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Selected topics in HIV-associated skin pathology
Current Diagnostic Pathology (2000) 6, 113–124 © 2000 Harcourt Publishers Ltd doi:10.1054/cdip.2000.0025, available online at http://www.idealibrary.com on
MINI-SYMPOSIUM: PATHOLOGY OF INFECTIOUS DISEASES
Selected topics in HIV-associated skin pathology P. K. Ramdial Department of Pathology, Faculty of Medicine, University of Natal, Private Bag 7, Congella, 4013, Kwazulu Natal, South Africa
KEYWORDS HIV, AIDS, dermatoses, infection, neoplasms, virus, fungi, parasites, folliculitis, photosensitivity, drugs
Summary The cutaneous manifestations of human immunodeficiency virus (HIV) infection have been the subject of intense scrutiny because the skin is the most commonly affected organ in HIV infected individuals. Infectious and non-infectious HIV-induced skin diseases may not only serve as the marker of HIV infection, but also as a marker of the stage of HIV disease. Although the cutaneous manifestations of opportunistic infections may serve as the sentinel lesion of a widely disseminated, life threatening infection, the majority of HIV-induced cutaneous diseases are not life threatening, but are cosmetically disfiguring and jeopardise the quality of life of HIV infected patients. The morphology of HIV-induced skin lesions is often unusual and clinically non-diagnostic. Histopathological appraisal is therefore pivotal in the accurate diagnosis of many HIV-induced skin diseases. Despite the changing trend of HIV-induced cutaneous manifestations following the use of highly active anti-retroviral therapy (HAART) in some countries, in developing countries where HAART is not readily and widely available, the skin continues to be ravaged by HIV infection. This review discusses selected HIV-related cutaneous infections and a range of dermatoses and neoplasms, and highlights the role of the histopathologist in the management of HIV infected patients. © 2000 Harcourt Publishers Ltd
INTRODUCTION
INFECTIONS
HIV and the AIDS epidemic have had a profound impact on the spectrum and diagnosis of cutaneous disease. Skin disorders may be present in up to 92% of HIV-positive patients, and may be the first or the only organ affected throughout the course of the disease.1 Recognition of the expanded range of HIV-induced cutaneous manifestations is crucial, not only for the diagnosis and treatment of the skin lesions, but also for improvement of the quality of life of those afflicted. The occurrence of common diseases in unusual settings, increased severity of minor skin diseases, failure to respond to routine treatment and the unusual appearance of skin lesions are the clinical cutaneous clues of HIV infection.2 Because of the unusual disease presentation and clinical mimicry of disease processes, biopsy and histopathological assessment of clinically non-diagnostic skin lesions has become pivotal in the definitive diagnosis of a range of HIVinduced pathology, which is evolving and changing continuously. This review highlights selected HIV-related cutaneous infections and a range of inflammatory dermatoses and neoplasms in HIV-infected patients.
Severe depletion of T-helper lymphocytes in the advanced stages of HIV infection paves the way for opportunistic infections. A spectrum of infections of viral, fungal, bacterial and parasitic origins occur alone or in combination with each other.
Correspondence to: PKR. Tel: +27 (0) 31-2604497; Fax: +27 (0) 312052711; E-mail: [email protected].
Viral infections Herpes virus infections In HIV seropositive patients, this group of viruses can produce extensive, destructive lesions. Herpes Simplex Virus Infection (HSV): Cutaneous HSV infections occur in approximately 20% of patients with AIDS.3 Reactivation of HSV occurs frequently in patients with AIDS at all levels of immunocompetency, resulting in chronic mucocutaneous disease with severe and extensive skin ulcers. With advanced HIV disease, recurrent HSV infection becomes persistent and progressive.4 Sites of occurrence are the perianal, genital, orofacial and digital skin. Histopathology: Intra-epidermal acantholytic vesicles and epithelial cytopathic effects are seen together with chromatin margination, ballooning nuclear degeneration and intranuclear and intracytoplasmic nuclear inclusions. Epidermal necrosis may be extensive and abundant viral inclusions are seen, not only in keratinocytes, but also in
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hair follicle, eccrine and sebaceous epithelium (Fig. 1). Viral inclusions may be elusive in lesions with extensive ulceration. The clues to HIV and HSV co-infection are: 1. failure to respond to Acyclovir: resistance is due mainly to the emergence of HSVs which lack thymidine kinase activity, 2. ulceration in the natal cleft/ perirectal distribution, and, 3. ulcerative HSV lesions lasting more than 1 month.5 Varicella Zoster Virus Infection (VZV): The spectrum of VZV infections includes that of uncomplicated primary varicella, disseminated varicella, an increased incidence of disseminated or localised herpes zoster and chronic varicella zoster.4 Coalescence of individual lesions, haemorrhagic bullae, extensive ulceration with epidermal necrosis and black eschars may be seen. Histopathology: The histopathological spectrum is identical to that of HSV. Type-specific polymerase chain reactionbased assays on lesional tissue is a means of differentiating HSV from VZV. Clues to HIV and VZV co-existence include: 1. the occurrence of herpes zoster in younger patients, 2. recurrent attacks that are more severe, more frequent and of longer duration, 3. resistance to Acyclovir.5
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Molluscum contagiosum (MC) MC in immunocompetent hosts occurs in the anogenital area and trunk, and undergoes spontaneous resolution within a year of occurrence. In HIV-positive patients, MC presents as persistent papules over the face, neck, eyelid, intertriginous area, axillae, perianal area and buttocks.8 The head and neck lesions are the most common. Between 10–20% of patients with HIV infection and AIDS have MC. Individual lesions may be solitary and large, measuring up to 2 cm in diameter. Those more than 1 cm have been referred to as ‘giant’ MC. Warty verrucous papules may be seen in addition to the typical umbilicated papules. Histopathology: Cup-shaped lesions extend down and expand the follicular infundibulum. The majority of the viral inclusions are in the follicular infundibulum (Fig. 2). Retraction artefacts are seen in the surrounding stroma with 3–6 layers of CD34 positive spindle / dendritic cells and their immediate stroma attached to the follicular infundibulum containing viral inclusions. Smith at al have recently demonstrated that the bulk of the viral load is localised in hair follicles.9 Based on the absence of palm and sole lesions and the presence of CD34 positive cells surrounding cup-shaped epithelial proliferations containing molluscum bodies, they have suggested that the adhesion molecules for MC are
Cytomegalovirus Infection (CMV): Although CMV is the most commonly isolated virus in AIDS patients, with up to 90% developing acute active CMV infection at some stage in their illness, primary skin involvement by CMV is rare. The clinical picture is that of maculopapular eruptions, ulcers, nodules, vesicles, generalised morbilliform eruptions and verrucous and hyperpigmented indurated plaques.6 Histopathology: Biopsied tissue is characterised by epidermal necrosis and CMV inclusions in endothelial cells and fibroblasts. A variable number of inflammatory cells, leucocytoclastic vasculitis, haemorrhage and necrosis may be present.7
Figure 1 Herpetic ulcer with extensive dermal and adnexal necrosis. Inset: Necrosis of sebaceous gland epithelium and herpetic inclusions (arrows).
Figure 2 Molluscum contagiosum: Viral inclusions in follicular infundibulum and stromal retraction artefact (arrow).
