Fungal infections of the oral cavity

FUNGAL INFECTIONS OF THE
ORAL CAVITY
BY DR SUNITA PATHAK

INTRODUCTION
• Candidiasis is also known as Candidosis, moniliasis or thrush.
• Caused by yeast like fungus , Candida (Monilia) albicans.
• Although other species such as C. Tropicalis, C. Parapsilosis, C.
stellatoidea, C. krusei, C. guilliermondii, C. dubliniensis, C.
glabrata may also may be involved.

• Candida exists in three forms namely pseudohyphae, yeast
and chlamydospore forms.
• Reproduces by asexual budding and forms pseudohyphae.
• These species grow rapidly at 25-37 degree centigrade.
• Candida species differ from each other but can be identified
by the formation of pseudohyphae or the biochemical tests.

Chlamydospores of C albicans
Pseudohyphae of C albicans

• Candida is a relatively common inhabitant of the oral cavity,
gastrointestinal tract, and vagina of clinically normal persons.
• When the favourable condition develops, the organism
transforms into pathogenic form that is the yeast form
transforms into hyphae.
• It appears that mere presence of the fungus is not sufficient
to cause the disease but there must be actual penetration of
the tissues.
• Most opportunistic infection in the world.

• Its occurrence increases with the use of antibiotics which
destroy the normally inhibitory bacterial flora and
immunosuppressive drugs particularly corticosteroids and
cytotoxic drugs.
• This is the chief cause of this disease in patients with
leukemia, lymphoma, and other tumours.
• It is reported that more than 90% of patients with HIV
infection develop oral candidiasis during some part of their
disease.
• Oral candidiasis usually remains a localized disease but may
show extension to the pharynx, or even to the lungs often
with a fatal outcome.

CLINICAL FEATURES
• Candidal infection may range from mild superficial mucosal
involvement to severe , fatal disseminated form seen in
immunocompromised individuals.
• The classification proposed by Samarnayake in 1991 and
modified by Axell et al in 1997 divides candidiasis into two
major categories.
(1)Primary oral candidiasis (infection exclusively confined to
oral and perioral tissues)
(2) Secondary oral candidiasis (oral lesions as a manifestation
of systemic mucocutaneous candidiasis)

CLASSIFICATION OF ORAL CANDIDIASIS AS PROPOSED BY SAMARNAYAKE
(1991) AND MODIFIED BY AXELL ET AL (1997)
PRIMARY ORAL CANDIDIASIS
ACUTE FORMS
• Pseudomemebranous
• Erythematosus
CHRONIC FORMS
• Hyperplastic
• Nodular
• Plaque like
• Erythematosus
• Pseudomembranus
CANDIDA ASSOCIATED LESIONS
• Denture stomatitis
• Angular cheilitis
• Median rhomboid glossitis
SECONDARY ORAL CANDIDIASIS
• Oral manifestations of systemic
mucocutaneous candidiasis as a
result of diseases such as thymic
aplasia and candidiasis
endocrinopathy syndrome
KERATINIZED PRIMARY LESIONS
SUPERINFECTED WITH CANDIDA
Leukoplakia
Lichen planus
Lupus erythemaosus

PSEUDOMEMBRANOUS CANDIDIASIS
• Also known as thrush and is one of the
most common forms of the candidiasis.
• May occur at any age but especially
known to occur in debilitated or
chronically ill patients or the infants.
• In healthy individuals it may be due to
immune suppression due to HIV
infection or due to systemic
corticosteroid therapy.
• Oral lesions are characterized by soft,
white, slightly elevated plaques, most
frequently occurring on the buccal
mucosa and tongue but also seen on
the palate, gingiva and floor of the
mouth.

• These plaques resemble milk
curds and consist chiefly of
tangled masses of fungal hyphae,
with intermingled desquamated
epithelium, keratin, fibrin,
necrotic debris, leucocytes and
bacteria.
• White plaque can usually be
wiped away with a guaze leaving
either a relatively normal
appearing mucosa or an
erythematous area.
• In severe cases the entire cavity
may be involved.

