Chapter 13 13 Common Fungal Infections

With respect to the mode of presentation and propa- 13.1.1 gation in tissue there are three categories of fungi: Clinical Appearance 1. fungi (unicellular fungi) exist only as spores Different parts of the body may be affected. With re- and produce new spores by budding. spect to the location, the eruption may have a more or 2. Filamentous fungi produce filaments (hyphae), but less characteristic appearance. This is the reason why not yeast cells. Some kinds of filamentous fungi the disease is named after the part of the body affected: form septate hyphae (i.e., the hyphae consist of a (includes trunk and limbs), , chain of cells separated by septa); other kinds pro- , , tinea pedis, , duce non-septate hyphae. Filamentous fungi may , and tinea unguium. brake up into spores called arthrospores. A con- For example, tinea circinata is the characteristic glomeration of hyphae is called mycelium. lesion usually seen in tinea corporis. It presents as a 3. Dimorphic fungi are able to form both hyphae and rounded, erythematous, slightly infiltrated, more or yeast spores. They produce new yeast cells by bud- less scaling plaque, which extends gradually at the pe- ding from spores as well as from hyphae. riphery and becomes circinate or annular due to cen- The most common kinds of fungal skin infections are tral healing. The active border is clearly defined and , furfur/pityrosporum in- slightly raised and may contain pustules. fections, , and . However, not always do lesions express the pattern described as typical for the location or typical for a fungus lesion in general. They may be mainly papular, 13.1 vesicular, pustular, follicular, or nodular. The intensity Dermatophytosis (Ringworm, Tinea) of the inflammatory reaction depends on several fac- are species of pathogenic filamentous tors such as the type of fungus, the degree of follicular fungi, which belong to one of three genera: Trichophy- invasion, and the immune state of the patient. Thus, in ton, Microsporum and Epidermophyton (see Table 30.1). contrast to the anthropophilic T. mentagrophytes, the They infect the stratum corneum of the skin and many zoophilic variant gives rise to vesicular and/or pustu- of them also hair and/or nails. According to their nat- lar lesions. Nodular lesions are caused by infection of ural setting they can be categorized as: anthropophilic deep-seated hair follicles. fungi, which primarily infect humans and spread from Tinea capitis, infection of the scalp, may be inflam- one person to another; zoophilic fungi, which primar- matory or non-inflammatory. Usually M. audouinii ily infect animals and can be transmitted to humans; and M. canis give rise to only a slight inflammatory and geophilic fungi, which reside in the soil and oc- reaction. However, M. canis is sometimes the cause casionally infect animals and humans. of celsi, a painful tumefaction due to a puru- rubrum and T. mentagrophytes are lent infection in the dermis and subcutaneous tissue common dermatophytes with a worldwide distribu- that is always combined with cervical lymphadenitis. tion. , which is anthropophilic, Trichophyton schoenleinii is the most common cause prevails in the western world, where it is the most of a purulent infection of the scalp, called , char- common cause of chronic fungal infections. Tricho- acterized by thick yellow crusts consisting of hyphae phyton mentagrophytes exists as an anthropophilic and and cellular debris (Hay et al. 1992; Elewski 1992). a zoophilic variant. Another common and ubiquitous zoophilic is M. canis. Handling an af- fected animal can result in infection. 13.1 Dermatophytosis (Ringworm, Tinea) 87

Fig. 13.1 Dermatophytosis. a Top: segmented hypha in the Bottom: close-up shows the hypha indicated above. The arrows horny layer; PAS. Middle: a string of arthrospores in the horny indicate two septa. PAS. c In this case the horny layer is mark- layer; PAS. Bottom: a row of arthrospores located between the edly thickened. The indicated superficial area of the horny layer hair shaft and the internal root sheath of a hair follicle. H&E (arrowhead) is permeated by thin, black structures, hyphae. (detail from Fig. 13.5b). b Top: there is a single hypha in the d Close-up demonstrates a substantial number of tightly seg- horny layer (arrow). The epidermis is slightly spongiotic and in mented hyphae, one of which is branching (arrow). PAS the papillary dermis there is a sparse infiltrate of lymphocytes. 88 13 Common Fungal Infections

