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Cutaneous protothecosis.

Cutaneous protothecosis is an uncommon indolent condition occurring primarily in immunocompromised individuals. The infective organism, a Prototheca sp, is an achlorophyllic and ubiquitous algae. The first description of the Prototheca sp was made by Davies and colleagues in 1964. (1-5) The organism has been isolated from a variety of reservoirs, including soil, water, animal, and food items. Protothecosis has been found on every continent, except Antarctica. Its prevalence in the United States is concentrated in the southeast. The 3 main clinical presentations of Prototheca sp infections are cutaneous lesions, olecranon bursitis, and disseminated systemic disease. (6-9) This review will focus on the disease manifestations of cutaneous protothecosis and its similarities to deep tissue fungal infections. To our knowledge, at least 77 cases of cutaneous protothecosis have been described in the literature at the present time. (1,2)

CLINICAL FEATURES

Cutaneous protothecosis usually presents as an erythematous plaque that can be vesiculobullous or, less commonly, ulcerative, with crusting and purulent discharge (Figure 1). (1,10-11) It can also manifest as verrucous, hypopigmented, and atrophic lesions. (1,8) Most of these cutaneous infections occur in immunocompromised patients with risk factors, including human immunodeficiency virus/acquired immunodeficiency syndrome, diabetes mellitus, underlying malignancy, and prolonged use of systemic corticosteroids. (3,4) Steroid use appears to be the most common risk factor for infection. Protothecosis can present in any adult but is most common in the elderly. Children are rarely infected. (1) The presentation in immunocompetent patients is often localized papules and pustules. Lesions may be present for months to years, changing gradually in size and shape. The most commonly involved sites are the face and extremities. (1-4)

Prototheca wickerhamii is the Prototheca sp most commonly responsible for human infections. (2) The postulated mode of cutaneous infection is through traumatic inoculation, and characteristically, the trauma is subtle and not noticed or remembered by the patient. (1-3) The incubation period for disease presentation is not well documented and is speculated to range from a week to months. (4,12) The typical clinical course of cutaneous protothecosis is chronic and indolent. (4) Most patients described in the literature were initially suspected to have deep tissue infections, but the corrected diagnosis was rendered by skin biopsy and later, confirmed with tissue culture. (1-2) Disseminated disease from cutaneous protothecosis is rare, occurring only in 8 patients with severe immunosuppression. The mortality rate is high, however, with a fatal outcome directly resulting from disseminated disease in 5 of those cases. (1) The pathogenesis is not well understood because there are few reported cases. Neutrophilic response is thought to be the principle defense of the host through ingestion and eradication of the Prototheca organisms. It has been reported that a polymorphonuclear neutrophil can engulf P wickerhamii in about an hour. (1) Neutropenia does not appear to alter infection rates. Rather, it alters defects in neutrophilic function. Result in the loss of neutrophil ability to engulf and kill the Prototheca organisms may be implicated in the development of protothecosis. (1) Three cases of progressive, cutaneous disease have been reported in patients with neutrophilic defects. (2)

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LABORATORY AND MICROBIOLOGY FINDINGS

Prototheca spp are considered achlorophyllic mutants of the green alga genus Chlorella. (1) They are spherical, unicellular, nonbudding organisms that range from 3 to 30 mm and consist of sporangia with thick, double-layer walls filled with multiple endospores. They reproduce asexually through internal septation and release the endospores when the parent cell ruptures. (2) Although protothecosis can be diagnosed on biopsy, culture of the organism on a media such as Sabouraud dextrose agar is required for definitive diagnosis. (1,2) Prototheca spp also grows on blood, Tween 80, eosin-methylene blue, and MacConkey agars. (1,5)

One of the difficulties in identifying Prototheca spp is the overgrowth of bacteria and fungi on the culture medium. (1,13) The metabolic demands of Prototheca spp are simple, and they can be grown on a wide variety of culture media. Some of these media, however, lack inhibitors to bacteria and fungi, which prevent Prototheca growth. The ideal method for growing Prototheca spp, it has been suggested, is through an isolation medium, with fungal and bacterial inhibitors for selective cultivation. (14) The optimum growth temperature is 30[degrees]C for colonization to thrive, although they will grow at temperatures up to 35[degrees]C. (3) Prototheca spp will usually present within 48 hours as soft, wet, yeastlike, white to light tan colonies. (1,2) A wet mount of the culture can demonstrate the endosporulating sporangia if stained with lactophenol cotton blue or calcofluor white. These sporangia are the hallmark of the Prototheca spp and tend to form morula-like structures that have an internal septation with a cartwheel-like appearance. (1-4) The morula forms appear symmetrical in P. wickerhamii, whereas in other species of the Prototheca genus, the morula have a more random structure without the cartwheel-like appearance. (1,14)

