ORAL GRANULOMATOUS DISEASES

DEFINITION

INTRODUCTION

PATHOPHYSIOLOGY OF GRANULOMA FORMATION

CLASSIFICATION OF GRANULOMATOUS DISEASES

GRANULOMATOUS LESIONS OF ORAL CAVITY

CONCLUSION

REFERENCES

DEFINITION:

Defined as a specific variety of chronicinflammation in which cells of the mononuclear phagocytesystem are predominant & take the form of macrophages,epithelioid cells & multinucleated cells. These cells areaggregated into well demarcated focal lesions calledgranulomas.

Granulomatous diseases have plagued humans for million years, with evidence of tuberculosis infection in Egyptians mummies & description of the syphilis described by Hippocrates & was recognized as a venereal disease in the fifteenth century.

In seventeenth century, the minute granules (milliary) in host tissues were noted. Robert koch developed a method of staining & identified bacteria & was able to differentiate infectious, noninfectious granulomatous diseases.

Actinomycosis was isolated in vivo & associatedwith sulfur granule production in the late nineteenth century

Granulomas are inflammatory lesions that evolve in response to irritation, infectious agents, and foreign bodies.

Localized masses of fibrovascular granulation tissue accompaniedby a nonspecific chronic or sometimes subacute inflammatory infiltrate as seen microscopically are simple granulomas.

In the oral cavity, lesions of this nature are most frequently encountered intraosseously as endodontically related periapical granulomas.

Simple granulomas in the oral cavity are generally localized to the gingiva, yet may actually arise anywhere in the mouth or on the facial skin, where they appear as cherry-red tumefactions, termed pyogenic granulomas.

The peripheral giant cell granuloma of the gingiva and alveolar ridge is a reactive lesion without an infectious etiology.

specific granulomas are usually associated with mycobacteria or deep invasive fungi, appearing microscopically as caseating and noncaseating granulomas.

Two types:

Foreign body granuloma

Immune granuloma

Foreign body reaction:

The foreign material is composed of particles that are usually too

large to be phagocytosed by macrophages. Because the

material is typically inert, it usually does not evoke an immune

response.Instead, in an attempt to eliminate the foreign substance

steady streams of macrophages are recruited to the site. There they

become activated, transform into epithelioid macrophages &

organize into granuloma.

Distinct form of delayed-type (cell mediated) hypersensitivity.

Immune granulomas typically develop in response to infection by various mycobacterial & fungal organisms.

initial exposure to a non-degradable antigen derived from an organism (usually a protein), there is an accumulation of predominantly, (CD4- positive) T- lymphocyte around blood vessels in the area where the antigens lie. Over time, the T cellsdifferentiate, become activated T- helper (Th) cells, & begin secreting various cytokines that recruit macrophages to the site of the foreign antigen.

If the antigens persist & remain nondegradable, the recruited macrophages eventually transform into epitheliod cells, organize & form granuloma.

Bacterial Fungal Spirochetal Parasitic

Tuberculosis Histoplasmosis Syphilis. Leishmaniasis

leprosy Blastomycosis Myiasis

Non tuberculous

Mycobacterial

infections

Phycomycosis

(Mucormycosis)

Toxoplasmosis

Actinomycosis Aspergillosis.

Klebsialla

rhinoscleromatis

Candidiasis.

Anthrax Cryptocoecosis

Brucellosis Rhinosporidiosis

1.Infection

2) Traumatic Etiology:

i) Pyogenic granuloma

ii) Reparative granuloma

3) Foreign Body etiology:

i) Oral foreign body reactions.

(Suture, hair, amalgam, endodontic sealer,

hyaluronic acid etc.)

ii) Cholesterol granuloma

iii) Cocaine induced midline granuloma

iv) Gout

4) Neoplastic

i)Histocytosis X

a)Eosinophilic granuloma

b) Hand schuller Christian Disease.

c) Letterersiwe disease.

ii) Benign Fibrous histiocytoma

iii) Neorotizing sialometaplasia.

iv) Polymorphic recticulosis (lethal midline

granuloma)

5) Unknown Etiology:i) Sarcoidosis,ii) Crohn’s disease

6) Autoimmune & Vascular disease:i) Wegener’s Granulomatosisii) Systemic Lupus erythematosesiii) Sjogren’s syndrome.

7) Developmental:Melkerson Rosenthal syndrome

8) Congenital chronic Granulomatous disease ofChildhood.

Histopathological features: Highly vascular tissue – granulation tissue.

Endothelium lined channels – engorged with RBC.

Lobular channels.

Surface – ulcerated – thick fibrinopurulent membrane.

Neutrophils, plasma cells, lymphocytes.

Neutrophils – ulcerated surface.