13.1.2 Histopathologic Appearance In sections stained with H&E and vG, hyphae and spores are transparent, and therefore, in most cases, are difficult or impossible to detect. For that reason it is necessary to use special fungal stains, such as PAS or silver stains (Gomori, Grocott). Hyphae and spores are stained red with PAS and black with silver stains. Both types of staining methods give equally good re- sults, but the PAS reaction is faster and the procedure is less complicated than that for silver impregnation. Dermatophytes are filamentous fungi which in tis- sue produce only septate hyphae and arthrospores (Fig. 13.1). These are found in the stratum corneum, Fig. 13.2 Dermatophytosis. There is a bilocular intraepider- hair follicles, hair shafts, and nails. Hyphae are distinct mal vesicle which except for small aggregates of neutrophils is structures which, properly stained, are easily detected empty. The roof of the vesicle consists only of stratum corneum. at low magnification. The length and thickness of the In the subepidermal area there are perivascular infiltrates of in- segments are highly variable. Occasionally one or sev- flammatory cells. One of the few hyphae observed in the horny eral segments are inflated or ballooned. Sometimes layer is shown in Fig. 13.1a. PAS hyphae are branching. Now and then they are broken up into arthrospores, which at first are arranged like strings of pearls and later become dispersed. This phe- frequency of septae are not discriminative. For identi- nomenon can be seen relatively often in hair follicles, fication culture is necessary. In culture the genera and hair shafts and nails, and less often in the stratum cor- species (see Glossary) can be discriminated by means neum. of different forms of spores (conidia) and other char- It is not possible to differentiate one kind of derma- acteristic structures emerging from the hyphae such tophyte from another. Features of the hyphae such as as spirals, nodules, racquets, combs, and antlers (Hay thickness, presence or absence of ballooning, and the et al. 1992; Elewski 1992).

Fig. 13.3 Dermatophytosis. a There are arthrospores arrow-( ferent levels. Cross sections may be mistaken for spores which, heads) in the superficial part of the horny layer.b A hair fol- however, are not present. The presence of keratin around the licle in the upper dermis contains hyphae. These are lying in the hair shaft indicates that the follicle is cut above the entrance of keratin that surrounds the hair shaft. The hyphae are cut at dif- the sebaceous ducts. PAS 13.1 Dermatophytosis (Ringworm, Tinea) 89

Fig. 13.4 Dermatophytosis. a Papular and slightly scaling erup- the area indicated in c shows a conglomeration of hyphae which tion on the trunk. b Follicular papules on the buttock. c Biopsy are tightly segmented and focally slightly ballooned. Bottom: specimen from the patient in b. A superficial hair follicle is di- close-up of the demonstrates hyphae breaking up into lated and filled with necrotic material. The orifice is blocked by spores and free-lying spores. PAS (c and d bottom are repro- a keratin plug which contains hyphae (arrow). d Top: close-up of duced from Brehmer-Andersson 1970, with permission)

The intensity of the inflammatory tissue reaction (Fig. 13.1b,c). However, usually there are moderate to differs substantially from one case to another and is dense cell infiltrates with dominance of neutrophils in in harmony with the clinical expression. There may be both the dermis and the epidermis and sometimes ve- only small infiltrates of lymphocytes in the papillary siculopustules (Fig. 13.2). dermis and slight or no spongiosis in the epidermis In vellus hair-bearing skin, sometimes also called 90 13 Common Fungal Infections