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present or are more abundant within the basal layer of the infundibulum of the hair follicle. MC is associated with significant immunosuppression. Verrucous and giant MC occur in the late stage of the disease with peripheral CD4 T-lymphocyte counts of < 50/mm3 and with viral loads > 100 000. Husak et al report a CD4 / CD8 ratio of 0.2 and a median survival of 12 months.10
or culture-proven mucocutaneous lesions of histoplasmosis. Although histoplasmosis is transmitted by inhalation and skin involvement is usually secondary to lung involvement, ‘primary’ skin infection from direct inoculation may occur in a solitary or disseminated form. In the setting of HIV infection, human-to-human cutaneous transmission may occur. The clinical lesions may be macular, papular, nodular, herpes-like, fistulous, pustular or plaque-like.4,15
Human papillomavirus infection (HPV)
Histopathology: There is a diffuse dermal infiltrate of histiocytes and neutrophils. The inflammatory component may be minimal. Intra- and extracellular oval yeast forms are present (Fig. 3). Free-lying dermal organisms and leucocytoclasis are also present. Necrotising vasculitis may also be seen.
Infection with HPV is the commonest group of viral infections in the skin.4,11 There is a higher incidence of HPV-associated common and genital warts, and intraepithelial and invasive squamous carcinoma of the cervix. Global natural killer cell deficiency and T lymphocyte defects have been speculated as factors predisposing HIV infected individuals to HPV infection.12 As with organ transplant recipients, HPV-related mucocutaneous lesions are more likely to undergo malignant transformation. Different HPV types are associated with different clinical lesions. HPV types 6 and 11 are commonly isolated in anogenital condylomata acuminata but exophytic lesions in this setting may contain high risk HPV types such as HPV 16 and 18. The manifestations of condylomata acuminata, reported in 20% of HIV-infected homosexual men, range from soft sessile lesions with smooth or rough surfaces to exuberant cauliflower plaques.11 Because of the risk of dysplasia in perianal condyloma, Croxson et al advise excision of these lesions in AIDS patients.13 Common warts occur more frequently in HIV seropositive patients than in non-infected people. Valle reported an 18% incidence in seropositive as opposed to a 1% incidence in seronegative controls.14 Multiple verrucae vulgares, multiple plantar warts and extensive flat and filiform warts on the bearded area of the face are seen in HIV positive patients. They may be more extensive and form coalescent plaques, some of which may be associated with hypopigmentation and resemble epidermodysplasia verruciformis (EDV). HPV types 3, 5, 8 and 10 are known to infect patients with EDV. Bowenoid papulosis, a variant of in situ squamous cell carcinoma on the genitalia, is associated with HPV types 16 and 18.
Cryptococcosis Cryptococcosis is the second most common fungal infection in HIV-positive patients. Skin involvement occurs in 6–7% of patients with cryptococcosis.15 The mucocutaneous lesions are polymorphous.16,17 Histopathology: There is diffuse pallor of the dermis because of the abundance of dermal yeasts with mucoid capsules that stain positively with Southgate’s mucicarmine stain (Fig. 4). Inflammation is often minimal.
Fungal infections Although mucocutaneous fungal infections (FI) may occur at any stage of HIV disease as disseminated or localised disorders, they may serve as the initial marker of HIV infection, being diagnosed in approximately 10% and 20% of HIV-positive patients with cryptococcosis and histoplasmosis respectively.4 Sporotrichosis, blastomycosis, paracoccidiodomycosis and coccidiodomycosis are reported infrequently. The morphological spectrum is clinically non-diagnostic.
Histoplasmosis Approximately 17% of reported HIV-infected patients with disseminated histoplasmosis have histological and/
Figure 3 Histoplasmosis: Histiocytic palisade (asterisks) bordering aggregates of Histoplasma capsulatum. Inset: Oval yeast forms of H. capsulatum [Grocott X 120].
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ing exudate which, on silver staining, highlights numerous pneumocystis microorganisms.
Penicillium marneffei infection Cutaneous manifestations include generalised, crusted or necrotic papules, ulcers, molluscum-like lesions, abscesses and subcutaneous nodules.20 Histopathology: Non-caseative, necrotising granulomatous inflammation is present in which intracellular and extracellular round to oval, blunt-ended yeastlike microorganisms, 2–8 µm in diameter are seen.
Other fungal infections Chronic mucocutaneous and disseminated cutaneous candidiasis are common in AIDS patients.21 The histopathological features of disseminated cutaneous candidiasis include dermal microabscesses and associated leucocytoclastic vasculitis. Aggregates of candidal hyphae and spores are found within microabscesses or in areas of vascular damage. Blastomycosis is an uncommon fungal infection in AIDS patients, occurring in the advanced stage of the disease. In addition to 8–15 µm, thick-walled multinucleate yeast forms, 2 µm microforms, 30 µm macroforms and filamentous forms are described.22 Figure 4 Dermal pallor and replacement by infiltrate of Cryptococcus neoformans. Inset: Carminophilic mucoid capsule of C. Neoformans [Mucicarmine 3 240].
Sporotrichosis Sporotrichosis in HIV-infected individuals occurs as a result of haematogenous dissemination of the fungus rather than from local cutaneous inoculation.18 Skin lesions range from papules, pustules, ulcers and erythematous violaceous nodules to plaques.4,17 Histopathology: Although granulomatous inflammation with micro-abscesses and few oval or ‘cigar-shaped’ spores may be present, fungal spores may also be identified within histiocytes and giant cells or may be lying free in the dermis.
Pneumocystosis Cutaneous pneumocystosis is unusual and occurs as a consequence of the use of Pentamidine sprays in patients with prior pneumocystis pneumonia, or in patients receiving prophylaxis because of CD4+ lymphocyte counts less than 200 cells / mm3. Although these sprays sterilise the respiratory tract, they do not offer systemic protection against Pneumocystis carinii. Cutaneous lesions manifest as molluscum-like plaques, bluish cellulitic plaques and deep-seated abscesses.19 Histopathology: There is diffuse infiltration of the dermis and subcutaneous tissue with pale-staining foamy-appear-
Arthropod reactions Demodicosis Demodex mites are 1–5 mm cutaneous parasites that usually inhabit the hair follicles and sebaceous glands. Demodex folliculorum and Demodex brevis are the species that usually inhabit human skin.4 A range of pruritic and follicular lesions occur in HIV-infected patients.23 Histopathology: Follicular mites and a dense lymphoeosinophilic inflammatory infiltrate in the papillary and mid-reticular dermis and perifollicular area are present (Fig. 5).
Scabies Scabies, reported in 20% of HIV infected individuals, comprises a papulosquamous eruption mimicking atopic dermatitis or seborrheic dermatitis, crusted plaques or scattered pruritic papules.21 Histopathology: There is epidermal crusting, acanthosis and hyperkeratosis with myriads of mites visible within the cornified layer of the hyperplastic epidermis. A superficial and mid-to-deep perivascular and interstitial infiltrate of lymphocytes and a predominance of eosinophils is present. In nodular scabies, the dermal infiltrate may resemble pseudolymphoma with large numbers of eosinophils and a dearth of identifiable mites.
