Oral ulcerative and granulomatous conditions

Objectives:

By the end of this series of lectures and with further reading you should be able to:

• List the causes of ulceration affecting the oral cavity

• Define clinical lesions
• Describe their aetiology and pathogenesis
• Describe the clinical features
• Describe the histology of the more important and common oral lesions
• Discuss the role of special investigations in establishing a diagnosis
• Distinguish between the different lesions on clinical and pathological criteria
• Outline the principles of patient management

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Ulcerative conditions

An ulcer is defined as loss of epithelium covering a mucosal or skin surface. Ulcers that
are preceded by vesicles or bullae represent a different set of conditions. Ulcers are the
most common oral soft tissue lesions.

Oral ulcers can be classified in several ways. The following is a classification based on
aetiology. Not all the listed entities will be described in these notes as some (e.g.
neoplasms) are discussed elsewhere.

Aetiologic classification of oral ulcers:

Traumatic
accidental
iatrogenic
factitious

Bacterial infections
syphilis
gonorrhoea
tuberculosis
leprosy
actinomycosis
noma

Fungal infections
deep fungal infections- histoplasmosis, coccidiodomycosis, blastomycosis,
cryptococcosis
phycomycosis
aspergillosis
sporotrichosis

Immunologic diseases
aphtous ulcers
Behçet’s syndrome
Reiter’s syndrome
drug reactions
contact allergies
Wegener’s granulomatosis
erythema multiforme
idiopathic orofacial granulomatosis
cyclic neutropaenia

Neoplasms
oral squamous cell carcinoma
maxillary sinus carcinoma

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 neoplasms of minor salivary glands (ulcerated tumours are usually malignant)
Lymphoma
Other malignant neoplasms – sarcomas, melanoma

Other oral ulcers:

necrotising sialometaplasia (probably ischaemic aetiology)

I. Traumatic ulcers
The vast majority of oral ulcers are caused by simple mechanical trauma and a cause and
effect relationship is usually obvious. Most such ulcers occur as a result of accidental
injury.
Chronic traumatic ulcers are more difficult to diagnose than acute traumatic ulcers
because the patient may not associate such ulcers with trauma and because they may have
a worrying clinical appearance that mimics that of a malignant ulcer. Because of this an
ulcer that does not heal within two weeks should be biopsied in order to exclude
malignancy. The table below lists the main differences between acute and chronic
traumatic ulcers.

Acute ulcer Chronic traumatic ulcer

Painful Usually painless

White base, red halo White-yellow base, rolled margins

History of trauma +/- history of trauma

Heals in 7 – 10 days Delayed / no healing

Clinical features mimic carcinoma / infectious

ulcers

An eosinophilic ulcer, also known as traumatic ulcerative granuloma with stromal

eosinophilia (TUGSE), is a deep traumatic ulcer that extends down to muscle and which
has an inflammatory cell infiltrate rich in eosinophils. Atypical endothelial and
inflammatory cells are also present. It is most commonly seen on the tongue but can
occur on any site within the oral cavity. Most patients are middle aged but may also be
seen in infants. Riga-Fede disease is a variant of TUGSE that occurs in the anterior
portion of the tongue as a result of trauma from natal or deciduous teeth.
The problem with TUGSE is that these ulcers can be misdiagnosed as a malignant
process both clinically (because of the clinical features, especially induration), and
histologically (because of the presence of markedly atypical cells). The clinical course is
however benign and ulcers will eventually heal slowly on their own. Not all such ulcers
are associated with trauma. Alternate theories on aetiology postulate a self-limiting T cell
lymphoproliferative disorder or immune dysfunction. Biopsy is usually carried out
because of the worrying clinical appearance. Once a diagnosis is established, ulcers may

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be treated with antibiotics if infected. Ulcers which fail to heal on their own may need to
be surgically excised.

Traumatic ulcers can also be iatrogenic or self-inflicted (factitious). The latter are
difficult to diagnose as well as to treat and referral to a psychologist may be of benefit.

Other causes of traumatic oral ulceration, which may be iatrogenic, accidentally self
inflicted or, more rarely, factitious, include thermal and chemical burns. Thermal burns
may be seen following intake of hot food, especially after contact of hot cheese with the
palate. Thermoplastic impression materials have also resulted in thermal burns. Examples
of chemical burns include aspirin burns, and iatrogenic burns caused during inattentive
dental treatment with dental materials containing phenol, acid etching agents and
oxidising agents such as bleaching materials, amongst others.

Radiation induced ulceration and mucositis are seen in patients undergoing radiotherapy.
These typically are seen approximately ten days following commencement of
radiotherapy.