Fig. 13.5 Dermatophytosis. a A hair follicle located deep in the subcutaneous tissue is lying in a large abscess. b Close-up of the follicle shows that the hair shaft is permeated by hyphae and arthrospores. The upper arrow indicates arthrospores arranged like a roll of coins between the shaft and the internal root sheath (also shown in Fig. 13.1a). The lower arrow indicates an area in the hair shaft permeated with hyphae. H&E. c Detail of a sub- cutaneous abscess with a fragment of hair shaft which contains arthrospores and hyphae (right arrow). Theleft arrow indicates a foreign body giant cell surrounded by neutrophils. PAS

the glabrous skin (see Glossary), hair follicle infec- well as histopathologically. He infected children and tions are mostly superficial and thus an integral part adults by inoculating the scalp with spores from these of the infection in the stratum corneum (Fig. 13.3). fungi. He found two types of infection: scalp infection Rarely the infection is confined only to superficial (i.e., infection of the stratum corneum only), and hair follicles (Fig. 13.4). Now and then deep infection (i.e., infection of the follicle and hair shaft and perifolliculitis with abscess formation in the sur- only). These two types of infection could exist together rounding tissue are seen (Fig. 13.5a,b). In such cases or each separately. The scalp infection corresponded fragments of hair shaft with fungal structures and/or to tinea corporis on the vellus hair-bearing skin and spores lying free in an abscess may be the only clue had the same course and gross appearance. to the diagnosis. Ruptured follicles may give rise to Kligman found that from the outermost part of the granulomas consisting of histiocytes, epithelioid cells follicular orifice hyphae enter the infundibulum of the and multinucleated giant cells (Fig. 13.5c). follicle and grow downwards on the outside of the hair shaft in a potential space between the horny layer of the external root sheath and the hair shaft. At about 13.1.3 the level of the entrance of the sebaceous ducts, hy- Relevant Investigations phae also penetrated the hair and continued to grow Kligman (1952, 1955) thoroughly studied tinea capi- downwards in the hair, but stopped at the upper limit tis caused by M. audouinii and M. canis, clinically as of the keratogenous zone (the matrix). Above the ma- 13.1 Dermatophytosis (Ringworm, Tinea) 91 trix, the fungus invaded the newly formed keratin at hyphae were tightly segmented, and at the surface the same pace as the hair was growing. The fungus some of them had broken up into arthrospores. Even was then passively carried out with the hair. The fungi being aware of their presence, it was impossible to never invaded the hair matrix. Because of the shape identify hyphae in sections stained with H&E. of the matrix, the dividing line between infected and In all probability this is a case of non-infected tissue acquired the form of an inverted V. caused by Phaeoanellomyces wernickii (former name This line is called the Adamson fringe. Arthrospores Exophiala wernickii); it is not a dermatophyte, but is are thought to develop outside as well as inside the usually grouped together with dermatophytes. Clinical hair shaft and are therefore called ectothrix and endo- characteristics are asymptomatic coin-sized, nonscaly, thrix spores, respectively. The opinion of Kligman was brown or gray patches on soles and palms; histo- that M. audouinii and M. canis can produce only ecto- pathologic characteristics are a thickened stratum thrix spores, and thus he called them ectothrix fungi corneum with branching septate hyphae and very in contrast to fungi which give rise only to little inflammatory reaction in the dermis (Elewski endothrix spores. 1992) (Fig. 13.1c,d). Later Graham (1972) studied biopsy specimens from many patients with tinea capitis that had oc- Case 3. Dermatophytosis curred naturally and was caused by different types of The patient had a vesicular and scaling eruption of the Microsporum and Trichophyton fungi. He found that sole of one foot. Cultures were negative, and thus bi- M. audouinii, M. canis, M. gypseum, T. mentagrophytes, opsy was performed. T. schoenleinii and T. rubrum are able to form both Microscopic investigation showed a large and well- ectothrix and endothrix spores, and therefore called demarcated bilocular vesicle, empty except for small them ecto-endothrix fungi. The only endothrix fungi aggregates of neutrophils. PAS-stained sections dis- observed by Graham were T. violaceum, T. tonsurans played hyphae only in the keratinous roof of the vesi- and T. sulfureum. cle. In the dermis there were perivascular infiltrates of inflammatory cells, mainly lymphocytes (Figs. 13.1a top, 13.2). 13.1.4 An important differential diagnosis in a case like Examples this is pustulosis palmoplantaris (Fig. 23.5).