ERYTHEMATOUS CANDIDIASIS
• Also known as antibiotic sore mouth.
• Usually occurs as a sequela to a
course of broad spectrum
antibiotics, corticosteroids or any
disease which suppress the immune
system, more commonly HIV
disease.
• Includes central papillary atrophy of
the tongue and cheilocandidiasis.
• The lesions appear red or
erythematous rather than white,
thus resembling the
pseudomembrane type in which the
membrane has been wiped off.

• Redness is due to increased vascularity.
• It has diffuse border and can occur at
any site.
• Only variety of candidiasis which is
consistently painful.
• Central papillary atrophy of the tongue
is an asymptomatic, symmetric
erythematous lesion of the dorsal
aspect in the posterior region.
• Erythematous appearance occurs due to
loss of the filliform papillae.
• A strong relationship exists between
this lesion and chronic smoking and C.
albicans.

CHRONIC HYPERPLASTIC CANDIDIASIS
• Also known as leukoplakia
type of candidiasis.
• Oral lesions consist of firm,
white persistent plaques.
• Occurs usually on the lips,
tongue, and cheeks and
appear similar to
leukoplakia.

• These lesions may be homogenous
or speckled (nodular)and persist for
periods of years.
• Cawson and Binnie have presented
data that indicates that indicates
that a definite relationship exists
between chronic candidiasis and
oral epidermoid carcinoma, basing
this relationship on the finding that
chronic candidiasis is a cause of
leukoplakia and thus must be
regarded as having possible
premalignant potential.
• These lesions completely resolve
following antifungal therapy.

• Some cases of chronic hyperplastic candidiasis have been
associated with iron and folate deficiency and defective cell
mediated immunity.
• A few keratotic lesions may be superimposed by candida
infection like leukoplakia, lichen planus and lupus
erythematosus.
• They appear similar to chronic hyperplastic candidiasisis
clinically but do not regress with antifungal treatment.

CANDIDA-ASSOCIATED LESIONS
DENTURE STOMATITIS
• Considered synonymous
with the condition known as
denture sore mouth, which
is diffuse erythema and
edema of the denture
bearing area, often
occurring with angular
cheilitis.

• Usually asymptomatic except for the soreness.
• There is no age limit and some studies have shown that
women are more affected than men.
• Mandibular mucosa is rarely affected.
• Denture related candidiasis may be the most common form of
the oral disease.

SECONDARY ORAL CANDIDIASIS
CHRONIC MUCOCUTANEOUS CANDIDIASIS
• Chronic mucocutaneous candidiasis is a group of different
forms of the infection, some of which may have multiple
features in common.
• In general it is characterized by chronic candidal involvement
of the skin, scalp, nails and the mucous membrane.
• The patients exhibit varying abnormalities in their immune
system like impaired cell mediated immunity, isolated IgA
deficiency and reduced candidacidal activity.
• They are usually resistant to the common forms of the
treatment.

CHRONIC MUCOCUTANEOUS CANDIDIASIS

CHRONIC FAMILIAL MUCOCUTANEOUS CANDIDIASIS
• It is an inherited disorder, probably an autosomal inherited
disorder.
• It occurs usually before the age of five years and has an equal
gender distribution, oral lesions occur in these children.

CHRONIC LOCALIZED MUCOCUTANEOUS CANDIDIASIS
• It is a severe form of the disease which also occurs early in life
but there is no genetic transmission.
• There is widespread skin involvement and granulomatous and
horny masses occur on the face and scalp.
• There is an increased incidence of other fungal and bacterial
infections.
• Oral cavity is the common primary site for the typical white
plaques and nail involvement is usually present.

CHRONIC LOCALIZED MUCOCUTANEOUS CANDIDIASIS

CANDIDIASIS ENDOCRINOPATHY SYNDROME
• Genetically transmitted condition characterized by candida
infection of the skin, scalp, nails and the mucous membranes.
• Lesions are classically associated with either hypoadrenalism
(Addisons disease), hypoparathyroidism, hypothyroidism,
ovarian insufficiency or diabetes mellitus.
• The endocrine manifestations may be multiple but may not
appear clinically for many years after the appearance of
thrush in children.
• Enamel hypoplasia has been seen to be associated with
autoimmune polyendocrinopathy – candidiasis syndrome.