Diagnosis:
• History is very important
• Position of ulcer should correspond to cause
• Remove cause and ulcer should resolve within a few weeks
• If the ulcer doesn’t resolve, then suspect other causes and biopsy – as a rule of
thumb an ulcer should be biopsied if it does not start to regress within two weeks
of removing the suspected cause.
• Biopsy is mandatory for any n0n-healing ulcer for which a cause has not been
established

II. Infectious diseases

Many bacterial and fungal infections can present with oral ulcers. Oral ulceration can be
the sole manifestation of infection in certain cases; more commonly, oral ulceration
occurs together with other signs and symptoms.

Bacterial infections

1. Syphilis
Syphilis is a sexually transmitted disease the incidence of which had declined
significantly in Western countries but which made a comeback in the 1990s due to an
association with HIV infections and intravenous drug abuse. Locally there is a worrying
prevalence of syphilis mostly due to changing lifestyles and inadequate protective
measures taken by individuals who have multiple sexual partners.

Aetiology: Caused by the spirochete Treponema pallidum

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Can be acquired by:
sexual contact
transfusion of infected blood
transplacental transmission

The disease can be divided into primary, secondary and tertiary stages. A congenital form
also occurs.

Primary syphilis:
Transmitted by sexual contact. The hallmark of primary syphilis is the chancre, which is
a hard, deep, painless ulcer with a dark red, brown or purple base and rolled edges, that
forms at the site of spirochete entry. HIV infected patients often develop multiple primary
lesions. The location is usually the genital region. Other sites include the anus, lips, oral
cavity and fingers. Painless regional lymphadenopathy also occurs. The ulcer presents as
a small firm nodule which ulcerates and becomes crusted. These ulcers are highly
infectious. At this stage serology is usually negative. Diagnosis is usually made by PCR.
Spirochaetes may be identified in smears however they may be difficult to distinguish
from commensual organisms. The chancre heals spontaneously after several weeks and
the patient enters into a latency period.

Secondary syphilis
Occurs several weeks after primary syphilis, roughly 2-3 months after the initial exposure
to the spirochete. Patients infected during blood transfusion start with secondary syphilis
and skip the primary stage. At this stage of the disease the infecting organism is
disseminated widely.
Secondary syphilis is characterised by spirochetaemia, fever, flu-like symptoms,
lymphadenopathy and mucocutaneous lesions. The latter includes:
• a widespread reddish-brown maculopapular rash
• mucosal ulcers covered by mucoid exudate know as ‘mucous patches’.
Ulcers may coalesce to produce lesions of irregular outline known as
‘snail-track ulcers’
• broad-based verrucal plaques on skin/mucosa known as Condyloma lata
• inflammatory lesions that may affect any organ
Serology is positive at this stage.

Untreated secondary syphilis will also resolve spontaneously and is followed by a second
latency period. Relapses to secondary syphilis may occur in some patients.

Tertiary syphilis
This stage of syphilis occurs several years after the initial encounter with the infectious
agent and is rare because in most cases the infection is eradicated before the tertiary stage
is reached. Tertiary syphilis develops is approximately one third of untreated patients.
There is a predilection for the CNS and cardiovascular system and manifestations include
general paresis, tabes dorsalis (neural syphilis) and aortic and other aneurysms (vascular
complications). Gummata (granulomatous lesions) may form in any organ and the
inflammatory cytokines produced can result in extensive tissue destruction. Intraorally

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the palate is most commonly affected and palatal perforation may occur. Glossitis with
mucosal atrophy is another manifestation of tertiary syphilis. Malignant transformation
may occur in this atrophic mucosa and tertiary syphilis is practically the only situation
when squamous cell carcinoma may develop on the dorsal surface of the tongue, which is
a very uncommon site for oral cancer.

Congenital syphilis
Congenital syphilis occurs in the latter half of pregnancy when Spirochetes cross the
placental barrier into the foetus’ bloodstream resulting in Spirochetaemia. This may lead
to abortion or may result in inflammatory lesions in many sites. Manifestations of
congenital syphilis may affect any organ system. Some features are characteristic:
saddle nose
sabre shin
Hutchinson’s triad – inflammatory reaction in the cornea
(interstitial keratitis), eight nerve deafness and dental abnormalities
(notched incisors, mulberry molars, hypodontia).

Histopathology
The basic tissue response to Treponema pallidum consists of an inflammatory reaction
rich in plasma cells with arteritis. The gummata of tertiary syphilis consist of
granulomatous inflammation, however sometimes non-specific inflammation only maybe
seen.

Diagnosis
Spirochetes may be demonstrated in biopsy lesions or in exudate from active lesions by
special stains. Several tests are available to confirm the diagnosis. These include VDRL,
ELISA, PCR. A more recent and more specific test is fluorescent treponemal antibody
absorption test.

Differential diagnosis
When the chancre of primary syphilis occurs in the oral cavity, it must be distinguished
from a malignant or chronic traumatic ulcer. Other infectious processes such as oral
tuberculosis may also present with a similar clinical picture.
Secondary syphilis has to be distinguished from other infectious and non-infectious
conditions that present with a generalised rash.
Tertiary syphilis of the palate may resemble carcinoma, lymphoma or Wegener’s
granulomatosis (see notes on these entities).