Case 1. Dermatophytosis Case 4. Dermatophytosis A 45-year-old male presented with widespread annular A 55-year-old male presented with vesicles on the erythematous and slightly scaling lesions on the upper palms of the hands. Fungal infection was not sus- half of the trunk, hips and thigh. The only suggestion pected. on the request form was multiple lesions of erythema The biopsy specimen showed vesiculopustules in migrans. the epidermis and dense cell infiltrates and hemor- The histopathologic changes were slight spongiosis rhages in the dermis. PAS revealed a fair number of in scattered small areas of the epidermis and sparse hyphae and arthrospores throughout the horny layer. infiltrates of lymphocytes in the upper dermis. The It was then possible to identify some hyphae and ar- PAS staining revealed only a few hyphae: out of seven throspores as slightly basophilic structures in H&E- sections, one contained no hyphae and the others only stained sections. Culture yielded T. mentagrophytes one or two; they were not possible to detect in sec- (Fig. 13.1a middle). tions stained with H&E or vG. The patient recovered after treatment. However, he suffered mul- Case 5. Dermatophytosis tiple relapses, and a culture taken during one of these A 56-year-old male suffered from diabetes mellitus. yielded T. rubrum (Fig. 13.1b). He presented with annular erythema beneath surgical stockings. Fungal infection was not suggested. Case 2. Dermatophytosis A biopsy specimen showed hyphae and arthrospores A 24-year-old female presented with light brown mac- in the stratum corneum and moderate inflammatory ulae on the sole of the left foot. Clinical suggestions infiltrates in the dermis. In a hair follicle located in the were fungal infection and lichen ruber. upper half of the dermis hyphae surrounded, but did In a thick stratum corneum PAS disclosed a sub- not penetrate, the hair shaft. In this case the folliculitis stantial number of hyphae without any inflammatory was an integral part of tinea circinata infection. Cul- reaction in the horny layer, epidermis or dermis. The ture yielded T. rubrum (Fig. 13.3). 92 13 Common Fungal Infections

