Subcutaneous phaeohyphomycosis caused by Cyphellophora pluriseptata

ARTICLE

Phaeohyphomycosis encompasses a class of mycoses whose etiologic agents develop in their host's tissues as dark-walled, septate mycelial elements [1]. In a survey of the literature in 1996, a total of 57 genera and 104 species of dematiaceous fungi were linked to the etiology of phaeohyphomycosis [2]. Four distinct clinical presentations have been described: a) superficial; b) cutaneous/corneal including dermatomycosis, onychomycosis, and mycotic keratitis; c) subcutaneous; d) systemic [2]. The subcutaneous form, improperly named phaeohyphomycotic cyst, is the most common presentation and also includes cases with exclusive or predominantly dermal involvement [3]. Subcutaneous phaeohyphomycoses are frequently associated with debilitating diseases or immunosupressive status, however infection may also affect healthy individuals [3].

A great number of genus and species of fungi have been considered as the causative agent of subcutaneous phaeohyphomycosis, however Exophiala and Phialophora are the most commonly reported genus [4].

Infection occurs in 85% of the cases in the upper and lower limbs but less frequently lesions are localized on the buttocks, face, neck and scalp [4]. They usually appear as solitary subcutaneous cysts or abscesses, firm to fluctuant, usually sparing the overlying skin [7-9]. However on some immunocompromised patients the lesions appear as solid subcutaneous masses or red indurated lesions. Other dermatological aspects, such as keratotic plaques, pustules, sinus tracts, ulcers, crusts, eczematous rash, papulo-nodular, exophytic or verrucous lesions have also been described [3, 4, 8-14].

The histopathological pattern of subcutaneous phaeohyphomycosis is considered to be the same regardless of the agent and the anatomical site. They consist of a cystic structure or, rarely, dispersed granulomas surrounded by a dense fibrous capsule, with central area of suppurative necrosis. The internal cyst wall presents aggregates of epithelioid and giant cells [5]. The lesions are usually described as involving the deep dermis and subcutaneous tissue [6, 7, 15, 16] but in immunodeficient patients they can be exclusively or predominantly situated in the upper and lower dermis [3, 8, 11, 17]. More recently, three different histopathological patterns have been described: 1) suppurative and granulomatous processes in the dermis associated with epidermal hyperplasia, and epidermal abscesses; 2) intradermal multiloculated cysts lined by granulomas, with abscesses, and a normal epidermis; 3) dermal unilocular cysts containing neutrophils and lined by granulomas, with normal epidermis. The first pattern is similar to chromoblastomycosis and the differentiation between these two entities can be made through the identification of the fungal morphology in tissue [3].

The purpose of this paper is to report the first case of subcutaneous phaeohyphomycosis caused by Cyphellophora pluriseptata in a healthy individual and discuss the unusual clinicopathological aspects.

Case report

The patient was a 38-year-old male, mullato, airport clerk, from Lauro de Freitas (Bahia) living in an urban area. He presented a 10 year history of lesions over the left ear. He was unaware of preceding trauma and had no other complaints. He had never used immunosupressive therapy. Two years previously he went to a public ambulatory clinic for leprosy and was treated during five months for leprosy without result. For this reason he was sent to our University Hospital. On physical examination there was only a lesion found in the left ear. The entire helix, the lobule, and part of the antihelix presented a reddish diffuse infiltration (Fig. 1). The diagnosis of borderline leprosy was suspected and the patient was submitted for a biopsy where the diagnosis was phaeohyphomycosis. Another biopsy was performed in order to obtain material for culture and half of it was submitted to a second histopathological study. Laboratory tests, including blood counts, erytrocyte sedimentation rate, and fasting blood sugar were all normal. Serology for HIV and HTLV-I yielded negative results. Otorhinolaringological examination and X-rays of the chest and of the facial sinuses were normal.

Histopathology

The histopathological aspects observed in both biopsies were similar. A dense inflammatory reaction was present in the upper and lower dermis sparing only a narrow subepidermal band of collagen. The epidermis was atrophic and without inflammatory cells. The infiltration consisted of lymphocytes and multinucleated giant cells. The giant cells were disposed at random or less frequently, forming compact granulomas (Fig. 2). In hematoxylin-eosin sections brown elongated or ovoid structures surrounded by a halo were seen inside giant cells (Fig. 3A). By Grocott method the fungal elements were better visualized (Fig. 3B): scarce hyphae of different lengths, irregularly swollen to toruloid and infrequently branched. A few yeast-like cells were seen with a single bud. Smaller fungal elements predominated and were seen inside giant cells.

Mycology

The colonies grew rapidly in Sabouraud agar. They were velvety and dark grey (Fig. 4). Microscopically smooth-walled, pale-brown hyphae with terminal, intercalary or lateral phialides, with a conspicuous collarette at the tip, were seen. The conidia were pale-brown, cylindrical to fusiform, with rounded ends, 1-5 septate, straight or slightly curved (Fig. 5). The fungus identification was done by Dr. Lester Pasarell in the Medical Mycology Research Center of the University of Texas Medical Branch at Galveston, Texas, USA. The culture is registered in this laboratory under the number 5056.