Treatment
Penicillin and other antibiotics such as tetracyclines are effective at all stages of the
disease.

2. Gonorrhoea
Aetiology
Caused by the gram-negative diplococcus Neisseria gonorrhoeae. The disease is
transmitted by sexual contact.

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Clinical features
The organism typically infects the columnar epithelium of the lower genital tract, rectum,
pharynx and eyes. There are no specific oral features however oral and pharyngeal
infection can occur through orogenital contact. Pharyngeal infection is more common
than oral infection, probably because the oropharyngeal mucosa is less resistant to trauma
and oropharyngeal mucosal lining epithelium may be more prone to infection. Oral
ulceration and generalised mucosal erythema can however also occur. Oral infection is
often symptomless.

Diagnosis
This requires culture of the organism. Immunofluorescence may be used to demonstrate
the organism in biopsy specimens.

Differential diagnosis
Any condition with generalized oral ulceration or mucosal erythema will need to be
considered.

Treatment
Penicillin or ciprofloxacin.

3. Tuberculosis
This disease is currently making a comeback and multidrug resistant TB and extensively
drug resistant TB are becoming a problem, especially in Africa, Russia, China and India.
More recently, total drug resistant TB (also known as extremely drug resistant TB) has
also emerged.

Aetiology
Caused by the acid fast gram negative bacillus Mycobacterium tuberculosis. Spread is by
droplet infection.

Risk factors
Overcrowding, immunocompromised host, debilitation.

Clinical features
The initial infection, which is usually in the lungs, can be symptomless. Manifestations,
when they occur, include fever, night sweats, malaise and weight loss. Primary infection
may occasionally be arrested by the host’s immune system with the organism being
destroyed completely. More commonly the infection is controlled, however the
Mycobacterium is not eradicated and remains latent in a lung scar that may partly calcify.
Under certain conditions, e.g. immunosuppression or reinfection, the disease is
reactivated and progression occurs. Latency can last for many years. In some cases the
disease might progress without an intervening latent phase.

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With progression cough, haemoptysis and chest pain occur. Any organ may become
involved as the organism spreads via the haematogenous route resulting in a variable
clinical picture.

The oral mucosa can be infected by direct inoculation from sputum or by haematogenous
spread. Even more rarely, primary infection of the oral cavity may occur. The estimated
prevalence of oral tuberculous lesions ranges from 0.05 to 5%. Rare cases of primary
tuberculous involvement of oral structures have been reported. Oral tuberculous lesions
are nonspecific in their clinical presentation, and their consideration in the differential
diagnosis requires a high degree of awareness. Any intraoral site may be affected,
however, the palate and dorsum of the tongue are more frequently affected. Pain and
cervical lymphadenopathy commonly accompany oral lesions. A rare case of tuberculous
osteomyelitis of the mandible and several cases of tuberculous parotitis have been
documented.

Oral infection, whether primary or secondary, manifests itself as a chronic, painless,

undermined ulcer.

Miliary tuberculosis or disseminated tuberculosis occurs when the mycobacteria gain

access to the arterial system and seed many organs, predominantly the liver, bone
marrow, spleen, adrenals, kidneys and meninges.

Histopathology
Granulomatous inflammation with central caseous necrosis. Special stains, e.g. Zeihl-
Neelsen are used to demonstrate the acid fast bacilli in the tissues. The organisms are
very difficult to demonstrate histologically as there may be very few of them.

Diagnosis:
Chest x ray
Positive skin test
Demonstration of acid fast bacilli in lesion
Culture
PCR on tissue sample

Treatment:
Multidrug therapy for six months. Treatment may at times be extended, occasionally up
to two years. First line drugs include isoniazid, rifampicin, pyrazinamide and ethanbutol.
Streptomycin is the most commonly used second line drug. The development of new
drugs is necessary to combat the increasing problem of multidrug resistant TB.

Bacille Calmette Guerin (BCG) vaccine is effective in controlling childhood TB but is

less effective in adulthood. New vaccines are under investigation.

4. Leprosy
Aetiology:

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Infection caused by the acid fast bacillus Mycobacterium leprae or Mycobacterium
lepromatosis. The disease is not easily transmissible and transmission requires frequent
contact with an infected individual over a long period. Spread is by droplet infection.

Clinical features:
M. leprae is an acid fast obligate intracellular organism that grows best at 32 -340C. Once
inhaled, the organism is taken up by alveolar macrophages and disseminates through the
blood but grows only in the relatively cool tissues of the skin and extremities.
The disease occurs in two clinical forms: a limited form known as tuberculoid leprosy
and a generalised form termed lepromatous leprosy. Which form occurs depends on the
interaction between the host’s immune response and the infecting organism.

