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SECTION 2
Challenging Morphology in
Fungal Infections Requiring
Culture/Ancillary Tests
III-2-2
Scedosporiosis III-2-4
Scopulariopsis Infections III-2-6
Trichosporonosis III-2-8
FUSARIOSIS AND OTHER HYALOHYPHOMYCOSES
Gross photo shows ecthyma gangrenosum over a toe,
which may be seen in disseminated fusariosis. Black
gangrenous changes are seen on a red, indurated base
. (From DP: Nonneoplastic Derm.)
TERMINOLOGY
Synonyms
Fusariosis
Hyalohyphomycosis
ETIOLOGY/PATHOGENESIS
Infectious Agents
Any of the rare infections of humans caused by a
hyaline fungus (nondematiaceous) where tissue form
is mycelial (hyphal) in appearance
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
Genera include Fusarium, Paecilomyces, Purpureocillium,
Trichoderma, Chaetoconidium, Chrysosporium,
Microascus, Acremonium, and others
Necrotizing , granulomatous synovitis is shown in a
patient with disseminated fusariosis. Although classically
the disease is suppurative, more chronic lesions can be
seen, depending on host.
Laboratory Tests
Peripheral blood cultures for fungi: Positive in
disseminated disease
Severe neutropenia
-1,3-glucan: Highly suggestive of invasive fungal
disease of any type (except Mucorales infection)
Galactomannan: Highly suggestive of invasive
Aspergillus infection (excluding other fungal causes)
Treatment
Voriconazole or posaconazole are first-line agents
(resistant infections reported)
Prognosis
Due to severe immunosuppression of hosts and
difficulty in identifying infecting agents and
susceptibilities, mortality with disseminated disease is
high
CLINICAL ISSUES
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Presentation
Keratitis with abscess formation: After traumatic
introduction or cataract surgery
Onychomycosis of fingernails and toenails
Invasive disease in immunosuppressed patients;
involves any organ
Bone marrow transplant recipients, leukemia/
lymphoma patients, corticosteroid recipients,
cytotoxic chemotherapy recipients
Severe neutropenic or granulocytopenic state with
fever on antibiotic therapy
Localized swelling or pain in face (sinus
involvement)
Skin (with eschar): Multiple lesions; disseminated
disease
Respiratory symptoms: Pneumonia or cavitary mass
Neurological symptoms: Meningoencephalitis or
solitary/multiple abscesses
Disseminated disease: Sepsis-like syndrome with
multiple organs involved
MICROBIOLOGY
Culture
Due to number of species and similarity to Aspergillus,
culture is primary tool for definitive identification
Routine fungal culture media (Sabouraud dextrose
agar): Growth and further differentiation
Morphologic diagnosis of most species is possible on
fungal culture with visualization of macroconidia
and other culture-formed structures
MACROSCOPIC FEATURES
Skin
Distinctive punched-out dark eschar of skin with
surrounding erythema is common (less likely in
aspergillosis)
2
FUSARIOSIS AND OTHER HYALOHYPHOMYCOSES
Etiology
Rare infections of humans, hyaline hyphae-forming
fungi (nondematiaceous)
Fusarium, Paecilomyces, Acremonium, and others
Clinical Issues
Severe neutropenic or granulocytopenic state with
fever on antibiotic therapy
Pain in face (sinus involvement)
Skin (with eschar)
MICROSCOPIC PATHOLOGY
Histologic Features
Inflammation may be variable neutrophilic infiltrates
(depending on level of neutropenia) or granulomatous
Fungal hyphal forms are invasive, same size/
appearance as Aspergillus, and can display vascular
destruction with infarction
ANCILLARY TESTS
Histochemistry
Periodic acid-Schiff stain and methenamine silver
stains are positive for fungal hyphal forms and allow
for better morphology
Gram stain should be negative (to differentiate from
Candida)
Key Facts
Pneumonia or cavitary lung mass
Microscopic Pathology
Variable neutrophilic infiltrates (depending on level
of neutropenia)
Invasive fungal forms are same size/appearance as
Aspergillus, with vascular invasion
Infarction common
Top Differential Diagnoses
Aspergillosis, mucormycosis, candidiasis
Culture results, galactomannan, and PCR are primary
tools for distinguishing
Mucormycosis
Mucorales occur in same clinical population but are
usually more rapid infections, less inflammatory, and
have wide, thick ribbon-like hyphal forms that branch
in all directions
Candidiasis
Candidal infections with mostly hyphal forms can be
challenging, but yeast forms (when present) will be
gram-positive
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
Severe neutropenia with mass-forming disease
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
PCR
28S rRNA PCR with sequencing is a rapid way to
identify fungi that can be especially helpful in severely
ill, immunosuppressed patients
DIFFERENTIAL DIAGNOSIS
Aspergillosis
Aspergillus is morphologically indistinguishable from
most of the species that cause hyalohyphomycoses
IMAGE GALLERY
Pathologic Interpretation Pearls
Due to severe nature of disease, invasive fungi in
this group, like Aspergillus and Mucorales, should be
reported immediately to clinical team
SELECTED REFERENCES
1. Morrissey CO et al: Galactomannan and PCR versus culture
and histology for directing use of antifungal treatment
for invasive aspergillosis in high-risk haematology
patients: a randomised controlled trial. Lancet Infect Dis.
