ARTICLE
Auteur(s) : Chao-Kai Hsu, Mark Ming-Long Hsu, Julia Yu-Yun Lee
Department of Dermatology, National Cheng Kung University
Medical Center, 138 Sheng-Li Rd, Tainan, Taiwan
accepté le 9 Novembre 2005
Fusarium species are molds distributed worldwide and prevalent in
the soil and in air. It has recently become the second most common
pathogenic mold in immunocompromised patients, most of them with
hematologic malignancies and neutropenia [1]. Fusarium infection in
humans may cause local, focally invasive, or disseminated disease.
Skin is affected in most patients and commonly manifests as red or
gray macules, papules, pustules, as well as subcutaneous nodules
[2]. We report a case of Fusarium infection in a man with CD8+
cutaneous T cell lymphoma (CTCL). The infection occurred in a large
ulcerated lymphomatous lesion on the leg and was successfully
treated with oral voriconazole.
Case
A 45-year-old man with CTCL was admitted in June 2004 because of an
ulcerated tumor on the left shin that had been present for 8
months. The ulceration worsened recently with the appearance of a
black eschar on the surface (figure 1A). The patient had
a very long history of chronic skin lesions, which began with a
white patch on the back since grade school. Slowly, red plaques
appeared within the white patch over time (figure 2A) and multiple
patches and plaques also appeared over other parts of the trunk and
proximal extremities over the last 2-3 decades. Since 1996,
multiple 0.5 to 2 cm erythematous maculopapules with necrosis
and ulceration began to appear episodically on his trunk and
extremities. Biopsies of three of these lesions revealed changes
consistent with lymphomatoid papulosis. Biopsies of a red scaly
plaque located within a white patch from the right forearm and a
plaque on the right arm revealed lichenoid infiltrates of small to
medium lymphocytes with epidermotropism and wiry collagen in the
papillary dermis, consistent with mycosis fungoides. A biopsy
specimen from the white patch on the midback revealed epidermal
hypopigmentation with a lichenoid infiltrate of lymphocytes with
epidermotropism and Pautrier’s microabscesses, consistent with
hypopigmented mycosis fungoides. Immunophenotyping of these 3
specimens was carried out, using the labeled streptavidin-biotin
peroxidase method (LSAB kit, Dako) with anti-CD4 (1: 60,
Novocastra, Newcastle upon Tyne, UK; Dako high pH solution for
antigen retrieval) and anti-CD8 (1:50, Dako, Carpinteria, CA;
citrate buffer for antigen retrieval). CD4 was expressed in the
great majority of the dermal lymphocytes and about 20-40% of the
infiltrate expressed CD8+. The infiltrate in the epidermis also
consisted of a mixed population of CD4+ and CD8+ cells; CD8+ cells
were either as numerous as or more numerous than CD4+ cells.
Since the patient worked in China, he was only able to receive
therapy periodically when he returned to Taiwan, during which time
he received systemic retinoids (etretinate or acitretin 10 mg tid)
and subcutaneous interferon alfa-2b 3 million units 3 times a week
intermittently for 8 years prior to 2004. Beginning in 1999,
asymptomatic erythematous to brownish infiltrating annular plaques
began to appear on the extremities; most of these lesions developed
central necrosis (figure
2B) and healed in weeks. However, an infiltrating plaque on
the left shin continue to enlarge and became ulcerated. The surface
turned into a black eschar in June 2004 (figure 1A). The clinical
differential diagnoses were gangrenous fungal or bacterial
infection, pyoderma gangrenosum or necrosis of lymphoma and the
patient was admitted for further management.
A biopsy specimen from the area of black eschar showed abundant
fungal hyphae throughout the necrotic tumor tissue, but the hyphae
were more numerous superficially. Biopsy specimens from the
infiltrating border of the tumor on the left shin and an annular
plaque on the left thigh revealed extensive infiltration of
lymphocytes with atypical medium to large nuclei in the dermis and
epidermis with many necrotic keratinocytes in the epidermis (figure 3). Many
eosinophils were present in the dermis. The atypical lymphocytes
were CD8-positive but CD4, CD30, CD56 and EBER-1 negative. The
findings were consistent with CD8+ CTCL.
Fusarium species was isolated, and the morphology was suggestive
of Fusarium solani (figure 4). Further
identification was performed by polymerase chain reaction (PCR)
amplification using primer pairs Internal Transcribed Spacer (ITS)1
(5’-TCCGTAGGTGAACCTGCGG-3’) and ITS2 (5’-TCCTCCGCTTATTGATATGC-3’)
targeting the conserved regions of 18S and 28S rDNAs. Sequence
analysis was carried out using the web-based BLAST programs of
National Center for Biotechnology Information
(http://www.ncbi.nlm.nih.gov/BLAST/), and showed 100% homology with
Nectria haematococca, the teleomorph of F. solani.
The necrotic tumor was debrided to as deep as the fascia and
muscle layer. Unfortunately, there was a rapid recurrence of
gangrenous change of the wound bed accompanied by fever in 2 days.
Systemic amphotericin B therapy was initiated with a starting dose
of 20 mg for the first day and 50 mg for the second day. It was
discontinued afterwards due to the high fever, headache and nausea.
Oral voriconazole 200 mg bid was initiated 3 days later. Repeated
blood cultures yielded negative results. One 1.5 cm nodule
with central cavity formation was noted in the left lower lung
field (figure
5). A gallium tumor scan showed gallium-avid tumor in the
left lower lung field with lymphadenopathy. Lymphoma or infection
was suspected. The patient tolerated voriconazole well except for
experiencing transient blurring vision and seeing wavy or zigzag
lines on the outline of objects in the first day. The abnormal
vision lasted a few hours shortly after taking voriconazole.