Tuberculoid leprosy begins with localised skin lesions that are at first flat and red but
which enlarge and develop irregular shapes with indurated, elevated, hyperpigmented
margins and depressed pale centres. Nerve involvement is prominent and skin anaesthesia
renders the patient prone to trauma with the development of skin ulcers. Contractures,
paralyses and autoamputation of fingers or toes may occur.

Lepromatous leprosy involves the skin, peripheral nerves, anterior chamber of the eye,
upper airways, testes, hands and feet. Vital organs and CNS are rarely affected
presumably because the core temperature is too high to allow for growth of M. leprae.
Macular, papular or nodular lesions develop in face, wrists, elbows and knees. With
progression the nodular lesions coalesce, resulting in a distinctive leonine facies.

Oral lesions are seen almost exclusively in lepromatous leprosy and occur in
approximately 50% of patients. They take the form of nodular masses that tend to
ulcerate and heal with fibrosis. The palate, anterior maxillary gingiva and tongue are the
most commonly affected intraoral sites.

Histopathology:
Granulomatous inflammation and inflammation of peripheral nerves are seen in
tuberculoid leprosy.
In lepromatous leprosy, the immune system is unable to mount an effective response to
the infection. Little inflammation occurs and no granulomata are formed. Instead
lepromatous lesions contain large aggregates of lipid-laden macrophages known as lepra
cells. These are often filled with masses of acid fast bacilli.

Diagnosis:
History of contact with an infected person or of living in an endemic area provides an
important clue to the diagnosis. Skin and peripheral nerve involvement are an additional
clue. The diagnosis can be confirmed by biopsy. If no acid fast bacilli are detected in a
biopsy PCR can be used to detect the infecting organism.

Treatment:
Multidrug therapy for a prolonged period, typically years. The drugs most commonly
used include dapsone, rifampicin, clofazimine and minocycline.

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5. Actinomycosis
Aetiology:
An infection caused by Actinomyces israelii or other Actinomyces species. Rarely
Nocardia asteroides infection produces a similar clinical picture.
A. israelii is a commensual organism and infection occurs after trauma, surgery or in
immunocompromised patients. The disease is not contagious. Dental infection, oral
surgery and infection predispose to the development of this condition. Men between 30
and 60 years of age are predominantly affected.

Clinical features:
Most infections occur in the thorax, abdomen and in the head and neck. In the head and
neck area, the mandible is the most common site. Here a bony swelling with draining
sinuses is seen. The pus draining from the lesion contains yellow (sulphur) granules. An
irregular, ill-defined radiolucency is seen radiographically. Infection of the skin or of
muosa may also occur. The skin/mucosa in such cases has a hard consistency.

Histopathology:
Abscesses with gram positive filamentous bacterial colonies.

Diagnosis:
The disease must be differentiated from osteomyelitis due to other causes and from other
infections. Diagnosis requires identification of organisms by:
examination of exudate
biopsy
culture – this is usually from pus which includes sulphur granules.
Actinomyces species are slow growing and the laboratory should be warned that
actinomycosis is suspected when sending material for culture so that the appropriate
medium will be used and the culture is kept long enough to grow.
Diagnosis may be difficult in cases where penicillin in insufficiently high doses has been
given previously. This may make it very difficult to isolate the organisms and confirm the
diagnosis. Such cases should be empirically treated as actinomycosis.

Treatment:
Long-term, high-dose penicillin, i.v. in severe cases. Tetracycline or erythromycin are
also effective. Drain abscesses, surgical excision of sinuses.

Further reading:
More information about actinomycosis, including actinomycosis of the jaws can be found
here: http://emedicine.medscape.com/article/211587-overview

This is another good review which includes discussion of oro-facial actinomycosis:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094581/

6. Noma (cancrum oris, gangrenous stomatitis)

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Aetiology:
An opportunistic infection in malnourished or debilitated children caused by various
pathogens e.g. Fusobacerium necrophorum, Borrelia vincentii and Staphylococcus
aureus.

Clinical features:
There is initial ulceration of the gingiva or buccal mucosa. The ulcers spread and become
necrotic with bone exposure, necrosis and sequestration. Extensive soft tissue destruction
occurs.

Treatment:
Antibiotics e.g. clindamycin, gentamycin
Debridement of necrotic tissue
Treat underlying cause

Prognosis:
Almost all untreated patients die.
Mortality occurs in 5-10% of treated patients.

Fungal infections

1. Deep fungal infections

These fungal infections are characterised by primary involvement of the lungs. From here
the infection disseminates to involve many other organs. The oral cavity can be involved
in: histoplasmosis
coccidioidomycosis
blastomycosis
cryptococcosis.
Organism in infected sputum can inplant in the oral cavity. Alternately oral infection can
follow haematogenous spread.