Older lesions – fibrous appearance.

Clinical:

Peripheral giant cell granuloma.

Peripheral ossifying fibroma.

Primary or metastatic malignancy.

Histopathological:

Gingival fibromas.

Polypoid capillary hemangioma.

Inflammed lobular hemangioma.

Granulation tissue type hemangioma.

•Plasma cell granuloma.

•Kaposi’s sarcoma.

•Angiosarcoma.

•Conventional granulation tissue.

•Hyperplastic gingival inflammation.

•Kaposi’s sarcoma.

Tuberculosis (TB)

Tuberculosis is a systemic infectious

disease of worldwide prevalence & of

varying clinical manifestations caused by

bacillus mycobacterium tuberculosis.

Mycobacterium tuberculi, is an important

cause of life–threatening disease, especially

in individuals infected with HIV.

As the lesion progresses tubercles coalesce toform a confluent area of consolidation.

This may convert to fibro calcified scar or walledby hyaline collageneous connective tissue, underfavorable conditions in their late lesion, themultinucleated giant cells tends to disappear.

A Biopsy exhibiting granulomatous inflammation& microscopic evidence of mycobacterialorganisms is often suggestive of Tuberculosis.

Histopathologically tuberculous

granulomas are composed of epithelioid

cells surrounded by a zone of fibroblasts &

lymphocyte that usually contains langhans

giant cells & some necrosis (caseation) is

usually present in the center of the

tubercles

Hansen’s Disease Or LeprosyLeprosy is a slowly progressive infectious

disease caused by Mycobacterium leprae. Affecting skin & peripheral nerves, resulting in disabling deformities.

Histopathologically the typical Granulomatous nodule shows collections of epithelioid cells & lymphocytes in a fibrous stroma.

Langhans type giant cells are variably present with vacuolated macrophages called lepra cells these are scattered throughout the lesions & often contain the bacilli.

Sarcoidosis:Sarcoidosis is a relatively common multisystemdisease of unknown etiology.

Histopathologically-classic noncaseatingGranulomas, each composed of an aggregate of highly clustered epitheloid cells, often with langerhans or foreign body type gaint cells and in chronic cases a fibrous rim may be seen. Although various inclusion bodies, such as Schaumann bodies (laminated concretions composed of calcium and proteins) and Asteroid bodies (stellate inclusions ) are seen in over 90% of cases, though they are not pathognomonic for sarcoidosis.

Photomicrograph showing granulomas with

lymphocytes and epitheloid cells with

Langhans giant cells

Actinomycosis: Actinomycosis is a chronic infectious

disease caused by the organisms of the order Actinomycetase.

Actinomyces are strict facultative anerobes. They require an organic nitrogen source and an atmosphere containing atleast 5% CO2 for their growth.

A.isrelli is an organism most commonly incriminated in the human bodies.

Histopatologically the actinomycotic granulomaisolated mass of granulomatous inflammatory response with a central area of suppurativenecrosis or a multitude of microscopic suppurative field in the centre of necrosis.

Sulfur granules are found, in the form of masses of filaments extending in a radiating, sporelikefashion as a “sunburst radiation” or fiery appearance.

Colonies are surrounded by polymorphonuclearinfiltration peripheral to which are plasma cells, lymphocytes,multinucleated giant cells, macrophages and a fibrous capsule are usually seen surrounding these inflammatory focus

The filamentous mass is mineralized and cemented by host calcium

phosphate resulting from phosphatase activity from tissue

inflammation.

At the end of these filaments are club shaped extensions or rossets

formed by the adherence of neutrophils.

They are also encased in a polysaccharide protein complex. The

central core of the rosette stains basophilic& the peripheral clubs

stains eosinophilic with H & E stain.

Methanamine silver is useful because they color older filaments very

well.

Crohn’s Disease

Crohn’s disease is a chronic Granulomatous disorder that may

involve any portion of the GIT including the oral cavity.

The exact etiology remains unknown.

Crohn’s disease is a Th1 disorder, Environmental and genetic

factors seem to play an important role in the pathogenesis.

Recently mutations in the CARD15 /NoD2 gene on the Chromosome

16 also have been identified in 25% of patients with crohn’s disease.

Histopathology: – noncaseating Granulomatous inflammation in

50% of cases and in the remaining cases of nonspecific perivascular

lymphocytic infiltrate.

Gut biopsies characteristically show transmural inflammation.

A classic triad - nodular lip swellings, fissured tongue, and unilateral facial palsyClinically, the lower lip is involved more diffusely than the upper lip, being enlarged with palpable nodularity throughout the submucosa.

Microscopically, multiple granulomas are seen to replace or infiltrate the lip minor salivary glands. Nodular tumefactions that are firm to palpation may be encountered in the buccal mucosa, vestibule, and tongue.