HISTOPATHOLOGY

Cutaneous biopsies demonstrate a pandermal, granulomatous, inflammatory infiltrate often admixed with lymphocytes, neutrophils, and eosinophils. Necrosis may be observed within the granulomas, but is not necessary to make the diagnosis. (2,14) Multinucleated giant cells and plasma cells are usually present; however, the inflammatory response may be minimal in some cases. (1-3,6) Other findings include hyperkeratosis and parakeratosis, pseudoepitheliomatous hyperplasia of the epidermis, and hyperplastic lymphoid tissue. (1,2,14) Prototheca spp can be observed on hematoxylin-eosin-stained sections and are found in clusters, as solitary structures, within granulomas and giant cells, and in necrotic foci (Figure 2, A and B). (1) They can also (rarely) be observed in the stratum corneum of the epidermis. (4) The organisms are readily apparent with the use of special histochemical stains, such as Gridley fungus stain, periodic acid-Schiff (with or without diastase), and Gomori methenamine-silver stain (Figure 3). (2,9,13)

DIFFERENTIAL DIAGNOSIS

The main consideration in the differential diagnosis is a deep, cutaneous mycosis, and common pathogens include Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Cryptococcus neoformans (Table). The similarities in clinical presentation make it difficult to determine the causative agent of the infection. Thus, biopsy and tissue culture are necessary to identify the implicated organism. The size of the sporangia often aids in distinguishing Prototheca spp from other cutaneous, nonsporulating fungi. (1,2) Sporangia from Coccidioides spp are typically larger than those of Prototheca spp but have smaller endospores. (2,14) They differ lacking reproductive budding and pseudomycelia. Protothecosis may also resemble green algae in tissue. In comparison to their mutant algal counterparts, a green algae or Chlorella sp has chloroplasts and a triple-layered wall, in contrast to the double-layered wall and absence of chloroplasts of Prototheca sp, as seen on electron microscopy. (1,2) The Chlorella sp also has numerous cytoplasmic starch granules that are negative for periodic acid-Schiff following diastase digestion, and thus, periodic acid-Schiff staining with diastase digestion can be beneficial in differentiating protothecosis from other green algae cells in tissue.

CURRENT TREATMENT AND PROGNOSIS

A standard treatment regimen has not been defined, and treatment may vary case by case. Aggressive therapy should be reserved for those patients with underlying comorbidities and immunosuppression. (2) The most common pharmaceutical agents used are antifungal agents, such as ketoconazole, itraconazole, fluconazole, and conventional Amphotericin B. Amphotericin B appears to be the most effective of these agents against Prototheca spp. (1) Disseminated and visceral infections are usually treated with Amphotericin B, whereas the azole antifungal agents, especially itraconazole, are used for more localized infections. (1-4,14) The antifungal agents target the Prototheca sp cell wall, which is composed of 4% ergosterol. (2)

Surgical excision of localized lesions has also proved beneficial and is especially effective against superficial cutaneous infections without deep dermal or subcutaneous involvement. (2) With the deeper and more extensive infections, treatment usually requires a combination of surgical excision and antifungal agents. (1-4) Difficult lesions may persist and can spread to other cutaneous sites if not treated effectively.

CONCLUSION

Prototheca sp, albeit ubiquitous, is a rare cause of opportunistic cutaneous infections. Various forms of immunosuppression, such as human immunodeficiency virus/acquired immunodeficiency syndrome, diabetes mellitus, and systemic corticosteroid use, are predisposing factors. Microscopic findings on tissue biopsy and tissue culture are essential to the final diagnosis. Without proper treatment, such as antifungal agents and surgical excision, lesions may persist and spread to other sites. Thus, cutaneous protothecosis must be considered when working up a lesion that is suspicious for the more common fungal infections.

We thank Mary Ann Sanders, MD, PhD, for her contribution to this article and case review.

References

(1.) Lass-Florl C, Mayr A. Human protothecosis. Clin Microbiol Rev. 2007; 20(2):230-242.