Aetiology:
Fungal spores are inhaled and lodge in the lungs. Cryptococcosis most often occurs in the
setting of immunosuppression and is the commonest mycosis seen in patients with AIDS.

Clinical features:
Cough, fever, chest pain, haemoptysis, weight loss – all related to the chest infection
If the organisms disseminate to the oral cavity, chronic non-healing ulcers form.

Histopathology:
granulomatous inflammation
the organisms can be identified by use of special stains (e.g. PAS, Grocott-
Gomori's methenamine silver stain)

Diagnosis requires fungal culture

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Treatment:
antifungal therapy – ketoconazole, fluconazole, amphotericin B
surgical treatment of lung lesions may be necessary

2. Sporotrichosis
A predominantly subcutaneous infection which may have oral manifestations.

Aetiology:
Caused by Sporothrix schenckii. The organism is inoculated in the skin or mucosa from
contaminated soil or thorny plants.

Clinical features:
Subcutaneous nodules form at the site of inoculation and spread along lymphatic
channels (lymphateginous spread). They frequently become ulcerated.
Intraoral lesions present as chronic ulcers.

Histopathology:
Granulomatous inflammation sometimes with central abscess formation.
Pseudoepitheliomatous hyperplasia of the overlying epithelium is characteristic.

Diagnosis:
Requires identification of the organism in biopsy material or by culture.

Treatment:
Potassium iodide or ketoconazole. There is usually a good response to treatment.

3. Phycomycosis (mucormycosis, zygomycosis)

Aetiology:
An opportunistic infection caused by members of the Mucor, Rhizopus and occasionally
other genera found in bread mould or decaying fruit and vegetables. Infection occurs
either in the respiratory tract (inhalation of spores) or GIT (ingestion). Diabetes is a
predisposing factor and most cases occur in diabetic patients. Infections are also seen in
immunocompromised patients, in patient with advanced malignancy and in patients
receiving radiotherapy as well as in the setting of iron overload.

Clinical features:
The infection is more common in the nasal cavity as opposed to the oral cavity. Pain,
swelling and ulceration are the most common presenting symptoms. The organism
invades tissues especially arteries; therefore haemotogenous spread, thrombosis and
infarction frequently occur. Necrosis may cause perforation of the palate.

Histopathology:
The organism invades the tissues and there is acute and chronic inflammation. Branching
non-septate fungal hyphae can be identified by special stains. Necrotic inflamed blood
vessels are characteristic.

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Treatment:
Amphotericin B
Surgical debridement

Prognosis:
This infection is associated with high mortality.

4. Aspergillosis
Aspergillus is a ubiquitous organism that causes opportunistic infections in
immunocompromised patients. It is a cause of allergic fungal sinusitis in healthy patients.
Like mucormycosis, infection occurs either in the respiratory tract or the GIT.

Clinical features, histopathology, treatment and prognosis are similar to those of

mucormycosis.

III. Diseases with an immunologic component

1. Aphtous ulcers (recurrent oral ulceration, canker sores)
Aphtous ulcers are the most common non-traumatic mouth ulcers.
Aetiology: unknown; may be due to focal localised T-cell dysfunction, but the causative
agent is unknown. A minority of cases are associated with vitamin B12, folic acid or iron
deficiency.
Triggers for aphtous ulceration include trauma, stress, diet, hormones and depressed
immunity.
Aphtous-like ulcers are sometimes seen in patients with malabsorption conditions e.g.
celiac disease, inflammatory bowel disease and in HIV-positive individuals.

Pathogenesis: There is considerable evidence that aphtous ulcers are related to a focal
immune dysfunction involving T-lymphocytes. The initiating stimulus remains unknown.

Clinical features:
Ulcers frequently start in childhood and increase in frequency until young adulthood and
then wane. Aphtous ulceration is rare in the elderly and aphtous-like ulcers in the elderly
are usually associated with nutritional deficiency. Smoking appears to protect against
aphtous ulceration and most affected individuals are non-smokers. Higher socio-
economic groups are more often affected.

Aphtous ulcers occur in three clinical forms:

minor aphtous
major aphtous
herpetiform aphtous ulceration

All three are considered to be part of the same disease spectrum. The table below
highlights the clinical features of the different types of aphtous ulcers and the treatment
applicable to each type.

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 Herpetiform
Minor aphtae Major aphtae
aphtae

Size ‹5mm ›5mm ‹‹5mm

Ragged oval,
Shape oval Oval
crateriform

Number 1 -5 1 -10 10 – up to 100

Location nonkeratinised mucosa nonkeratinised any intraoral site

mucosa
corticoteroids, corticosteroids corticoteroids
Treatment
tetracycline immunosuppression tetracycline

Histopathology: Because of their characteristic clinical appearance and history of

recurrent ulceration, aphtous ulcers are rarely biopsied. All three types of aphtous ulcers
have similar histological features of non-specific ulceration.