Bacterial infections The commoner bacterial infections are those caused by
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pleomorphic, ulceronodular form of the disease that responds well to Penicillin therapy.26,27 Histopathology: Lues maligna comprises a dense lymphocytic infiltrate in the upper and mid-dermis, in addition to a pronounced perivascular inflammatory cell infiltrate involving superficial and deep vessels. Endothelial cell swelling, proliferation and fibrinoid necrosis of the vessel walls resulting in necrotising vasculitis are noted. The number of spirochaetes is variable. Plasma cells are a consistent finding, especially in perineurial and intraneurial locations. The pathogenesis of lues maligna is not dependent on inoculum size or strain virulence but on host resistance.
Bacillary angiomatosis (BA) The cutaneous lesions are red to violaceous domeshaped papules, nodules, polyps, ulcers or cellulitis.4,21
Figure 5 Demodex mite in follicular infundibulum (arrow), follicular spongiosis and inflammation and dermal inflammation (asterisks).
Staphylococcus aureus and Streptococcus pyogenes, the former being the most common cutaneous and systemic bacterial pathogen encountered in HIV-infected individuals.4,21 A variety of lesions occur, none of which is HIV-disease specific. Banal manifestations such as impetigo and folliculitis are common, especially in more immunocompetent individuals. Fatal cellulitis, abscesses and necrotising fasciitis may also occur.
Mycobacterial infections
Histopathology: There is lobular vascular proliferation containing a dense proliferation of capillary-calibre vessels with plump endothelial cells. Neutrophils are seen in association with intervening interstitial granular amphophilic debris in which clusters of organisms are identified on silver staining (Fig. 6). These organisms have been identified as Bartonella henselae or quintana. The course of BA is variable with spontaneous regression, resolution following antibiotic therapy and haematogenous dissemination to other organs being possible outcomes.
DERMATOSES Papulosquamous disorders Seborrheic dermatitis (SD) SD is a benign dermatosis of unknown aetiology with a prevalence of 1–3% in the general population. An incidence of 46–83.3% has been reported with AIDS.8,28 In addition to being more severe, a predominance of inflammatory and papular facial lesions has been seen in contrast to the mild erythematous scaling plaques that are seen on the scalp and face of HIV-negative patients.
HIV-associated mycobacterial infection may have unusual modes of presentation including macules, acneiform papules, indurated crusted plaques, and draining sinuses.24 Mycobacteria, especially Mycobacterium avium-intracellulare and M. haemophilum, may induce cutaneous lesions in up to 10% of patients with systemic mycobacterial infection. Other mycobacteria causing disease in HIV-infected individuals include M. marinum, M. chelonae, M. bovis following BCG immunisation and M. thermoresistible.
Syphilis The advent of AIDS has resulted in an increased incidence of syphilis, which pursues a more aggressive course in HIV seropositive patients.25 There is an increase in the number of reported cases of lues maligna, a
Figure 6 Bacillary angiomatosis: Vascular channels lined by plump endothelial cells. Interstitial neutrophils and granular debris (arrows). Inset: Aggregates of organisms [Warthin Starry 3 480].
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Munoz-Perez et al also reported frequent genital localisation.29 Severe SD is associated with involvement of more than two anatomical sites, occurrence in the late stage of HIV disease with low CD4+ lymphocyte counts and greater resistance to therapy. Histopathology: In addition to the usual features of seborrheic dermatitis, there is keratinocyte necrosis, dermal perivascular neutrophils with leucocytoclasis and leucoexocytosis. Malassezia furfur is implicated in the pathogenesis of HIV-associated SD.4,8
Psoriasis vulgaris HIV infection can trigger proriasis or exacerbate preexisting disease.2,4,8 Although the incidence of 1.3–2.0% in HIV-positive patients is not greater than that in the general population, the disease manifests in a more severe form as the degree of immunodeficiency increases.4 Histopathology: Although the features may be similar to PV in HIV-negative patients, it may differ by displaying acanthosis without supra-papillary thinning, slight spongiosis, necrotic keratinocytes, more dermal plasma cells, fewer T lymphocytes, and decreased epidermal Langerhans cells (Fig. 7). The decrease in epidermal Langerhans cells is postulated to parallel the deterioration in the clinical state. The role of Langerhans cells in PV is unclear, but a postulate is that either a direct HIV-induced cytotoxic effect results in their decrease, or, HIV stimulates autoreactivity resulting in an auto-immune process similar to graft versus host reaction, resulting in a decrease in Langerhans cells.
CURRENT DIAGNOSTIC PATHOLOGY
perivascular lymphocytic infiltrate. There are associated melanophages in the papillary dermis, indicative of pigmentary incontinence. Civatte bodies are seen at the dermo-epidermal junction. There is hyperkeratosis, marked acanthosis and hypergranulosis of the epidermis (Fig. 8). The immunohistochemical features of the cellular infiltrate reveals a predominance of T lymphocytes in the lichenoid and perivascular components and in the epidermis.30 CD68+ macrophages are present in the lichenoid and dermal components. In the dermal component there is an approximately equal number of T-helper and T-suppressor lymphocytes. The T-suppressor lymphocytes closely approximate and hug the dermoepidermal junction while T-helper cells are present in the papillary dermis. Epidermal lymphocytes are almost entirely of T-suppressor phenotype. Langerhans cells are present within the stratum spinosum and in the papillary and superficial reticular dermis. HLA-DR antigen is also identified on the surface of basal and spinous layer keratinocytes. Lymphocytes aggregate around Langerhans cells in the epidermis. NK cells, monocytes and lymphocytes expressing IL-2 receptor are also a component of the dermal infiltrate. LP in the immunocompromised host differs in its distribution, being confined to the extremities in immunocompetent patients and being more widely distributed
Hypertrophic lichen planus (LP) HIV-associated LP presents with a generalised hypertrophic form of the disease on the trunk, face and extremities, which may have been previously involved by a photosensitivity eruption.30 Histopathology: A band-like lymphocytic infiltrate is present at the dermo-epidermal junction together with a
Figure 7 Psoriasis vulgaris: Psoriasiform epidermal hyperplasia, Munro microabscess, spongiosis and dermal inflammation.
Figure 8 Hypertrophic lichen planus: Extensive epidermal hyperkeratosis, acathosis, hypergranulosis and a dense lichenoid inflamatory infiltrate.
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on the face and extremities in AIDS. There is no definite histological difference in the density and nature of the lymphocytic infiltrate or the severity of basal keratinocyte destruction. The immunohistochemical features of the lichenoid and dermal infiltrate are similar in both groups of patients, but in contrast to findings in HIVnegative patients, the intra-epidermal lymphocytes are predominantly of T-suppressor phenotype in AIDS. This may represent either differences in antigen presentation and response by immunocompromised patients to immune stimuli or may be a secondary phenomenon to the systemic depression of circulating T-helper lymphocytes.
Gianotti-Crosti syndrome (GCS) This is a distinctive self limiting acral papular or papulovesicular eruption associated with an underlying viral illness.31 Histopathology: There are focal parakeratotic mounds, scattered necrotic keratinocytes, exocytosis, a moderate perivascular lymphocytic infiltrate and extravasated erythrocytes. Diagnosis of HIV-GCS is dependent on the exclusion of other viral causes of GCS since there are no histopathological distinguishing features.