(2.) Kantrow SM, Boyd AS. Protothecosis. Dermatol Clin. 2003;21(2):249-255.

(3.) Polk P, Sanders DY. Cutaneous protothecosis in association with the acquired immunodeficiency syndrome. South Med J. 1997;90(8):831-832.

(4.) Chao SC, Hsu M, Lee JY. Cutaneous protothecosis: report of five cases. Br J Dermatol. 2002;146(4):688-693.

(5.) Davies RR, Spencer H, Wakelin PO. A case of human protothecosis. Trans R Soc Trop Med Hyg. 1964;58(5):448-451.

(6.) Huerre M, Ravisse P, Solomon H, et al. Human protothecosis and environment [in French]. Bull Soc Pathol Exot. 1993;86(5, pt 2):484-188.

(7.) Iacoviello VR, DeGirolami PC, Lucarini J, Sutker K, Williams ME, Wanke CA. Protothecosis complicating prolonged endotracheal intubation: case report and literature review. Clin Infect Dis. 1992;15(6):959-967.

(8.) Leimann BC, Monteiro PC, Laztera M, Candanoza ER, Wanke B. Protothecosis. Med Mycol. 2004;42(2):95-106.

(9.) Hightower KD, Messina JL. Cutaneous protothecosis: a case report and review of the literature. Cutis. 2007;80(2):129-131.

(10.) Kuo TT, Hsueh S, Wu JL, Wang AM. Cutaneous protothecosis: a clinicopathologic study. Arch Pathol Lab Med. 1987;111 (8):737-740.

(11.) Goldstein GD, Bhatia P, Kalivas J. Herpetiform protothecosis. Int J Dermatol. 1986;25(1):54-55.

(12.) Woolrich A, Koestenblatt E, Don P, Szaniawski W. Cutaneous protothecosis and AIDS. J Am Acad Dermatol. 1994;31(5, pt 2):920-924.

(13.) Pore RS. Selective medium for the isolation of Prototheca. Appl Microbiol. 1973;26(4):648-649.

(14.) Boyd AS, Langley M, King LE Jr. Cutaneous manifestations of Prototheca infections. J Am Acad Dermatol. 1995;32(5, pt 1):758-764.

(15.) Baron J, Finegold SM. Bailey and Scott's Diagnostic Microbiology. 12th ed. St Louis, MO: CV Mosby Co; 2007.

Paul B. Hillesheim, DO; Soon Bahrami, MD

Accepted for publication June 1, 2010.

From the Departments of Pathology and Laboratory Medicine (Drs Hillesheim and Bahrami) and Medicine, Division of Dermatology (Dr Bahrami), University of Louisville School of Medicine, Louisville, Kentucky.

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the 45th annual meeting of the American Society of Dermatopathology, San Francisco, California, October 16-19, 2008.

Reprints: Paul B. Hillesheim, DO, Department of Pathology and Laboratory Medicine (Hospital Basement), 530 S Jackson St, Louisville, KY 40202 (e-mail: pbhill01@gwise.louisville.edu).
Differential Diagnosis of Organisms Causing Soft Tissue Fungal
Infections (a)

Fungal Species Size, Histological Appearance
 [micro]m

Prototheca 3-30 Spherical; nonbudding; sporangia
 wickerhamii with thick, double-layer wall;
 morula-like appearance; filled
 with multiple endospores

Coccidioides 10-200 Spherules vary in size; some
 immitis contain nonbudding endospores

Blastomyces 8-15 Large, double-refractile cells;
 dermatitidis buds are single, connected by a
 broad base
Paracoccidioides 5-60 Cells have a mariners-wheel
 brasiliensis appearance (large cells with
 peripheral buds)

Cryptococcus 2-15 Cells are spherical to football
 neoformans shaped; polysaccharide capsule

Fungal Species Clinical US Geographic
 Forms Distribution

Prototheca Achlorophyllic Southeast
 wickerhamii algae

Coccidioides Spherules, Southwest
 immitis endospores

Blastomyces Yeast South-central;
 dermatitidis Midwest

Paracoccidioides Yeast Not typical in
 brasiliensis USA; Central and
 Latin America

Cryptococcus Yeast West
 neoformans

(a) Data modified from Baron and Finegold. (15)
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Author:Hillesheim, Paul B.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jul 1, 2011
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