. The chronic inflammationpresent in the diseased gingiva does notadversely affect the healing process andactually may provide some stimulus forhealing to take place.

Healing of extraction wound◼ The healing of an extraction wound does not

differ from the healing of other wounds of thebody except as it is modified by the peculiaranatomic situation which exists after theremoval of a tooth.

◼ IMMEDIATE REACTION FOLLOWINGEXTRACTION

◼ After the removal of a tooth, the blood whichfills the socket coagulates, red blood cells beingentrapped in the fibrin meshwork, and the endsof the torn blood vessels in the periodontalligament become sealed off. The hours aftertooth extraction are critical, for if the blood clotis dislodged, healing may be greatly delayed andmay be extremely painful.

◼ Within the first 24 to 48 hours after extraction, a varietyof phenomena occur which consist principally ofalterations in the vascular bed. There are vasodilatationand engorgement of the blood vessels in the remnantsof the periodontal ligament and the mobilization ofleukocytes to the immediate area around the clot. Thesurface of the blood clot is covered by a thick layer offibrin, but at this early period visible evidence ofreactivity on the part of the body in form of layering ofleukocytes here is not particularly prominent. The clotitself shows area of contraction. It is important torecognize that the collapse of the unsupported gingivaltissue into the opening of a fresh extraction wound is ofgreat aid in maintaining the clot in position.

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7

◼ FIRST –WEEK WOUND◼ Within the first week after tooth extraction,

proliferation of fibroblasts from connective tissuecells in the remnants of the periodontal ligamentis evident and these fibroblasts have begun togrow into the clot around the entire periphery.This clot forms an actual scaffold upon whichcells associated with the healing process maymigrate. It is only a temporary structure;however, it is gradually replaced by granulationtissue.

◼ The epithelium at the periphery of the woundexhibits evidence of proliferation in the form ofmild mitotic activity even at this time. The crestof the alveolar bone which makes up the margin

or neck of the socket exhibits beginningosteoclastic activity. Endothelial cell proliferationsignaling the beginning of capillary ingrowthmay be seen in the periodontal ligament area.

◼ During this period, the blood clot begins toundergo organization by the ingrowth aroundthe periphery of fibroblasts and occasional smallcapillaries from the residual periodontalligament. Remnants of this periodontal ligamentare still visible, but as yet there is no evidence ofsignificant new osteoid formation, although insome cases it may have just commenced. Anextremely thick layer of leukocytes has gatheredover the surface of the clot, and the edge of thewound continues to exhibits epithelialproliferation.

◼ SECOND-WEEK WOUND

◼ During the second week after extraction ofthe tooth, the blood clot is becoming organizedby fibroblasts growing into the clot on thefibrinous meshwork . At this stage, new delicatecapillaries have penetrated to the center of theclot. The remnants of the periodontal ligamenthave been gradually undergoing degenerationand are no longer recognizable as such. Insteadthe wall of the bony socket now appears slightlyfrayed.

◼ In some instances, trabeaculae of osteoid can beseen extending outward from the wall of thealveolus. Epithelial proliferation over the surfaceof the wound has been extensive, although the

wound is usually not covered particularly in thecase of large posterior teeth. In smaller sockets,epithelization may be complete. The margin ofthe alveolar socket during the extraction areseen in the process of resorption orsequestration .

◼ THIRD –WEEK WOUND

◼ As the healing process continues into the thirdweek, the original clot appears almostcompletely organized by maturing granulationtissue. Very young trabeaculae osteoid oruncalcified bone are forming around the entireperiphery of the wound from the socket wall.This early done is formed by osteoblasts derivedfrom pluripotential cells of the originalperiodontal ligament which assume anestrogenic function.

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8

◼ The original cortical bone of the alveolarsocket undergoes remodeling so that it nolonger consists of such a dense layer. Thecrest of the alveolar bone has beenrounded off by osteoclastic resorption. Bythis time the surface of the wound mayhave become completely epithelized.

◼ FORTH WEEK WOUND

◼ During the forth week after extraction, thewound begins the final stage of healing, in whichthere is continued deposition and remodelingresorption of the bone filling the alveolar socket.However, this maturative remodeling willcontinue for several more weeks. Much of thisearly bone is poorly calcified, as is evident from

its general radiolucency on the roentgenogram..

◼ Roentgen graphic evidence of boneformation does not become prominentuntil the sixth or eight week after toothextraction. There is still roentgen graphicevidence of differences in the new bone ofalveolar socket and the adjacent bone foras long as four to six months afterextraction

◼ Because the crest of the alveolar boneundergoes a considerable amount of osteoclasticresorption during the healing process andbecause the bone filling the socket does notextend above the alveolar crest, it is obviousthat the crest of the healed socket is below thatof the adjacent teeth. Surgical removal of teeth ,during which the outer plate of bone is removed,nearly always results in loss of bone from thecrest and alveolar ridge than after simpleforceps removal of teeth . This may be ofconsiderable significance in the preparation of aprosthetic appliance.

Comparison of the repair responses in skin and teeth. No epithelial

response occurs in teeth, but the connective tissue response is similar in

both tissues and involves (1) polymorphs, (2) macrophages, (3)

fibroblasts (by division of undamaged pulpal and perivascular cells), and

(4) the production of scar tissue (collagen), which mineralizes in the tooth

to form dentin.

Repair response after tooth extraction. A, The tooth in situ. B, After

extraction the socket is filled with clot. C, The clot resolves by (1) the

polymorph response, (2) the macrophage response, and (3) the

fibroblast response. In addition, the bony defect becomes colonized by

new osteoblasts (4) that form new bone as the collagen scar is

remodeled (D).

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Complications in the healing of

extraction wound ◼ The “dry socket “ is basically a focal

osteomyelitis in which the blood clot hasdisintegrated or has been lost , with theproduction of a foul odor and severe pain , butno suppuration , The condition derives its namefrom the fact that after the clot is lost the sockethas a dry appearance because of the exposedbone. The condition is most frequentlyassociated with difficult or traumatic extractionand thus most commonly follows removal of animpacted mandibular third molar.

◼ Fibrous healing of extraction wound

◼ Usually following difficult or surgical extraction of tooth.

◼ The lesion is usually asymptomatic and is discovered only during routine extraction

◼ Well circumscribed on radiographic examination, mistaken for residual cyst or granuloma.

Healing of fracture

◼ Immediate effects of factures

◼ When fracture of occurs, the haversianvessels of the bone are torn at thefracture site.

◼ The bone cells or osteocytes of thehaversian system supplied by this vesselsdies.

◼ Callus formation◼ The callus is the structure which unites the

fractured ends of bone, and is composed ofvarying amounts of fibrous tissues, cartilage andbone.

◼ The external callus consists of the new whichforms around the outside of the two fragmentsof bone.

◼ The internal callus is the new tissue arising fromthe marrow cavity.

◼ The periosteum and endosteum are importantstructures for formation of callus

◼ Remodeling of callus

◼ The external and internal callus must beremodeled because there is always anoverabundance of new bone produced tostrengthen the healing site.

Complications of fracture

healing

◼ Non union

◼ Occurs when callus of osteogenic tissue from both ends fail to unite

◼ Common in elder individuals

◼ Fibrous union

◼ Occurs due to lack of immobilization of damagedarea

◼ Lack of calcification

◼ Occurs due to dietary deficiency or mineralimbalance

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ORAL BIOPSYPresented by:

Dr. Manish JainProfessor & HeadDepartment of Oral & Maxillofacial Pathology & MicrobiologyMahatma Gandhi Dental College & Hospital, M. G. U. M. S. T.

DEFINITION

INDICATION

TYPES

(1)EXCISIONAL

(2)INCISIONAL

(3)PUNCH

(4)SHAVE

(5)FNAC

(6)EXPLORATION BIOPSY

(7)UNEXPECTED/ UNPLANNED BIOPSY

ARMAMANTARIUM

TECHNIQUE

FIXATIVES

COMPLICATION AND COMMON ERROR

PREPARATION OF SPECIMEN FOR

HISTOLOGICAL STUDY

RESULTS

THE BIOPSY REPORT

HEALING OF BIOPSY WOUND

The term biopsy (“Bios” – Life “Opsis” – Visions-

Greek word) implies an examination of tissue

removed surgically.

Biopsy is “Removal of tissue from living organism for

the purpose of , Microscopic analysis, Bacterial

analysis, Chemical analysis or combination of them

and diagnosis.” The word biopsy appear to have been

cioned by the french dermatologist Ernest Henri

Besnier in 1879.

DEFINITION :

INDICATIONS

1) For Diagnosis of Pathologic Lesion.

2) To Determine the nature of lesion not responding

to conservative treatment.

3) In case of suspicion of Neoplasia.

4) Grading the Tumors for accurate Diagnosis and

Treatment.

5) To check weather excision is proper or not.

6) For assessment of progress of chemotherapy or

radiotherapy.

7) To identify nature of intraosseous lesions

8) Identification or exclusion of tumor metastasis

to lymph nodes & other tissue .

TYPES OF BIOPSY

1) Excisional Biopsy

2) Incisional Biopsy

3) Punch Biopsy

4) Shave biopsy

5) Fine Needle Aspiration Biopsy

6) Exploration Biopsy

7) Unexpected Biopsy

EXCISIONAL BIOPSY

“ Total excision of a small lesion for

microscopic study”is called Excisional

biopsy”

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It is preferred if site of the

lesion should be such that it

may be removed along with a

margin of adjacent normal

tissue and wound be closed

primarily.

An elliptical surface incision

which converge to a ‘v’ in the

underlying tissues.

INCISIONAL BIOPSY

“Removal of a portion of a lesion along with

normal tissue" is called Incisional or diagnostic

biopsy.The desirable Incisional biopsy is one

which is deep and narrow rather than shallow

Process of Incisional biopsy

Indications:

• Large lesions which may be treated by some means other

than surgery once the diagnosis is made

• Lesions in which the diagnosis will determine if

treatment is conservative.

• Less deformity might result from radiation therapy than

surgical excision

• Multiple small biopsies are preferred over a solitary

biopsy of a large lesion.

PUNCH BIOPSY

Punch biopsy can be either incisional or excisional

depending on the size of lesion

It can be rapidly and conveniently obtained with the

patient under local anesthesia and can sample multiple

sites.

Punch is held perpendicular to the oral mucous membrane

and gently rotated with firm downward pressure until the

subcutaneous fat is reached. The incisional column of

tissue in the punch is lifted , and the pedicle is cut. The

tissue is then carefully removed from the punch. The

defect can be closed easily with one or two suture.

SHAVE BIOPSY

When the lesion is raised shave biopsy can be

obtained for selected lesion. Using either a scalped

blade or a double edged razor blade. This technique

provides specimen lees deep, and the wound often

heals with less obvious cosmetic defects.

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3

Used for obtaining material from deep seated lesions

e.g. Bone

Aspiration through a needle with large lumen.

Needle biopsy has little value in diagnosis oral lesion.

FINE NEEDLE ASPIRATION BIOPSYEXPLORATION BIOPSY

• Used for inrtaosseous lesions of maxilla and mandible

• Instruments:

Chisel, Bone burs, Periosteal Elevator

UNEXPECTED/ UNPLANNED BIOPSY

• When as a result of surgical procedure (Tooth

extraction) some suspicious tissue is obtained

unexpectedly.

ARMAMANTARIUM• Local Anesthesia and syringe

• Colorless topical Antiseptic

• Surgical scissor

• Tissue forceps

• Suture material

• Needle holder

• Cotton, sponges

• Wide mouth bottles with 10% formalin

• Culture tubes and swabs

• Retractors

• Punch for punch biopsy

• Sharp scalpel, cautery

• High frequency cutting knife

1) Carefully select the area that can produce good diagnostic

specimen.

• Deep biopsies are preferred over shallow biopsies.

• Specimen should contain border of normal tissue

• Sections from center or surface should be avoided

as that areas are often necrotic.

2) Clean and paint the area with non-colored antiseptic

solution.

3) Give Local Anesthesia( preferably infiltration) at the

peripheral part to prevent the bulging of interested site.

4) Wait for the effect of anesthesia.

5) Make the incision – Use sterile and sharp scalpel/blade

6) Incision should involve normal tissue along with the

pathologic tissue.

TECHNIQUE

7) Vigorous manipulation of lesion should be avoided

if it is suspected to be tumor as it can increase the

tumor cell emboli in venous drainage

8) Take tissue specimen and put in to the wide mouth

container with 10% Formalin.

9) Tissue should never be put on gauze, cotton or paper,

as it can lead to dehydration of tissue specimen.

10) Suturing is done, if required with black silk suture.

11) Multiple samples must be adequately labeled.

12) Orientation of the sample is also very important.

so samples should be properly oriented with diagram

of original lesion.

13)If culture is desired, take material for bacteriologic

study before fixing the specimen.

A good fixative is one which

penetrates, kills ,fixes and hardens the

tissue with sufficient rapidity to prevent

structural alteration in the process of

dehydration, embedding, staining,

cleaning and mounting. Commonly used

is 10% formalin which is prepared by

adding nine volumes of distilled water or

saline to one volume of commercial

formalin(40% formaldehyde solution).

Others are zenker’s fluid, Bouin’s fluid.

FIXATIVES

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COMPLICATION

1.Haemorrahage –

Immediate or subsequent haemorrhage can be serious problem

following biopsy.

a.) Of highly vascular tissue (haemangioma of the liver)

b.) In a region where venous pressure is markedly increased (e.g.

a supraclavicular lymph node biopsy in the presence of superior

vena caval obstruction)

c.) From a large friable tumor mass

d.) Where an adjacent blood vessel of moderate size may be

severed and allowed to retract.

e.) When the wound becomes infected and late secondary

haemorrhage occurs.

.

2. Infection –

When tumors on the various skin or mucosal surfaces are

biopsied, there is always a possibility that already

present bacteria, may thus gain access to the depths of

the tumor and to the adjacent normal tissue. Aspectic

technique must always be observed

3. Poor wound Healing

Unsatisfactory healing of the incision may be due to

a. Ischemia of the skin overlying a tumor mass (tension)

b. Implantation of tumor cells

c. Previous X-ray therapy

d. Other more general factor mentioned previously in some

instance, avoidance of certain wound complication can be

avoided by perfoming the incision for biopsy through

normal skin at the base of the elevated lesion. Aspiration or

needle biopsy through healthy skin rather than Incisional

biopsy may be the procedure of choice in some cases.

4. Spread of tumor cells –

Contamination of the local wound with tumor cell often

occurs but with care this complication can be minimized when

Incisional biopsy is used and it can be avoided when wide

Excisional biopsy is employed. Many tumors exfoliate or

release cells more or less continuously, which enter lymphatic

or blood vascular channels. Gross manipulation of tumor may

increase the no. of cell in venous blood flowing from the

tumor. On the other hand most of these free cells flow to form

distant metastases. Gentle Incisional or Excisional biopsy

should minimize channel spread.

.

Prominent reasons for local tumor cell contamination

are the following:

a. Lack of awareness that the spread of tumor cells

commonly occurs and is increase by prolonged and

unnecessary manipulation of tissue.

b. Careless protection of the tissue during the Incision

or Excision of malignant neoplasm.

c. Failure to change contaminated drapes, instruments

or material when indicated

5. Injury to adjacent organs –

a. Injury may occur to surrounding structure

(blood vessels)

b. Structures through which the biopsy is

accomplished may be injured. Certain of the vital

structures must be avoided in needle biopsy

(blind methods) and the adequate surgical

exposure is essential when the biopsy is taken

with a scalpel. Injuries are uncommon and rarely

serious when proper technique and adequate

precautions are employed.

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5

1.Inadequate tissue specimen

The specimen may be deficient in several ways.

a) It may be inadequate in size for the pathologist to work with

effectively.

b) It may be inadequate in depth, so that only the superficial skin,

fat, granulation or fibrous tissue, is included in the specimen.

c) The specimen may have been the taken from only one side of

the suspected neoplasm or other lesion which may contain only

normal tissue. A single piece of the tissue taken from the most

likely sites of pathology may result in failure to make a positive

diagnosis. In contrast several pieces taken from likely sites of

pathology, will markedly increase the percentage of positive

diagnosis. Various tumors and many organ present a different

histological appearance, in different areas and malignant foci in an

apparently benign tumors, may be missed unless an adequate

amount of the tissue is situated.

COMMON ERRORE 2.Lost specimen:

The value of entire hospital admission for diagnosis

biopsy, is all too frequently negated by the loss of

specimen. This can be prevented only by a definite and

formed routine which is rigidly enforced by the

pathology department.

3.Mislabeling of specimen:Another error which can easily occur is for the specimens

to be improperly labeled, so that material from one

patient becomes confused with that from another, or the

biopsy from one site is confused with that from another.

A meticulous routine of immediate labeling of all

material will minimized such error.

4. Failure to fix specimen properly:

Tissue removed from body will undergo serious autolysis

within a few hours, unless it is properly fixed in formalin ,

alcohol or some other suitable preservative.

5.Crushing, Cauterizing or other disfigurement

of specimen:

It is important not to produce artifacts in the tissue by

pinching the small biopsy specimen with forceps, or by

cauterizing the material that is being sent to the pathologist.

Genteelness in obtaining and handling the specimen will

result in greater facility and precision in microscopic

diagnosis. Where possible, a sharp knife should be used in

taking the specimen.