Case 6. Dermatophytosis with PAS there was no hair follicle, only an abscess Two days after childbirth a 32-year-old woman be- containing a few spores (Figs. 13.1a bottom, 13.5a,b). came aware of a widespread papular and slightly scal- ing eruption on the trunk, the right upper arm, and Case 9. Dermatophytosis the left side of the neck. She was treated topically with A 70-year-old woman had multiple red infiltrates on corticosteroids without effect, and thus a biopsy speci- the right lower leg, which clinically was thought to be men was taken from a fresh lesion. Fungus infection . was not suggested. The biopsy specimen showed a huge abscess which Histologic investigation revealed two small hair involved both the dermis and subcutaneous tissue and follicles surrounded by dense inflammatory cell also contained scattered small epithelioid cell granulo- infiltrates in the upper dermis. In one of them PAS mas and foreign body giant cells. The only sign of fun- disclosed hyphae and arthrospores. The patient was gus infection was a disintegrating fragment of a hair referred to the dermatology outpatient clinic. The shaft permeated with hyphae and spores lying in the whole specimen was cut in series and every section subcutaneous abscess. Neutrophils, macrophages and was scrutinized. Nowhere were fungal structures multinucleated giant cells surrounded the fragment found in the horny layer encompassing the follicle (Fig. 13.5c). (Fig. 13.4a). At the age of about 6 weeks the baby also showed lesions, highly suspected to be due to fungal infec- 13.1.5 tion, on the trunk and neck. Direct microscopy and Comment repeated cultures on scrapings from both the mother It has been asserted that the diagnosis of superficial and the untreated child were negative. The mother was fungal infections is rarely dependent on histologic in- given oral, and the child topical, antifungal treatment vestigation (Montgomery 1967; Hay 1992). However, and both healed. if staining for fungi with PAS is routinely used for all biopsy specimens taken from non-tumorous skin le- Case 7. Dermatophytosis sions, histopathologic investigation is an easy and ef- Every summer the last 16 years this 41-year-old man fective way to detect even clinically unexpected cases had suffered from spells of folliculitis on the buttocks, and to confirm suspected cases negative on direct mi- resistant to antibacterial treatment. croscopy (see Glossary) and/or culture. Clues such as A biopsy revealed folliculitis with septate hyphae in the so-called sandwich sign with a cleft in the horny the infundibulum and an intrafollicular abscess with layer (Gottlieb and Ackerman 1986) and the presence hyphae and arthrospores. No hyphae were found in of neutrophils in the horny layer in H&E-stained sec- the stratum corneum outside the follicle. Later on a tions (Ackerman 1979) are not of value when there are biopsy specimen taken for culture yielded T. rubrum only scattered hyphae and/or the inflammatory reac- (Fig. 13.4b–d). tion is weak, or if the only inflammatory cells are lym- phocytes. Case 8. Dermatophytosis The presence of hyphae always indicates infection. A 38-year-old man, otherwise healthy, suffered from The detection of only one hypha is probably enough to tinea cruris. He presented with a subcutaneous nodule settle the diagnosis. However, careful searching usu- located on the medial aspect of the left thigh. The skin ally discloses a few more. The observation of spores above was unaffected, thus there was no connection only in the horny layer is not enough for diagnosis, with the tinea cruris lesion. The nodule was thought to though scattered spores in close to or affect- be a pilomatricoma. ing hair follicles, or located in the dermis–subcutis Histologic investigation revealed a large subcutane- should arouse suspicion. ous abscess without granulomatous reaction. In the Negative results of culture and direct microscopy middle of the abscess was a hair follicle with a dis- may be due to the presence of only scattered hyphae, integrating hair shaft. The shaft was permeated with as demonstrated in Case 1, or to the reality that the hyphae, some of them breaking up into arthrospores. infection is strictly confined to hair follicles, as shown There was also a row of arthrospores located between in Case 7 and Case 8. If the histopathologic investi- the hair shaft and the internal root sheath. Both hy- gation shows that only follicles are involved, a biopsy phae and spores were easily identified in sections specimen instead of scraped material should be taken stained with H&E. No fungal structures were found in for a new culture. An early or a late stage of the lesion epidermis or in other follicles. In new sections stained may explain a sparse number of hyphae in the stratum 13.2 /Pityrosporum infections 93 corneum. This is in accordance with the investigations 13.2.1.2 of Kligman (1952, 1955), which proved that when a Histopathologic Appearance scalp infection, analogous to tinea corporis on the vel- In pityriasis versicolor the stratum corneum is usually lus hair-bearing skin, reaches its maximum size, the thickened. Malassezia furfur structures (i.e., hyphae hyphae in the stratum corneum disappear. Dermato- and spores) are found at all levels of the horny layer phyte infections do not appear secondary to other der- and often also in the loose keratin of the outermost matoses, but can occasionally coexist with other skin part of the follicular orifices without signs of follicu- diseases. litis. Such a finding should not be interpreted as Mal- assezia folliculitis. Both hyphae and spores are easily recognized in sections stained with H&E, though 13.2 they are accentuated by PAS staining (Fig. 13.6). Hy- Malassezia furfur/Pityrosporum infections phae are segmented, slender, even, and in histologic The yeastsP. orbiculare and P. ov al e are present in sections mainly long structures. A characteristic phe- small amounts as saprophytes in the stratum corneum nomenon is two hyphae arranged one after the other of normal skin, especially in areas containing seba- with abruptly “cut” ends separated by a small even gap. ceous glands, but can also be found in large aggregates Rarely single such gaps can be seen also in Candida in- in the scales of, for example, actinic keratoses and fections. The are mostly spherical (P. orbiculare), discoid erythematosus. They are today thought sometimes oval (P. ov al e ). They have double-con- to be variants of the same yeast which, depending on toured walls, and often lie in groups. Some of them are predisposing factors, can change into the pathogen budding. Spores can be missing. In such cases identi- fungus M. furfur (Faergemann 1992). Malassezia fur- fication is based on the easily detected long and short fur is dimorphic and lipophilic (i.e., to grow in culture hyphae and typical gaps in routinely stained sections. the medium needs supplementation with fatty acids). In the dermis there is usually only a slight inflam- It is the cause of pityriasis (tinea) versicolor. The yeasts matory reaction with small perivascular infiltrates of may give rise to Pityrosporum folliculitis, and under lymphocytes. special conditions to systemic manifestations.