13(6):519-28, 2013
(Left) Silver stains strongly stain the hyphae and demonstrate the spread from lumen to surrounding tissue. Mucorales are larger and often
variably or lightly stained on silver. (Center) Although Fusarium can be indistinguishable from Aspergillus, it may produce odd angle branching
or yeast-like forms (not seen in aspergillosis). (Right) Fusarium in cartilage from a patient with disseminated disease demonstrates a rare
continuous chain of yeast-like cells .
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SCEDOSPORIOSIS
Scedosporium in the synovium of a patient post lung
transplant presenting with polyarthritis is shown with
methenamine silver stain. (Courtesy J. Brock, MBBS, PhD.
and L. Sholl, MD.)
TERMINOLOGY
Definitions
Latin: Scedo (scida = leaf of paper); Greek: Sporium
(spora = seed)
Latin: Apio (fasten or join)
Latin: Prolificans (proles = descendent)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Can be caused by 2 members of Scedosporium genus
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
Scedosporium apiospermum (asexual form)
Telemorph state, Pseudallescheria boydii (sexual
form)
Scedosporium prolificans (no sexual stage)
Scedosporium in the retina is shown with methenamine
silver stain in a patient presenting with eye pain and loss
of vision post lung transplant. (Courtesy J. Brock, MBBS,
PhD. and L. Sholl, MD.)
Skin infection (mycetoma, most commonly on feet
and lower limbs)
Altered mental status or mass effect with CNS
infection
Pulmonary infection, congestive heart failure
Arthritis or bone pain
Presentation with Scedosporium infection may be 1st
presentation of underlying hematopoietic malignancy
Treatment
Extremely resistant to a variety of antifungals
Voriconazole and echinocandins are recommended as
first-line therapy but effectiveness is limited
Surgical debridement can be performed depending on
site of infection
Prognosis
Extremely poor
Mortality 50-100% in immunocompromised
CLINICAL ISSUES
Epidemiology
Found in soil, sewage, compost, and polluted water
Increasingly recognized as a cause of infection in solid
organ transplant patients
Accounts for 25% of non-Aspergillus mold infections in
transplant patients
Infection can be from direct traumatic inoculation
into skin or through inhalation of airborne conidia
Site
In immunocompromised: Lungs, disseminated
infection and sepsis
Hematogenous dissemination can lead to brain
abscesses, meningitis, fungal endocarditis, and
osteomyelitis
IMAGE FINDINGS
Radiographic Findings
Ring-enhancing lesion on head CT in cases of cerebral
infection
MICROBIOLOGY
Fungal Features
Saprophytic filamentous mold
Septate hyaline hyphae branching at 45 angles seen
in vivo
Grows in enriched fungal media
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Presentation
Presentations may include
SCEDOSPORIOSIS
Clinical Issues
Accounts for 25% of non-Aspergillus mold infections
in transplant patients
Disseminated disease in immunocompromised has
mortality rate of 50-100%
Voriconazole and echinocandins are recommended
as first-line therapy, but effectiveness is extremely
limited
Key Facts
Microscopic Pathology
Septate, nonpigmented, branching hyphae at 45
angle
Indistinguishable morphologically from Aspergillus
Top Differential Diagnoses
Aspergillus, Fusarium, Acremonium
Diagnostic Checklist
Culture is needed for definitive diagnosis
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
MACROSCOPIC FEATURES
Culture Characteristics