6.Failure to note orientation of the specimen:Failure to identify the orientation of the mass of tissue removed in

enbloc dissection, will result in confusion, if the pathologist

reports that the tumor was inadequately excised at one point.

7. Failure to obtain a margin of adjacent normal

tissue when desirable, as with skin biopsies:It is of much help to have not only a portion of the margin of

tumors, but also a margin of adjacent normal skin , so that the

point of transition can be examined carefully. E.g. This is of

particular assistance in distinguishing certain amelanotic

melanomas from basal cell epithelioma.

Now the fixed tissue has to be embedded in paraffin

wax but as it has water which is immiscible with wax hence

the tissue is DEHYDRATED using ascending strengths of

alcohol. But alcohol is also not soluble in fat/ wax & so

specimen is again treated with xylene. Xylene is miscible

with wax. Now the tissue can be easily embedded into the

melted paraffin wax. Melted wax is placed in the mould & the

tissue is inserted right at the bottom of the mould. After

solidification the block of paraffin with tissue embedded into

it is ready for sectioning.After that cut a thin sections of

paraffin block up to depth of 5µ with microtome. These thin

sections are lifted on to the slides.

Preparation of specimen for histological study

Now to stain the slides with H & E stain the wax inside

the specimen should be replaced with water as H & E is

miscible with water & not with wax. After sectioning

when slides are placed in xylene, wax is removed & it

becomes clear & hence xylene is wax CLEARING

AGENT. Then the slides are put in descending

strengths of alcohol, so that the water gets incorporated

with in cells to enable tissue to receive H & E.

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6

Stain with hematoxylin for 6-8 min

Wash in tap water 5 min

Remove excess stain by decolorizing agent

i:e 0.5-1% HCL in 70% alcohol for few sec.

Wash in water (alkaline - NH3) for 5 min

Counter stain with eosin.

STAINING Since tissue is containing water, mounting

can’t be done . So dehydrate the tissue in ascending

grades of alcohol & then into xylene.

Mounting will Done with D.P.X. mounting media

. A cover slip is applied to protect & preserve the

specimen. D.P.X. is a mixture of distrene,a plasticizer

& xylene. Firm adhesion of the cover slip to the

section will take some hours at room temperature.

Nuclei - Blue or Black

Cytoplasm - Pink

Calcium and Calcified bone – Purplish Blue

RBCs, -Orange red

Keratin - pink

Collagen /Osteoid – Light Pink

RESULTS:

The report of the biopsy is usually returned to the operator within in few days unless some special procedures such as decalcification of tooth or bone substance or application of special stains is necessary. A negative biopsy report or diagnosis not in conformity with the expected diagnosis should not be considered final. A repeat biopsy should always be performed when there is any doubt about the adequacy or representative nature of the original specimen.

THE BIOPSY REPORT

The healing of biopsy wound of the oral cavity is

identical with the healing of a similar wound in any

other part of the body and thus may be classified as

either primary or secondary healing.The nature of

the healing process depends upon whether the edge

of the wound can be brought in to apposition, often

by suturing, or whether the lesion must fill in

gradually with granulation tissue.

Healing of biopsy woundPRIMARY HEALING. Primary healing,

healing by primary intention or healing by first

intention is that type of healing which occurs

after the excision of a piece of tissue with the

close apposition of the edges of the wound.

This is the form of healing one might expect

after the excision of a lesion in an area of the

oral cavity where the pliability of the tissues is

such that the wound may be drawn together

and sutured.

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7

When the edges of the wound are brought into

contact and held in place by sutures, the blood

clots., and in matter of hours numerous leukocytes

are mobilized to the area. Connective tissue cells

in the immediate vicinity undergo transformation

into fibroblasts which in turn undergo mitotic

division, and the new fibroblasts begin to migrate

into and across the line of incision.

In time, these cells from thin, delicate collagen

fibrils which intertwine and coalesce in a general

direction parallel to the surface of the wound. At

the same time, endothelial cells of the capillaries

begin to proliferate, and small capillary buds grow

out and across the wound. These buds eventually

form new capillaries which fill with blood, and a

rich network of young capillaries and capillary

loops is formed

When there is a close apposition of the edgesof the wound, the surface epitheliumproliferates rapidly across the line of incisionand reestablishes the integrity of the surface.The delicate connective tissue fibrilseventually coalesce into denser bundles andusually contract, so the in time all that is leftto indicate the biopsy area is a small linearscar which may be depressed below thesurface.

SECONDARY HEALING. Secondary healing, healing by

second intention, healing by granulation or healing of an

open wound occurs when there is loss of tissue and the

edges of the wound cannot be approximated. Healing of this

type is often spoken of as a process in which the wound

“granulates in,” since the material which fills the defect

during the healing process is called granulation tissue. This

type of wound is a result of biopsy of a lesion in an area of

the oral cavity in which the tissue are not pliable and in

which the edges cannot be approximated.

After the removal of the lesion, the blood filling the

defect clots and the repair process begins. It is

basically identical with healing by primary intention

except that the fibroblasts and capillaries have a

greater distance to migrate; more granulation tissue

must form, and of necessity the healing is slower.

Cellular proliferation begins around the periphery of

the wound, and the fibroblasts and endothelial cells

grow into the clot along fibrin strands.

In adition, polymorphonuclear leukocytes and,

later, lymphocytes, and mononuclear

phagocytes migrate into the granulation tissue

from the adjacent vessels and tissues. Large

numbers of leukocytes also accumulate on the

surface of the wound. As the granulation

tissue matures, it becomes more fibrous

through condensation of collagen bundles,

and the surface of the granulation tissue

becomes epithelized. As in healing by primary

intention, the collagen fibrils coalesce; the

lesion becomes somewhat less vascular, and

eventually the only evidence of the wound

may be a small depressed area of the

mucosa.

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8

THANK YOU

.

1

Presented by:

Dr. Manish Jain

Professor & Head

Department of Oral & Maxillofacial Pathology &

Microbiology

Mahatma Gandhi Dental College & Hospital,

M. G. U. M. S. T.

Primordial cyst1. PRIMORDIAL CYSTS:

PATHOGENESIS:

• It is formed by cystic degeneration and liquefaction of the stellate

reticulum in an enamel organ before any calcified enamel or dentin

has been formed.

• Thus, primordial cysts is found in place of the teeth.

• It may originate from a supernumerary tooth organ so that a

normal complement of teeth is present in some cases.

CLINICAL FEATURES:

• A less common type of odontogenic cyst.

• It is found early in life

• It varies widely in size and have the potential for expanding bone

and displacing teeth by pressure.

• It is occasionally associated with a retained, erupted deciduous

tooth.

• It is not painful unless secondarily infected.

RADIOGRAPHIC FEATURES:

• The cyst appears as a round or ovoid, well defined radiolucent

lesion which may show a sclerotic or reactive border and which

may be unilocular or mulltilocular.

• It may be situated below the roots of teeth, between the roots of

adjacent teeth or near the crest of the ridge in place of a

congenitally missing tooth, particularly an upper or lower third

molar.

PRIMORDIAL CYST: Radiograph showing

unilocular radiolucency with a sclerotic border in

place of missing tooth.

PRIMORDIAL CYST

situated between the

teeth causing divergence

of roots of the teeth.

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2

HISTOLOGIC FEATURES:

• The cyst is lined by an intact or uninterrupted layer of stratified

squamous epithelium. In some cases, it may be nonkeratinized

and exhibits a very prominent spinous layer and sometimes

confluent retepegs and a basal layer that is present but no

prominent.

• In other instances, the epithelium am exhibit a surface layer of

orthokeratin, while the spinous layer may be relatively thin or of

moderate thickness with flattened basal layer.

• In still other cases, the epithelium is covered by a layer of

parakeraitin and exhibits a typical corrugated appearance with

a uniform thickness, a prominent palisaded basal layer with

the cells arranged in “picket fence” or tombstone pattern and

showing no rete pegs formation..

• The CT wall is composed of parallel bundles of collagen

fibers.

• The presence of chronic inflammatory cells in subepithelial

zone of the connective tissue is a variable findings.

TREATMENT: surgical removal with thorough curettage

.

1

Salivary Gland

Tumors: -Histogenesis

-Morphogenesis

-IHCPresented by:

Dr. Manish Jain

Professor & Head

Department of Oral & Maxillofacial Pathology & Microbiology

Mahatma Gandhi Dental College & Hospital,

M. G. U. M. S. T.

CONTENTS

1. Classification of salivary glands

2. Development & Structure

3. Formation, Composition & Function of saliva

4. Pathology of salivary glands

5. Salivary gland neoplasms

Theories of neoplasm formation

Histogenesis & Morphogenesis

Grading & Staging of Salivary gland neoplasms

Benign & malignant lesions

Classification of

Salivary Glands

A. Size & location:

Major – Parotid, Sub-mandibular & Sub lingual

Minor- Labial & Buccal, Glossopalatine, Palatine,

Lingual

Sesam Atlas of Anatomy: Internal Organs. 12th Ed

B. Histochemical nature of secretion:

Serous – Parotid, Posterior lingual, Submandibular,

Mucous – Sub lingual, Labial & Buccal, Anterior

lingual, Glossopalatine & Palatine. Development

&

Structure

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2

Development

Origin:

Parotid : Ectodermal

Sub-mandibular & Sub-lingual : Endodermal

Time:

Parotid & Sub-mandibular: 6 wks IU

Sublingual : 8 wks IU

Minor : 3 months IU

Completed : 8-9 months after birth

Increase in size till 2 yrs

Branching morphogenesis(formation of hollow, tubular glands from an initial

flat epithelial surface)

1. Epithelial downgrowth.

2. Formation of solid cords, lumen, ducts &

secretory units.

a. Interaction between epithelium &

mesenchyme.

b. Contraction of microfilaments

c. Apoptosis of central cells

d. Differentiation of cells

Epithelial – mesenchymal interaction

◼ Mesenchyme essential for normal growth and

development of salivary epithelium

◼ Fibroblast growth factor 7 (keratinocyte growth

factor) – stalk elongation

◼ Epithelial growth factor & its receptor ,

transforming growth factor– branching process

◼ Interactions between laminin & cell membrane

syndecan α, β1 integrins – acinar cell

differentiation

Branching morphogenesis

Garrant,s: Cells

Structure

◼ Components:

Secretory units

Duct system

Orban,s 11th edition

Structure

◼ CELLS:

Luminal cells: a. Acinar cells- Mucous & serous

b. lining cells of ducts

IHC – All luminal cells : CK 14 –ve,

Lining cells: CK 19 +ve

Non luminal: a. Myoepithelial cells b. Basal cells

IHC – All non-luminal cells : CK 14 +ve,

Myoepithelial cells - actin +ve, however neoplastic myoepithelial cells show 50% positivity

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3

Duct system

◼ Intercellular canaliculi -----> intercalated duct--->

striated duct ----->excretory duct

a. Intercellular canaliculi: Increase surface area

b. Intercalated ducts: Add lysozyme, lactoferrin &

fluid component

c. Striated duct: resorption & excretion of

electrolytes (Na & Cl), Add Kallikrein.

d. Excretory ducts

Formation, Composition

& Function of saliva

Composition

◼ Total vol: 750 ml/day

60%: Submandibular, 30%: Parotid, 5% or less: sublingual, 7% minor salivary glands

◼ Ph: 6.7-7.4

◼ Ions: Na, K, Cl, HCO3, also- Ca, Mg, F, I

◼ Enzymes: Lactoferrin, lysozyme, Peroxidase, Kallikrein, Amylase, Lipase.

◼ Serum constituents: Albumin, Ig’s, clotting factors

Function

◼ Digestion

◼ Deglutition

◼ Speech

◼ Protection

a. Chemical & thermal insult

b. PRP & Statherin: Ca & K supersaturation

c. Peroxidase, thiocynate & lysozyme : Bactericidal

d. Ig : Inhibit bacterial adherence

e. Lactoferrin: enhances affect of Ab

PATHOLOGY OF

SALIVARY GLANDS

Pathology (Non – neoplastic)

a. Developmental: Heterotopic glands,

Adenomatois hyperplasia, Polycystic disease

b. Obstructive disorder: Mucous retention

phenomena, Mucous retention cyst

c. Infectious disease: bacterial, viral,

Granulomatous

d. Idiopathic: Necrotizing sialometaplasia, Cyst,

cheilitis glandularis,

e. others: Sjogrens syndrome

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4

Salivary gland

Neoplasms

TUMORS OF THE SALIVARY GLANDS

◼ Incidence : 3/1,00,000

◼ 3% of all body tumors

◼ 2% of head and neck neoplasms

◼ Location of salivary gland tumors :

60% - 80% PAROTID

7% - 11% SUBMANDIBULAR

< 1% SUBLINGUAL

9% - 23% MINOR SALIVARY GLANDS

BENIGN MALIGNANT

PAROTID 85% 15%

SUBMANDIBULAR 55% 45%

SUBLINGUAL 10% 90%

MINOR 50% 50%

Tumors of the salivary glands (Stats)

◼ Sex : females more commonly affected but variation with tumor is seen

◼ Age: Benign & Malignant – 2nd half of 4th

decade

Peak at 6th decade

◼ Pleomorphic adenoma 50% of all tumors

◼ MEC most common malignant tumor

◼ Duct adenomas & PLGA in minor glands

◼ Warthin’s tumor almost exclusively in Parotid

Etiology

I. Radiation

a. Dose-response pattern

b. Mostly parotid

Commonly mucoepidermoid carcinoma & Warthin tumor

II. Viruses

• Consistent association of EBV with lymphoepithelial

carcinoma of the salivary gland & commonly associated with

Warthin’s tumor

• Other viruses: HPV 16 & 18, CMV, SV 40

Etiology (?) - Predisposing Factors III. Genetic Factors

Many genetic alternations :

• allelic loss

• structural rearrangement

• monosomy & polysomy

IV. Occupation

• Silica dust or wood dust

• Rubber manufacturing

• Plumbing industries

• Beauty parlors

V. Life style and nutrition

• Cigarette smoking & alcohol ?

• Use of kerosene as cooking fuel

.

5

VI. Hormones

• Estrogen receptors

• Progesterone receptors

•Androgen receptors HISTOGENESIS &

MORPHOGENESIS

Histogenesis

Anatomy: Formation of tissue from

undifferentiated cells of germ layers

Pathology: Cell of origin

Semipluripotential Bicellular Reserve Cell Theory

Excretory duct reserve cells Intercalated duct reserve cells

Squamous cells

Columnar cells

Mucous cells

Columnar cells

Cuboidal cells

Acinar cells

Mucoepidermoid ca

Squamous cell ca

Pleomorphic adenoma

Adenoid cystic ca

Acinic cell ca

depending on the stage of development at which the stimulus acts

Highly differentiated cells (acinar cells) : minimal role

◼ Counter points:

- Main proliferating cells are striated duct cells &

acinar cells.

Pluripotential Unicellular Reserve Cell Theory

Reserve cell progenitors in intercalated duct

Neoplastic transformation

Specific salivary gland neoplasm

Capacity of generation of squamous / epidermoid elements /

intercalated duct like cells / acinar elements

Elaboration of specific differentiation factor

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6

◼ Counter point:

- Proliferating cells are seen at all levels of the

duct system.

- Acinar cells proliferate the most.

All mature cells are capable of proliferation

Each tumor originates from a distinctive type of cell

•Acinous tumors - from the acinar cells

• Oncocytic tumors - from the striated duct cells

• Mixed tumors - from the intercalated duct and myoepithelial cells

• Squamous cell and mucoepidermoid carcinomas - from the

excretory duct cells

MULTICELLULAR THEORY

Martinez-Madrigal, F et al. Am J Surg Pathol 1989

Morphogenesis

Anatomy: Development of the shape of

an organ or part of body

Pathology: Process of differentiation

leading to the development of the

histological characteristics

Morphogenesis

◼ Concept is based on:

1. Differentiation of luminal and/or non

luminal cells, eg. PA, BCA or Acinic cell ca

2. Proportion of luminal to non luminal cells,

eg PA

3. Synthesis & distribution of extra cellular

material.