Treatment:
Occasional ulcers usually need no treatment or just a bland mouthwash such as sodium
bicarbonate. Frequent and / or painful ulcers can be treated by corticosteroids (topical for
minor / herpetiform and systemic for major aphtae).
Tetracycline mouth rinses (250mg in 30ml of warm water, four times daily – made up
fresh each time because tetracyclines break up in solution) may also be useful.
Immunosuppressive drugs (other than corticosteroids) are rarely justified and should only
be used to control disease in very severely affected patients with major aphtous
ulceration.

Nutritional deficiencies need to be excluded in patients with recurrent aphtous ulceration,

especially if the patient is elderly.

Further reading:
Chavan M, Jain H et al. Recurrent aphtous stomatitis: a review. J Oral Pathol Med 2012;
41: 577-583.

Baccaglini L, Lalla R et al. Urban legends: recurrent aphtous stomatitis. Oral Dis 2011;
17:755-770. This review paper can be accessed here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192917/

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2. Behçet’s syndrome
A multisystem disease involving the gastrointestinal tract, cardiovascular system, CNS,
respiratory system, joints, eyes, skin and mucosal sites. Essentially the disease is a
systemic vasculitis of small vessels. Clinical features include:
minor apthous ulcers – mouth and genital mucosae (resembling aphtous ulcers)
eyes – inflammation (conjunctivitis, retinitis, uveitis)
skin – erythema nodosum, pseudofolliculitis, papulo-pustular lesions, ulcers
polyarthritis – wrists, knees, ankles
CNS – headaches, nerve palsies, inflammation
cardiovascular manifestations – vasculitis and thrombosis
The disease can manifest in four main patterns: mucocutaneous, arthritic, neurological
and ocular. Each of these patterns may occur alone or in combination with one or more of
the other patterns.
Aetiology: Unknown, immunodysfunction with vasculitis probable. A strong genetic
predisposition is present.
Diagnosis: is based on clinical signs and symptoms. There are no specific histologic
features or laboratory tests.
Treatment: Systemic corticosteroids, immunosuppression. Tacrolimus and cyclosporin
are the commonest drugs used. Anti tumour necrosis factor drugs are a more recent
option.

3. Reiter’s syndrome
Triad of:
non-specific urethritis
conjunctivitis
arthritis
Oral manifestations include aphtous-like ulcers and tongue lesions resembling geographic
tongue.
Reiter’s syndrome occurs 1-3 weeks after bacterial dysentery or a sexually transmissible
disease; mostly in men in the 3rd decade of life. The disease is of acute onset with
systemic symptoms.
Pathogenesis: an aberrant immune response to bacterial antigens in genetically
susceptible individuals (over 70% of patients have HLA-B27 genotype).
Treatment: NSAIDS +/- antibiotics.

4. Chronic ulcerative stomatitis

A condition with oral erosive or ulcerative lesions with a unique direct
immunofluorescence pattern. Affects predominantly elder women.
Clinical features: ulcers, occasional vesicles, desquamative gingivitis, sometimes white
striae. Lesions occur mostly on the tongue followed by buccal mucosa and gingivae.
Skin lesions may be present.
Diagnosis: Histology - similar to lichen planus
Direct immunofluorescence – perinuclear IgG deposition in basal and
parabasal keratinocytes.

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Treatment: hydroxychloroquine is the drug of choice.

Further reading:
Islam MN, Moen DM et al. Chronic ulcerative stomatitis: Diagnostic and management
challenges – four new cases and review of the literature. Oral Surgery, Oral Medicine,
Oral Pathology, Oral Radiology and Endodontology 2007; 102: 194-203.

5. HIV-associated oral ulcers

Aphtous-like ulcers may occur in HIV-positive patients. Ulcers in such patients resemble
one of the three patterns of recurrent aphtous ulceration but major and herpetiform ulcers
are more common in these patients. Ulcers which do not fit one of the three patterns are
termed HIV-associated ulcers.

6. Crohn’s disease
Idiopathic inflammatory bowel disease with sharply delimited affected bowel segments
separated by intervening normal “skip” areas.
Characteristics:
sharply delimited transmural inflammation of bowel
non-caseating granulomas
fissuring with the formation of fistulae

In mouth:
aphtous-like ulcers may be seen
occasionally, cobblestone appearance of oral mucosa with linear, serpentine
ulcers and fissuring
granulomata

Because granulomata can be sparse and deep it is essential to go right down to muscle
and submit a large biopsy for histology (at least 1 – 1.5 cm in size) to increase the
likelihood of a positive biopsy.