Melkersson-Rosenthal syndrome. A, Fissured tongue; B,

granulomatous cheilitis; C, facial nerve palsy.

Granulomas located as multiple nodules throughout thelips constitute cheilitis granulomatosa, provided theselesions are the only manifestation of the condition.

lip granulomas with identical appearance to cheilitisgranulomatosa are encountered in the Melkersson-Rosenthal syndrome.

The lower, upper, or both lips may be involved Although the swelling may appear to be diffuse, palpation discloses multiple and often confluent nodules within the submucosa.

Biopsy shows multiple noncaseating granulomas replacing minor salivary lobules

Cheilitis granulomatosa. A, lip lesions are diffuse; B, noncaseating

granuloma (arrow) replacing the minor salivary glands located

in the submusoa.

Wegener granulomatosisOften included as a form of midline lethal granuloma, Wegener

granulomatosis represents an inflammatory destructive disease that

may have widespread systemic involvement.

The granulomas of Wegener granulomatosis are usually localized in

the lung and kidneys. The middle ear, gingiva, and nasal mucosa are

also commonly affected.

Microscopically, vasculitis is a dominant finding, along with fibrinoid

necrosis. The adjacent granulation tissue is often infiltrated with

eosinophils and occasional multinucleated giant cells are seen.

Antibodies directed to neutrophil cytoplasmic antigens (ANCA) are

detected using indirect immunofluorescence with neutrophils as

substrate, being positive in over 90% of cases.

HISTOPLASMOSIS: Common systemic fungal

infection in the united states.

Caused by histoplasmacapsulatum, is dimorphic, growing as a yeast at body temperature in the human host and as a mold in its natural environment.

Air-borne spores of the organism are inhaled,passinto the terminal passages of the lungs &germinate.

TYPES : Acute,chronic,disseminatedhistoplasmosis.

HISTOPATHOLOGICAL FEATURES:

Diffuse infiltrate of macrophages or more commonly collections of macrophages organized into granulomas.

Multinucleated giant cells are seen in association with the granulomatousinflammation.

Special stains such as the PAS & Grocott-Gomarimethenamine silver methods.

Synonyms- Mucormycosis,Phycomycosis

Zygomycota are extremely abundant saprobicfungi found in soil, water, organic debris, and food.

Genera most often involved are Rhizopus, Absidia, and Mucor.

Usually harmless air contaminants invade the membranes of the nose, eyes, heart, and brain of people with diabetes and malnutrition, with severe consequences.

ORAL MANIFESTATIONS:

Rhinocerebral form is most relevant to the

oral health care provider.

Zygomycosis is noted especially in insulin-

dependent diabetics who have uncontrolled

diabetes and are ketoacidotic.

Ketoacidotic inhibits the binding of iron to

transferin, allowing serum iron levels to rise.

H/P: Extensive necrosis

with numerous large (6-30 micro m)

branching nonseptate hyphaeat the periphery.

The hyphae tend to branch at 90°angles.

Coccidioides immitis - causes coccidioidomycosis

Distinctive morphology – blocklikearthroconidia in the free-living stage and spherules containing endospores in the lungs

Lives in alkaline soils in semiarid, hot climates and is endemic to southwestern U.S.

Arthrospores inhaled from dust, creates spherules and nodules in the lungs

Amphotericin B treatment

Blastomyces dermatitidis- causes blastomycosis

DimorphicFree-living species distributed in soil of a

large section of the midwestern and southeastern U.S.

Inhaled 10-100 conidia convert to yeasts and multiply in lungs

Symptoms include cough and fever.Chronic cutaneous, bone, and nervous

system complicationsAmphotericin B

HISTOPATHOLOGICAL FEATURES:

Mixture of acute inflammation and

granulomatous inflammation surrounded

by yeasts.

These organisms are 8-20 micro meter in

diameter.

B.dermatitidis can be detected-special

stains such as gromatt-Gomori

methenamine silver&PAS.

Very common airborne soil fungus600 species, 8 involved in human disease; A.

fumigatus most commonlySerious opportunistic threat to AIDS,

leukemia, and transplant patients Infection usually occurs in lungs – spores

germinate in lungs and form fungal balls; can colonize sinuses, ear canals, eyelids, and conjunctiva

Invasive aspergillosis can produce necrotic pneumonia, and infection of brain, heart, and other organs.

Amphotericin B and nystatin

TOXOPLASMOSIS:

Common disease caused by the obligate intracellular

protozoal organism T. gondii.

T. godii multiplies in the intestinal tract of the cat by

means of a sexual life cycle, discharging numerous

oocysts in the cat feces. Another animal or human can

ingest these oocysts , resulting in the production of

disease.