Both S. apiospermum and S. prolificans are fast-growing
on solid media
These dematiaceous (containing melanin in the cell
wall) fungi grow as pigmented colonies
Hyphae are hyaline (nonpigmented) in
histopathological sections
MICROSCOPIC PATHOLOGY
Histologic Features
S. apiospermum
Conidia (4-12 m) are unicellular and oval with
truncate base
Hyphae are hyaline and septate with branching at
45 angles with a single terminal conidia
S. prolificans
Conidia are unicellular and oval with truncate base
Hyphae are hyaline and septate with annelids
having swollen base and elongated neck
Conidia may grow singly or in clusters along hyphae
Background tissue will display inflammation with
neutrophilic and monocytic infiltrate, granulomatous
changes or necrosis
May display angioinvasion
Unicellular adventitious forms may be visible in blood
cultures, which is not seen in Aspergillus infection
DIFFERENTIAL DIAGNOSIS
Systemic Fungal Infection
Hyaline hyphomycetes: Aspergillus, Fusarium,
Acremonium, Paecilomyces
These fungi are virtually indistinguishable
histologically; therefore, culture is required to make
definitive diagnosis
Bacterial and Viral Infection
Consider clinical picture, risk factors, culture results,
and serological testing
DIAGNOSTIC CHECKLIST
Pathologic Interpretation Pearls
Unicellular adventitious forms, which are not seen in
Aspergillus infection, may be present in blood
Culture plus evidence of tissue invasion is needed for
definitive diagnosis
SELECTED REFERENCES
1. Campa-Thompson MM et al: Clinical and morphologic
findings in disseminated Scedosporium apiospermum
infections in immunocompromised patients. Proc (Bayl
Univ Med Cent). 27(3):253-6, 2014
2. Cortez KJ et al: Infections caused by Scedosporium spp.
Clin Microbiol Rev. 21(1):157-97, 2008
IMAGE GALLERY
(Left) Hematoxylin and eosin stain of a thigh debridement shows yeast forms and septate hyphae of Scedosporium prolificans with necrotizing
granulomatous inflammation. (Center) Methenamine silver stain of a thigh biopsy demonstrates Scedosporium conidia . (Right) Scedosporium
is seen in the aortic intima with methenamine silver stain. (Courtesy J. Brock, MBBS, PhD. and L. Sholl, MD.)
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SCOPULARIOPSIS INFECTIONS
Scopulariopsis is seen in a lower limb ulcer on a
PAS stain with diastase. Note the branched hyphae
with conidiophores. A lack of inflammation in
immunosuppressed patients is not uncommon.
TERMINOLOGY
Definitions
Latin: "Scopula" (twigs or branches)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Scopulariopsis spp. are filamentous fungi that can be
hyaline or dematiaceous
5 species of Scopulariopsis have been associated with
human disease
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
Scopulariopsis brevicaulis (most common, hyaline)
Scopulariopsis brumptii (pigmented)
Scopulariopsis acremonium (hyaline)
Scopulariopsis fusca (pigmented)
Scopulariopsis koningii (hyaline)
CLINICAL ISSUES
Epidemiology
Saprophytes found worldwide in
Soil (primarily), plant debris
Air and moist environments
Feathers
Insects
Site
Nails
Onychomycosis
Skin
Superficial infection and subcutaneous abscesses
Respiratory tract
Fungal ball and pneumonia
Cardiovascular system
III
Fungal endocarditis
Nervous system
Endophthalmitis and brain abscesses
Branching fungal hyphae on silver stain demonstrate the
acute angle found in Scopulariopsis and agents of
hyalohyphomycosis and reiterates the need for culture.
(From DP: Transplant Pathology.)