Evolution

The patient was treated with itraconazole, 100 mg/day for 3 months with disappearence of the lesion, however the infiltration reappeared a few months later. He was then treated with amphotericin B (with a total dose of 1 g) with remarkable regression of the lesion but the treatment was interrupted due to side-effects of this drug. Later there was progression of the infiltration and now the patient is being treated with itraconazole at a higher dose (200 mg/day).

Comment

The case presented here constitutes a very atypical example of subcutaneous phaeohyphomycosis as regards the etiological agent as well as the anatomical site and the clinicopathological aspects.

For the first time Cyphellophora pluriseptata can be considered definitively as a pathogen. The fungus was described as a new species by De Vries et al. in 1986 [18], isolated from human skin and nails. According to these authors there was insuficient data to consider this fungus as a pathogen at this time.

It is important to emphasize that the patient had no clinical evidence of immunodeficiency and had not used immunosupressive therapy.

As far as we know the ear localization of phaeohyphomycosis has only been previously reported as an extension from primary facial lesions [4, 19]. In the present case the extensive and marked infiltration of the ear and the unilateral involvement simulated borderline leprosy and the patient was erroneously treated. Our case is also unusual in that the patient was apparently a healthy individual. Without an important immunological impairment it is indeed a rare occurrence for a fungus as yet not considered a pathogen to cause subcutaneous phaeohyphomycosis. Infection presumably originated exogeneously as it occurs in other subcutaneous mycoses [20], because no involvement was detected in any other area of the body. The patient has no history of trauma, but considering the long evolution of disease it is difficult for him to remember a previous injury.

The histopathological aspects of the present case are very different from the cases of phaeohyphomycosis described in the literature [1, 5]. Two skin biopsies showed the same aspect: an atrophic epidermis and a chronic granulomatous inflammation of the upper and lower dermis without necrosis, abscesses or infiltration by neutrophils. Even in the cases in the literature with exclusive dermal involvement and without cystic formation there is reference to a suppurative process [2, 3, 11, 14, 17, 21] or at least to a mixed inflammatory infiltration with neutrophils [10, 22].

The histopathological diagnosis of phaeohyphomycosis is always achieved by recognizing dematiaceous fungal elements that vary in their degree of pigmentation. The fungi appear in tissue as septated hyphae, irregularly swollen to toruloid, branched or unbranched. Less frequently yeast-like cells that present buds singly or in chains, and spherical to oval cells that reproduce by septation in only one plane, may be observed [5]. Any combination of these aspects can be observed in phaeohyphomycosis. In the present case the observation of pigmented fungal elements raised the importance of a differential diagnosis with chromoblastomycosis. The presence of mycelia, and the epidermal atrophy easily enabled the diagnosis of phaeohyphomycosis. In chromoblastomycosis there is always epidermal hyperplasia, and the diagnostic yeast-like cells (sclerotic cells) present septation in one or two planes [20]. These elements are the most frequent in chromoblastomycosis in contrast to the predominance of mycelium in phaeohyphomycosis.

As we have seen above, the host reaction varies in different cases, mainly in patients with immunodeficiency, and the diagnosis is based on fungal morphology in the tissue. The case reported here demonstrates that host reaction may be different from the classical aspect and that it is not necessary to find abscesses in order to diagnose phaeohyphomycosis. These findings emphasize that fungal morphology is the gold standard for the histopathological diagnosis of phaeohyphomycosis.

We are unable to determine if the different histopathological pattern observed in the present case, with a heavy infiltration of lymphocytes and absence of neutrophils, is related to this new species of fungus or constitutes an uncommon host reaction. Only the histopathological study of other lesions caused by Cyphellophora species will clarify this point.

The treatment of phaeohyphomycosis can be frustrating in most cases, and itraconazole has been an effective approach [23, 24]. This patient illustrates the therapeutic challenge, as he relapsed after the use of itraconazole, and the control of the disease required a higher daily dosage and a prolonged treatment.

Isolation and identification of the causative organisms of phaeohyphomycoses is of paramount importance in order to determine if the different species of fungi elicit diverse clinicopathological aspects and therapeutical responses.

Article accepted on 25/9/01

CONCLUSION

Acknowledgements

To Dr. Michael R. McGinnis chief of the Medical Mycology Research Center (University of Texas Medical Branch at Galveston) for the identification of the fungus.

REFERENCES

1. Rinaldi MG. Phaeohyphomycosis. Dermatol Clin 1996; 14: 147-53.

2. McGinnis MR. Chromoblastomycosis and phaeohyphomycosis: new concepts, diagnosis and mycology. J Am Acad Dermatol 1983; 8: 1-16.