The ulceration and necrosis of the tumor in the left shin
improved with appearance of granulation tissue with variconazole
therapy (figure
1B). The lung nodule resolved partially in one month.
Voriconazole was continued for 3 months. Completely resolution was
noted in a follow-up computer tomography (CT) scan in March 2004
(figure 5).
Repeated biopsy of the ulcer in January 2005 revealed edematous
granulation tissue without fungal infection. Another biopsy in
February 2005 revealed changes of CD8+ lymphoma. Staging and
chemotherapy were suggested, but the patient’s overseas job
precluded him from being admitted. While waiting for
hospitalization, the lymphoma in the left shin remained ulcerated
with yellowish necrotic debris. Repeated biopsy and fungal cultures
in June 2005 showed no evidence of recurrence of Fusarium
infection.
In July 2005, he was admitted for further treatment. Two new
nodules were detected in both lower lungs. Biopsy of one of the
nodules under CT guide revealed infiltration of CD8+ lymphoma
pathologically. The patient was transferred to the oncology ward. A
weekly cycle of chemotherapy consisting of endoxan, epirubicin,
oncovin and prenisolone was initiated in July 2005 with gradual
improvement of the ulcerated lesions.
Discussion
We described a case of cutaneous and pulmonary fusariosis in a
patient with underlying CTCL successfully treated with oral
voriconazole. Fusarium species, including F. solani, F. oxysporum,
and F. moniliforme, are important causative agents of
hyalohyphomycosis. Fusarium is characterized by hyaline septate
hyphae and fusoid macrocondidia (hyaline, multicellular,
banana-like clusters with foot cells) and microconidia (hyaline,
unicellular, ovoid to cylindrical in slimy head or chains) [3].
Fusarium may cause local, focally invasive, or disseminated
infection. Risk factors in localized disease, including skin
infection, keratitis, endophthalmitis, osteomyelitis, and septic
arthritis, are tissue breakdown caused by trauma, severe burns or
foreign bodies. Disseminated infection involves two or more
non-contiguous sites. Risk factors for disseminated fusariosis
include severe immunosuppression (mainly in patients with
hematological malignancies), tissue damage, and receipt of a graft
from an HLA-mismatched or unrelated donor [1, 4]. Skin involvement
was present in 70% of patients, especially in immunocompromised
hosts [3]. The skin lesions in disseminated infection typically
manifest multiple red or violaceous macules and nodules and the
center of the lesion often becomes necrotic and covered by a black
eschar [2, 4, 5].
The first clue of the Fusarium infection in the present case was
the development of a black eschar on the surface of a pre-existing
ulcerated tumor. Because this change occurred in a long-standing
ulcerated lymphoma, worsening of the lymphoma was considered
initially with gangrenous fungal or bacterial infection and
pyoderma gangrenosum as the differential diagnoses. Biopsy
specimens revealed a CD8+ T cell lymphoma with presence of numerous
fungal hyphae in the necrotic tissue, more numerous superficially.
These findings were initially thought to be superinfection of
necrotic lymphoma tissue before the fungus was isolated. Therefore,
systemic antifungal therapy was not started right away until two
days later when there was a rapid local recurrence of gangrenous
changes of the wound bed accompanied by high fever and appearance
of a nodular infiltrate in the left lower lung field. The
resolution of the pulmonary nodule following voriconazole therapy
was clinically suggestive of Fusarium infection, which however
could not be confirmed without tissue proof. The possibility of
lymphoma infiltrate in the lung could not be excluded.
The diagnosis of Fusarium infection may be made via
histopathology, Gram stain, fungal and blood cultures, serology and
PCR studies. In the present case, the isolated fungus displayed
features typical of F. lateritium, F. oxysporum, and F. solani [3].
Further identification of F. solani was done by PCR method. The
ribosomal DNA of fungus contains variable DNA sequence areas of the
intervening ITS regions. Amplification-based ITS assays could
provide a rapid and accurate diagnosis of invasive fungal
infections and improve the care and outcome for affected patients
[6]. The sequence analysis revealed F. solani, which is the most
commonly identified pathogen among Fusarium species [7, 8].
Fusarium species are moderately resistant to most antifungal
agents, but a positive outcome is more likely when an effective
antifungal agent is initiated early in the course of the infection
and immune reconstitution occurs. Successes have been reported with
amphotericin B and its lipid formulations [7, 9]. However, their
use is limited by toxicity, especially for the kidneys.
Voriconazole, available for both oral and intravenous forms, has
broad-spectrum activity against pathogenic yeasts, dimorphic fungi
and opportunistic moulds with satisfactory global responses in 50%
of the overall cohort [10]. Successful outcomes were observed in
47% of patients whose infections failed to respond to previous
antifungal therapy, and in 68% of patients whose infections had no
approved antifungal therapy. The efficacy rate was 45.5% for
fusariosis and 43.7% for aspergillosis. Voriconazole is generally
well-tolerated, and the most common treatment-related adverse
effects are visual adverse events, hepatic enzyme elevation and
skin reactions [11]. Our patient could not tolerate amphotericin B.
Voriconazole therapy was effective with only transient abnormal
vision.
In summary, we presented a case of cutaneous fusariosis in a
patient with long-standing CTCL successfully treated with oral
voriconazole. The present case is unusual in that the infection
occurred within a pre-existing, ulcerated lesion of cutaneous CD8+
lymphoma, resulting in confusion with pyoderma gangrenosum and
necrosis of lymphoma clinically. A high index of suspicion will
prompt a timely biopsy as well as isolation of the fungus, and
early institution of systemic antifungal therapy.
Acknowledgements
The authors are grateful to Shih-Sung Chuang, M.D. for assisting in
immunophenotyping.
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