Other
Case report of fatal disseminated infection following
bone marrow transplant
Presentation
Most commonly a cause of onychomycosis
Increasingly becoming a cause of opportunistic
infections
S. brevicaulis is most commonly associated with
opportunistic infections
Studies have shown that respiratory tract is most
common source of isolation
Treatment
Surgical debridement of infected and necrotic tissue if
feasible
Significant resistance to antifungals
Amphotericin B and voriconazole
In vitro studies suggest echinocandins may be more
effective
Prognosis
Overall, treatment is poorly effective (relapses and
death are common)
Estimated cure rate is ~ 40%
Mortality depends on site of infection
IMAGE FINDINGS
Radiographic Findings
Brain abscesses
Appear as ring-enhancing lesions on CT
Pulmonary fungus ball
MICROBIOLOGY
Fungal Features
Saprophytic mold
Rapid growth (mature in 5 days)
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SCOPULARIOPSIS INFECTIONS
Etiology
5 species have been associated with human disease
Clinical Issues
Soil saprophytes
Most commonly a cause of onychomycosis
S. brevicaulis is most commonly associated with
opportunistic infections
Colonies are initially white
Become light brown with a tan periphery ("buff
colored")
Reverse of colonies are tan/brown
MICROSCOPIC PATHOLOGY
Histologic Features
Septate hyaline or pigmented hyphae (depending on
species) with short branched conidiophores (terminal
buds)
Annellides (branch points) can be single or groups
Can be tenpin-shaped
Hyphae are very similar in appearance to other molds
Aspergillus
Scedosporium
Fusarium
Definitive speciation requires culture but pigment
detection may guide treatment
ANCILLARY TESTS
PCR
Real-time PCR has been shown to be sensitive and
specific for detection of Scopulariopsis from infected
human tissue
Key Facts
Microscopic Pathology
Septate hyaline hyphae with short branched
conidiophores (terminal buds)
Annellides (branch points) can be single or groups
Hyphae are very similar in appearance to other molds
Top Differential Diagnoses
Aspergillus
Scedosporium
Fusarium
DIFFERENTIAL DIAGNOSIS
Other Opportunistic Molds
Aspergillus
Scedosporium
Fusarium
Agents of phaeohyphomycosis
Distinguishing these species morphologically alone
can be challenging or impossible
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
High clinical suspicion for invasive mold on surgical
inspection should warrant careful rapid or permanent
section evaluation
Pathologic Interpretation Pearls
Fungal morphology may be difficult, so early use of
ancillary methods (IHC, PCR) is required
SELECTED REFERENCES
1. Sandoval-Denis M et al: Scopulariopsis, a poorly known
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
Can be distinguished from Scopulariopsis based on
culture characteristics
opportunistic fungus: spectrum of species in clinical
samples and in vitro responses to antifungal drugs. J Clin
Microbiol. 51(12):3937-43, 2013
MICROSCOPIC FEATURES
(Left) Invasive Fusarium infection is seen in the lung of an immunocompromised patient. Note the branching hyphae with conidiophores that
are similar to those of Scopulariopsis. (Center) Invasive Scedosporium infection has a similar histological appearance to Scopulariopsis. (Right)
Invasive aspergillosis has a similar appearance to Scopulariopsis with branched hyphae and conidiophores . Aspergillus often shows
terminal swellings of hyphae .
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TRICHOSPORONOSIS
A colony of Trichosporon within human tissue in
disseminated disease shows hyphal forms , which
end in boxcar-shaped arthroconidia. Note the lack of
inflammation.
TERMINOLOGY
Definitions
Greek: "Tricho" (hair) + "spora" (seed)
ETIOLOGY/PATHOGENESIS
Environmental Exposure
Ubiquitous fungus found on human skin as a
colonizing organism that has been isolated from soil,
cheese, insects, bird feces, and water sources
Infectious Agents
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
Trichosporon species include several dozen yeast species
that have no teleomorphic (sexual) stage
Important species include Trichosporon asahii
(formerly beigelli), Trichosporon asteroides, Trichosporon
cutaneum, Trichosporon dermatis, Trichosporon dohaense,
Trichosporon inkin, Trichosporon loubieri, Trichosporon
mucoides, and Trichosporon ovoides
CLINICAL ISSUES
Low-power view of a disseminated lesion of
trichosporonosis on silver stain shows a large area of
necrosis in which the fungus is thriving.