7. Drug reactions
These are more common in skin but occasionally occur in the oral cavity. Practically any
drug can elicit an adverse reaction, however some drugs have a greater ability to do so
than others.
Skin manifestations and very varied and may develop rapidly as in anaphylaxis,
angioedema and urticaria or manifest after several days of drug use e.g. maculopapular
rashes, erythema, urticaria, ulcers and target lesions.
Lesions in the oral cavity may be erythematous, vesicular or ulcerative. They may also
mimic lichen planus (lichenoid drug reactions). Diagnosis requires a high index of
suspicion and careful history taking.
Mechanisms: Hyperimmune responses (allergies) are mediated by mast cells coated with
IgE, antibody reaction to cell-bound drug or by the deposition of antigen-antibody
complexes.

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 Non-immune mechanisms include the direct release of inflammatory
mediators by mast cells, overdose, toxicity and side effects.
Histology: variable, the presence of eosinophils is suggestive.
Treatment: identification and withdrawal of the causative agent. If this is not possible,
antihistamines and corticosteroids may be helpful.

8. Contact allergies
These are also more common in skin.
Pathogenesis: contact allergies are caused by antigenic stimulation by a large number of
foreign antigens. The immune response is predominantly mediated by T-lymphocytes.
Epithelial Langerhans cells present foreign antigens to T-cells after which T-lymphocytes
secrete mediators of inflammation that result in the clinical and histologic manifestations
of contact allergies.
Causative agents in the mouth include toothpaste, mouthwash, chewing gum, topical
drugs, denture base material and denture adhesives.
Clinical features: Lesions occur directly adjacent to the causative agent and may be
erythematous, ulcerative or white and lichenoid.
Histology: inflammatory changes especially a lichenoid inflammatory pattern (see notes
on lichen planus in white lesions), epithelial oedema, occasional eosinophils.
Diagnosis: requires careful history taking to establish a cause and effect relationship. A
biopsy might be helpful to confirm the diagnosis.
Treatment: remove cause +/- steroids.

8. Erythema Multiforme
A self-limited hypersensitivity reaction in two forms:
minor – usually triggered by viruses or idiopathic
major (Stevens-Johnson syndrome) – usually triggered by drugs
Aetiology and pathogenesis: the basic cause is unknown but a hyoersensitivity reaction to
viruses or drugs is suspected. It has been suggested that antigen-antibody complexes
depositing in small vessels in skin and mucosa produce the clinical features.
Clinical features: Multiple oral ulcers (sometimes preceded by short-lived vesicles or
bullae) and/or skin target lesions (concentric erythematous rings with intervening normal-
looking skin). Other skin lesions include vesicles/bullae, macules, papules and urticarial
plaques.
Histology: epithelial hyperplasia and spongiosis with apoptotic keratinocytes at all levels
of the epithelium with a dense lymphocytic infiltrate.
Treatment: supportive therapy (e.g. keeping mouth clean with bland mouth rinses such as
sodium bicarbonate). Corticosteroids are required in Stevens –Johnson syndrome.

Toxic epidermal necrolysis is considered to be on the same disease spectrum. This

condition is triggered by drugs and results in extensive necrosis and sloughing off of the
epidermis. This is a life threatening condition – death may happen as a result of severe
fluid and electrolyte loss or due to sepsis. Treatment requires hospitalisation and patients
are treated similarly to individuals with severe burns.

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IV Neoplasms
See separate notes on epithelial and haematolymphoid neoplasms.

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 Granulomatous conditions

A granuloma is an aggregate of epithelioid histiocytes (histiocytes that have abundant

amounts of cytoplasm and so appear histologically similar to epithelial cells).
Multinucleated giant cells may be seen in granulomas but do not define granulomas i.e.
you do not need giant cells in order to call an accumulation of histiocytes a granuloma.
Giant cells form when a number of epithelioid histiocytes fuse together. This happens
most frequently when particulate matter which is indigestible by macrophages
accumulates or when the material to be ingested is too large to be ingested by one
macrophage. Necrosis in a granuloma is suggestive of TB but not diagnostic of it because
necrosis may also be seen in other conditions.

Classification
Caseating granulomas (i.e. granulomas with caseating necrosis):
TB
Non-caseating granulomas:
Leprosy and atypical Mycobacterial infections
Some fungal infections
Crohn’s disease
Wegener’s granulomatosis
Sarcoidosis
Merlkerssohn-Rosenthal syndrome
Foreign body reactions
Idiopathic orofacial granulomatosis
Chronic granulomatous disease

Refer to notes on infections and see above for Crohn’s disease.