Morphogenesis

A. Luminal cells

B. Luminal & Non luminal

C. Luminal, non luminal & ECM

D. Non luminal

E. Non luminal & ECM

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7

Grading & Staging

◼ Primary tumor (T)TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

T1: Tumor 2 cm or less in greatest dimension without extraparenchymal extension*

T2: Tumor more than 2 cm but 4 cm or less in greatest dimension without extraparenchymal extension*

T3: Tumor more than 4 cm and/or tumor having extraparenchymal extension*

T4a: Tumor invades skin, mandible, ear canal, and/or facial nerve

T4b: Tumor invades skull base and/or pterygoid plates and/or encases carotid artery

The American Joint Committee on Cancer (AJCC)

◼ Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but 6 cm or less in greatest dimension; or in multiple ipsilateral lymph nodes, 6 cm or less in greatest dimension; or in bilateral or contralateral lymph nodes, 6 cm or less in greatest dimension ◼ N2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but 6

cm or less in greatest dimension

◼ N2b: Metastasis in multiple ipsilateral lymph nodes, 6 cm or less in greatest dimension

◼ N2c: Metastasis in bilateral or contralateral lymph nodes, 6 cm or less in greatest dimension

N3: Metastasis in a lymph node more than 6 cm in greatest dimension

◼ Distant metastasis (M)

MX: Distant metastasis cannot be assessed

M0: No distant metastasis

M1: Distant metastasis

◼ Stage I

T1, N0, M0

◼ Stage II

T2, N0, M0

◼ Stage III

T3, N0, M0

T1, N1, M0

T2, N1, M0

T3, N1, M0

◼ Stage IVA

T4a, N0, M0

T4a, N1, M0

T1, N2, M0

T2, N2, M0

T3, N2, M0

T4a, N2, M0

◼ Stage IVB

T4b, any N, M0

Any T, N3, M0

◼ Stage IVC

Any T, any N, M1

American Joint Committee on Cancer

(AJCC ) Stage Groupings

Classifications

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8

Foote & Frazell - 1954

◼ Benign

Mixed tumor

Warthin,s tumor

Oxyphilic adenoma

Sebaceous cell adenoma

Benign lymphoepithelial lesion

Unclassified

◼ Malignant

Malignant mixed tumor

MEC

SCC

Adenocarcinoma

Adenoid cystic

Trabecular or solid

Anaplastic

Mucous cell

Pseudoadamantine

Acinic cell

Unclassified

Evans & Cruickshank - 1970

◼ Epithelial : Benign – included Mucinous cyst

mucoepidermoid tumor

acinic cell adenoma

Malignant

◼ Connective tissue tumors

◼ Miscellaneous

◼ Metastatic tumors

WHO 1972◼ Epithelial tumors

Adenomas:

Pleomorphic adenoma

Monomorphic adenoma

Adenolymphoma, oxyphilic adenoma, others

ME tumor

Acinic cell tumor

Carcinomas:

ACC, Adenocarcinoma, SCC, Undifferntiated ca, Ca in PA

◼ Non epithelial tumors

◼ Unclassified tumors

◼ Allied conditions:

Benign lymphoepithelial lesion, Sialosis, Oncocytosis

Batsakis - 1979◼ Benign:

Mixed tumor

Warthin’s tumor Oncocytoma

Monomorphic tumors

( Basal cell, Glycogen rich, clear

cell, membranous adenoma,

myoepithelioma)

Sebaceous tumors

(Adenoma,lymphadenoma)

Benign lyphoepithelial lesion

◼ Malignant:

Ca ex PA

Malignant mixed tumor

MEC

Adenoid cystic ca

Acinic cell ca

Adenocarcinoma

Oncocytic ca

Clear cell ca

SCC

Hybrid BCA

Undifferentiated CA

Epithelial myoepithelial Ca

WHO (2005) CLASSIFICATION ADENOMAS :

1. Pleomorphic Adenoma

2. Myoepithelioma (spindle, epitheloid, plasmacytoid, clear)

3. Warthin Tumor

4. Oncocytoma

5. Duct Adenomas

i) Basal cell adenoma

ii) Canalicular adenoma

6. Sebaceous Adenoma

7. Lymphadenoma (Sebaceous & non sebaceous)

7. Duct Papillomas

i) Inverted duct papilloma

ii) Intraductal papilloma

iii) Sialadenoma papilliferum

8. Cystadenoma (papillary & mucinous)

BENIGN TUMORS

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9

PLEOMORPHIC ADENOMA

( Mixed Tumor )

The term was first suggested by Willis in 1948

Definition (WHO):

Pleomorphic adenoma is a tumour of variable capsulation

characterized microscopically by architectural

rather than cellular pleomorphism.

Epithelial and modified myoepithelial elements intermingle

most commonly with

tissue of mucoid, myxoid or chondroid appearance.

Histogenesis:

• Myoepithelial cells (Hubner et al 1971)

• Intercalated duct reserve cells (ductal, myoepithelial) (Regezi et al

1977)

• Neoplastically altered epithelial cells with potential for

multidirectional differentiation (Dardrik et al 1982)

- Myoepithelial cells & intercalated duct reserve cell

PLEOMORPHIC ADENOMA

• C/Fs:

Most common SG tumor

• 70% of parotid tumors

• 50% of submandibular tumors

• 45% of minor salivary gland tumors

• 6% of sublingual tumors

Age: 3rd - 5th decade of life (mean 41.5 yrs)

Sex: F > M (3:2)

Painless, slow but continuous growing, firm mass

PLEOMORPHIC ADENOMAPLEOMORPHIC ADENOMA

PLEOMORPHIC ADENOMA PLEOMORPHIC ADENOMA

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10

Gross pathology

◼ Well-demarcated

◼ Smooth/Bosselated surface

◼ Generally encapsulated

◼ Maybe soft

◼ May show areas of

haemorrhage

PLEOMORPHIC ADENOMA

Histopathology :

• Foote & Frazell categorized it into 4 types:

1. Principally Myxoid (36%)

2. Myxoid & Cellular components present in equal proportion (30%)

3. Predominantly Cellular (22%)

4.Extremely Cellular (12%)

PLEOMORPHIC

ADENOMA

Capsule Infiltration

PLEOMORPHIC

ADENOMA Cellular Differentiation

Luminal cells:

◼ Squamous keratinization

◼ Mucinous cells

◼ Oncocytic cells

◼ Sebaceous cells

◼ Myoepithelial cells:

◼ Squamous cells

◼ Plasmacytoid cells

◼ Myxochondroid cells

◼ Hyaline material

◼ Clear cells

Histopathology : PLEOMORPHIC

ADENOMA

Epithelial and myxoid components

Ductal pattern

Cellular pleomorphic adenoma

.

11

Hyalinization: basal lamina produced by

myoepithelial cells

PLEOMORPHIC

ADENOMA Plasmacytoid myoepithelial cells

PLEOMORPHIC

ADENOMA

Myxoid areas: accumulation of basophilic mucoid material between

myoepithelial cells separates them into small groups or narrow strands

Chondroid areas: more extensive accumulation of basophilic mucoid

material around individual myoepithelial cells which undergo vacuolar

degeneration

Osteoid tissue – may form in chondroid areas or by metaplasia

PLEOMORPHIC

ADENOMASquamous Metaplasia

.

12

Lipomatous Differentiation

◼ Other features include:

- Sebaceous or serous cell

- Mucous metaplasia

- Multinucleated epithelial cells

- Oncocytic change

Differential diagnosis

◼ Basal cell adenoma: When there is almost complete absence of myxochondroid structure.

Clear demarcation between fibrous stroma and basal cells in Basal cell adenoma

◼ Myoepithelioma: When myoepithelial cells predominate.

1-2 ducts per high power field

◼ Adenoid cystic ca: When cribriform structures are present. Intact boundary of myoepithelial cells around intercellular spaces

◼ MEC: When Mucous cell are seen.

Basal cell hyperplasia accompany mucous cells in MEC. Absence of plasmacytoid cells in MEC. No myxochondroid stroma in MEC.

Differential diagnosis

◼ Carcinoma ex pleomorphic adenoma

Mitotic figures are few in PA

◼ Adenocarcinoma: When Cellular pleomorphic adenoma is seen.

Search for mitotic figures.

◼ Oncocytoma: when oncocytes are seen

◼ Schwannoma, myxoma, myxoid malignant fibrous histiocytoma : when eosinophilic plump, spindle shaped cells seen.

Ductal pattern in PA

IMMUNOPROFILE :

Luminal cells : Cytokeratin 3, 6, 10, 11, 13, and 16

Moderately reactive to EMA & CEA

Neoplastic myoepithelial cells

Irregularly positive for cytokeratin 13, 16, and 14

Vimentin and pan-cytokeratin positivity

Variably positive for S-100 protein, a-smooth muscle actin,

GFAP, calponin, CD10 and muscle-specific actin

Chondroid areas

• non-lacunar cells – vimentin and pan- cytokeratin expression

• lacunar cells – vimentin expression

• spindle-shaped neoplastic myoepithelial cells - BMP expression

• inner ductal cells and the lacunar cell - express BMP-6

• chondroid matrix – type II collagen and chondromodulin-I

•Aggrecan – chondroid matrix & myxoid stroma

IMMUNOPROFILE :

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13

Cytogenetics

approximately 70% of the tumours are karyotypically abnormal

Four major cytogenetic subgroups -:

• Tumours with rearrangements involving 8q12 (39%)

• Tumours with rearrangements of 12q13-15 (8%)

• Tumours with sporadic, clonal changes not involving 8q12 or

12q13-15 (23%)

• Tumours with an apparently normal karyotype (30%)

I subgroup - t(3;8)(p21;q12) and t(5;8)(p13;q12)

II subgroup - t(9;12)(p24;q14-15) or ins(9;12)(p24;q12q15)

Genetics

Molecular genetics

The target gene in pleomorphic adenomas with 8q12

abnormalities is PLAG1

The tumor

• contains Simian virus 40 (SV40) DNA sequences

• expresses the SV40 large T antigen

suggesting that this oncogenic virus may be

involved in the genesis and/or progression of this tumor

Treatment:

- Complete surgical excision

- Parotidectomy with facial nerve preservation

- Submandibular gland excision

- Wide local excision of minor salivary gland

◼ Avoid enucleation and tumor spill

The possible reasons for recurrences or persistence

Sheldon 1943

Definition (WHO) : Myoepithelioma is a benign salivary gland

tumour composed almost exclusively of sheets, islands or cords

of cells with myoepithelial differentiation that may exhibit

spindle, plasmacytoid, epithelioid or clear cytoplasmic features

MYOEPITHELIOMA

(Myoepithelial adenoma, benign myoepithelial tumor)

◼ Considered by some as a variant of Pleomorphic adenoma

◼ 1.5 % of all salivary neoplasms

◼ 3rd-6th decades

◼ F = M

◼ Parotid, followed by minor glands of palate

◼ Presentation: slow growing asymptomatic mass

.

14

Histopathology

Spindle cell variant: interlacing fasciclesEpithelioid variant: Nest or cords of cells. Stroma is collagenous or mucoid

Plasmacytoid variant Clear cell variant: Cells with glycogen content.

Intercellular microcystic spaces

IMMUNOHISTOCHEMICAL FEATURES :

Cytokeratin 7 & 14 positivity

Spindle cells : variable for

α - SMA

MSA

Calponin

S-100

GFAP

smooth muscle myosin heavy chain

Epithelioid cells : reactive for MSA

Plasmacytoid cells & clear cells : non-reactive for MSA

Vimentin – variable, Plasmacytoid cells : +ve

α-SMA

CK 7

.

15

Differential diagnosis

◼ Pleomorphic adenoma

◼ Clear cell variants of :

MEC, Acinic cell ca, epithelial myoepithelial ca,

Oncocytoma, Clear cell ca.

Non infiltrative & well circumscribed.

Characteristically CK 7 & 14 positive

◼ Spindle cell variant : Fibrous histiocytoma,

leiomyoma, Schwannoma

Structural alterations of chromosomes 1, 9, 12 & 13:

• t (1;12) (q25;q12)

• del (9) (q22.1q22.3)

• del (13) (q12q22) in a parotid myoepithelioma

Mutations of TP53 have been observed (25%) myoepitheliomas

GENETICS

Hildebrad (1895) first described it as congenital cyst of neck

Warthin (1929) was the first to coin the term

Definition (WHO):

◼ A tumour composed of glandular and often cystic

structures, sometimes with a papillary cystic

arrangement, lined by characteristic bilayered

epithelium, comprising inner columnar eosinophilic or

oncocytic cells surrounded by smaller basal cells. The

stroma contains a variable amount of lymphoid tissue

with germinal centers.

WARTHIN TUMOR

(Adenolymphoma, Cystadenolymphoma,

Papillary Cystadenoma Lymphomatosum)

Histogenesis:

• From ectopic salivary tissue (Neisse-Nicholson rests) in

intra- and paraparotid lymph nodes (Albecht et al 1910)

• Hypersensitivity reaction (Allegro et al, 1971) - higher

frequency of autoimmune disorders in patients with WT

Etiology:

•Smoking: Exact mechanism not known

•Radiation: High frequency in atomic bomb survivors

•Metaplastic variant may be due to trauma

•EBV

Theories of morphogenesis

◼ Heterotopic theory:

Salivary gland tissue entrapped in lymphnodes during development

Neoplastic proliferation of nests

Histological Classification (Seifert et al ):

Subtype III: Lymphoid predominance

Subtype I: Typical (Lymphoid + Epithelial)

Subtype II: Epithelial predominance

Counterpoint:

Amount of pathologic lymphoid tissue exceeds normal lymphoid tissue.

Distribution of germinal center suggests the reverse

◼ (Aguirre et al 1998)

Stimulus within node → Epithelial proliferation

(Seifert type II)

Proliferation and infiltration of the lymphoid Component.

Epithelial component growth→ Papillary projections and cystic

cavities

(Seifert type I)

More prominent lymphoid stroma (Seifert type-III)

.

16

◼ Immune theory:

Benign epithelial neoplasm or proliferation with

associated Lymphoid reaction

Stimulant

Oxyphilic metaplasia of striated ducts

Papillary formations

Cyst formation

Immune cells invade basement membrane

Lymphoid cell proliferation

•Hypersensitivity theory (Allegro 1971)

• Site - parotid area (exclusively parotid lesion)

• 2 -15 % of parotid gland tumors

• It is generally superficial, lying just beneath the

parotid capsule or protruding through it (inferior pole)

• Age: 4th –7th decade (mean : 62 years)

• Sex : M>F

• Bilateral occurrence (5-14%)

• Additional sub-clinical lesions in 50% of cases

Clinical features:

Gross pathology :

◼ Encapsulated

(thin & tough)

◼ Smooth / lobulated surface

◼ Cystic spaces of variable size,

with fluid of variable viscosity

◼ Lining – irregular with multiple

papillae

◼ Solid areas with white nodules

representing lymphoid follicles

Papillary +Cyst +adenoma +Lymphomatosum Bilayered epithelium, lymphoid connective tissue, germinal centers

.

17

Mucous metaplasia

Infarcted Warthin Tumor

IHC profile :

• Special stains and immunohistochemistry have little role to play in

diagnosis

• Lymphoid marker studies :

- B (CD20), NK (CD56) and T (CD3) cells

- Helper (CD4) and suppressor (CD8) subtypes

• Papillary cystadenoma: Minor salivary gland, lymphoid

tissue is scanty

•MEC : (Mucus differentiation). Bilayered epithelium in WT

•SCC: ( Squamous differentiation). Bilayered epithelium in

WT

•Other lymphoepithelial cystic lesions such as :

Simple benign lymphoepithelial cyst

Lymphoepithelial sialadenitis (LESA) with cystically

dilated ducts

Cystic lymphoid hyperplasia of AIDS

MALT lymphoma with cystically dilated ducts

•Variant of papillary thyroid carcinoma described as “Warthin-

like”: IHC expression of thyroglobulin

• Sebaceous lymphadenoma

Differential diagnosis:

Complications:

Malignant transformation of WT into

• Squamous cell carcinoma

• Mucoepidermoid carcinoma

• Oncocytic carcinoma

• Adenocarcinoma

• Merkel cell carcinoma

• Undifferentiated carcinoma

3 main stemline groups :

• with a normal karyotype dec

• with numerical changes only

loss of Y chromosome or trisomy or monosomy 5

• involving structural changes

with one or two reciprocal translocations

Genetics :

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18

First described by Schutz 1926

Kleinsasser & Klein coined the term 1967

Definition (WHO 2005) :

It is a rare benign neoplasm characterized by

the basaloid appearance of the tumour cells &

absence of the myxochondroid stromal component

present in pleomorphic adenoma

Basal Cell Adenoma Clinical Features:

◼ 1-3% of salivary gland neoplasms

◼ 7th decade

◼ Female predilection (2:1)

Membranous type 1:1

◼ Most common in parotid (75%)

◼ Solitary, well defined, firm encapsulated movable nodules

◼ Membranous type : multinodular / multifocal

Sheets/ islands with peripheral palisading. Separated by strands of dense collagenous tissue

Solid type

Narrow strands, trabaculae or cords, cellular & vascular stroma

Trabecular type

Ductal structures are prominent. Lined by double layer of cells

Tubular type

Prominent eosinophilic bands around nests

Membranous type

.

19

Differential diagnosis

◼ Pleomorphic adenoma: Ductal pattern seen.

BCA: sharp distinction between nests & stroma

Chondroid differentiation is rare in BCA

◼ Adenoid cystic ca: cribriform pattern is seen

BCA: encapsulated. No perineural &

perivascular invasion. Presence of whorling.

Immunoprofile -

Immunopositivity for :

• Luminal cells : Keratin, EMA, CEA

• Non luminal: Vimentin, sometimes Actin

Indicate ductal and myoepithelial differentiation

Non-recurrent tumor except for membranous type (recurrence rate : 25%)

Genetics:

Not well documented. Trisomy 8 & 7;13 translocation and/or inv 13

CK7 in ductal cells

SMA in myoepithelial cells

First described by Schaffer 1897

Hamperl used the term oncocyte 1931

Definition (WHO):

Benign tumour of salivary gland origin composed exclusively of large

epithelial cells with characteristic bright eosinophilic granular

cytoplasm (oncocytic cells)

ONCOCYTOMA

(Oncocytic adenoma, Oxyphilic adenoma, acidophilic adenoma)

Sites where oncocytes can be seen :

Salivary gland

Kidney

Lung

Thyroid gland

Parathyroid gland

Pancreas

Breast

◼ Histogenesis:

Not known.

Degenerative change – Schaffer 1897

Metaplastic, hyperplastic or neoplastic change –

Hamperl – 1962

Nodular hyperplasia – Blanck et al 1970

.