13.2.2 13.2.1 Pityrosporum folliculitis Pityriasis (Tinea) Versicolor Pityrosporum folliculitis, which is a disease separate Pityriasis versicolor is a worldwide chronic skin dis- from pityriasis versicolor, was first described in some ease, which is most common in areas with high tem- detail by Potter et al. (1973). It is, as mentioned above, peratures and high relative humidity. Predisposing caused by the yeasts P. orbiculare and P. ov al e . factors are seborrhea and hyperhidrosis and treatment with corticosteroids. The disease is mainly present in adults with a peak in the third decade. It is equally 13.2.2.1 common in men and women. Clinical Appearance Discrete, erythematous, and/or pustular follicular lesions up to 4 mm in diameter are scattered on the 13.2.1.1 back, chest, and upper arms. The papules may be se- Clinical appearance verely itchy. Predisposing factors are, as in pityriasis Malassezia furfur infection gives rise to well-demar- versicolor, a warm and humid climate, occlusion, and cated, finely scaling, light to reddish-brown, oval treatment with corticosteroids. patches which often coalesce into large areas. In un- tanned patients the affected areas are darker than the surrounding skin; in tanned patients they are paler, 13.2.2.2 and thus can be misinterpreted as . Typical lo- Histopathologic Appearance and Pathogenesis cations are seborrheic areas such as the upper part of Due to obstruction of the orifice by a keratin plug, the trunk, but even other parts of the body including the follicle in Pityrosporum folliculitis is markedly the face and scalp may be affected. The hair, nails and dilated. The dermal part of the follicle shows more or mucous membranes are never affected. less widespread necrosis. Both in the plug and in the follicle there are dense aggregates of spores, some of which are budding (Fig. 13.6c,d). Hyphae are not seen. 94 13 Common Fungal Infections

Fig. 13.6 a Pityriasis versicolor. The horny layer contains ag- gregates of hyphae and spores (arrow). b The slender hyphae show typical gaps (arrows). c Pityrosporum folliculitis. The di- lated hair follicle contains keratin and a hair shaft (arrowhead). In the dermis a large part of the follicle wall is destroyed and the surrounding tissue is infiltrated by dense inflammatory cell infiltrates. d Close-up of the orifice arrow( in c) reveals keratin and spherical spores, some of which are budding. H&E