3. Ronan SG, Uzoaru I, Nadimpalli, Guitart J, Manaligod JE. Primary cutaneous phaeohyphomycosis: report of seven cases. J Cutan Pathol 1993; 223-8.

4. Kwon-Chung KJ, Bennett JE. Phaeohyphomycosis. Medical Mycology Philadelphia, Lea & Febiger, 1992: 620-77.

5. Chandler FW, Watts JC. Phaeohyphomycosis. In: Connor DH, Chandler FW, Schwartz DA, Manz HJ, Lack EE, editors. Pathology of Infectious Diseases. Stanford: Appleton & Lange 1997: 1059-66.

6. Ziefer A, Connor DH. Phaeohyphomycotic cyst. A clinicopathologic study of twenty-five patients. Am J Trop Med Hyg 1980; 29: 901-11.

7. O'Donnell PJ, Hutt MSR. Subcutaneous phaeohyphomycosisa: a histopathological study of nine cases from Malawi. J Clin Pathol 1985; 38: 288-92.

8. Annessi G, Cimitan A, Zambruno G, Di Silverio A. Cutaneous phaeohyphomycosis due to Cladosporium cladosporioides. Mycoses 1992; 35: 243-6.

9. Duffill MB, Coley KE. Cutaneous phaeohyphomycosis due to Alternaria alternata responding to itraconazole. Clin Exp Dermatol 1993; 18: 156-8.

10. Noel SB, Greer DL, Abadie SM, Zachary JA, Pankey GA. Primary cutaneous phaeohyphomycosis. Report of three cases. J Am Acad Dermatol 1988; 18: 1023-30.

11. Romano C, Valenti L, Miracco C, Alessandrini C, Paccagnini E, Faggi E, Difonzo EM. Two cases of cutaneous phaeohyphomycosis by Alternaria alternata and Alternaria tenuissima. Mycopathologia 1997; 137: 65-74.

12. Sughayer M, DeGirolami P, Khettry U, Korzeniowski D, Grumney A, Pasarell L, McGinnis MR. Human infection caused by Exophiala pisciphila: case report and review. Reviews Infect Dis 1991; 13: 379-82.

13. Viviani MA, Tortorano AM, Laria G, Giannetti A, Bignotti G. Two new cases of cutaneous alternariosis with a review of the literature. Mycopathologia 1986; 96: 3-12.

14. Zackheim HS, Halde C, Goodman RS, Marchasin S, Buncke J. Phaeohyphomycotic cyst of the skin caused by Exophiala jeanselmei. J Am Acad Dermatol 1985; 12: 207-12.

15. Bambirra E, Miranda D, Nogueira AM, Barbosa CS. Phaeohyphomycotic cyst: a clinicopathologic study of the first four cases described from Brazil. Am J Trop Med Hyg 1983; 32: 794-8.

16. Hachisuka H, Matsumoto T, Kusuhara M, Nomura H, Nakano S, Sasai Y. Cutaneous phaeohyphomycosis caused by Exophiala jeanselmei after renal transplantation. J Int Dermatol 1990; 29: 198-200.

17. Hsu MM, Lee JY. Cutaneous and subcutaneous phaeohyphomycosis caused by Exserohilum rostratum. J Am Acad Dermatol 1993; 28: 340-4.

18. DeVries GA, Elders, MCC, Luykx, MHF. Description of Cyphellophora pluriseptata sp. nov. Antonie van Leeuwenhoek 1986; 52: 141-3.

19. Padhye AA, Ajello L, Chandler FW, Banos JE, Hernandez-Perez E, Llerena J, Linares LM. Phaeohyphomycosis in el Salvador caused by Exophiala spinifera. Am J Trop Med Hyg 1983; 32: 799-803.

20. Bittencourt AL, Londero AT. Tropical mycotic diseases. In: Doerr W, Seifert G, eds. Tropical Pathology. Berlin: Springer-Verlag 1995: 707-98.

21. Romano C, Fimiani M, Pellegrino M, Valenti L, Casini L, Miracco C, Faggi E. Cutaneous phaeohyphomycosis due to Alternaria tenuissima. Mycoses 1996; 39: 211-5.

22. Tam M, Freeman S. Phaeohyphomycosis due to Phialophora richardsiae. Australas J Dermatol 1989; 30: 37-40.

23. Sharkey PK, Graybill JR, Rinaldi MG, Stevens DA, Tucker RM. Peterie JD, Hoeprich PD, Greer DL, Frenkel L, Counts GW, Goodrich J, Zellner S, Bradsher RW, van der Horst CM, Israel K, Pankey GA, Barranco CP. Itraconazole treatment of phaeohyphomycosis. J Am Acad Dermatol 1990; 23: 577-86.

24. Tendolkar UM, Kerkar P, Jerajani H, Gogate A, Padhye AA. Phaeohyphomycosis ulcer caused by Phialophora verrucosa: successful treatment with itraconazole. J Infect 1998; 36: 122-5.