20

Clinical features:

◼ Rare: 1% of salivary gland tumors

◼ 6th- 8th decade

◼ 20% of patients : history of radiation therapy /

occupational exposure

◼ M:F = 1:1

◼ Parotid : 84 %

Submandibular gland : 9 %

Minor salivary glands : lower lip

palate

buccal mucosa

Pharynx

Technetium-99m :Increased uptake of technetium-99m that does

not disappear following sialogogue administration due to Presence of

oncocytes & increased mitochondrial content

Stains:

PAS +ve, PTAH +ve

Mucicarmine, Alcian blue, acid mps -ve

IHC:

CK +ve, S100, Actin -ve

Cells having granular acidophilic cytoplasm, arranged in clusters, with thin fibrovascular stroma

Oncocytoma - clear cell variant

Differential diagnosis

◼ Salivary duct ca: When we see large eosiniphilic cells

Cribriform pattern of SDCa

◼ MEC: Intermediate grade shows intermediate & squamous cells with pink cytoplasm

Oncocytoma: Encapsulated & many foci of oncocytic change

◼ Acinic cell ca: When ACC cells are acidophilic or clear cell variant.

Oncocytoma: pyknotic nuclei, PTAH –ve

◼ Plasmacytoid myoepithelioma:

Plasmacytoid myoepithelioma: Eccentric nuclei, hyaline cytoplasm fibrous to myxoid stroma

Treatment :

• Surgical excision

• Radiotherapy – not indicated as oncocytes are radioresistant

• Recurrence is extremely rare

.

21

CANALICULAR ADENOMA( Basal cell adenoma - canalicular type,

monomorphic adenoma - canalicular type, adenomatosis

of minor salivary glands )

Definition (WHO) : The tumour is composed of columnar

epithelial cells arranged in thin, anastomosing cords often with

a beaded pattern. The stroma is characteristically paucicellular

and highly vascular.

Clinical features:

◼ 1% of all salivary neoplasms

◼ Peak in 7th decade (mean age 65 yrs)

◼ F:M = 1.8:1

◼ Most common in minor salivary glands of the upper lip

(80%)

◼ Rarely involves major glands

◼ Painless submucosal mass

◼ May be multifocal

Gross pathology:

◼ Shows cystic spaces with gelatinous mucoid material

Histopathology:

◼ May have fibrous capsule

◼ Two rows of columnar cells situated opposite each other – close & separated

◼ Stroma is pauci cellular & vascular

◼ Psammoma bodies can be seen

◼ Mucous or oncocytic cells may be seen

Beaded pattern, paucicellular stroma, high vascularity

Canalicular adenomas

positivity for -

• keratin

• vimentin

• S-100

Variable staining with GFAP

negativity with -

• smooth muscle actin

• smooth muscle myosin heavy chain

• calponin

IHC profile

.

22

Differential diagnosis

◼ Basal cell adenoma: tubulo-trabacular variant.

BCA has double layered ducts

◼ PLGA: when Canalicular adenoma is resected as fragments or are cystic.

PLGA shows infiltration and perineural invasion.

◼ Adenoid cystic ca:

It shows pseudocystic spaces,infiltration and perineural invasion.

◼ Papillary cystadenocarcinoma:

When canalicular adenoma shows single large cystic space.

CA shows parallel arrangement of epithelial cells and vascularised stroma

Basal cell adenoma

-Luminal & non luminal cells

-Fibrocellular stroma

-Less vascularity

PLGA

-Destructive infiltration

-Perineural invasion

Adenoid cystic Ca

-Invasion: Surrounding tissue & neural

-Luminal & non luminal cells

-Lack of highly vascularised stroma

It is a rare, usually well-circumscribed tumour composed of irregularly

sized and shaped nests of sebaceous cells without cytologic atypia, often

with areas of squamous differentiation and cystic change.

Definition (WHO):

SEBACEOUS ADENOMAClinical features:

◼ 0.1% of all salivary gland tumors

◼ Age: 58 yrs mean

◼ M:F – 1.6:1

◼ 50 % in parotid, 17 % in buccal mucosa

◼ Clinical features: painless mass

◼ 0.4 - 3 cm in size

.

23

Gross Pathology:

◼ Usually encapsulated

◼ Greyish – white to yellow

Histopathology:

◼ Sebaceous cell nests of variable size with salivary ducts

◼ Areas of squamous differentiation may be seen

◼ May show microcystic spaces

◼ Oncocytic cells maybe seen

◼ Giant cells are seen

Multiple, variably sized nests of sebaceous cells in a slightly fibrotic stroma

Solid nests of sebaceous tumour cells.

Bland tumour cells with lightly eosinophilic

vacuolated cytoplasm

Sebaceous lymphadenoma is a rare, well-circumscribed to encapsulated

tumour composed of variably sized and shaped nests of sebaceous

glands without atypia often intermixed with different proportions of

variably sized ducts, within a background of lymphocytes and lymphoid

follicles. Lymphadenoma is a similar tumour lacking sebaceous

differentiation.

Definition (WHO):

Sebaceous Lymphadenoma

Clinical Features:

◼ Few reported cases of sebaceous lymphadenoma

◼ 90 % in parotid

◼ 6th -8th decade

◼ M=F

◼ Presents as painless mass

Gross pathology:

◼ Usually encapsulated

◼ Solid, multicystic or unicystic

◼ Contain sebum

Histopathology:

◼ Variable sized sebaceous glands with salivary

ducts in lymphoid stroma

◼ Histiocytes & foreign body giant cells seen

.

24

Multicystic variant lined

by squamous epithelium

Differential Diagnosis

◼ Clear cell variants may be seen in

a. MEC

b. Acinic cell Ca

◼ MEC: No foreign body giant cells. Clear cells

not associated with microcysts.

◼ ACC: Clear cell change is not much. PAS +ve

cytoplasm of clear cells

Lymphoepithelial cyst

-Lined by flat single layer of stratified

squamous epithelium or pseudostratified

Colmnar

-Lymphoid tissue completely surrounds the

cyst and germinal centers are seenDuctal papillomas are a group of relatively rare, benign, papillary

salivary gland tumours known as Inverted ductal papilloma,

Intraductal papilloma, and Sialadenoma papilliferum. They

represent adenomas with unique papillary features with a common

relationship to the excretory salivary duct system, a non aggressive

biologic behaviour, and a predilection for the minor salivary glands

Definition (WHO):

DUCTAL PAPILLOMAS

Definition (WHO):

Inverted ductal papilloma is a luminal papillary proliferation

arising at the junction of a salivary gland duct & the oral mucosal

surface epithelium & exhibits an endophytic growth pattern that

forms a nodular mass

Inverted Ductal Papilloma

( Epidermoid papillary adenoma )• Male predilection

• All reported cases in the minor salivary glands

• Mean age 5th decade

• Lower lip followed by buccal mucosa/mandibular vestibule

• A painless nodular submucosal swelling

• A dilated pore or punctum at the surface of the swelling

Clinical features :

.

25

Histopathology:

◼ Well circumscribed

◼ Variable sized central cystic cavity

◼ Lumen is narrowed

◼ Lining epithelium is continuous with the oral mucosa,

having goblet cells

◼ Proliferation of epitheloid & basaloid cells which may

show clear cell change

Endophytic growth Pushing margins

Columnar epithelium with mucous cells

DD: MEC- since both have epidermoid & mucinous cells. IDP show papillary growth and no

Multicystic, multinodular and infiltrative growth pattern

Definition (WHO)

It is a luminal papillary proliferation of duct epithelium that arises

from a segment of the interlobular or excretory duct and causes

unicystic dilatation

Intraductal Papilloma

Clinical features:

◼ Very rare

◼ M=F

◼ 6-7th decade

◼ Site: lips & buccal mucosa > parotid

◼ Painless, well differentiated solitary mass

Gross pathology:

◼ Well circumscribed cyst with lumen containing papillary

projections

Histopathology:

◼ Cystic dilatation of excretory duct

◼ Cyst wall lined by cuboidal to columnar epithelium

◼ No proliferation into cyst wall

.

26

Exophytic & papillary growth Unicystic cavity, branching papillary elements, lined by columnar cells

Papillary cystadenoma

-Multicystic

-Proliferation of lining epithelium

-Oncocytic cells maybe seen

Inverted ductal papilloma

-Epitheloid cells seen

-Proliferation into lamina propria

Sialadenoma Papilliferum

Definition: (WHO)

It is an exophytic papillary and endophytic proliferation

of mucosal surface and salivary duct epithelium

Clinical features:

◼ Exophytic surface growth

◼ Predominently minor salivary glands

◼ Mean age : 59 years

◼ Male predilection 1.5 : 1

◼ Minor salivary glands – hard &/or soft palate

buccal mucosa

upper lip

.

27

Gross pathology:

◼ Round to oval well circumscribed lesion

◼ Sessile or pedunculated

◼ Papillary growth

◼ Small cystic spaces may be seen

Histopathology:

◼ Exophytic & endophytic proliferation of epithelium

◼ Papillary projections with fibrovascular core

◼ Surface epithelium is stratified squamous

◼ Ductal epithelium lining cysts is bi layered

◼ Scattered mucous cells may be seen Exophytic papillary growth with underlying salivary gland tissue

Irregular pseudostratified epithium

Ductal space with luminal thickenings

Ductal structure lined by cuboidal

and columnar cells

Squamous Papilloma

-No ductal or glandular structures

Papillary cystedenoma

-Multicystic

-Lining epithelium is bi layered

-Encapsulated

.

28

MEC

-No exophytic papillary configuration

-Admixed mucous & ductal cells ( Monomorphic adenoma, cystic duct adenoma,Warthin tumour

without lymphoid stroma, intraductal papillary hyperplasia,

oncocytic cystadenoma )

Definition :(WHO)

It is a rare benign epithelial tumour characterized by

predominantly multicystic growth in which the epithelium

demonstrates adenomatous proliferation. The epithelial

lining is frequently papillary and rarely mucinous.

CYSTADENOMA

Clinical features:

◼ 4.2-4.7% of benign tumours

◼ M:F – 1:2

◼ 6-8 decade

◼ Average age : 57 years

◼ 45% in parotid

55% in minor salivary glands ( lips and buccal mucosa )

◼ Smooth nodules that may be compressible

Gross Pathology:

◼ Multiple small cystic spaces or a single large cyst surrounded by lobules of salivary gland or by connective tissue.

Histopathology:

◼ Circumscribed with variable number of cystic spaces

◼ Cystic lining varies from flattened to columnar, one to three cells thick

◼ Shows papillary projections with connective tissue core

◼ Sometimes oncocytic change is seen

◼ Lymphoid elements may be seen

Lumen contains eosinophilic material

Oncocytes seen in uni or bi layered

papillary structures

.

29

Ranula

-Unilocular

- Lined by simple squamous epithelium

Warthin’s tumor

-lymphoid tissue is prominent

-Papillary growths are more prominent

MEC

-Squamous cells seen

-Intermediate cells seen below and

surrounding the lumen

-Solid nests having admixed squamoid,

goblet and intermediate cells

Papillary cystic Acinic cell ca

-Microcysts are seen

-Invasion

-PAS +ve diastase resistant tumor

cells◼ Malignant lesions……………..

.

1

MALIGNANT SALIVARY

GLAND NEOPLASMS

Presented by:

Dr. Manish Jain

Professor & Head

Department of Oral & Maxillofacial Pathology & Microbiology

Mahatma Gandhi Dental College & Hospital,

M. G. U. M. S. T.

Comparative features of benign and

malignant salivary gland neoplasm

• Benign tumors

• Slow growing

• Soft or rubbery in

consistency

• 85% of parotid

tumors are benign

• Do not ulcerate

• No associated nerve

sign

• Malignant tumors

• Fast growing

• Hard consistency

• 45% of sub lingual and

minor salivary gland

tumors are malignant

• Ulcerate and invade

bone

• cause facial nerve palsy

Grading & Staging

• Primary tumor (T)TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Tumor 2 cm or less in greatest dimension without extraparenchymal extension* T2: Tumor more than 2 cm but 4 cm or less in greatest dimension without extraparenchymal extension* T3: Tumor more than 4 cm and/or tumor having extraparenchymal extension* T4a: Tumor invades skin, mandible, ear canal, and/or facial nerve T4b: Tumor invades skull base and/or pterygoid plates and/or encases carotid artery

The American Joint Committee on Cancer (AJCC)

• Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but 6 cm or less in greatest dimension; or in multiple ipsilateral lymph nodes, 6 cm or less in greatest dimension; or in bilateral or contralateral lymph nodes, 6 cm or less in greatest dimension – N2a: Metastasis in a single ipsilateral lymph node, more than 3

cm but 6 cm or less in greatest dimension

– N2b: Metastasis in multiple ipsilateral lymph nodes, 6 cm or less in greatest dimension

– N2c: Metastasis in bilateral or contralateral lymph nodes, 6 cm or less in greatest dimension

N3: Metastasis in a lymph node more than 6 cm in greatest dimension

• Distant metastasis (M)

MX: Distant metastasis cannot be

assessed

M0: No distant metastasis

M1: Distant metastasis

.

2

• Stage I

T1, N0, M0

• Stage II

T2, N0, M0

• Stage III

T3, N0, M0

T1, N1, M0

T2, N1, M0

T3, N1, M0

• Stage IVA

T4a, N0, M0

T4a, N1, M0

T1, N2, M0

T2, N2, M0

T3, N2, M0

T4a, N2, M0

• Stage IVB

T4b, any N, M0

Any T, N3, M0

• Stage IVC

Any T, any N, M1

American Joint Committee on Cancer

(AJCC ) Stage Groupings

MUCOEPIDERMOID

CARCINOMA

Mucoepidermoid Carcinoma(Mixed epidermoid and mucus secreting

carcinoma)

WHO ( Definition):

Mucoepidermoid carcinoma is a malignant

glandular epithelial neoplasm characterized

by mucous, intermediate and epidermoid

cells with columnar, clear cell and

oncocytoid features.

Mucoepidermoid Carcinoma

CLINICAL FEATURES:

• Most common malignant salivary gland tumor

• 5-9% of salivary neoplasm

• 3:2, female predilection, occurs in 3-5 decades of life

Site:

• 45% MEC occur in the parotid gland (mostly in superficial lobe)

• 20% occur on the palate.

• Presenting Features-

Extra oral : Firm, fixed painless swelling

Intra oral : Blue-red color,

Paraesthesia, Facial nerve palsy, dysphagia, trismus, numbness and ulceration may be associated symptoms

-

Mucoepidermoid Carcinoma

• Presentation

– Low-grade: slow growing, painless mass

– High-grade: rapidly enlarging, +/- pain, +/- ulceration

– Minor salivary glands: may be mistaken for benign or

inflammatory process

• Mucocele

• Hemangioma

• Papilloma

• Tori

Mucoepidermoid Carcinoma

.

3

Mucoepidermoid Carcinoma

• Gross pathology

– Well-circumscribed to

partially encapsulated

to unencapsulated

– Solid tumor with cystic

spaces

– Cystic space may

contain translucent

mucoid material that is

blood tinged

Grading system for MEC

Histopathological features Point value

- Cystic component< 20% 2

- Neural invasion 2

- Necrosis 3

- 4 or more mitotic figures/ hpf 3

- Anaplasia 4

Tumor Grade:

Low 0-4

Intermediate 5-6

High 7 or more

Mucoepidermoid Carcinoma

Histopathology is characterized by :

- Mucous cells: abundant pale foamy cytoplasm that stain

+vely with mucin stains.

- Intermediate cells: basaloid cells, progenitor of mucous

and epidermoid cells

- Epidermoid cells: polygonal cells with intercellular

bridges but lacks keratinization

Alone or in varying degrees of admixture in a solid or cystic

pattern

Mucoepidermoid Carcinoma

Low-grade

– Mucus cell > epidermoid cells

– Prominent cysts

– Mitotic figures rare

Cystic spaces lined by cuboidal or

columnar cells

Mucinous and epidermoid cells

Extravasated mucin

Mucin cells with foamy cytoplasm

Little or no cellular pleomorphism

Mucoepidermoid Carcinoma

Intermediate- grade

– Mucus = epidermoid

– Fewer and smaller cysts

– Increasing but little pleomorphism and mitotic figures

Cells lining cyst are mucus & epidermoid

Intermediate cells

Epidermoid cells

Mucoepidermoid Carcinoma

High-grade

– Epidermoid > mucus

– Solid tumor cell proliferation

– Squamous cells may be predominant

Few mucus cells

Cellular & nuclear pleomorphism

Mitotic figures numerous

.

4

• Low grade tumors shows well formed glandular

structures and prominent mucin filled cyst spaces,

minimal cellular atypia and high no of mucous

cells

• Intermediate grade tumors shows solid areas of

epidermoid and basaloid cells, less prominent

cyst formation

• High grade tumors consist of solid nests and

cords of basaloid abd epidermoid cells.

Promonant nuclear pleomorphism and mitotic

activity noted. Cystic component is less than 20%.

Necrosis and perineural invasion may be present.