The degree of inflammatory tissue reaction is variable. provoke an inflammatory reaction (Faergemann However, in spite of extensive necrosis, the inflam- 1992). matory cell infiltrate is often sparse. If the follicle is ruptured, there can be perifollicular abscesses and a granulomatous reaction with foreign body giant cells. 13.2.3 Predisposing factors and follicular occlusion may Systemic Manifestation stimulate the propagation of yeasts. Free fatty acids Systemic spreading of Pityrosporum yeasts has been and other products generated from the yeasts then described in neonates and older children who had re- 13.3 Candidiasis 95 ceived prolonged intravenous lipid infusion (Redline • Erythematous candidiasis presents as ill-defined et al. 1985). erythematous areas that may be painful. It is associ- ated with treatment with broad-spectrum antibiot- ics and corticosteroids, and with HIV infection. 13.3 • Hyperplastic candidiasis consists of firm white Candidiasis plaques, difficult to remove, on the tongue or bucca. Candida species are dimorphic fungi, some of which The condition is particularly seen in smokers and give rise to candidiasis. The most common isC. albi- may be secondary to a precancerous lesion or carci- cans. Other less-common species are C. glabrata noma. and C. parapsilosis. As commensal yeast organisms, • Candida-associated denture stomatitis is related to Candida spores may be present without symptoms dental plates or braces. in the mouth and the gastrointestinal tract of most • Angular cheilitis (i.e., fissures and soreness at the individuals, and in the vagina of some women, but angles of the mouth) may be due to Candida infec- usually not on the skin. As a pathogenic dimorphic tion emanating from the oral cavity; it is often as- fungus producing both hyphae and spores, it may sociated with denture stomatitis affect mucous membranes, skin, and nails. It is oppor- tunistic (i.e., it is more common in individuals with a predisposing factor such as immunosuppression or 13.3.1.3 diabetes mellitus than in healthy persons). Candidi- Mucocutaneous Infection asis may also be secondary to other skin and mucous Mucocutaneous infection may give rise to Candida membrane disorders such as diaper dermatitis (of vulvovaginitis or Candida balanitis. which it may also be the primary cause), inverse , oral , and mucous membrane malignancies including squamous cell carcinoma (Ray 13.3.1.4 1992). Chronic Mucocutaneous Candidiasis Chronic mucocutaneous candidiasis occurs in a het- erogeneous group of syndromes due to different kinds 13.3.1 of defects of the cell-mediated immune system, and Clinical Appearance sometimes also includes endocrinopathy. The infec- The appearance varies with respect to the area af- tion usually starts in early childhood and affects skin, fected. nails and mucous membranes.

13.3.1.1 13.3.1.5 Skin Lesions Systemic Manifestation In the skin, Candida infection usually affects intertrig- Systemic manifestations due to hematogenous dis- inous regions. The lesions, which form erythematous, semination are rare, but are seen in immunocompro- oozing, or pustular areas, may be pruritic or give rise mised patients, especially if they are suffering also to a burning sensation. Pustules outside the main le- from neutropenia. sion are considered typical.

13.3.2 13.3.1.2 Histopathologic Appearance Oral Lesions As a produces both presents in different forms: yeast spores and hyphae (Fig. 13.7). The fungal struc- • Pseudomembranous candidiasis or thrush appears tures are found in a thickened and parakeratotic horny as one or several well-demarcated patches covered layer. Spores are oval or round (when transversely cut), with white membranes, which are easily detached and are on average bigger than Pityrosporum spores. and leave an erythematous denuded surface. The Some spores are budding. Spores seem to aggregate condition is seen in newborn children, in HIV-in- in the outermost part of the stratum corneum, which fected and other immunocompromised individuals, is easily detached during the taking and processing of severely ill patients, and in patients treated with the samples. This could be the reason why spores are corticosteroids. often missing in sections. 96 13 Common Fungal Infections

Fig. 13.7 Candidiasis. a The horny layer is strikingly thickened rows). d Hyphae pervade the horny layer and some are “diving” and permeated with hyphae running in all directions. In the towards the epithelium. They are septate and in the right upper outermost and partly detached fraction there is aggregation of corner one is slightly ballooned. e In this case the hyphae are spores. b Close-up of this part shows oval spores. In the cen- long, slender and branching. Thearrow indicates a septum in ter there is a budding spore. c The micrograph demonstrates a long hypha giving off three branches. Below the arrow some so-called pseudohyphae in necrotic material from a ureter (ar- hyphae seem to be penetrating into the epithelium. PAS