CHRONIC DIFFUSE MUCOCUTANEOUS CANDIDIASIS
• It is the least common forms of the disease and appears to be
of late onset.
• Patients exhibit raised crusty sheets involving the limbs, groin,
face, scalp and shoulders, as well as the mouth and the nails.
• There is no familial history and the patients have no other
abnormality.
• Clinical appearance and the site of the lesions is the same as
that in the chronic hyperplastic candidiasis.

HISTOLOGIC FEATURES
• Fragments of the plaque material
may be smeared on the
microscopic slide, macerated with
20% potassium hydroxide and
examined for the typical hyphae.
• Presence of multiple branching
septate pseudohyphae in clusters
of grape like budding spores.
• Pseudohyphae measure from 2 to
4 µm in diameter and the ovoid
spores vary from 3 to 5 microns.

• The organism may be cultured
in a variety of media including
blood agar, cornmeal agar,
sabouraud’s broth to aid in
establishing the diagnosis.
• The typical discrete yeast
colonies of Candida albicans
usually appear within 3 days
of culture on Saboraud's
modified agar.

• Histologic sections from the biopsy
of the lesion of oral candidiasis show
the presence of the yeast cells and
hyphae and mycelia in the
superficial and deeper layers of the
involved epithelium.
• Slight parakeratosis
• Scattered neutrophils in the upper
epithelium.
• Pseudo-hyphae of Candida albicans.
• Epithelial hyperplasia.
• A dense lymphoplasmacytic infiltrate
and many dilated vessels in the
lamina propria.

• The organisms are easily
visualized if the sections are
stained with PAS or
methenamine silver.
• Chlamydospores are seldom
seen on oral smears or
histologic sections.

CANDIDA AND ORAL CANCER
• Candida has been suggested to play a role in initiation of OC.
• Candida albicans is the yeast most commonly isolated from
the oral cavity but increasing numbers of non-albicans
Candida albicans (NACA) are seen - particularly in medically
compromised patients.
• Candida in general is more prevalent on carcinoma lesions
than on healthy mouth mucosa: NACA strains have emerged
increasingly in oral cancer patients.
• Yeasts may invade oral epithelium and may be causally
involved in dysplastic changes.

• Candidal leukoplakias may sometimes develop into
carcinomas.
• Clinical studies have reported that nodular leukoplakia
infected with Candida has a tendency for higher rate of
dysplasia and malignant transformation.
• It has also been shown that epithelium of the chick embryo,
when infected with Candida albicans show squamous
metaplasia and higher proliferative phenotype.

Disease/Condition Signs & Symptoms Differentiating tests
CANDIDIASIS Asymptomatic/Symptomatic with
burning sensation
-Due to candida infection
-White plaques can be scraped off.
Smear exam and periodic
acid-Schiff staining will be
Positive for yeast forms or
hyphae.
CHEMICAL BURNS -Asymptomatic.
-Due to contact with chemical agent.
-White plaques cannot be scraped off.
Negative smear. After
elimination of the etiologic
factor, lesions will resolve
in 7-14 days
CANDIDIASIS CHEMICAL BURN (ASPIRIN)

CANDIDIASIS -Asymptomatic/Symptomatic with
burning sensation.
hyphae.
REACTIVE KERATOSIS -Usually Asymptomatic.
-Chronic irritation (e.g., a faulty dental
restoration, an ill-fitting denture, or
parafunctional habits.
Negative smear. Definitive
diagnosis by Biopsy &
histologic evaluation.
CANDIDIASIS REACTIVE KERATOSIS