Variants of MEC

• Sclerosing mucoepidermoid carcinoma: • extremly rare

• Intense central scerosis

• Peripheral infiltration of plasma cells, eosinophilic and

lymphocytes

• Introsseous mucoepidermoid carcinoma:• Develop within jaws commonly in mandible

• Form by malignant trasformation of epithelial lining of

odontogenic cysts

• Histologically low grade mailgnancy

DD – Pleomorphic adenoma : Focally

PA cellular area

Differentiating features:

-Squamous keratinisation

-Plasmacytoid cells

-Duct like structures present

-Myxoid & Chondroid areas seen

Mucicarmine stain +ve

PAS +ve diastase resistant : MEC

Keratin pearl formation in SCC

DD – SCC: Predominantly solid tumor

DD - Cystadenoma & Cystadenocarcinoma: Cystic

Differentiating features:

-Papillary projections

-Little fibrous stroma

DD – PLGA : Cellular Proliferation

Differentiating features:

-No epidermoid differentiation

-Perineural invasion

.

5

Mucoepidermoid Carcinoma

• Treatment

– Influenced by site, stage, grade

– Stage I & II

• Wide local excision with preservation of facial

nerve

– Stage III & IV

• Radical excision

• +/- neck dissection

• +/- postoperative radiation therapy

ACINIC CELL CARCINOMA

Acinic Cell Carcinoma

• Definition (WHO)

Acinic cell carcinoma is a malignant epithelial

neoplasm of salivary glands in which at least

some of the neoplastic cells demonstrate serous

acinar cell differentiation, which is chracterised

by cytoplasmic zymogen secretory granules.

Salivary ductal cells are also a component of this

neoplasm

Acinic Cell Carcinoma

(Acinic cell adenocarcinoma, Acinous cell carcinoma)

• 2nd most common malignant neoplasm

• 17% of all salivary gland tumors

• Parotid - 83 %

• 2nd to 7th decade

• F>M (3:2)

• Bilateral parotid disease in 3%

• Presentation

– Solitary, slow-growing, often painless mass

– Short duration reported mostly < 1 yr

– Sometime pain tenderness and facial nerve weakness

may be seen.

Acinic Cell Carcinoma

• Gross pathology

– Well-demarcated

– Mostly mono nodular

– capsulated

Acinic Cell Carcinoma

• Histology– Appears in four growth patterns

– Solid

– microcystic

– Follicular

– Papillary-cystic patterns

– One pattern predominant but

combination can occur

– Characteristic cells have

abundant granular basophilic

cytoplasm with small, dark,

eccentric nuclei

– PAS +ve cells

.

6

Solid Variant

• Histopath:

-Solid sheets, cords or nodules of tumor cells

-Acinar cells predominant

-Basophilic cytoplasm with zymogen granules

-Absence of striated ducts

Microcystic variant

• Histopath:

-Proliferation of acinar

and ductal cells

-Microcystic spaces

uniform in size

Follicular variant

• Histopath:

-Flattened or cuboidal cells line follicle like spaces

-Variable size of glandular spaces

-Most cells are ductal cells

-Little or no fibrous stroma

Papillary cystic variant

• Histopath:

-Cystic spaces contain

papillary projections

-Papilla with or without

fibrovascular core

-Predominantly ductal

cells

• IHC Profile: (Non specific)

- +ve : cytokeratin, transferrin, lactoferrin,

CEA, amylase.

DD - Cystadenocarcinoma

Differentiating features:

-No microcystic formation

-Perineural invasion

.

7

DD – Papillary & follicular thyroid carcinoma

Differentiating features:

-Stain for thyroglobulin

DD – Normal salivary gland – no ductal structures

Acinic Cell Carcinoma

• Treatment

– Complete local excision

– +/- postoperative XRT

• Prognosis:

• Poor prognostic features are pain, fixation, gross

invasion, mocroscopic features of desmoplasia,

atypia, increase mitotic activity

– 5-year survival: 82%

– 10-year survival: 68%

– 25-year survival: 50%

ADENOID CYSTIC

CARCINOMA

ADENOID CYSTIC CARCINOMA(Cylindroma, adenocystic carcinoma, adenocystic

basal cell carcinoma, pseudoadenomatous basal cell

carcinoma, basaloid mixed tumor)

• Definition (WHO):

Adenoid cystic carcinoma is a basaloid tumor

consisting of epithelial and myoepithelial cells in

variable morphological configurations, including

tubular, cribriform, solid and cystic patterns. It

has a relentless clinical course and usually a

fatal outcome.

ADENOID CYSTIC CARCINOMA

Clinical features:• 5th most common malignant neoplasm after MEC, Adeno

ca, Acinic cell ca and PLGA

• Some studies shows it is 2nd most common salivary gland malignant neoplasm

• Peak incidence is in sixth decade

• Slight female predilection

• Mostly involve the major salivary glands

• In major salivary glands, presents as a unilocular mass which is firm on palpation

• Pain and tenderness: +ve/-ve

• 3rd most common malignancy of tongue

ADENOID CYSTIC CARCINOMA

• Facial nerve paralysis or weakness maybe the

initial symptom

• Bone invasion occurs frequently. There are no

radiographic changes initially as there is

infiltration through the marrow spaces

• Metastasis is often seen in lungs

• The tumor has tendency to invade the perineural

spaces

.

8

• Gross pathology:

- Solid, well

circumscribed mass

- Infiltrative

ADENOID CYSTIC CARCINOMA

Cribriform variant:

- Nests, cords or sheets of

basaloid epithelial cells

arrange to form multiple

cylindrical cyst like pattern

resembling a Swiss cheese

or honey comb pattern

- Most classic and recognized

pattern

-Duct like spaces, lumen of

these spaces are filled with

PAS +ve

mucopolysaccharide material

-Minimal mitosis

ADENOID CYSTIC CARCINOMA

• Histopath:

Tubular variant:

-Bilayered ducts

-lined by stratifed cuboidal

epithelium

Inner ductal cells & outer

myoepithelial cells

-Collagenous stroma

-Pseudocysts seen

ADENOID CYSTIC CARCINOMA

• Histopath:

Solid variant:

-solid nests of cuboidaal

tumor cells

-minimal small duct like

structures

-least common, high

grade with high

recurrence

-Thin fibrous stroma

separating nests

Adenoid Cystic Carcinoma

• Treatment

– Complete local excision

– Tendency for perineural invasion: facial nerve sacrifice

– Postoperative XRT

• Prognosis

– Local recurrence: 42%

– Distant metastasis: lung

– Indolent course: 5-year survival 75%, 20-year survival 13%

• IHC profile (non specific)

- Ki 67, CD44, E-cadherin helpful in

assessing biological behaviour

- In dedifferentated areas overexpression of

p53, cyclin D1 and high index og Ki 67

seen.

.

9

DD – PLGA – Mixed architecture

Differentiating features:

-Lumen formation in nests of cells not seen

-Pseudocyst formation absent

DD – Basal cell adenoma

Differentiating features:

-Encapsulated

-No perineural invasion

DD – Pleomorphic adenoma : cribriform

Differentiating features:

-No Pseudocyst formation

-No discrete cell clusters

DD – Canalicular adenoma : cribriform

Differentiating features:

-Vascularisation

-No myoepithelial cell proliferation

DD – Epithelial myoepithelial carcinoma:

clear cell appearance

Differentiating Features:

-Cribriform pattern lacking

-Glycogen -ve AdCC

POLYMORPHOUS LOW

GRADE ADENOCARCINOMA

.

10

PLGA

(Terminal duct carcinoma, lobular

carcinoma)

• Definition (WHO):

A malignant epithelial tumor chracterised by

cytological uniformity, morphological diversity,

an infiltrative growth pattern and low metastatic

potential

PLGA

Clinical features:

• 2nd most common intra oral malignant tumor

• F:M = 2:1

• Most common 5th – 7th decade

• 60 % cases involve palate

• Presents as painless mass.

• Bleeding or ulceration of overlying mucosa is

rare

• Gross pathology:

- Firm & circumscribed

• Histopathology:

- Invasion

- Sheet like or solid

nodules

- Lobules with peripheral

palisading

- Single or bilayered

ductal structures

- Hyaline stroma

Targetoid appearance with

encirclement of nerve fiber

Papillary cystic formation

Cribriform pattern

• IHC profile:

- Strongly +ve : cytokeratin, vimentin, S-100

- Moderately +ve: CEA

- Weakly +ve: GFAP, MSA, EMA

DD – Pleomorphic adenoma

Differentiating features:

-Invasion

-No chondroid differentiation

-Non luminal cells are few

.

11

DD – ACC – Mixed architecture

Differentiating features:

-Lumen formation in nests of cells not seen

-Pseudocyst formation absent

DD

• Basal cell adenoma:

- Greater variation in PLGA

- Invasion

• Cystadenoma:

- Well circumscribed

EPITHELIAL MYOEPITHLIAL

CARCINOMA

Epithelial Myoepithelial carcinoma(Adenomyoepithelioma, clear cell adenoma,

glycogen rich adenocarcinoma, clear cell

carcinoma, tubular solid adenoma)

Definition (WHO):

A malignant tumor composed of variable

proportions of two cells types, which typically

form duct like structures. The biphasic

morphology is represented by an inner layer of

duct lining, epithelial type cells and an outer

layer of clear myoepithelial type cells.

Epithelial Myoepithelial carcinoma

• Clinical features:

- 1% of all salivary gland tumors

- F:M =2:1

- Peak in 6th -7th decade

- Parotid – 60% and major glands. Minor glands

also involved

- Presents as painless, slow growing mass

- Minor gland lesions may show surface ulceration

and ill defined borders

• Gross pathology:

- Multinodular without capsule

- Cystic spaces may be seen

- Histopathology:

- Inner cuboidal cells & outer clear cells

- Clear cells show cytoplasmic glycogen. PAS +ve, diastase labile

- Microcysts may be present

- Squamous differentiation may be seen in luminal cells

- Nodules separated by bands of connective tissue

.

12

• IHC profile:

- Smooth muscle actin, calponin stain clear

cells

- Cytokeratin stains luminal cells

DD

• MEC: MEC shows goblet cells,

intermediate cells, cells with

intracytoplasmic mucinous secretions.

• ACC: Luminal & non luminal cells are

admixed

• AdCC: Generalized cribriform spaces with

prominent GAG & basal lamina.

ADENOCARCINOMA NOS

Adenocarcinoma

• Definition (WHO):

Adenocarcinoma NOS is a malignant

salivary gland tumor that exhibits ductal

differentiation but lacks any of the

histomorphologic features that chracterise

the other defined types of salivary

carcinoma.

Clinical features:

• Account for 17 % of malignant salivary

neoplasms

• 2nd most common malignancy of salivary glands

• Female predominance

• Average age 58 yrs

• Major glands : minor glands = 60:40

• Presents as solitary painless mass.

• Minor gland tumors may show ulceration

• Bone erosion seen in minor gland involvement

Adenocarcinoma

• Gross pathology:

-Partially circumscribed,

irregular periphery.

-May show areas of necrosis

or hemorrhage

• Histopathology:

– Invasion

– Presence of duct &

glandular structures

– No cystic change

– Nests of epithelial cells

– Necrosis & hemorrhage

.

13

Adenocarcinoma

• Treatment

– Complete local excision

– Neck dissection

– Postoperative XRT

• Prognosis

– Local recurrence: 51%

– Regional metastasis: 27%

– Distant metastasis: 26%

– 15-year cure rate:– Stage I = 67%

– Stage II = 35%

– Stage III = 8%

BASAL CELL

ADENOCARCINOMA

Basal cell adenocarcinoma( Basaloid salivary carcinoma, carcinoma ex

monomorphic adenoma, malignant basal cell

tumor, basal cell carcinoma)

Definition (WHO):

Dominated by basaloid epithelial cells, basal cell

adenocarcinoma is cytologically and

histomorphologically similar to basal cell

adenoma but is an infiltrative epithelial neoplasm

with potential for metastasis.

Basal cell adenocarcinoma

Clinical features:

• Rare tumor

• M=F

• Average age 60 yrs

• Parotid - 90%

• Presents as painless swelling

Basal cell adenocarcinoma

• Gross pathology:

- Vary from well circumscribed to unencapsulated

to invasive

- Homogenous

- Sometimes cystic

Basal cell adenocarcinoma

• Histopathology:

- Growth pattern generally solid or tubulo-trabecular

- Tumor shows pushy margins

- Basaloid cells form the bulk of the lesion

- Luminal cells present among basaloid cells

- Few ductal structures seen

- Mitotic figures evident

- Focal necrosis & hemorrhage may be seen

- Infiltration into surrounding structures seen

.

14

Invasion into surrounding tissue

Basal lamina around nests

DD – Adenoid cystic carcinoma:

Cribriform pattern

Differentiating features:

-Angular Separated basaloid cells

-Ductal structures seen

DD - PLGA:

Differentiating features:

-Ductal structures composed of single type of cell

-Peripheral palisading is minimal and in smaller lobules

DD – Basal cell adenoma

• Differentiating features:

- Invasion

- Increased mitotic figures

MALIGNANT MIXED TUMORS

Malignant Mixed Tumors

• Carcinoma ex-pleomorphic adenoma• Carcinoma developing in the epithelial

component of preexisting pleomorphic

adenoma

• Carcinosarcoma• True malignant mixed tumor—carcinomatous

and sarcomatous components

• Metastatic mixed tumor• Metastatic deposits of otherwise typical

pleomorphic adenoma

.

15

Carcinoma Ex- pleomorphic adenoma

• Definition (WHO):

Carcinoma ex pleomorphic adenoma is defined as

a pleomorphic adenoma from which an epithelial

malignancy is derived

Carcinoma Ex-Pleomorphic

AdenomaClinical features:

• 2-4% of all salivary gland neoplasms

• 12% of salivary malignancies

• 6th-7th decades

• Parotid > submandibular > palate

• Risk of malignant degeneration• 1.5% in first 5 years

• 9.5% after 15 years

• Presentation• Longstanding painless mass that undergoes sudden

enlargement

Carcinoma Ex-Pleomorphic Adenoma

• Gross pathology

– Poorly circumscribed

– Infiltrative

– Hemorrhage and

necrosis

Carcinoma Ex-Pleomorphic Adenoma

• Histopathology:

– Malignant cellular

change adjacent to

typical pleomorphic

adenoma

– Carcinomatous

component

• Adenocarcinoma

• Undifferentiated

Pleomorphic adenoma

Carcinoma

-Infiltration

-Nuclear hyperchromatism

& pleomorphism

-Inner ductal cells show

carcinomatous change

-Dilated ducts

Carcinoma Ex-Pleomorphic Adenoma

• Treatment

– Radical excision

– Neck dissection (25% with lymph node

involvement at presentation)

– Postoperative XRT

• Prognosis

– Dependent upon stage and histology

.

16

Carcinosarcoma

Definition (WHO):

Carcinosarcoma is a malignant tumor composed of

a mixture of both carcinomatous and

sarcomatous elements.

Carcinosarcoma

• Rare: <.05% of salivary gland neoplasms

• 6th decade

• M = F

• Parotid > Submandibular > Palatal

• History of previously excised pleomorphic

adenoma,

• Presents as a mass which may be painful

Carcinosarcoma

• Gross pathology

– Poorly circumscribed

– Infiltrative

– Cystic areas

– Hemorrhage, necrosis

– Calcification

Carcinosarcoma

• Histopathology

– Biphasic appearance

– Sarcomatous

component

• Osteosarcomatous

• chondrosarcomatous

– Carinomatous

component

• Moderately to poorly

differentiated ductal

carcinoma

• Undifferentiated

Carcinosarcoma

Chondrosarcomatous differentiation

Osteosarcomatous differentiation

Carcinosarcoma

• Treatment

– Radical excision

– Neck dissection

– Postoperative XRT

– Chemotherapy (distant metastasis to lung,

liver, bone, brain)

• Prognosis

– Poor, average survival less than 2 ½ years

.

17

Metastasizing Pleomorphic adenoma(Metastasizing benign mixed tumor, )

Definition (WHO):

A histological benign pleomorphic adenoma

that inexplicably manifests local or distant

metastasis.

Metastasizing Pleomorphic adenoma

• 40 cases reported till date

• Recurrent Pleomorphic adenoma undergoing repeated surgery might metastasize through venous circulation

• Parotid > Submandibular > Palatal

• Well circumscribed at primary & secondary sites

• Lung & lymph nodes involved

• Histopathology is benign

CYSTADENOCARCINOMA

Cystadenocarcinoma(Papillary cystadenocarcinoma, mucus producing

adenopapillary carcinoma, malignant papillary

cystadenoma, low grade papillary adenocarcinoma of

the palate)

Definition (WHO):

Cystadenocarcinoma is a rare malignant tumor

chracterised by predominantly cystic growth that

often exhibits intraluminal papillary growth. It

lacks any additional specific histopathological

features that chracterise the other types of

salivary carcinomas showing cystic growth.

Clinical features:

- M=F

- Predominantly after 50 yrs of age

- Major glands 65%, parotid> submandibular

- Minor glands: buccal mucosa> lips> palate

- Slow growing, compressible, asymptomatic mass

Cystadenocarcinoma

Gross Pathology:

- Multiple cystic spaces

- Filled with mucin

Histopathology:

- Multiple cysts variable in size

- Papillary projections in cyst lumen

- Focal mucous, pseudostratified, flattened epithelial cells

- Focal necrosis occasional, hemorrhage more common

- Perineural & vascular invasion rare

- Infiltration in surrounding tissue

.

18

Muticystic appearance with focal lymphoid tissue

Cystic spaces lined by low cuboidal cells

and separated by acellular fibrous stroma

Papillary cystic

Differential diagnosis

• Cystadenoma: Lacks infiltration

• PLGA: Perineural invasion with concentric

layering around nerves. Variable histology

with mixed patterns. Cystic formation is

minimal

• ACC: Shows solid and multicystic pattern.