Hyphae are septate, mostly unevenly thick, in ar- thelium and seem to penetrate into its outermost vital eas ballooned, and may be branched. They are found cell layer. Now and then so-called pseudohyphae are throughout the thickness of the horny layer and are seen. By pseudohypha is meant a series of yeast spores disorderly running in all directions; however, now and which have remained attached to each other. It is often then they look as if they are “diving” towards the epi- said to be a common and characteristic phenomenon 13.4 Aspergillosis 97

in Candida infections. However, in the experience of 13.4 the author, pseudohyphae are rare in skin and mucous Aspergillosis membrane lesions, and are usually short. Figure 13.7c The most important species of are A. fu- shows pseudohyphae in necrotic material removed migatus, A. niger, and A. flavus. They are opportunistic from the ureter in a patient suffering fromCandida and are seen in immunocompromised patients with sepsis. chronic neutropenia. However A. niger is also able to In immunocompetent persons the inflammatory infect immunocompetent humans. reaction is often strong. The epithelium is thickened, there is marked hyper- and parakeratosis, neutrophils and pustules in the epithelium, and in the subepithelial 13.4.1 tissue dense inflammatory cell infiltrates. In immuno- Clinical Appearance compromised patients there are hyper- and parakera- In primary infection of the skin, the lesions usually tosis but no or very few inflammatory cells. appear in a location exposed to trauma. They may oc- In a skin lesion it is not possible to differentiate be- cur in several forms such as erythematous and crusted tween Candida and dermatophytes if there are only plaques, hemorrhagic vesicles, bullae, or necrotic nod- hyphae and no yeasts or arthrospores. However, a ules (Khardori et al. 1989). Systemic manifestations “diving” pattern and a tendency to penetrate into vital mostly start in the lungs where the fungus grows into epithelium indicate Candida. Also Candida hyphae vessels leading to widespread dissemination (Binford are mostly easier to identify in sections stained with and Dooley 1979). H&E than are dermatophyte hyphae. The presence of only yeasts is never enough to establish the diagnosis of candidiasis. 13.4.2 Histopathologic Appearance Aspergillus produces septate hyphae that branch regu- 13.3.3 larly and dichotomously with acute angles. They are Examples possible to identify in sections stained with H&E, but are easier to find when PAS stained. For the discrimi- Case 10. Candidiasis nation of species, culture is necessary (Binford and An 80-year-old male patient presented with a rather Dooley 1979). large and infiltrated lesion on the mucosa of the lower In the lungs and paranasal sinuses, besides hyphae lip. The lesion was covered with crusts and small su- and spores, the lesions may contain conidiophores perficial ulcers had been noticed over about 18 months. (fruiting bodies) which are structures seen in culture Culture yielded Candida albicans, but because of un- but usually not in tissue. Presumably the exudate in successful treatment and the risk of underlying squa- alveoli and sinuses serves as a culture medium. mous cell carcinoma the whole lesion was excised. Histologic investigation showed Candida hyphae and spores in large numbers, conspicuous epithelial 13.4.3 hyperplasia, a dense inflammatory cell infiltrate, and Examples moderate cell atypia (Fig. 13.7a,b). Case 13. Aspergillus Cases 11 and 12 The patient was suffering from AIDS and had small The patients were two young men who were suffering white patches on the tongue border. from advanced HIV infection and clinically had le- A biopsy specimen showed multiple scattered hy- sions on the tongue border suspected to be so-called perkeratotic foci. These contained a superficial con- hairy . glomeration of spores from which dichotomously Histologic investigation showed the same pattern branching hyphae grew down towards the epithelium. in both patients. The horny layer was markedly thick- No culture was done, but the characteristic growth ened and permeated by Candida hyphae. There were pattern with dichotomously dividing hyphae permits strikingly few inflammatory cells in the epithelium as a presumptive diagnosis of Aspergillus (Figs. 13.8a,b). well as in the submucosa (Fig. 13.7d,e). Case 14. Aspergillus The patient was an otherwise healthy 26-year-old male. For 2 years he had had a right-sided blocked nose, na- 98 13 Common Fungal Infections

sal catarrh and pain over the right maxilla. During a Caldwell-Luc operation (see Glossary) a thickened and markedly changed mucous membrane with a large core of necrotic yellow–black tissue was found. Histologic investigation revealed brownish hyphae, spores and conidiophores easily identified in H&E- stained sections. Culture yielded Aspergillus niger (Fig. 13.8c).

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