1. Granulomatosis with polyangiitis (Wegener’s granulomatosis)

A serious systemic inflammatory condition of unknown aetiology.
Pathogenesis: Although the aetiology is unknown, Wegener’s granulomatosis probably
represents a hypersensitivity reaction to an unknown antigen, possibly inhaled infectious
or environmental agents. The presence of granulomas and the dramatic response to
corticosteroid therapy also strongly suggest an immunologic mechanism, probably cell-
mediated. There is an association with genes that modulate immune responses.
Clinical features: Males are more frequently involved. There is a peak incidence in the5th
decade.
Triad of involvement of:
upper respiratory tract – vasculitis, granulomatous inflammation
lungs – granulomas
kidneys – focal necrotising glomerulitis
Lesions may also be present in oral cavity as well as elsewhere.
Patients are usually middle aged and present with sinusitis, rhinorrhoea, blocked nose and
epistaxis. Upper respiratory tract ulceration with necrosis is characteristic. This
sometimes perforates the nasal septum or palate.

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In the mouth red hyperplastic granular lesions on the attached gingiva (strawberry
gingivae) can occur. Sometimes a perforated palate can be seen due to extension of lesion
with necrosis from the nasal cavity.
Histology: The essential feature is necrotising vasculitis with granulomatous
inflammation.
Diagnosis requires histology, confirmation of lung/kidney lesions and demonstration of
circulating cANCAs. cANCAs are circulating antineutrophil cytoplasmic antibodies
predominantly directed against proteinase-3.
Treatment: Cytotoxic agent cyclophosphamide with corticosteroids. Response to
corticosteroids is often dramatic; 80% of untreated patients die with one year of
developing the manifestations of the disease.

2. Sarcoidosis
An idiopathic disease characterised by the formation of non-caseating granulomas in
many tissues, most often in lungs followed by skin, eyes and salivary glands.
Prevalence is higher in women and in blacks and occurs in all age groups but mostly in
the 2nd-4th decades.
Aetiology: Unknown. Immunologic abnormalities in genetically predisposed individuals
exposed to certain environmental antigens is probable.
Presentation: chance finding on a chest x-ray
peripheral lymphadenopathy,
skin or eye lesions,
hepatomegaly or splenomegaly
uveoparotid fever or xerostomia
nodular oral lesions
Lung lesions and hilar lymph nodes are the most frequently involved sites.
Histology: small non-caseating granulomas with only a few lymphocytes.
Diagnosis: The histological diagnosis is a diagnosis by exclusion. Angiotensin I-
converting enzyme assay is very useful for establishing the diagnosis and elevated levels
of this enzyme together with a positive chest x-ray have high diagnostic reliability. The
Kveim test was a very reliable test in which spleen extract from an affected patient was
injected into the skin. If granulomas developed this was indicative of saroidosis. Because
of the risk of transmission of infectious diseases this test is no longer used.
Clinical course: Generally good but unpredictable. Sarcoidosis can be a progressive
chronic disease. In other patients periods of activity alternate with remissions.
Spontaneous remissions have occurred. With treatment, 65-70% of patients recover with
no or minimal damage; 20% remain with permanent lung or ocular damage and 10-15%
succumb to progressive pulmonary fibrosis, cor pulmonale or CNS or cardiac
involvement.
Treatment: corticosteroids.

3. Melkersson-Rosenthal syndrome (also known as granulomatous chelitis)

A clinical triad of:
oral granulomas
fissured / plicated tongue

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 facial nerve palsy.
Oral granulomas tend to affect the lips which become swollen at first intermittently and
eventually chronically. The disease occurs equally frequently in males and females with
an onset usually in young adult life.
Aetiology: Unknown but a genetic element is suspected.
Diagnosis requires clinico-pathological correlation. A lip biopsy is useful to establish the
presence of granulomas.
Treatment: nonsteroidal anti-inflammatory drugs; corticosteroids, tetracycline. Surgery
may be used to reduce lip size in severs cases (for aesthetic purposes).

4. Chronic granulomatous disease

A rare inherited disease (x linked or autosomal recessive) caused by mutations in one of
the genes coding for NADPH oxidase (nicotinamide adenine dinucleotide phosphate
oxidase) complex components.
Lack of NADPH oxidase leads to less efficient killing of bacteria by neutrophils because
they cannot form reactive oxygen species.
Clinical manifestations: mouth ulcers which are recurrent and persistent. Frequent and
persistent infections. The disease also affects lymph nodes, lungs, liver, spleen, bone and
skin.
Histology: granulomas in GIT, GUT and skin.

5. Foreign body granulomas

Granulomas form around foreign bodies as macrophages attempt to engulf and digest the
foreign material which can be either exogenous (e.g. suture material, dental restorative
materials) or endogenous (e.g. cholesterol in a periapical granuloma, keratin from a
ruptured cyst).

6. Idiopathic orofacial granulomatosis.

A condition in which granulomas form in the oral mucosa and perioral skin,
predominantly in the lips. Although the aetiology is unknown, it is suspected that the
majority of patients have a mild version of Crohn’s disease. In fact intestinal lesions may
be found with careful endoscopy either at presentation or some time after the oral lesions
develop.
Treatment: corticosteroids. Endoscopy is mandatory to investigate for Crohn’s disease.

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