CANDIDIASIS -Asymptomatic/Symptomatic with
burning sensation.
Smear exam and periodic acid-
Schiff staining will be Positive
for yeast forms or hyphae.
HAIRY LEUKOPLAKIA Often Asymptomatic.
-May complain of a ‘burning’
sensation, which is often due to
secondary infection with Candida.
-White plaques cannot be scraped
off.
diagnosis is through biopsy and
histologic evaluation.
In situ hybridization technique
demonstrates the presence of
EBV in the tissue.
CANDIDIASIS HAIRY LEUKOPLAKIA

burning sensation.
hyphae.
PLAQUE TYPE LICHEN
PLANUS
-Usually Asymptomatic.
-May be other lichenoid lesions in
other areas of the skin.
-White lesions cannot be scraped off.
diagnosis is through biopsy
and histologic evaluation of
the lesion.
Immunoflorescence
staining can be done.
CANDIDIASIS PLAQUE TYPE LICHEN PLANUS

constant burning sensation.
hyphae.
EROSIVE LICHEN
PLANUS
Lesions are painful, but mostly when
eating. Mucosal erosions and
lichenoid lesions elsewhere on the
skin may be present
the lesion.
CANDIDIASIS EROSIVE LICHEN PLANUS

Disease/Conditio
n
Signs & Symptoms Differentiating tests
CANDIDIASIS -Asymptomatic/Symptomatic with burning
sensation.
hyphae.
PREMALIGNANT
LEUKOPLAKIA &
CARCINOMA
-Asymptomatic, unless the expansion of
malignancy encroaches on anatomic
relationship between tissues. Regional lymph
nodes may be enlarged.
the lesion.
Imaging techniques such as
x-ray or CT are useful to
determine local invasion of
carcinoma.
CANDIDIASIS PREMALIGNANT LEUKOPLAKIA AND CARCINOMA

CANDIDIASIS Asymptomatic/Symptomatic.
hyphae.
THERMAL BURNS Usually painful and difficult to distinguish
from erythematous candidiasis based on
symptoms.
-Due to burn with food.
Negative smear. Lesions
resolve in 7-14 days with no
intervention.
No differentiating tests
required.
CANDIDIASIS THERMAL BURNS

constant burning sensation.
hyphae.
MIGRATORY GLOSSITIS -Usually Asymptomatic. Burning is
associated with eating spicy or sour
food or alcohol-containing liquids.
-Atrophic zones of migratory glossitis
are commonly patchy and are usually
surrounded by elevated
hyperkeratotic margins.
Negative smear. In the
absence of clinically
distinguishable features,
histologic exam of the
tissue may be necessary.
CANDIDIASIS MIGRATORY GLOSSITIS

TREATMENT NYSTATIN
• Antifungal agent such as Nystatin has been very beneficial in
the treatment of candidiasis.
• Suspensions of Nystatin held in contact with the oral lesions
have been successfully used in chronic as well as severe cases.
• Other drugs of value are Clotrimazole, Amphotericin B and
Miconazole.
• Some occasional cases of candidiasis may be refractory to the
treatment of Nystatin and they have frequently been
associated with endocrinopathies and immunologic
abnormalities.

• Infection- Pathogen
• Candidiasis- Candida albicans, C. tropicalis, C. glabrata, C.
parapsilosis, C. krusei, C. kyfer, C. dubliniensis
• Aspergillosis- Aspergillus fumigatus
• Cryptococcosis- Cryptococcus neoformans
• Histoplasmosis- Histoplasma capsulatum
• Blastomycosis- Blastomyces dermatitidis
• Zygomycosis- Orders Mucorales and Entomophthorales
• Coccidioidomycosis- Coccidioides immitis
• Paracoccidiomycosis- Paracoccidioides brasiliensis
• Penicilliosis- Penicillium marneffei
• Sporotrichosis- Sporothrix schenckii
• Geotrichosis- Geotrichum candidum
Oral fungal infections

UNCOMMON ORAL FUNGAL
INFECTIONS

ASPERGILLOSIS
• Aspergillus organism is ubiquitous and can be found in soil
and in decaying vegetation.
• Most species of Aspergillus do not grow at normal human
body temperature, only the pathogenic species have the
ability to do so.
• Aspergillus fumigatus is the species most often implicated in
human diseases.
• Does not usually cause disease in the immunocompetent
population.
ASPERGILLUS FUMIGATUS

• Immunocompromised patients, invasive pulmonary
aspergillosis occur, following inhalation of the spores.
• Aspergillosis is reportedly the second most common
opportunistic fungal infection after candidiasis.
• Fungus either invades blood vessels, causing thrombosis and
infarction of surrounding tissue or invades the sinuses,
progressively causing palatal and tongue lesion.