Mixed luminal & non luminal cells

ONCOCYTIC CARCINOMA

Oncocytic carcinoma

Definiton (WHO):

Oncocytic carcinoma is a proliferation of

cytomorphologically malignant oncocytes and

adenocarcinomatous architecture phenotypes,

including infiltrative qualities. These may arise de

novo, but are usually seen in association with a

pre existing oncocytoma

Oncocytic carcinoma

Clinical features:

-<1% of all salivary gland tumors

-M>F = 2:1

-Mean age 62 yrs

-Parotid-80%, Submandibular-8%, rest minor

glands

-Presents as painless, slowly growing mass

Oncocytic carcinoma

Gross Pathology:

-Firm, unencapsulated, unilocular or multilocular mass

Histopathology:

- Moderate to large cells with granular cytoplasm

- Sheet or nest like pattern

- Mitosis frequent and abnormal

- Perineural, intravascular and intralymphatic invasion

- Infiltration of surrounding tissue

.

19

Infiltration in surrounding tissue

Prominent nuclei & granular cytoplasm

Perineural invasion

• Ki 67 helps in distinguishing benign from

malignant

• These are high grade tumors showing

recurrence and metastasis

SALIVARY DUCT

CARCINOMA

Salivary duct carcinoma(Cribriform salivary carcinoma of excretory duct,

high grade salivary duct carcinoma)

Definition (WHO):

An aggressive adenocarcinoma that resembles

high grade breast ductal carcinoma

Clinical features;

-9% of salivary gland malignant tumors

-M:F=4;1

-Parotid most commonly involved

-Recent onset rapidly growing swelling

Salivary duct carcinoma

Gross Pathology:

- Firm, solid with cystic component

Histopathology:

-Large duct like structures

-Ducts lined by epithelium

-lumen may or may not contain necrotic tissue

-Mitotic activity, nuclear atypia seen

-Perineural , vascular, periductal invasion seen

-Infiltration into adjacent tissue

-Duct like spaces surrounded

by eosinophilic cells

- Necrosis within the ducts

Duct like structures surrounded by

Tumor cells showing pleomorphic

nuclei

.

20

IHC Profile:

- +ve for cytokeratin, CEA, EMA

- -ve for S 100

Highly aggressive

-33% local recurrence

-46% metastasis

-10 yr survival rate- 35%

DD – ACC

ACC lacks necrosis within lumen

ACC shows luminal & non luminal cell proliferation

DD - PLGA

Differentiating features:

-Variable growth patterns

-Papillary growth is minimal

-Ductal structures are small

• MEC: shows mucus secreting,

intermediate and epidermoid cells

• Papillary cystadenocarcinoma: Shows

columnar and mucus cells. Does not show

necrotic debris in lumen.

MYOEPITHELIAL

CARCINOMA

Myoepithelial carcinoma(Malignant myoepithelioma)

Definition (WHO):

Myoepithelial carcinoma of the salivary glands is

a neoplasm composed almost exclusively of

tumor cells with myoepithelial differentiation,

chracterised by infiltrative growth and potential

for metastasis.

.

21

Myoepithelial carcinoma

Clinical features:

-< 2% of malignant salivary neoplasms

-M=F

-mean age 54 yrs

- Major glands more affected

- Parotid -75% > submandibular > minor glands

- Presents as painless mass

Gross Pathology:

- Well circumscribed, unencapsulated

- Nodular spaces with cystic component

Histopathology:

- Infiltration of adjacent tissue

- Cellular pleomorphism, abnormal mitotic figures

- Focal necrosis and hemorrhage

- Perineural and perivascular invasion

- Focal chondroid and squamous differentiation

may be seen

Infiltration into surrounding tissue

Multinodular growth pattern

Pleomorphic myoepithelial cells

Plasmacytoid cells with mitotic activity

Focal squamous differntiation

• IHC Profile:

• -ve for cytokeratin

• +ve for SMA, calponin, GFAP

Aggressive lesion

33% die of disease

33% have recurrence

Differential diagnosis

• Spindle cell squamous carcinoma: -ve for

SMA, GFAP, S100

• Metastatic spindle cell melanoma: +ve for

HMB 45

.

22

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma

• Definition (WHO):

A primary malignant epithelial tumor composed of

epidermoid cells,which produce keratin and/or

demonstrate intercellular bridges by light

microscopy.

Restricted to major glands

Squamous Cell Carcinoma

• < 1% of salivary gland neoplasms

• 6th-8th decades

• M:F = 2:1

• H/O prior radiotherapy

• Parotid gland - 80%, 20% submandibular

• Presents as a rapidly growing mass, frequently painful

• Firm & fixed

Squamous Cell Carcinoma

• Gross pathology

– Unencapsulated

– Ulcerated

– Firm

Squamous Cell Carcinoma

• Histopathology:

– Invasion

– Nests of tumor cells

– Well differentiated

• Keratinization

– Moderately-well

differentiated

– Poorly differentiated

• No keratinization

Squamous Cell Carcinoma

• Treatment

– Radical excision

– Neck dissection

– Postoperative XRT

• Prognosis

- High grade aggressive lesion

– 5-year survival: 24%

– 10-year survival: 18%

• Local recurrence – 50 %

• Metastsis – 20 %

.

23

Others

• Adenosquamous carcinoma

• Undifferentiated Carcinoma

– Large-cell

– Small cell

– Lymphoepithelial type

Clear Cell Carcinoma

• Palate and parotid

• 6th-8th decade

• M = F

• Histology• Uniform, round or

polygonal cells

• Peripheral dark nuclei

• Clear cytoplasm

• Treatment• Complete local

excision

.

1

Presented by: Dr. Manish Jain

Professor & HeadDepartment of Oral & Maxillofacial Pathology & Microbiology

Mahatma Gandhi Dental College & Hospital, M. G. U. M. S. T.

There is lot of interest in this field since the salivary glands have the most histologically heterogonous group of morphologic features among their cells and tissues.---as told by Irving Dardick

Salivary gland tumors commonly pose problems in diagnosis

Each of the many different types of salivary gland tumors can exhibit a very broad morphologic spectrum, with overlapping features among the different types just taking the example of Acc, it can manifest as cribriform variant, tubular variant, solid variant, e.t.c

The histogenesis of salivary gland tumors,with their morphologic subtypes & myriad histologic growth patterns has recently evoked considerable interest

It is important to know the histogenesis since there is particular need to investigate various developmental processes, the cell types, and the forms of differentiation involved in salivary gland tumors & to produce improved criteria for the segregation of individual types of tumors.

In order to understand or classify the salivary gland tumors, two terminologies regarding its pathogenesis are to be understood properly

Histogenesis ------------histogenetic concepts

&

Morphogenesis----------morphogenetic concept

Histogenesis

formation or development of tissues from the undifferentiated cells of germ layers of the embryo.

Pathologists use it synonymously with the cell of origin for a neoplasm (histogenetic concepts)

Undifferentiated pluripotential cell

Excretory ductal cells

-columnar

-squamous

-goblet Intralobular

ductal cells

Myoepithelial cell

Acinar cell

Sebaceous cell

Ectodermal progenitor cell mass

Proximal cell mass Distal (End of Terminal Bulb)

cell mass

Excretory

ducts

Proximal

intra &interlobular

striated ductsDistal

intralobular

striated ducts

Intercalated duct/

Terminal tubule

complex

Striated duct

system Acinar elements

Intercalated ducts

Main excretory

ducts

.

2

Morphogenesis

The evolution and development of form as the development of the shape of a particular organ or part of the body

Form & structure of the S.G is determined mainly by the epi-mesenchymal interaction & also by the basal lamina & myoepithelial cells.

According to pathologists it’s a process of differentiation inherent in neoplasms & the resulting histopathology characteristic for that particular tumor(morphogenetic concepts)

Histogenetic concepts of salivary gland tumorigenesis

Histogenetic conceptThere are two theories of histogenesis of salivary gland neoplasms,

Differentiated cells undergo a process of de-differentiation into multiple cell types giving varied histologic neoplasms- i.e a neoplastically altered epithelial cell with the potential for multidirectional differentiation results in salivary gland neoplasm.

Progenitor cells

present in the

intercalated duct and

excretory duct to

explain differentiation

into various

histologically varied

neoplasms.

A variety of histogenetic concepts for salivary gland tumors have evolved, but central to histogenetic concepts has been the determination of what type or types of cells (progenitor cells) in the normal salivary gland are involved in the induction of neoplasia. The exact population of cells however in the various salivary gland responsible for cell renewal & therefore the cells most at risk for neoplastic transformation has not been determined specifically.

There are very few publication that have addressed histogenetic concepts of salivary gland tumours and it so it is not clear how these concepts have evolved.

.

3

Concepts of salivary gland tumor histogenesis

Basal reserve cell theory

Pluripotential unicellular reserve cell theory

Semipluripotential bicellular reserve cell theory

Multicellular theory

Basal cell reserve theory

Don’t know who published

Basal cells of both excretory and intercalated ducts responsible for differentiation of the functional units.

•Basal reserve cell

theory

•Pluripotential

unicellular reserve

cell theory

•Semipluripotential

bicellular reserve

cell theory

•Multicellular

theory

In 1971, Eversole proposed two histogenic schemes

The first proposal is the

Pluripotent unicellularreserve cell theory

This theory asserts that the excretory duct reserve cell may possess the ability to generate intercalated like cells and therefore acinar elements. In essence, basal cells of the excretory duct responsible for development of all remaining salivary gland units.

•Basal reserve

cell theory

•Pluripotential

unicellular

reserve cell

theory

•Semipluripoten

tial bicellular

reserve cell

theory

•Multicellular

theory

In this scheme, basal cells of the excretory duct form intercalated duct units, and luminal progenitor cells of the latter are then responsible for the development of intercalated, striated and acinar units.

The second theory outlined Eversole is the

Semipluripotential bicellular theory:•Excretory duct reserve

(basal) cells originate

tumors such as

mucoepidermoid and

squamous carcinomas,

• Intercalated duct

reserve(luminal) cells

originate tumors such as

PA and Monomorphic

adenomas, ACC, and

acinic cell carcinomas

Multicellular theory(1990)

There is no direct evidence to support semipluripotential bicellular theory. Dardick et al challenged this theory and concluded that dividing cells are not limited to basal cells of excretory duct and luminal cells of intercalated ducts. Dardick et al then proposed the new theory

any one of the multiple cell types in the normal

salivary gland may have the potential to give rise

to any of the various types of tumor occurring in

these tissues.

The variety of differentiated tumor cells & the

neoplasms with myoepithelial/basal cells that are

reported in the literature are summarized as followsNeoplasm Types of cells

Pleomorphic adenoma Luminal

Acinar

Myoepithelialmyoepithelioma Myoepithelial

Rarely luminal

Basal cell adenoma Luminal

Myoepithelial/basal

AcinarWarthin’s tumor Luminal

Basal/Myoepithelial

Epithelial-myoepithelial

carcinoma

Luminal

Myoepithelial

.

4

Adenoid cystic

caricinoma

Luminal

Myoepithelial

Acinic cell

carcinoma

Acinar

Intercalated duct

Myoepithelial

Mucoepidermoid

carcinoma

Goblet

Luminal

Squamous

Myoepithelial/basal

Salivary duct

carcinoma

Luminal

Myoepithelial

PLGA Luminal

Myoepithelial

Adenocarcinoma,

NOS

Luminal

Myoepithelial

Malignant mixed

tumor

Luminal

Squamous

Myoepithelial

All SG tumors originate at some point along this

salivary duct unit,the more aggressive the tumor, the

further distal along the unit it Originates(as stated by

Carlson Oral & Max Surg Cli of NA(1995)

Undifferentiated

Differentiated

Primary

regulation

Tertiary regulation

Secondary

regulation

Modulation

Within

Adult stage

Developmental increase

SG cytodifferentiation & morphodifferentiation

Batsaki’s graphic presentation of SG cytodifferentiation

& morphodifferentiation(1980)

Undifferentiatedcarcinomas

Undifferentiated

Basaloid&ACC

PA

High grade Acinous

cell carcinomas

Low grade acinous

cell carcinomas

Differentiated-adult

Salivary gland tumor: relation to

cyto & morpho differentiation

The genome of the normal cell contains all the information

necesssary for the expression of malignant as well as normal

phenotype. If the cells become the oncogenic targets, along the

development, at that TIME, neoplasia results

MORPHOGENETIC CONCEPTS OF THE SALIVARY GLAND TUMORIGENESIS

Morphogenetic concepts:Morphogenetic approach focuses on tumor cell differentiation and other cellular processes that critically influence the histomorphology

Morphogenetic processes determine the specific features allowing histologic recognition of each normal organ and tissue

Similar mechanisms of differentiation allow classification of salivary gland tumors based on the histology

Variable proportions of different cell types & distribution of extra cellular products, underlie the diversity of salivary gland tumors, both between subtypes & within them.

.

5

Tumor cell production

results in a dual

population that combines

recognizable luminal and

/or Acinar cells with

myoepithelial and /or

basal cells

Tumor cell

differentiation results

in 3 basic models

Ductoacinar concept

Luminal cells

only

Luminal+nonluminal

+matrix materials

Luminal+nonluminal

Basal/myoepithelial cells

Basal/myoepithelial

cells+matrix materials

Production of extracellular materials

results in five main categories

Pleomorphic adenoma1. origin from neoplastic elements of both epithelium &

mesenchymal tissues

2. origin solely from neoplastic epithelial cells that in turn, produce the other tissue components, either directly or by transformation into mesenchymal cells and

3. the tumors are derived from cells that undergo a metaplasia to cartilage. Etc.,

There is now universal agreement that the salivary gland mixed tumor is entirely of epithelial origin.

Ultra structurally two types of cells:

-ductal epithelial & myoepithelial.

-Other cells: mesenchymal cells & indeterminate cells.

The myoepithelial cell assumes an important role in determining the overall composition

Dardick; a neoplastically altered epithelial cells with potential for multidirectional differentiation may be histogenetically responsible for pleomorphic adenoma.

Chromosomal abnormalities:

chromosomal rearrangements-

chr 8(band q12)

chr 12(q13-15)

Luminal+

Nonluminal

With

Extracellular

Materials

Separation of

NonluminalCells

Some resemble

chondrocytes

Nonluminal

cells

With

extracellular

Materials

Gradial

differentiation

to chondrocytes

Merging 2 or > = results in endless stream of histology in PAIf only this model develops it results in myoepithelioma

Adenoid cell carcinoma:

Morphological resemblance of ACC cells to intercalated duct cells

But the presence of myoepithelial and myoepithelial like cells, suggest that both intercalated ductal epithelial + myoepithelial make up the cell of origin.

.

6

Cribriform variant

This classic feature is

dependent on the development

of pools of

Glycosoaminoglycans & basal

lamina b/n basal/myoepithelial

cells in highly controlled

manner

Solid: results from excess

proliferation of

neoplastic basal/myoepithelial

cells along with small numbers

of ductal structures

Mucoepidermoid carcinoma and squamous cell carcinoma

All cells of salivary gland unit carry the potential to keratinize or become squamous in type under appropriate circumstances because of their origin from surface epithelium. The cells of excretory duct would be expected to have the greatest potential

smoking or infection --- squamous metaplasia and occasionally mucous metaplasia of excretory ducts

So neoplastic transformation of such metaplastic excretory ducts may result in squamous cell carcinoma or mucoepidermoid carcinoma

Mucoepidermoid carcinomas are composed of essentially 3-6 cell types.

Maternal cells

Intermediate cells

Epidermoid cells

Clear cells

Columnar cells

Mucous cells

Goblet cells

epidermoid

clear

mucous

columnar

prickle

Goblet cell

Glycogen laden

clear cells

Squamous

cell

Glycogen laden

clear cells

Nonspecific

Basal cells

Intermediate cells

Cuboidal or

coloumnar cells

Ductoacinar unit

PLGADisordered & random Differentiation. Myriadhistologic patterns resultfrom controlled developmentof tumor cells with varyingarrangements from region to region

Oncocytic tumors:

Oncocytes are cells that contain hyperplastic & pleomorphic mitochondria. These cells are generally not present in salivary gland of younger individuals, but are commonly seen with increasing age.

May be found anywhere along salivary gland unit, but are most frequently encountered among intercalated duct cells & acinar cells

Cell of origin- excretory duct reserve cells or intercalated duct reserve cells

.

7

Warthins tumor:

The first theory suggests that the tumor arises as a result of proliferation of salivary gland ducts entrapped within paraparotid or intraparotid lymph nodes during embryogenesis.

- Most accepted currently

The second theory suggests that the tumor arises within the gland from ductal epithelium with secondary lymphocytic infiltration

Smoking?

Gallo has found antibodies to EBV and postulated a role for this virus in the pathogenesis

Intraosseous salivary gland tumor:

Pathogenesis:

1. Ectopic salivary gland tissue that may arise from ectopic salivary gland tissue that was developmentally entrapped within the jaws.

2. Maxillary tumors may arise from gland of the sinus lining.

3. Most likely source is odontogenic cyst linings

Myoepithelial cells:

These cells lie between the epithelial cells and the basal lamina of acini, intercalated ducts, and probably also exist in the union of the striated and intercalated ducts

The myoepithelial cell is a two-sided cell. This is expressed by their position: on the one hand it is connected with secreting epithelium and on the other to mesenchymal tissues.