Folliculitis Apart from bacterial and fungal folliculitis, HIVassociated necrotising and eosinophilic folliculitis have been reported.32–33
Figure 9 Eosinophilic folliculitis: Follicular spongiosis and infiltration by eosinophils and lymphocytes (asterisk). Eosinophil degranulation in dermis. Inset: Flame figure in adjacent dermis.
enhances eosinophil and macrophage migration. Interleukin 5 increases eosinophil survival. Papulopruritic eruption:34–35 Smith et al described variably pruritic, skin-coloured, 2–5 mm diameter, papules on the head, neck and upper trunk with a waxing and waning chronic course.35 It occurs in 20% of HIVpositive patients in any stage of HIV infection. PPE has been speculated to be part of the spectrum of HIV-EF.35 Histopathology: The histopathological features are those of perivascular lymphocytes and histiocytes and variable eosinophils, folliculitis and granuloma formation. Epidermal excoriation may be present.
HIV-associated photosensitivity Eosinophilic folliculitis (EF) HIV-associated eosinophilic folliculitis manifests in the late stage of HIV disease. Multiple discrete, erythematous, crusted, follicular papules on the head, neck and trunk, measuring 3–5 mm in diameter are described.33–34 HIV-EF is associated with pruritus, variable decrease in leucocytes, relative or true eosinophilia and a CD4 cell count 5–80 cells / mm3. IgE levels may be raised. Histopathology: The histopathological features are those of a follicular and perifollicular infiltrate of lymphocytes and eosinophils together with spongiosis of the follicular infundibulum or sebaceous gland (Fig. 9). The adjacent dermis contains large numbers of eosinophils and mast cells and eosinophil degranulation and ‘flame figures’ may be prominent (Fig. 9). The pathogenesis of HIV-EF is not known, but contributory roles for mast cells, sebum and a hypersensitivity reaction to dermatophytes have been implicated. Innocuous follicular antigens such as Pityrosporum yeasts, Demodex mites and bacteria may become antigenic in a Th2-dominant environment and produce interleukins-4 and 5. The former results in isotype switching of antibodies from IgG to IgE with resultant enhanced local and systemic IgE levels. In addition, interleukin-4 causes the production of vascular cell adhesion molecule, which
Valerie and Rosenberg have shown that ultraviolet light (UVL) can activate the HIV promoter, the gene sequence responsible for driving viral gene expression. It is not clear how UVL activates HIV.36 It has been speculated that during the repair of UVL-damaged DNA, viral genes that are incorporated into host cells are stimulated, undergo replication and host cells are subsequently destroyed. HIV-induced photosensitivity reactions include porphyria cutanea tarda, pseudoporphyria cutanea tarda, chronic actinic dermatitis, photosensitive granuloma annulare and photodistributed hyperpigmentation.37,38,39
Chronic actinic dermatitis (CAD) The diagnostic criteria for CAD include a chronic photodermatitis in the absence of continued exposure to photosensitisers, abnormal phototest responses and histological changes consistent with photodermatosis.39 It may be the presenting marker of HIV infection and advanced disease. Histopathology: There is psoariasiform epidermal hyperplasia and variable interface dermatitis. A lichenoid inflammatory cell infiltrate and a variable number of necrotic keratinocytes and eosinophils are identified.
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The pathogenesis and prognosis of CAD is unknown. HIV infected individuals are susceptible to CAD because they often require treatment with multiple medications which act as photosensitising agents and because they are known to have non-specific elevation of polyclonal immunoglobulins and circulating immune complexes with defective removal of these complexes by the reticuloendothelial system. Heightened awareness of the clinicopathological manifestations of CAD is necessary, since phototherapy, which is a treatment modality for a range of HIV dermatoses, is also a known cause of CAD.
Photosensitive granuloma annulare (PGA)
A
The presentation of PGA includes that of a generalised or localised eruption. Circulating lymphokines are detected in these patients, hence, T-helper cells are implicated in the pathogenesis of PGA. Th-1 cells, producing interleukin-2 and involved in delayed hypersensitivity reactions, interact with macrophages in the skin. PGA occurs in the early stages of the disease when Th-1 cells are still retained.
Photodistributed hyperpigmentation Photodistributed hyperpigmentation is associated with advanced HIV infection. The exact cause of this solarinduced melanogenesisis is not known, but hormonal, endocrine and drug related interactions do not appear to be related. Skin biopsies reveal pigmentary incontinence and increased melanin along the dermo-epidermal junction and within keratinocytes.
Lichenoid photo-eruptions Lichenoid photoeruptions are frequently seen as the CD4 cell count decreases. They may be related to photosensitising drugs, some of which may be used in the treatment of HIV related disease.
Cutaneous drug eruptions
B
Cutaneous drug eruptions are the most common manifestation of drug hypersensitivity in HIV-infected individuals.21 Trimethoprim-sulphamethoxazole is the most commonly implicated drug causing adverse skin eruptions in 50–60% of HIV positive individuals.21,40 A variably desquamative maculopapular eruption is seen in addition to Stevens–Johnson syndrome and toxic epidermal necrolysis. Lichenoid papular and severe exanthematous eruptions may occur in patients on zidovudine.
Histopathology Maculopapular lesions demonstrate variable vacuolar alteration of the basal layer of the epidermis, exocytosis, pigmentary incontinence and dermal inflammation (Figs. 10A–C). Individual necrotic keratinocytes are seen. The superficial dermis contains a variable number of mononuclear cells, including eosinophils. Toxic epidermal
C Figure 10 Cutaneous drug reactions: (To Trimethoprimsulphamethoxazole). A) Interface change with necrotic keratinocytes (arrows) and exocytosis. B) Interface change and denser inflammatory component. C) Marked epidermal hyperkeratosis and pigmentary incontinence.
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necrolysis, Stevens–Johnson syndrome and erythema multiforme are characterised by more pronounced interface changes and extensive keratinocyte necrosis. In toxic epidermal necrolysis, confluent epidermal necrosis is seen in the absence of dermal inflammation.21
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lular immunity is compromised because of a decrease in the number and functional capacity of T-helper lymphocytes and relative increase in T-suppressor and cytotoxic cells. Aberrations in the ratio and function of T-helper lymphocytes and T-suppressor lymphocytes may play an important role in the development of HIV-ID.
Miscellaneous inflammatory conditions Acute HIV exanthem This occurs in approximately 23% of patients and represents an acute seroconversion reaction.41 The eruption may be macular over the trunk with roseolalike features on the extremities, or, maculopapular with scattered haemorrhagic and necrotic blisters. The macular lesions are 3–11 mm in diameter and erythematous with darker centres. Histopathology: Early lesions reveal a perivascular lymphohistiocytic infiltrate and little or no epidermal changes. Advanced lesions demonstrate spongiosis, intra-epidermal vesiculation and ballooning degeneration and epidermal necrosis. Inflammatory cells are of T-helper/T-inducer and T-suppressor immunophenotype. Confirmation of the diagnosis necessitates proof of seroconversion.