• Marginal gingiva and the gingival
sulcus have been cited as the
portal of entry of the spores.
• Painful gingival ulcerations and
mucosal soft tissue swellings with
gray or violaceous hue have been
reported.
• Can advance to extensive necrosis
and present clinically as a yellow
or black ulcer with facial swelling.

Aspergillosis
DOES NOT TAKE H & E STAIN
48

Histopathology
• Hyphae: Relatively
smaller in size (3 – 6
μm)
• Regular
• Dichotomously
branching at 45° angle
• Distinct cross - septa

Dichotomous branching
• Repeated division into two parts
(bifurcation).
• In dichotomous branching, the
branches form as a result of an
equal division of a terminal bud
(i.e., a bud formed at the apex of
a stem) into two equal branches.

Differential Diagnosis
• The main differential diagnoses for oral aspergillosis are
mucormycosis and pseudomonas oral infection.
• Palatal ulcerative presentations of aspergillosis could mimic lesions
such as
• Tuberculous ulcer,
• Leprosy,
• Syphilitic ulcer,
• Wegener’s granulomatosis,
• Systemic lupus erythematosus,
• Polyarteritis nodosa,
• Crohn disease,
• Sarcoidosis,
• Necrotizing sialometaplasia
• Neoplastic lesions such as squamous cell carcinoma and lymphoma

Diagnosis
• Confirmed by PAS-stained sections, culture, serodiagnosis and
polymerase chain reaction.
• Invasive aspergillosis, the detection of circulating antigen
galactomannan (GM), a component of the cell wall of
Aspergillus species, and/or specific antibodies in the serum
are useful markers for diagnosis.
• Primary oral or paranasal sinus lesions, biopsy can provide a
definite diagnosis.

HISTOPLASMOSIS
• Caused by Histoplasma capsulatum
• Acquired by inhalation of dust containing spores of fungus
• Two forms; pulmonary and mucocutaneous
• Mucocutaneous form cause ulcerative/erosive lesions on
tongue, palate and buccal mucosa
• Oral lesions: single ulcers, long term and may or may not be
painful
• Always misinterpreted as malignant ulcers
• Biopsy is mandatory

Clinical features
• Chronic low grade fever
• Productive cough
• Hepatosplenomegaly
• Lymphadenopathy
• Subcutaneous nodules
• Histoplasmin skin reaction
Histoplasma capsulatum

Oral manifestations
– Nodular, ulcerative, or
vegetative lesions
– Usually covered by
nonspecific gray membrane
– Indurated

Histopathological features
• Granulomatous
inflammation
• Organisms are found in
large numbers in
phagocytic cells

Mucormycosis
• Phycomycosis or Zygomycosis
• Caused by a saprophytic fungi found in soil, bread mold,
decaying vegetation etc.
• Involvement of the oral cavity is secondary to paranasal
sinuses or nasal cavity
• Usually present as a palatal necrosis or ulcerations
• Extends to adjacent structures causing extensive tissue
necrosis and invasion of brain
• Organ transplant and poorly controlled diabetic patients are
susceptible

• Two orders of Zygomyces that are of clinical concern are
Mucorales and Entomophthorales .
• Mucorales includes the genera Rhizopus, Mucor, Absidia and
Cunninghamella , which are more often implicated in human
diseases.
• This disease is caused by numerous Phycomycetes organisms
of the Eumycetes (true fungi) class characterized by the lack
of septation (coenocytic).

• These microorganisms are capable of causing deep fungal
infections that can rapidly deteriorate the condition of
immunocompromised patients.
•
• Entomophthorales causes infections mainly in
immunocompetent subjects following trauma, and are far less
invasive than Mucorales.
• Infection caused by Mucorales is known as mucormycosis,
while entomophthoramycosis is infection of the
Entomophthoral fungi.

• Often manifested in immunocompromised patients with
blood dyscrasia, diabetes, immunosuppressive therapy,
corticosteroid therapy, malignancy, hepatitis, tuberculosis, etc
.
• Prior to HIV/AIDS, diabetic acidosis accounted for about 50-
70% of patients reported with mucormycosis.
• Recently, this infection is encountered in HIV infection more
frequently.