The cell’s two sidedness is also evident by its ectodermal origin modified by a mesenchymal potential

ALTERED myoepithelial cells may manifest one of both characteristics( epithelial + mesenchymal structures ) which are now considered the key factor in the morphology of many salivary neoplasms and in the morphologic variability of some tumors.

MALIGNANT TUMORS CONTAINING MYOEPITHELIAL CELLS USUALLY TEND TO BE LESS AGGRESSIVE THAN TUMORS LACKING THESE CELLS

Stellate or

myxoid cellsSpindle shaped

or myoid cells

Hyaline or

plasmocytoid

cells

Clear or

epithelial

cells

Chondromyxoid

areas of PA

PA & some types of

myoepithelioma

Epithelial-

myoepithelial

carcinoma

Normal myoepithelial

cell

ALTERED

CELL

TYPES

Benign tumors Myoepitheliomas

PA

Basaloid adenomas

Malignant tumors Epithelial-myoepithelial carcinoma

ACC

PLGA

Basaloid carcinoma

Congenital tumors Sialoblastoma

Salivary gland anlage tumor

Salivary gland tumors with myoepithelial cell participation

.

8

Conclusion

Herein I have put the past & present concepts and speculations regarding the histogenesis of the salivary gland tumors in a nutshell. But none of the concepts discussed herein are accepted as of now. After going through the various concepts I am of the opinion that MULTICELLULAR CONCEPT is the one which seems to be most appropriate, but still lot of research can be done in this field of histogenesis of salivary gland tumorogenesis

.

1

TEMPORO MANDIBULAR JOINT

Presented by:

Dr. Manish Jain

Professor & Head

Department of Oral & Maxillofacial Pathology & Microbiology

Mahatma Gandhi Dental College & Hospital,

M. G. U. M. S. T.

TYPE OF THE JOINT:

Tmj is a synovial joint.

In human being masticatory process demands that mandible be capabale not only of opening and closing movements but also of protrusive, retrusive and lateral movements and combinations there of.

To achieve them, the condyle undertakes translatory and rotary movements therefore human tmj is synovial slidiry ginglymoid joint.

ANATOMY OF TMJ

Consist of

◼ Condyle (head) of the mandible

Articular disc

◼ Articular ligaments the articular disc is located between the condyle of the mandible and the temporalis bone. Two separate synovium-lined cavities are

formed.

Anatomy of TMJ Contd…

The condyle of the mandible has an articular surface located on its superior extremity.

Each condyle articulates with the articular disc interposed between it and the temporalis bone.

The condyle measures

Anatomy of TMJ Contd…

20mm through the long axis

10mm through the anteroposterior axis

The long axis is at right angles to the ramus of the mandible.

The condyle is more convex anteriorly and varies from individual to individual.

Several pairs of muscles insert in the mandible to provide its various movements.

.

2

Temporalis bone articulation

Is locted on the inferior aspect of the zygomatic process called the posterior slope of the articular tubercle (eminence).

The articular eminence is a strongly convex, bony elevation on the root of the zygomatic process that forms the most anterior boundary of the articular or glenoid fossa.

The tubercle is located on the lateral aspect of the articular surface, where the fibrous capsule and the TMJ ligament insert.

The roof of the glenoid fossa is formed by thin bone separating it from the middle cranial fossa.

Disc (meniscus)

Is a compact, oval-shaped, dense fibrous connective tissue

plate.

Lies between the mandibular condyle and the articular eminence of the temporalis bone.

Its inferior surface is concave, covering the convexity of the articular surface of the condyle.

Its superior surface conforms with the articular surface of the temporalis bone.

Is thicker at the periphery and thinner in the stress-bearing area of the joint.

Occasionally, has a central perforation. Is very vascular at its periphery, but its central area is avascular.

Articular covering

Comprise dense collagenous connective

tissue whose stress-bearing area is fibrocartilaginous.

Is avascular and is bathed in synovial

fluid, which nourishes lubricates the cellular coverings.

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3

Capsule

Encloses the entire articular area of the temporalis bone, disc, and mandibular condyle.

Superiorly, inserts to the circumference of the glenoid fossa.

Anteriorly, inserts around the articular eminence.

Inferiorly, is attached to the neck of the mandible.

The disc is located between the two articulating surfaces and its peripheral attachment to the wall o0f the capsule, causing the capsule to be divided into superior and inferior compartments.

Superior compartment

Is located between the disc and temporalis bone, which allows some freedom of movement between the disc and the articular eminence

Anteriorly, the disc and the capsule are tightly fused, which allows some fibers of the lateral pterygoid muscle to attach into the disc.

Medially and laterally, the capsule and the disc insert into the condyle margins, which necessitates the simultaneous movement of the condyle and the disc.

Inferior compartment

◼ Invests the entire neck of the mandible and is densely attached to the disc.

◼ This attachment prevents excessive movement between the disc and the condyle.

Ligaments

The capsule of the joint is reinforced medially and laterally by bundles of collagenous fibers.

sThe medial part is called the capsular ligament. The more pronounced part is called the lateral (temporomandibular) ligament.

Lateral (or temporomandibular) ligament

Consists of two separate bands whose directions are oblique to each other.

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4

Superficial band ligament

Is the largest, arising with broadband from the lateral surface of the articular eminence at the articular tubercle.

Narrows as it runs posteroinferiorly.

Inserts on the posterior aspect of the

mandibular neck just inferior to the lateral aspect of the condyle.

Medial band ligament

Is a small band arising from the crest of the articular tubercle.

Runs almost horizontally to insert on the lateral

surface of the condyle and the discs.

Since bilateral temporomandibular joints are connected through the mandible, the articulations work as a single unit.

The medial and lateral ligaments allow free

movement in the anteroinferior plane but check mediolateral motions of the joint.

ACESSORY LIGAMENTS OF TEMPOROMANDIBULAR JOINT

Sphenomandibular ligament

Is a derivartive of Meckele’s cartilage.

Is a flat band extending between the sphenoid spine and the ingula at the mandibular foramen.

Assists in limiting lateral movement of mandible.

Stylomandibular ligament

Is formed by a thickening of deep cervical fascia.

Extends as a thin band from the apex of the styloid process of the temporalis bone to the posterior margin of the angle and the ramus of the mandible.

Nerves to the temporomandibular joint

The joint capsule is heavily innervated by sensory endings from the mandibular nerve.

The majority of these are conveyed from branches of the auriculotemporal nerve.

Additional sensory supply to the joint is

derived from the masseteric branch of the mandibular nerve.

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Vessels to the temporomandibular joint

Are provided by branches of the superficial temporalis and the maxillary arteries.

Movement of the temporomandibular joint

Types of movement include. Ginglymus (hinge) movement, which occurs between the condyles and the inferior surface of the discTranslatory (gliding) movement, which occurs when the superior surface of the disc sli8des inferiorly at the articular eminence

The mandibular-disc movement is rotartory and the disc-temporalis bone movement is translatory.

Movement of the jaw includeOpeningClosing Protrusion RetrusionLateral rotation

Resting position

Occurs in an erect position with the muscles of mastication at rest.

There is a small space between the upper and the lower teeth, and the lips are touching

The anterior superior articulating surfaces are

opposite the posterior slopes of the articular eminence of the temporalis bone with the disc between the bones.

Jaw opening

Involves,

Translatory movement of both disc and the condyle down the slope of the articular eminence. (hinge) move

Rotatory movement of the mandibylar condyles against the disc.

The gliding phase causes a slight anteroinferior movement as the mandible slides down the eminence.

The rotatory action causes a center of suspension in the ramus. Therefore, the posterior part of the angle of the mandible moves slightly posteriorly while the body moves inferiorly to open the jaw.

The lateral pterygoid muscles start the action. This is followed by the action of the digastric, the geniohyoid, and the mylohyoid muscles, which lower the mandible (while the hyoid bone is fixed by the infrahyoid muscles).

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Jaw closing

Is a complicated action initiated by protrusion of the jaw as the condyles and the disc slide inferiorly and anteriorly on the articular eminence.

Is followed by condylar fixation and raising of the mandible coupled with depression and retraction.

The lateral pterygoid muscle is assisted by the medial pterygoid muscles to protrude the mandible, while the masseter and the temporalis muscles raise it.

Retrusion is accomplished by the deep portion of the masseter muscle and some fibers of the temporalis muscle.

Jaw protrusion occurs by contraction of the lateral pterygoid muscles, causing the disc and the condyle to slide forward and down the articular eminence.

Conversely, retrusion returns the jaw to a position posterior to the resting position; it is accomplished by portions of the temporalis muscles.

DEVELOPMENT OF JOINT

Meckels cartilage articulates with incal cartilage if any movement of early jaw occurs, it occurs between these two cartilages.

This primary jaw joint exists for about four months until cartilages ossify and become incorporated in the middle ear.

At three months of gestation two jaws joint the TMJ begins to form. The first evidence of TMJ development is appearance of two distinct regions of Mesenchymal condensation. -(The temporal and condylar blastoma)

Temporal blastoma appears before the condylar and initially both are positioned some distance from each other.

Ossification begins first in temporal blastoma. While condylar blastoma is still mesenchyme.

The condylar blastoma differentiate into cartilage and then second cleft appears in relation to temporal ossification that becomes the upper joint cavity.

CARTILAGE ASSOCIATED

WITH JOINT

fibro cartilage is associated with the articulation deep to fibrous layer in condyle and on articular eminence.

The condylar cartilage consists essentially of a proliferative layer of replicating cells that function as progenitor cells for growth cartilage.

These cells become chondroblasts and elaborate an extra cellular matrix of proteoglycans and type two collagen to form the extra cellular matrix o cartilage in which they become entrapped as chondrtocytes.

Following production of this cartilage, endochondral ossification occurs involving mineralization of cartilage, vascular invasion, loss of chondrocytes and differentiation of osteoblasts to produce bone on mineralized cartilaginous framework.

CARTILAGE ASSO WITH JOINT

CONT.

The mandibular condyle has multidirectional growth capacity and its cartilage can proliferate in any combnati0n if superior and posterior directions as needed to provide for best anatomic placement of mandibular arch.

Condylar cartilage existing until the end of second decade, the eminence cartilage lasting a much shorter time.

The proliferative activity of cells in proliferative layer ceases, but the cells persists.

The cartilage immediately below converts to fibro cartilage and in mandible eventually mineralizes to a degree even greater than that of mineralized bone. Thus fibro cartilage is found in mandible and on slope of articular eminence.

CAPSULES LIGAMENTS AND DISK OF JOINT

Capsule consists of dense collagenous membrane, that seals joint space and provide passive stability, as well as active stability from proprioceptive nerve endings in capsule.Extensions of capsule into joint cavity forms disks that function as articular surfaces and divide joint into two compartments.

Lateral aspect of capsule is thickened to form a fan shaped ligament, temporomandibular ligament. Two parts,(1) Outer oblique portion (2) Inner horizontal portionTwo other ligaments (1) Sphenomandibular(2) Stylomandibular

An inward circumferential extension of capsule forms a tough, fibrous disk that divide joint into two compartmentsDisk consists of dense fibrous tissue, and its shape conforms to that of apposed articular surfaces.

CAPSULES LIGAMENTS AND DISK OF JOINT CONT.

The type I collagen bundles that constitute the disk generally are arranged loosely and oriented randomly except in the central region where they are more tightly bound in organized bundles. Coronal sections of disk show it to be thicker medially.

The upper part of capsule or lamellae consists of fibrous and elastic tissue, inserts into squamo tympanic fissure.

The lower part of capsule, consisting of collagen only and nonelastic, blends with periostium of condylar neck.

Between these two lamella a space is created that is filled with a loose, highly vascular connective tissue. The disk is well supplied with vascular and neural elements at its periphery but is avascular and not innervated in its central region.

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SYNOVIAL MEMBRANE

The capsule is lined on its inner surface by a synovial membrane.

Synovial membrane is considered to live entire capsule withy folds or villi of membrane protruding into joint cavity, especially in its fornices anterior its upper posterior aspect. These folds increase in number with age and are also more prominent in joints affected by a pathologic process.

Synovial membrane consists of, two layers,

(1) cellular intima: resting on vascular subintima, which in turn blends with fibrous tissue of capsule.

(2) subintima: is a loose connective tissue containing vascular elements together with scattered fibroblast macrophages, mast cells, fat cells and elastic fibers, which prevent folding of membranes.

SYNOVIAL MEMBRANE CONT.

The cells forming discontinuous layer are of two types,

TYPE A (predominant – macrophage like) cells have surface filopodia, many plasma membrane invaginations and associated pinocytotic vesicles. Their cytoplasm contains mitochondria and lysosomal elements and prominent golgi complex. Phagocytic properties.

TYPE B (fibroblast like) contains any rough endoplasmic reticulum.Synthetic hyaluronate found in synovial fluid.

Synovial membrane has properties of viscosity, elasticity, and plasticity. Synovial fluid contains small population of Monocytes, lymphocytes, free synovial cells and occasionally pmns.

MUSCLE THAT CAUSE MOVEMENT

Muscle may be described in number of ways.

(1) By the arrangement of their fibre bundle or fasciculi(a) Strap muscles (b) Fusiform muscle

(c) fan shaped muscle

(2) Muscle has a central tendon extending into a fleshy belly to which bundles of muscle fibres attach in an oblique direction.

(a) unipennate (b) bipennate(c) multipennate

MUSCLE THAT CAUSE MOVEMENT –MUSCLE CONTRACTION

Muscle cells fibers that make up bundles (fasciculi) are long and narrow.

The cell membrane of the fiber is called the sarcolemma immediately beneath which nucleus of cell is found.

Sarcoplasmic reticulum, a branching endoplasmic network that surrounds each myofibril.

Sarcoplasm contains mitochondria, glycogen and myoglobin.

Distinction between red and white meat is familiar one. Great amount of myoglobin in red meat, which is, sustained contraction as opposed to rapidly contracting fast muscle of white meat.

MUSCLE CONTRACTION CONT.

They have distinct histochemistry, slow twitch fiber (type I) is narrower than fast twitch fiber (type II) has poorly defined myofibrils contain slow myosin, possesses many mitochondria and exhibits high oxidative enzyme and low phosphorylase activity.

By contrast type II or (fast twitch fiber) have fewer mitochondria, possess an extensive sarcoplasmic reticulum, contain fast myosin, and show a lower oxidative enzyme activity.

By varying ph of substrate during histochemical reaction, differentiating subtypes of type II fibers is possible. Type II A and Type II B fast myosin type II c mixture of slow and fast myosin.

MOTOR UNIT

Nerve complex is known as motor unit

and innervation is achieved through a structure known as motor end plate. Two other neuronal structures are described 1. muscle spindle 2. golgi tendon organ.

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MUSLES OF MASTICATION

The masseter and medial pterygoid muscle together

have a sling like configuration clasping the angle of mandible and ate principal elevators of jaw.

Analysis of fibre composition of these two powerful elevator muscles confirms regional differences. Both exhibit a preponderance of type I fibres, indicating a muscle that is adapted to resisting fatigue at low force levels.

The post portions of both muscles are characterized by possessing a high concentration of type II B fibers.

MUSCLES OF MASTICATION CONT.

Functionally temporalis acts as two muscles. Muscle shows variation in its fiber composition.

The bipennate superficial portion has 50% type II B fibers indicating capacity for acceleration coupled with an ability to develop tension.

The post portion, contains preponderance of type I fibers and many muscle spindles.

Thus in general masseter and medial pterygoid are power producers and temporalis is concerned more with moving and stabilizing the mandible.

INNERVATION OF JOINTThe innervation of any joint involves IVtypes if nerve endings.

Anatomic designation

functional designation

Ruffini’s corpuscle

posture proprioception dynamic and static balance

Pacini’corpuscle

dynamic mechanoreception movement accelerator

Golgi tendon organ

static mechano reception protection (ligament)

Free nerve ending

pain (nociception) protection (joint)

INNERVATION OF TMJ

Ruffini’s endings

Exists in clusters in superficial layers of joint capsule.

Active in every position of joint so that they signal static joint position, changes in intraarticular pressure and direction, amplitude and velocity of joint movements.

Pacini’s corpuscles:

Are rapidly acting mechano receptors with a low threshold found mainly in deeper layers of capsule that signal joint acceleration and deceleration

Golgi tendon:

Limited to ligaments and sparsely distributed to superficial layers of lateral ligaments, remain completely inactive in immobile joints, becoming active only when the joint is at the extremes range of movement. Free nerve ending:

Are secondary to roles of other specialized receptors. Yet are most frequently occurring terminal in a joint, are thought to be associated with nociceptions and are distributed widely

Immunocytochemical study shows that they may function to control the activity of macrophage like cells.

BLOOD SUPPLY TO JOINT

Vascular suppluy to TMJ comes from branches of, • Superficial temporal • Deep auricular • Anterior tympanic • Ascending pharyngeal

DISEASES OF TMJ

(1) Developmental disturbance of TMJ• Aplasia of mandibular condyle • Hypoplasia of mandibular condyle • Hyperplasia of mandibular condyle(2) Traumatic disturbances of TMJ• Luxation and subluxation • Ankylosis (hypermobility) • Injuries of articular disk • Fracture of condyle (3) Inflammatory disturbances of TMJ • Arthritis due to specific infection• Rheumatoid arthritis • Ostoarthritis • Traumatic arthritis (4) Neoplastic disturbances• Benign • Malignant(5) Extra articular disturbances of TMJ • Myofunctional pain dysfunction syndrom

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(1) DEVELOPEMENTAL DISTURBANCES OF TMJ

Aplasia of mandibular condyle

• Aplasia of mandibular condyle or failure of development of mandibular condyle is associated with defective or absent external ear, an underdeveloped mandible ramus or macrostomia.