Unusual chronic maculopapular rash associated with HIV This is associated with conversion from the PGL stage to overt AIDS with a decrease in circulating lymphocytes and T-helper cells.42 It comprises 5–15 mm dark brown macules and papules, mainly on extensor surfaces of arms and legs. Histopathology: There are perivascular mononuclear cells, with a predominance of lymphocytes, especially around superficial and deep dermal blood vessels. This rash is differentiated from PPE by the absence of eosinophils.
Interface dermatitis (ID) The age range of HIV-ID is 4 months to 48 years.43 Clinically, there are widespread erythematous macules, papules or plaques or localised 2 cm diameter acral papules. Histopathology: There is vacuolar interface change, aggregated necrotic keratinocytes and a superficial lymphocytic infiltrate. The basal layer changes are more intense than those seen in drug reactions. Eosinophils and neutrophils are absent. The aetiopathogenesis of ID in AIDS patients is not known but specific immunological changes initiated by HIV are implicated, including polyclonal B lymphocyte activation with circulating immune complexes, T-helper lymphocyte decrease and dysfunction, and Langerhans cell depletion. Langerhans cells play an important role in clearing antigen from the epidermis or may serve as target sites in immune mediated reactions, in addition to their role in antigen processing and presentation. Cel-
Papular neutrophilic xanthomas Papular neutrophilic xanthomas are distinctive papular facial xanthomas that may mimic folliculitis clinically.44 They may serve as a marker of HIV infection and represent a pattern of immunodysregulation, immunodeficiency and immunoproliferation seen in HIV disease. Histopathology: Lipid-laden macrophages, neutrophils, nuclear dust and histiocytes with phagocytosed nuclear debris are present in the papillary and mid-reticular dermis. Hyalinisation with areas of hyaline necrosis of collagen fibres are also seen.
AIDS trichopathy The majority of hair and scalp disorders occur when the CD4+ lymphocyte count is less than 150 mm3.45 Seborrheic dermatitis and psoriasis are the most common lesions followed by disorders of cell growth cycle regulation and trichokeratinisation. Staphylococcal furunculosis is seen in adults and children. Syphilitic involvement manifests as patchy hair loss and papulosquamous eruptions. In biopsies of Tinea capitis Trichophyton tonsurans and mentagrophytes are seen. Alopecia areata, alopecia totalis and universalis, are known to occur in association with HIV infection.46 Skin biopsies reveal a perifollicular lymphocytic infiltrate with infiltration of the hair bulb and miniaturisation of hair follicles.
MALIGNANCIES Malignant cutaneous neoplasms associated with HIV infection are Kaposi’s sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease and anorectal squamous carcinoma.4,21,47–51 As with other immunocompromised states, basal and squamous cell carcinomas occur with increased frequency. The risk factors for development of these tumours are similar, and include fair skin type and excessive sun exposure. Maurer et al suggested that p53 overexpression and not HPV infection played a role in the oncogenesis of these tumours.47 Cloacogenic carcinoma occurs with increased frequency in HIV-positive homosexual males. They tend to be more aggressive, are associated with increased morbidity and mortality and respond poorly to treatment.
Kaposi’s sarcoma (KS) In contrast to the original description of KS in 1872 of a rare, slowly-growing tumour that was confined to the skin of the lower extremities of elderly men, HIVassociated KS is the commonest HIV associated malig-
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nancy and presents in younger individuals as multiple skin lesions, which may cause cosmetic disfigurement. In the USA, it is 20 000 times more common in HIV seropositive patients than in the general population. The clinical lesions manifest as macules, plaques and nodules in varied dermatological patterns, including follicular and pityriasis-rosea-like patterns. In addition, oedema is a common associated finding. Common sites of cutaneous involvement include the trunk, legs, arms and face. Koebnerisation of KS may occur. The histopathological spectrum of KS is well described.21 Macular lesions may simulate granulation tissue. Histologically aggressive forms of Kaposi’s sarcoma have been described, especially in Africa. They are characterised by cellular pleomorphism and brisk mitotic activity and may possess dilated vascular channels. Angiosarcoma is simulated when these vascular channels are lined by atypical endothelial cells. The aetiopathogenesis of KS is multifactorial, and encompasses the roles of Human Herpesvirus Type 8 (HHV-8), genetic and HIV-associated factors.21 The sexual transmission of HHV-8 accounts for the high occurrence of KS in homosexual American males and heterosexual females in Africa, and, its rare occurrence in intravenous drug users and haemophiliacs. Vascular proliferation may also occur as a result of the release of cytokines such as interleukin-6 and fibroblast growth factor by HIV.21 Indirect evidence of the role of HIV in the induction of KS stems from the stimulated growth of AIDS-associated KS cells in vitro by HIV-tat protein, a phenomenon that can be blocked by an anti-tat antibody.21 The prognosis of KS is related to disease activity and the state of immunosuppression rather than to the tumour itself. With advanced immunodeficiency and opportunistic infections, the outcome is poor.
CURRENT DIAGNOSTIC PATHOLOGY
tumours were primary CNHLs that were characterised by frequent CD4+ T-lymphocyte origin, CD30 +/ALKphenotype and p53 protein overexpression. Nonepidermotropic B-cell CNHLs may also express CD30 positivity, and those bearing EBV sequences together with p53 overexpression occur mostly, if not solely, in HIV-infected patients.53
IMPACT OF HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART) The use of combination drug regimens that include protease inhibitors, known also as highly active antiretroviral therapy, in the management of HIV-infected patients, suppresses viral replication and results in repletion of CD4+ lymphocyte counts.21 This has altered the trend of HIV-induced cutaneous pathology in countries where such regimens are employed, with a decrease in the incidence of diseases associated with advanced AIDS being reported. Many of the skin disorders in patients receiving HAART are similar to those in immunocompetent patients because of the rise in CD4 levels.
CONCLUSION The impact of HIV and AIDS on the skin has far-reaching consequences. Although the HIV-induced skin lesions are not life-threatening, they may be the most debilitating element of the patient’s condition, seriously affecting their quality of life. Not only do skin lesions serve as a marker of HIV disease, but they also predict stage of HIV infection and disease activity. This is crucial in planning optimal management protocols of HIV-infected patients.
Cutaneous lymphoreticular malignancies Although patients infected with HIV are at increased risk for the development of Non-Hodgkin’s lymphomas (NHLs), cutaneous localisation of AIDS-NHL is a rare event. Cutaneous NHL (CNHL) manifests as papules or nodules on any site. A predominance of CNHLs of T-cell origin contrasts with that of B-cell origin in other organs. The pathogenesis of CNHL includes a combination of disrupted immunosurveillance mechanisms, chronic B-lymphocyte stimulation and an accumulation of multiple genetic abnormalities. Mycosis fungoides is rare during HIV infection and its occurrence may be co-incidental. Documented cases of mycosis fungoides are characterised by immunophenotypic heterogeneity (CD4+/CD8+ or CD4–/CD8–) and genotypic inconsistency.49,50 The diagnosis of mycosis fungoides in an HIV-positive patient must be made with caution, as CD8 T-cell predominant dermatoses may serve as a histological mimic.51 Beylot–Barry et al reported non-epidermotropic CNHLs, that developed at an advanced stage of immunosuppression, to be the most frequent in their series.52 The majority of these
PRACTICE POINTS
• Viral, fungal, bacterial and parasitic infections occur alone or in combination with each other • The histopathological spectrum of HSV and VZV is • • • • • •
identical—type-specific polymerase chain reaction based assays differentiate the two viruses Giant and warty verrucous mollusca contagiosa are markers of advanced HIV infection Disseminated candidiasis, histoplasmosis and cryptococcosis are the commoner deep fungal infections with skin involvement Nodular scabies may resemble a pseudolymphoma Biopsies of seborrheic dermatitis may display keratinocyte necrosis, and dermal perivascular neutrophils and leucocytoclasis In psoriasis vulgaris, acanthosis without suprapapillary thinning may be present Lichen planus manifests as a generalised hypertrophic form of the disease
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PRACTICE POINTS (cont)
• Extensive sectioning of pruritic, papular lesions may unmask eosinophilic folliculitis • HIV-induced photosensitivity reactions may be a • • •
side effect of treatment modalities employed in the management of HIV infected patients Cutaneous drug reactions are the most common manifestation of drug hypersensitivity in HIVinfected patients Aggressive Kaposi’s sarcoma may simulate angiosarcoma CD8 T-cell predominant dermatoses may mimic mycosis fungoides
11. 12.