Clinical features
• 2 types
– Superficial
• External ear
• Finger nails
• Skin
– Visceral
• Pulmonary
• Gastrointestinal
• Rhinocerebral

• May cause extensive necrosis and sloughing
• May resemble carcinoma
• The most common oral manifestations are palatal ulcers,
which are frequently necrotic, well-delimited, with well-
defined borders and may appear as either black or white.

Mucor
64
•Organism appear as large,
nonseptate hyphae with branching at
obtuse angles.
•Round or ovoid sporangia are also
seen
Gomori
Methenamine
Silver Stain

Histopathology
 Extensive necrosis of
the involved tissue.
 Hyphae: Larger in size (6
– 50 μm)
 Irregular
 Branching at 90° angle
 Ribbon like
 Devoid of septa

Wet mount smear
Potassium hydroxide wet mount preparation showing non-septate hyphae
of mucormycosis 66

Laboratory Methods for Detection and Diagnosis
of Mucormycosis
5) Culture
6) Molecular methods
 Direct sequencing of cultured
organism or formalin-fixed tissue
 Fluorescent in situ hybridization
 Quantitative PCR of blood.
1) Direct examination
 Wet mount
 Calcofluor
2) Cytopathological examination
 Periodic acid–Schiff stain
 Gomori methenamine silver
stain
3) Histopathological examination
 Periodic acid–Schiff stain
 Gomori methenamine silver stain
4) Immunohistochemistry analysis 67

BLASTOMYCOSIS
NORTH AMERICAN BLASTOMYCOSIS
• Gilchrist’s disease
• Caused by Blastomyces dermatitidis
• Two types
– Cutaneous
– Systemic
• Bones
• Liver
• Lungs
• Subcutaneous tissue
• Source of infection in humans is unknown

Clinical Features
• More common in males
• Middle age
• Small red papules that slowly increase in size and form tiny military
abscesses or pustules
• Ulcerate to discharge pus through a tiny sinus
Crateriform lesions are typical with indurated and elevated borders.
• Spreads through subcutaneous tissue and disseminates through
blood
• When inhaled, spores produce disseminated or local respiratory
infections
• Symptoms of pulmonary tuberculosis like fever, sudden weight
loss, productive cough.

• Oral manifestations
• Oral lesions are rare
• May produce ulcerated mucosal lesions in the oral cavity
– Seen in 25% of cases
– Resemble actinomycosis, but abscess formation may not be
prominent.
– Tiny ulcers
– May sometimes resemble oral cancer or epidermoid carcinoma
BLASTOMYCES DERMATITIDIS

• Nonspecific papillary
nodular lesion on the
hard palate
Extensive ulceration
involving the skin of
the face and neck.

• Chronic Granulomatous
inflammation
– Giant cells
– Macrophages
• Microabcess within the
epithelium
• Organism
– Round in shape
– Budding is often seen
– Doubly refractile capsule

PARACOCCIDIOIDOMYCOSIS
SOUTH AMERICAN BLASTOMYCOSIS
• Lutz’s disease
• Caused by Paracoccidioides brasiliensis
• Systemic lesions similar to those of blastomycosis
• Oral manifestations
– Sever lymphadenopathy
– Papillary lesions
– ulcers

• Granulomatous
inflammation
– Epithelioid macrophages
– Giant cells
• Scattered yeast like
organisms with multiple
buddings (“pilot wheel” or
“mickey mouse” appearance)
• Stains
– PAS
– Methenamine silver

Diagnosis of deep seated oral fungal infections
• Biopsy
• Pathologist should be given patients’ medical history
e.g. immune suppression
• Patients with deep oral fungal infections must be
referred to medical specialists for further evaluation
• Blastomycosis: smear/culture, Direct immunostaining,
DNA probes
• Cryptococcosis: microscopy/staining, serology
• Histoplasmosis: microscopy/staining, serology, skin
tests
• Mucormycosis: microscopy/Histology, smear/culture

Fungal infections of the oral cavity

Fungal infections of the oral cavity

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