Any patient with excessive blood transfusions,
hemochromatosis, or hemosiderosis with
immunosuppression is at risk
Laboratory Tests
Neutropenia
Cryptococcal latex agglutination assay: Positive in
trichosporonosis (cross-reactive)
Peripheral blood &/or urine (often 1st) fungal culture
usually positive in disseminated disease
-1,3-glucan: Carbohydrate of fungal wall present in
peripheral blood suggests invasive disease
Galactomannan: Carbohydrate of fungal wall in
peripheral blood suggests invasive aspergillosis
(negative in trichosporonosis)
Treatment
Voriconazole and posaconazole
Prognosis
White piedra and localized disease are easily treated
with low morbidity and mortality
Disseminated trichosporonosis, due to host setting,
has a high fatality rate
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Presentation
White piedra: Soft white nodules of fungus at bases of
human hair, asymptomatic (any host)
Summertime hypersensitivity pneumonitis presents as
a respiratory asthma-like illness associated with sauna
usage, particularly in Japan (any host)
Localized cutaneous trichosporonosis demonstrates
localized ulceration with erythema (any host)
Invasive/disseminated trichosporonosis with fever,
malaise, skin lesions, hepatosplenomegaly, abdominal
pain
Occurs in hematological malignancy patients
(acute myeloid leukemia) with iron overload due to
transfusions
MICROBIOLOGY
Culture
Sabouraud dextrose agar or malt yeast agar
Grow as white, dry to creamy colonies at 25 C with
deep transverse fissures
MICROSCOPIC PATHOLOGY
Histologic Features
Skin
Immunocompetent: Necrotic neutrophilic
dermatitis/cellulitis with granulomatous
inflammation (later) admixed with fungal elements
TRICHOSPORONOSIS
Etiology
Trichosporon species: Several dozen yeast, no
teleomorphic (sexual) stage
Clinical Issues
Invasive/disseminated trichosporonosis with
fever, malaise, skin lesions, hepatosplenomegaly,
abdominal pain
Hematological malignancy patients (acute myeloid
leukemia) with iron overload
Excessive blood transfusions, hemochromatosis, or
hemosiderosis with immunosuppression
Microscopic Pathology
Skin (immunocompromised): Fungal yeast/hyphal
elements with arthroconidia, lacks inflammation
Immunocompromised: Fungal yeast/hyphal
elements with arthroconidia often lacking
inflammatory component
Liver/spleen: Large necrotic masses without
inflammation, containing proliferating fungus with
definitive arthroconidia
Other organs: Minimal inflammation with
proliferating fungal elements, identifiable
arthroconidia, and necrosis
ANCILLARY TESTS
Histochemistry
Periodic acid-Schiff stain (variable depending on
viability) and methenamine silver positive in hyphal
forms
Gram stain should be negative
PCR
28S rRNA PCR with sequencing can definitively
speciate the organisms from tissue or fluids
DIFFERENTIAL DIAGNOSIS
Aspergillosis
Morphologically very similar to trichosporonosis
but lacks arthroconidia; serology positive for
galactomannan
Candidiasis
Yeast and pseudohyphae should be present; positive
on Gram stain (yeast)
Hyalohyphomycosis
Morphologically very similar to trichosporonosis
but lacks arthroconidia; serology negative for
galactomannan
Key Facts
Liver/spleen: Large necrotic masses without
inflammation, proliferating fungus with definitive
arthroconidia
Other organs: Minimal inflammation with
proliferating fungal elements and necrosis
Ancillary Tests
Periodic acid-Schiff stain (variable depending on
viability) and methenamine silver positive in hyphal
forms
Top Differential Diagnoses
Aspergillus
Candidiasis
Hyalohyphomycosis
Mucormycosis
Mucormycosis
Thick hyphae with variable branching, less
inflammatory reaction; serology negative for -1,3glucan
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
Immunosuppressed patients (neutropenia) with
significant transfusion history or iron overload
Pathologic Interpretation Pearls
Arthroconidia at ends of hyphae in correct host
should strongly suggest trichosporonosis
SELECTED REFERENCES
1. Padhi S et al: Fungemia due to Trichosporon mucoides in
2. Roman AD et al: Invasive trichosporonosis in an AIDS
3. Shah AV et al: Trichosporon mycotoxinivorans infection in
4. Dotis J et al: Non-Aspergillus fungal infections in chronic
5. Nakajima A et al: Familial summer-type hypersensitivity
6. Rastogi V et al: Non-healing ulcer due to Trichosporon
7. Janagond A et al: Trichosporon inkin, an unusual agent of
8.
9. Fan YM et al: Primary cutaneous trichosporonosis caused
a diabetes mellitus patient: a rare case report. Indian J Med
Microbiol. 32(1):72-4, 2014
patient: case report and review of the literature. Int J STD
AIDS. 25(1):70-5, 2014
patients with cystic fibrosis. J Clin Microbiol. 52(6):2242-4,
2014
granulomatous disease. Mycoses. 56(4):449-62, 2013
pneumonitis in Japan: two case reports and review of the
literature. BMC Res Notes. 6:371, 2013
loubieri in an immunocompetent host and review of
published reports. Mycopathologia. 176(1-2):107-11, 2013
fungal sinusitis: a report from south India. Indian J Med
Microbiol. 30(2):229-32, 2012
Moreno-Coutio G et al: Necrotic ulcer caused by
Trichosporon asahii in an immunocompetent adolescent.
Mycoses. 55(1):93-4, 2012
by Trichosporon dermatis in an immunocompetent man. J
Am Acad Dermatol. 65(2):434-6, 2011
Fungal Infections: Challenging Morphology in Fungal Infections Requiring Culture/Ancillary Tests
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