13. 14.
15.
16.
17.
RESEARCH DIRECTIONS
• The immunopathogenesis of eosinophilic folliculitis • The cutaneous immunological abnormalities in pruritic HIV associated lesions • The role of Langerhans cells in HIV-associated interface dermatitis • The spectrum and pathogenesis of HIV associated drug reactions at different stages of HIV infection • The effect of HAART on cutaneous drug reactions • The immunopathogenesis of HIV associated cutaneous tuberculous reactions • The relationship between HIV subtype and cutaneous manifestations
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21. 22.
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REFERENCES 1. Smith K J, Skelton H G, Yeager J et al. Cutaneous findings in HIV-1 positive patients: A 42–month prospective study. J Am Acad Dermatol; 1994; 31: 746–754. 2. Cockerell C J. Human Immunodeficiency virus infection and the skin. A crucial interface. Arch Intern Med 1991; 151: 1295–1303. 3. Goodman D S, Teplitz E D, Wishner A. Prevalence of Cutaneous Disease in Patients with Acquired Immunodeficiency Syndrome (AIDS) or AIDS-related complex. J Am Acad Dermatol 1987; 17: 210–220. 4. Johnson R A, Dover J S. Cutaneous manifestations of Human immunodeficiency virus disease. In: Fitzpatrick T B, Eisen A Z, Wolff K, Freedberg I M, Austen K F (eds). Dermatology in General Practice. McGraw Hill Publishers 1993: 2637–2689. 5. Crowe S M. Unusual features of herpes simplex or zoster infection that suggest HIV infection. Med J Austr 1993; 158: 186–187. 6. Garcia-Patos V, Pujol R M, Curell R, de Morages J M. Cytomegalovirus-induced cytopathic changes in skin biopsy specimens. Clinicopathological study in patients with the Acquired Immunodeficiency Syndrome and an active extracutaneous cytomegalovirus infection. Arch Dermatol; 128: 1552–1553. 7. Golden M P, Hammer S M, Wanke C A, Albrecht M A. Cytomegalovirus vasculitis. Case reports and review of the literature. Medicine 1994; 73: 246–255. 8. Dover J S, Johnson R A J. Cutaneous manifestations of Human Deficiency Virus Infection. Arch Dermatol 1991; 127: 1383–1391. 9. Smith K J, Yeager J, Skelton H G. Molluscum contagiosum: Its clinical, histopathologic and immunohistochemical spectrum. Int J Dermatol 1999; 38: 664–672. 10. Husak R, Garbe C, Orfanos C E. Mollusca contagiosa in HIV in-
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fection. Clinical manifestation, relation to immune status and prognostic value in 39 patients. Hautarzt 1997; 48: 103–109. Penneys N S. Cutaneous viral disease in AIDS. In: Marks R (ed). Skin manifestations of AIDS. Martin Dunitz: London 1990; 68–93. Barzegar C, Paul C, Saiag P et al. Epidermodysplasia verruciformislike eruption complicating human immunodeficiency virus infection. Br J Dermatol 1998; 139: 122–127. Croxson T, Chabon A B, Rorat E. Intraepithelial carcinoma of the anus in homosexual men. Dis Col Rect 1984; 27: 325–330. Valle S. Dermatologic findings related to Human immunodeficiency virus infection in high-risk individuals. J Am Acad Dermatol 1987; 17: 951–961. Cohen P R, Grossman M E. Recognising skin lesions of systemic fungal infections in patients with AIDS. Am Fam Physician 1994; 49: 1627–1634. Manfredi R, Mazzoni A, Nanetti A, Mastroianni A, Coronado O, Chiodo F. Morphologic features and clinical significance of skin involvement in patients with AIDS-related cryptococcosis. Acta Dermato-Venereol 1996; 76: 72–74. Cockerell C J. Cutaneous manifestations of HIV infection other than Kaposi’s sarcoma: Clinical and histologic aspects. J Am Acad Dermatol 1990; 22: 1260–269. Shaw J C, Levinson W, Montanaro A. Sporotrichosis in the acquired immunodeficiency syndrome. J Am Acad Dermatol 1989; 21: 1145–1147. Hennessey N P, Parro E L, Cockerell C J. Cutaneous Pneumocystis carinii infection in patients with Acquired Immunodeficiency Syndrome. Arch Dermatol 1991; 127: 1699–1701. Liu M T, Wong C K, Fung C P. Disseminated Penicillium marneffei infection with cutaneous lesions in an HIV-positive patient. Br J Dermatol 1994; 131: 280–283. Aftergut K, Cockerell C J. Update on the cutaneous manifestations of HIV infection. Dermatol Clin 1999; 17: 445–471. Tan G, Kaufman L, Peterson E M, de la Maza L M. Disseminated Atypical Blastomycosis in Two Patients with AIDS. Clin Infect Dis 1993; 16: 107–111. Ashack R J, Frost M L, Norins A L. Papular pruritic eruption of Demodex folliculitis in patients with acquired immunodeficiency syndrome. J Am Acad Dermatol 1989; 21: 306–307. Nunez M, Miralles E S, Hilara Y, Pintado V, Harto A, Ledo A. Concurrent cytomegalovirus, M.tuberculosis and M. avium intracellulare cutaneous infection in an HIV patient. J Dermatol 1997; 24: 401–414. Musher D M, Hamill R J, Baughn R E. Effect of Human Immunodeficiency Virus Infection on the course of Syphilis and on the Response to treatment. Ann Int Med; 1990: 113: 872–881. Tosca A, Stavropoulos P G, Hatziolou E, Arvantis A, Stavrianeas N, Hatzivassiliou M, Stratigos J D. Malignant syphilis in HIVinfected patients. Int J Dermatol 1990; 29: 575–578. Sands M, Markus A. Lues maligna, or Ulceronodular syphilis, in a man infected with Human Immunodeficiency Virus: Case Report and Review. Clin Inf Dis 1995; 20: 387–390. Penneys N S, Hicks B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol; 1985: 13: 845–852. Munoz-Perez M A, Rodriguez-Picardo A, Camacho F, Colmenero M A. Dermatologic findings correlated with CD4 lymphocyte counts in a prospective 3 year study of 1161 patients with human immunodeficiency virus disease predominantly acquired through intravenous drug abuse. Br J Dermatol 1998; 138: 33–39. Rippis G E, Becker B, Scott G. Hypertrophic lichen planus in three HIV-positive patients: A histologic and immunological study. J Cutan Pathol 1994; 21: 52–58. Blauvelt A, Turner M L. Gianotti-Crosti syndrome and Human Immunodeficiency Virus infection. Arch Dermatol 1994; 130: 481–483. Barlow R J, Schultz E J. Necrotising folliculitis in AIDS-related complex. Br J Dermatol 1987; 116: 581–584. Rosenthal D, LeBoit P E, Klumpp L, Berger T G. Human Immunodeficiency Virus-associated Eosinophilic Folliculitis. Arch Dermatol 1991; 127: 206–209. McCalmont T H, Altemus D, Maurer T, Berger T G. Eosinophilic