CLINICAL FEATURES:

Often Asymptomatic

If symptomatic they are usually mild and resemble

infectious mononucleosis.

Pt’s may have a low grade fever , cervical

lymphadenopathy.

In immunosuppressed patients ,

toxoplasmosis represent a new,primary

infection or reactivation of previously

encysted organism.

The principal groups at risk –

AIDS

Transplant recipients

Cancer patients

DIAGNOSIS AND TREATMENT:

Identification of rising serum antibody titers

to T.gondii within 10-14 days after

infection.

Biopsy of an involved lymphnode may

suggest the diagnosis and serologic

studies if possible.

Folinic acid and sulfadiazine,if allergic to

sulfa drugs clindamycin can be used.

HISTIOCYTIC:Eosinophilic granuloma(unifocal eosinophilic granuloma):

Lichtenstein and jaffe in 1940

A lesion of bone which is primarily a histiocytic proliferation with an

abundance of eosinophilic leukocytes but no intracellular lipid

accumulation.

Primarily in older children and young adults.

M:F- 2:1

C/F:

No physical signs & symptoms

Incidental radiographic findings.

Common sites: skull and mandible

Other sites: Femur,humerus,ribs & other bones.

Radiographic: Irregular radiolucent areas usually

involving superficial alveolar bone.

H/P:

Prmary cell is histocyte which grows in sheets or

sheetlike collections. The histiocyte may coalesce

& form multinucleated giant cells- uncommon.

Early lesion- large no of collections of

eosinophils,lesion matures , fibrosis occurs & less

no of eosinophils. Then similar H/P picture of hand

schuller christian disease.

Synonym: multifocal eosinophilic granuloma:Widespread skeletal & extraskeletal & a chronic clinical course.

It occurs primarily in early life, before the age of 5.

More common in boys than girls.

C/F:

Classic triad- single/multiple punched out bone destruction in the

skull

Unilateral or bilateral exophthalmos

Diabetic insipidus

the complete triad occurs only 25% of affected patients.

Eosinophilic

granuloma

Hand-schuller-

christian disease

Letter-siwe disease

Proliferative cell is

histiocyte

histiocytes histiocytes

Only bone is affected,

less soft tissue

Skeletal& soft tissue

involvement

Acute, fulminating

disease with skeletal &

extraskeletal& skin.

Oral manifestations:

oral involvement 5-75%

Often non specific & include sore mouth,with or without ulceratve

lesion

Halitosis

Gingivitis

Suppuration

Unpleasant taste

Loose & sore teeth.

Radiographic features:

Skull- sharply outlined

Jaws- more diffuse.

Histologic features:

Four stages:

A proliferative histiocytic phase-eosinophilic leukocytes scattered

throughout the sheets of histiocytes.

A vascular granulomatous phase-histiocytes & eosinophils(some

foam cells)

Diffuse xanthomatous phase-Abundance of foam cells

Fibrous or healing phase.

LAB FEATURES:

Anemia, leukopenia& thrombocytopenia-rare.

CHOLESTEROL

GRANULOMA

Photomicrographs showing

histopathological features of the

cholesterol granuloma; large number of

white spindle-shaped clefts

representing cholesterol clefts, with

lymphocytes(arrows) infiltration.

No epithelial cells are seen.

FOREIGN BODY SUTURE MATERIAL

Triad- Keratoconjuctivitis sicca

Xerostomia

Rheumatoid arthritis

Primary sjogren syndrome-

Dry eyes & dry mouth

Secondary sjogrens:

SLE

Polyarteritis nodosa

Scleroderma

Rheumatoid arthritis

Etiology:

Genetic

Hormonal

Infections & immunologic

c/f:

Females are more common over 40 yrs

Ratio- 10:1

Radiographic : cherry blossom or branchless

fruit laden tree effect.

H/P:

intense lymphocytic infiltration

Lobular architecture is preserved

Epimyoepithelial islands are present.

The lobular architecture of the

seromucinous glands is preserved. The

seromucinous acini show squamous

metaplasia with slight reactive atypia.

Non neoplastic inflammatory condition

Etiology:

Trauma

Radiation therapy/ surgery

Vascular ischemia

Tobacco – risk factor

C/F:

Minor salivary gland-palate

Others retromolar pad, BM,tongue,incisive

Canal & labial mucosa

Clinical presentation:

Crateriform ulcer of the palate that similates

A malignant process.

1-3cm & unilateral

H/p: Coagulative necrosis of glandular aciniSquamous metaplasiaMucin poolng is presentInflammatory infiltrate of

macrophages,neutrophils,& lymphocyes(less),plasma cells & eosinophils.

Pseudo epitheliomatous hyperplasiaD/D: Scc & mec