• In unilateral cases, there is obvious facial asymmetry and both occlusion and mastication altered.

Cont.

Hypoplasia of mandibular condyle

Congenital hyoplasia is of idiopathic origin and is characterized by unilateral or bilateral underdevelopment of condyle

Acquired hypoplasia may occur due to forceps deliveries, external trauma to condyle x-ray radiation.

Clinical deformity depends upon whether disturbance involving one or both condyles, degree of malformation, age of patient.

Unilateral involvement is common which leads to facial asymmetry often accompanied by limitation of lateral excursion on one side and exaggeration of antegonial notch of mandible on involved side.

Hyperplasia of mandibylar condyle

Condylar hyperplasia is rare unilateral enlargement of condyle. It is a local phenomenon.Patient exhibits unilateral, slowly progressive

elongation of face with deviation of chin away from the affected side.

(2) TRAUMATIC DISTURBANCES OF TMJ

Luxation and subluxation

Dislocation of TMJ occurs when head of condyle moves anterior over the articular eminence into such a position that it cannot be returned voluntarily to its normal position.

Luxation refers to complete dislocation. Subluxation refers to partial or incomplete dislocation a form of hypermobility.

The luxation is characterized by sudden locking and immobilization of jaws when mouth is open, accompanied by prolong spasmodic contraction of temporal, internal pterygoid and masseter muscle with protrusion of the jaw.

AnkylosisMost frequent cause is traumatic injuries and infections in

and about joint.

Abnormal intrauterine development.

Birth injury

Trauma to chin

Malunion of condylar fracture.

Injuries associated with fracture of malar-zygomatic compound.

Loss of tissue with scarring.

Congenital syphilis

Primary inflammation of joint. (rheumatoid arthritis) (ottitis media, mastoditis, osteomyelitis)

Inflammation of joint secondary to blood stream infection. (septicemia scarlet fever)

Metastatic malignancies.

Inflammation secondary to radiation therapy.

Ankylosis cont.

Patient may or may not be able to open his mouth to any appreciable extent depending on type or ankylosis.

Ankylosis can be, unilateral or bilateral.

Unilateral ankylosis occurs at early age. Chin is displaced laterally and backwards on the affected side because of a failure of development of mandible.

Bilateral ankylosis results in under development of lower portion of face, a receding chin and micrognathia.

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Ankylosis cont.

Two types. (Depending upon anatomic site of ankylosis with respect to joint itself)

Intra articular:

It undergoes progressive destruction of meniscus with flattening of mandible fossa, thickening of head of condyle and narrowing of joint space.

The ankylosis is basically fibrous.

Extra articular

It results in splinting of TMJ by a fibrous or bony mass external to joint proper, as in cases of infection in surrounding bone or extensive tissue destruction.

Injuries to the articular disk

Most common known causes of injury to meniscus is malocclusion. Acute trauma directly to jaws such as a blow or a full can act as a precipitating factor.

It is characterized by pain, snapping or clicking and crepitation in the joint area. The pain may be present only near completion of opening motion.

Fracture of condyle

Condylar fracture results from an acute traumatic injury to the jaw and is accompanied by limitation of motion, pain and swelling over the involved condyle, deformity noted upon palpation and loss of normal condylar excursion.

The fractured condyle fragment is frequently displaced anteriorly and medially into the intra temporal region because of forward pull of external pterygoid muscle and reduction of fracture is often difficult because of this displacement.

(3) INFLAMMATORY DISTURBANCES OF TMJ

Arthritis due to specific infection

Most common form of infectious TMJ arthritis is caused by direct extension of infection into joint as a result of an adjacent cellulites or osteomyelitis. Such an extension may follow dental infection, infection of parotid gland or even facial or ear infection.

Patient is having chief complain of severe pain in the joint with extreme tenderness on palpation or manipulation over the joint area.

Depending upon severity of involvement there is variable amount of destruction of articular cartilage and articular disk

Osteomylitis with destruction of bone the condyle may be present

The joint spaces become obliterated in the healing phase by development of granulation tissue and its subsequent transformation into dense scar tissue.

Rheumatoid arthritis

The disease is of unknown etiology. There is evidence to indicate that it may be a hypersensitivity reaction to bacterial toxins, specifically streptococci.

In early stages it may be manifested by slight fever, loss of weight and fatigability. The joints affected are swollen and patient complains of pain and stiffness.

Movement of jaw as during mastication or talking causes pain and may be limited because of stiffness.

Clicking and snapping may occur due to alterations in articular cartilage and meniscus.

Rheumatoid arthritis in children (still’s disease) it involves TMJ, may cause a malocclusion of class-2/1 with protrusion of maxillary incisors and anterior open bite.

Rheumatoid arthritis cont.

Deformation of mandible characterized by shortening of body and reduction in height of ramus due to failure of growth center in condylar area.

Radiographically often revealed flattening and stunting of condyles and haziness about the joint indicative of periarticular fibrosis.

Histologically it is characterized by ingrowth of granulation tissue to cover the articular surfaces, the invasion of cartilage and its replacement by granulation tissue and the ultimate destruction of articular cartilage. Eventually fibrous adhesions occur, the meniscus may become eroded and fibrous ankylosis results.

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Osteo arthritis

Etiology is unknown. It is a disease associated with the aging process. The joints first involved are weight-bearing joint subjected to continuous stress and strain.

Since TMJ is not a weight-bearing joint, changes here are insignificant even though arthropathy may be present in other joints.

Patient may complain of clicking and snapping in Tmj but pain is not necessarily a feature. This joint noise is probably due to atypical disk motion resulting from discordant mandibular condyle disk function on the basis of changes in articular cartilage.

Osteo arthritis cont.

Histologically the changes in the articular cartilage consist of elasticity and surface erosions of varying degree of severity with presence of vertical cracks extending often from the surface through cartilaginous plate into the subchondral bone.

The cartilage cells often exhibit degeneration and there may be complete destruction of cartilage in localized area. Dystrophic calcification may occur which lead to actual ossification.

Bony protuberances or exostoses are common finding in osteoarthritis. There may be bony lipping of condyle.

Articular disk may show cracks with fissure and may become hyalinized or even calcified. There may be necrosis or destruction of disk, particularly opposite the exostoses.

Traumatic arthritis

Traumatic arthritis of acute or chronic nature is a common form of TMJ arthropathy.

(4) NEOPLASTIC DISTURBANCES OF TMJ

Neoplasm and tumor like growths, benign and malignant may involve TMJ but such involvement is relatively uncommon.

Such tumors may originate from condyle, either the bone or articular cartilage or from the joint capsule.

As might be expected, the connective tissue cartilage and bone give rise to majority of these tumors.

(5) EXTRA ARTICULAR DISTURBANCES OF TMJ

Referred pain is a common source of arthralgia of this area.

Impacted teeth on same side as TMJ joint pain were implicated.

Sinusitis and middle ear disease

Infratemporal cellulites

Impingement of the coronoid process on the tendon of temporal muscle

Neuritis of third division of fifth cranial nerve

Auriculotemporal neuritis

Odontalgia

A foreign body in infratemporal fossa

Over closure of mandible accompanied by severe dental attrision

Costen’syndrom

Myofascial pain dysfunction syndrome

Etiology:Masticatory muscle spasm is principle factor for

MPDS.This muscle spasm can be initiated as a result of muscular overextension, muscular over contraction or muscle fatigue.

Most common cause of this syndrome is muscle fatigue caused by such chronic oral habits as grinding or clenching of the teeth. ➢ These habits are believed to be an involuntary tension relieving mechanism involving emotional as well as mechanical factors as etiologic agents. ➢ Thus this explanation of syndrome has been termed the “psycho-physiologic” theory.

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MPDS cont.

Clinical feature

These are four cardinal signs and symptoms.1. Pain 2. Muscle tenderness3. A clicking or popping noise in TMJ 4. Limitation of jaw motion, uni/bilaterally

in approximate an equal ratio

MPDS cont.

Two typical negative disease characteristics1. An absence of clinical, r/f, or biochemical evidence of organic changes in joints itself. 2. Lack of tenderness ion the joint when it is palpated through external auditory meatus.

Patient may give history of other psychophysiologic disease such as gastrointestinal ulcer, migraine headache or dermatitis.

Patient had significantly higher urinary excretion levels of 17-OH steroids and catecholamines, which have been linked to stress phenomenon than a comparable group of control patients.

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VIRAL INFECTIONS OF ORAL CAVITY

Presented by:

Dr. Manish Jain

Professor & Head

Department of Oral & Maxillofacial Pathology &

Microbiology

Mahatma Gandhi Dental College & Hospital,

M. G. U. M. S. T.

HERPES SIMPLEX

(PRIMARY HERPETIC

GINGIVOSTOMATITIS,HERPES LABIALIS)

➢ Primary herpetic gingivostomatitis is a relatively common viral infection of the oral mucosa.

➢ETIOLOGY:-Herpes simplex virus.there are 2 types of virus which mainly cause this disease:-

1)HSV1

2)HSV2

➢more details about HSV…..

80 known herpesviruses

8 of them are known to cause infection in humans

virus diseaseHSV1 Primary herpetic gingivostomatitis.

Secondary herpes infections,

meningoencephalitis, dermatitis

above the waist.

HSV2 genital herpes(lesions below the

waist)

Varicella zoster

CMV

HHV6

HHV7

HHV8

➢PATHOGENESIS:-

• Muscosal surfaces and abraded skin favors entry of virus and the initiation of replication in the cells of epidermis & dermis .

• Initial or primary infection is asymptomatic and occurs commonly in childhood or infancy.

•

• Once the virus gains its entry, it enters into sensory ,autonomic nerve endings & remains latent in ganglia.

• During latent phase, herpes DNA is detectable, but viral proteins are not.

• Virus replication occurs and spreads to other skin &

mucosal surfaces by centrifugal distribution of virions

through peripheral nerves.

• Disease manifests as characteristic vesicles containing

desquamated cells, multinucleated giant cells & free

virus with edema fluid.

• two types of infection with the herpes simplex occur

• primary infection : in a person who does not have circulating

antibodies

• recurrent infection: in persons who have such antibodies

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• During primary infection ,only a small % of individuals

show clinical signs & symptoms.

• Primary Infection is accompanied more frequently by

severe systemic manifestations & occasionally fatal.

• Reactivation can occur as a result of a number of factors

including peripheral tissue injury from trauma, sunburn,

fever, immunosuppression

➢Incubation period:-1 to 26 days

➢Transmission:- mainly through close contact,

kissing, sharing of glasses, cutlery or crockery.

CLINICAL FEATURES:-

• high fever,

• headache,

• malaise,

• anorexia,

• The affected mucosa is red and edematous, with numerous coalescing vesicles.

• New lesions continue to develop during the first three to five days.

• The ulcers heal in 10–14 days.

• Both the attached and non-attached oral mucosa may be affected.

• Gingival enlargement

• Edematous and painful erosions

➢HISTOLOGIC FEATURE:-

• The herpetic vesicle is an intraepithelial blister

filled with fluid.

• The infected cells are swollen and have pale

eosinophillic cytoplasm and large vesicular

nuclei described as ‘balloning degeneration

• It contains intranuclear inclusions known as

‘Lipschutz Bodies’.

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➢TREATMENT:-

✓Antiviral drugs like Acyclovir, valacyclovir,

gamicyclovir.

✓Antibiotic therapy

✓NSAIDS

✓Topical anesthetic gels can be used.

RECURRENT OR SECONDARY HERPETIC LABIALIS AND STOMATITIS

It is a relatively common oral and perioral disease that is due to reactivation of HSV-1.

➢ Clinical Features:-

• Occurs chiefly in young adults.

• Sites involved:-Site of primary inoculation or adjacent area of ganglion involved.

• The vesicles soon

rupture, leaving small

painful ulcers that heal

within 6–10 days.

• Prodromal symptoms are

burning, itching, tingling,

and erythema.

➢TREATMENT:-

✓Antiviral drugs as well as symptomatic

treatment.

CHICKEN POX

(PRIMARY VARICELLA ZOSTER)

• It is an acute ubiquitous and extremely

contagious disease usually occuring in

children, and is characterized by an

exanthamatous vesicular rash.

• it is most common in winter and spring

months.

➢ETIOLOGY:-

Varicella zoster virus.

➢CLINICAL FEATURES:-

• Symptoms:-headache, nasopharyngitis, anorexia

• Appearance:- Initially there is maculo-pappular

eruption of skin.

• These eruptions usually begin on trunks and

spread to involve face and extremities.

• These eruption than rupture, form a superficial

crust and heal by desquamation.

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ORAL MANIFESTATIONS:-

• Sites involved:-buccal mucosa tongue, gingiva,

oropharynx,palate.

• Appearance:-Small blister like lesions→form

raised vesicles→rupture soon→form ulcers.

➢TREATMENT:-

Symptomatic treatment.

HERPES ZOSTER(SHINGLES,ZONA)

It is an acute infectious viral disease of extremely

painful in nature characterized by inflammation of

dorsal root ganglion

It is an acute self-limiting viral disease caused by re-

activation of Varicella-zoster virus.

➢ETIOLOGY:-Varicella virus(same as that of chicken

pox)

ORAL MANIFESTATIONS:-

• Sites involved:-buccal mucosa tongue, gingiva,

oropharynx,palate.

• Appearance:-Small blister like lesions→form

raised vesicles→rupture soon→form ulcers.

➢TREATMENT:-

Symptomatic treatment.

Difference between Herpes zoster and

Chicken pox

➢Primary infection by V-Z virus results

clinically in chicken pox while recurrent

infection results clinically in herpes zoster

➢Herpes zoster is sporadic & varicella is

seasonal in occurrence.

➢CLINICAL FEATURES:-

• The virus propagate within ganglia, and the vesicular eruption.

• Thoracic and abdominal nerves are most frequently involved.

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• Vesicles are unilaterally

and stop at the midline

and extremely painful.

• Post herpetic neuralgia

may develop.

• Incubation period 1-3

weeks,

HERPANGINA

(Apthous pharyngitis,vesicular pharyngitis)

• Herpangina is an acute self-limiting viral infection,

usually caused by coxsackie virus group A.

➢ CLINICAL FEATURES:-

• fever,

• sore throat,

• dysphagia,

• headache,

• malaise,

• diffuse erythema

• vesicles. • The vesicles are small and numerous, and rupture

rapidly, leaving painful ulcers that heal within 7–10 days.

• Intraorally , soft palate uvula, tonsillar pillars, and posterior pharyngeal wall.

➢Histologic features:-

Intraepithelial vesicles with

an eosinophilic exudates.

Nuclear ballooning

degeneration of epithelial

cells is a feature.

➢ Treatment:-

Supportive treatment. The

disease is self limiting.

HAND FOOT AND MOUTH DISEASE

It is an acute self-limiting contagious viral infection

➢ETIOLOGY:-Enterovirus coxsackie A16

➢CLINICAL FEATURES:-

• Chiefly affects young children. age between 6mts to

5years.

• Skin lesions are not constant, and present as small

vesicles with a narrow red halo.

• The lateral borders and the dorsal surfaces of the

fingers and toes are the most common areas involved.

.

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➢ORAL MANIFESTATIONS:-

• Sites involved:- The

buccal mucosa, tongue,

and labial mucosa are the

most commonly affected

sites.

➢TREATMENT:-

✓ It is self limiting disease.

✓ Regresses within 1-2 weeks.

✓ Requires supportive treatment.

MEASLES

(RUBEOLA)

➢ETIOLOGY:-Paramyxovirus.

➢TRANSMISSION:-Occurs by:

1) by direct contact

2) droplet infection

➢CLINICAL FEATURES:-

• Incubation period:- 8-10 days.

• Fever malasise, cough, conjunctivitis, photophobia,

lacrimation, eruptive lesions of the skin and oral

mucosa.

➢ORAL MANIFESTATIONS:-

• Oral prodromal symptoms occur 2 to 3 days prior to

cutaneous lesions.

• The pathognomonic lesion of this disease are called

’KOPLIK’S SPOTS’.

• Site:- buccal mucosa

• Appearance:-They are small irregulary shaped flecks

which appear as bluish, white specks surrounded by

bright red margin

➢PREVENTION:-

• Measles vaccines (single or in combi. With

MMR)

• 1st dose at age of 9 mts.

• 2nd at age of 15-18 mts.

.

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RUBELLA

(GERMAN MEASLES)

➢It differs from measles. Here koplik’s spots do not occur.

➢Appearance:-Tongue is swollen red macules may appear on palate.

➢Sex prediliction:- women > men.

SMALL POX

(VARIOLA)

• It is an acute viral disease which was an epidemic in nature and accounted for laterally millions of deaths.

• On dec 9 1979, the WHO global commission for the certification of the small pox eradication declared:

MUMPS

(Epidemic Parotitis)

➢Mumps is an acute contagious viral infection charactrized chiefly by unilateral or bilateral selling of the salivary glands, usually parotid gland involved.

➢Transmitted :- respiratory route

➢ Incubation period:- 2-3 weeks.

• PROGNOSIS AND TREATMENT:-

• Overall it is good

• Antiviral drugs – Acyclovir, Ramcyclovir

• Treatment is conservative.