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folliculitis. The histologic spectrum. Am J Dermatopathol 1995; 17: 439–446. Smith K J, Skelton H G, James W D, Frissman D M, Barrett T L, Angritt P, Lupton G P. Papular Eruption of Human Immunodeficiency Virus Disease. Am J Dermatopathol 1991; 13: 445–451. Valerie K, Rosenberg M. Chromatin structure implicated in activation of gene expression by ultraviolet light. New Biologist 1990; 2: 712. Pappert A, DeLeo V. Photosensitivity as the presenting illness in four patients with Human immunodeficiency virus infection. Arch Dermatol 1994; 130: 618–623. Gregory N, DeLeo V A. Clinical manifestations of Photosensitivity in patients with Human Immunodeficiency Virus infection. Arch Dermatol 1994; 130: 630–633. Meola T, Sanchez M, Lim H W, Buchness M R, Soter N. Chronic actinic dermatitis associated with human immunodeficiency virus infection. Br J Dermatol 1997; 137: 431–436. Peters B S, Carlin E, Weston R J, Loveless S J, Sweeney J, Weber J Main J. Adverse effects of drugs used in the management of opportunistic infections with HIV infection. Drug Safety 1994; 10: 439–454. Goldman G D, Milstone L M, Shapiro P E. Histologic findings in acute HIV exanthem. J Cutan Pathol 1995; 22: 371–373. Wang C W, Parham D M, Herrod H G, Hughes W T. Unusual chronic maculopapular rash associated with Human Immunodeficiency Virus infection. South Med J 1989; 82: 386–389. Rico M J, Kory P W, Gould E W, Penneys N S. Interface dermatitis in patients with the acquired immunodeficiency syndrome. J Am Acad Dermatol 1987; 16: 1209–1218. Smith K J, Yeager J, Skelton H G. Histologically distinctive papular
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neutrophilic xanthomas in HIV-1 patients. Am J Surg Pathol 1997; 21: 545–549. Sadick N S. Clinical and laboratory evaluation of AIDS trichopathy. Int J Dermatol 1992; 32: 33–38. Stewart M I, Smoller B R. Alopecia universalis in an HIV-positive patient: Possible insight into pathogenesis. J Cutan Pathol 1993; 20: 180–183. Maurer T A, Christian K V, Kerschmann R L et al. Cutaneous squamous cell carcinoma in human immunodeficiency virusinfected patients. A study of epidemiologic risk factors, human papilloma virus, and p53 expression. Arch Dermatol 1997; 133: 577–583. Farthing C F, Staughton R C D, Rowland Payne C M E. Skin disease in homosexual patients with acquired immune deficiency syndrome (AIDS) and lesser forms of human T cell leukaemia virus (HTLV 111) disease. Clin Exp Dermatol 1985; 10: 3–12. Myskowski P. Cutaneous T-cell lymphoma and Human Immunodeficiency Virus. Arch Dermatol 1991; 127: 1045–1047. Nahaas G T, Kraffert C A, Penneys N S. Cutaneous T-cell Lymphoma associated with the acquired immunodeficiency syndrome. Arch Dermatol 1991; 127: 1020–1022. Zhang P, Chiriboga L, Jacobson M et al. Mycosis Fungoides like T-cell Cutaneous Lymphoid infiltrates in Patients with HIV Infection. Am J Surg Pathol 1995; 17: 29–35. Beylot-Barry M, Vergier B, Masquelier B et al. The Spectrum of Cutaneous Lymphomas in HIV Infection. A Study of 21 Cases. Am J Surg Pathol 1999; 23: 1208–1216. Beylot-Barry M, Vergier B, De Mascarel A, Beylot C, Merlio J P. p53 oncoprotein expression in cutaneous lymphoproliferations. A study of 51 cases. Arch Dermatol 1995; 131: 1019–1025.
MINI-SYMPOSIUM: PATHOLOGY OF INFECTIOUS DISEASES
Selected topics in HIV-associated skin pathology P. K. Ramdial Department of Pathology, Faculty of Medicine, University of Natal, Private Bag 7, Congella, 4013, Kwazulu Natal, South Africa
KEYWORDS HIV, AIDS, dermatoses, infection, neoplasms, virus, fungi, parasites, folliculitis, photosensitivity, drugs
Summary The cutaneous manifestations of human immunodeficiency virus (HIV) infection have been the subject of intense scrutiny because the skin is the most commonly affected organ in HIV infected individuals. Infectious and non-infectious HIV-induced skin diseases may not only serve as the marker of HIV infection, but also as a marker of the stage of HIV disease. Although the cutaneous manifestations of opportunistic infections may serve as the sentinel lesion of a widely disseminated, life threatening infection, the majority of HIV-induced cutaneous diseases are not life threatening, but are cosmetically disfiguring and jeopardise the quality of life of HIV infected patients. The morphology of HIV-induced skin lesions is often unusual and clinically non-diagnostic. Histopathological appraisal is therefore pivotal in the accurate diagnosis of many HIV-induced skin diseases. Despite the changing trend of HIV-induced cutaneous manifestations following the use of highly active anti-retroviral therapy (HAART) in some countries, in developing countries where HAART is not readily and widely available, the skin continues to be ravaged by HIV infection. This review discusses selected HIV-related cutaneous infections and a range of dermatoses and neoplasms, and highlights the role of the histopathologist in the management of HIV infected patients. © 2000 Harcourt Publishers Ltd
INTRODUCTION
INFECTIONS
HIV and the AIDS epidemic have had a profound impact on the spectrum and diagnosis of cutaneous disease. Skin disorders may be present in up to 92% of HIV-positive patients, and may be the first or the only organ affected throughout the course of the disease.1 Recognition of the expanded range of HIV-induced cutaneous manifestations is crucial, not only for the diagnosis and treatment of the skin lesions, but also for improvement of the quality of life of those afflicted. The occurrence of common diseases in unusual settings, increased severity of minor skin diseases, failure to respond to routine treatment and the unusual appearance of skin lesions are the clinical cutaneous clues of HIV infection.2 Because of the unusual disease presentation and clinical mimicry of disease processes, biopsy and histopathological assessment of clinically non-diagnostic skin lesions has become pivotal in the definitive diagnosis of a range of HIVinduced pathology, which is evolving and changing continuously. This review highlights selected HIV-related cutaneous infections and a range of inflammatory dermatoses and neoplasms in HIV-infected patients.
Severe depletion of T-helper lymphocytes in the advanced stages of HIV infection paves the way for opportunistic infections. A spectrum of infections of viral, fungal, bacterial and parasitic origins occur alone or in combination with each other.
Correspondence to: PKR. Tel: +27 (0) 31-2604497; Fax: +27 (0) 312052711; E-mail: [email protected].
Viral infections Herpes virus infections In HIV seropositive patients, this group of viruses can produce extensive, destructive lesions. Herpes Simplex Virus Infection (HSV): Cutaneous HSV infections occur in approximately 20% of patients with AIDS.3 Reactivation of HSV occurs frequently in patients with AIDS at all levels of immunocompetency, resulting in chronic mucocutaneous disease with severe and extensive skin ulcers. With advanced HIV disease, recurrent HSV infection becomes persistent and progressive.4 Sites of occurrence are the perianal, genital, orofacial and digital skin. Histopathology: Intra-epidermal acantholytic vesicles and epithelial cytopathic effects are seen together with chromatin margination, ballooning nuclear degeneration and intranuclear and intracytoplasmic nuclear inclusions. Epidermal necrosis may be extensive and abundant viral inclusions are seen, not only in keratinocytes, but also in
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hair follicle, eccrine and sebaceous epithelium (Fig. 1). Viral inclusions may be elusive in lesions with extensive ulceration. The clues to HIV and HSV co-infection are: 1. failure to respond to Acyclovir: resistance is due mainly to the emergence of HSVs which lack thymidine kinase activity, 2. ulceration in the natal cleft/ perirectal distribution, and, 3. ulcerative HSV lesions lasting more than 1 month.5 Varicella Zoster Virus Infection (VZV): The spectrum of VZV infections includes that of uncomplicated primary varicella, disseminated varicella, an increased incidence of disseminated or localised herpes zoster and chronic varicella zoster.4 Coalescence of individual lesions, haemorrhagic bullae, extensive ulceration with epidermal necrosis and black eschars may be seen. Histopathology: The histopathological spectrum is identical to that of HSV. Type-specific polymerase chain reactionbased assays on lesional tissue is a means of differentiating HSV from VZV. Clues to HIV and VZV co-existence include: 1. the occurrence of herpes zoster in younger patients, 2. recurrent attacks that are more severe, more frequent and of longer duration, 3. resistance to Acyclovir.5
CURRENT DIAGNOSTIC PATHOLOGY
Molluscum contagiosum (MC) MC in immunocompetent hosts occurs in the anogenital area and trunk, and undergoes spontaneous resolution within a year of occurrence. In HIV-positive patients, MC presents as persistent papules over the face, neck, eyelid, intertriginous area, axillae, perianal area and buttocks.8 The head and neck lesions are the most common. Between 10–20% of patients with HIV infection and AIDS have MC. Individual lesions may be solitary and large, measuring up to 2 cm in diameter. Those more than 1 cm have been referred to as ‘giant’ MC. Warty verrucous papules may be seen in addition to the typical umbilicated papules. Histopathology: Cup-shaped lesions extend down and expand the follicular infundibulum. The majority of the viral inclusions are in the follicular infundibulum (Fig. 2). Retraction artefacts are seen in the surrounding stroma with 3–6 layers of CD34 positive spindle / dendritic cells and their immediate stroma attached to the follicular infundibulum containing viral inclusions. Smith at al have recently demonstrated that the bulk of the viral load is localised in hair follicles.9 Based on the absence of palm and sole lesions and the presence of CD34 positive cells surrounding cup-shaped epithelial proliferations containing molluscum bodies, they have suggested that the adhesion molecules for MC are
Cytomegalovirus Infection (CMV): Although CMV is the most commonly isolated virus in AIDS patients, with up to 90% developing acute active CMV infection at some stage in their illness, primary skin involvement by CMV is rare. The clinical picture is that of maculopapular eruptions, ulcers, nodules, vesicles, generalised morbilliform eruptions and verrucous and hyperpigmented indurated plaques.6 Histopathology: Biopsied tissue is characterised by epidermal necrosis and CMV inclusions in endothelial cells and fibroblasts. A variable number of inflammatory cells, leucocytoclastic vasculitis, haemorrhage and necrosis may be present.7
Figure 1 Herpetic ulcer with extensive dermal and adnexal necrosis. Inset: Necrosis of sebaceous gland epithelium and herpetic inclusions (arrows).
Figure 2 Molluscum contagiosum: Viral inclusions in follicular infundibulum and stromal retraction artefact (arrow).
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present or are more abundant within the basal layer of the infundibulum of the hair follicle. MC is associated with significant immunosuppression. Verrucous and giant MC occur in the late stage of the disease with peripheral CD4 T-lymphocyte counts of < 50/mm3 and with viral loads > 100 000. Husak et al report a CD4 / CD8 ratio of 0.2 and a median survival of 12 months.10
or culture-proven mucocutaneous lesions of histoplasmosis. Although histoplasmosis is transmitted by inhalation and skin involvement is usually secondary to lung involvement, ‘primary’ skin infection from direct inoculation may occur in a solitary or disseminated form. In the setting of HIV infection, human-to-human cutaneous transmission may occur. The clinical lesions may be macular, papular, nodular, herpes-like, fistulous, pustular or plaque-like.4,15
Human papillomavirus infection (HPV)
Histopathology: There is a diffuse dermal infiltrate of histiocytes and neutrophils. The inflammatory component may be minimal. Intra- and extracellular oval yeast forms are present (Fig. 3). Free-lying dermal organisms and leucocytoclasis are also present. Necrotising vasculitis may also be seen.
Infection with HPV is the commonest group of viral infections in the skin.4,11 There is a higher incidence of HPV-associated common and genital warts, and intraepithelial and invasive squamous carcinoma of the cervix. Global natural killer cell deficiency and T lymphocyte defects have been speculated as factors predisposing HIV infected individuals to HPV infection.12 As with organ transplant recipients, HPV-related mucocutaneous lesions are more likely to undergo malignant transformation. Different HPV types are associated with different clinical lesions. HPV types 6 and 11 are commonly isolated in anogenital condylomata acuminata but exophytic lesions in this setting may contain high risk HPV types such as HPV 16 and 18. The manifestations of condylomata acuminata, reported in 20% of HIV-infected homosexual men, range from soft sessile lesions with smooth or rough surfaces to exuberant cauliflower plaques.11 Because of the risk of dysplasia in perianal condyloma, Croxson et al advise excision of these lesions in AIDS patients.13 Common warts occur more frequently in HIV seropositive patients than in non-infected people. Valle reported an 18% incidence in seropositive as opposed to a 1% incidence in seronegative controls.14 Multiple verrucae vulgares, multiple plantar warts and extensive flat and filiform warts on the bearded area of the face are seen in HIV positive patients. They may be more extensive and form coalescent plaques, some of which may be associated with hypopigmentation and resemble epidermodysplasia verruciformis (EDV). HPV types 3, 5, 8 and 10 are known to infect patients with EDV. Bowenoid papulosis, a variant of in situ squamous cell carcinoma on the genitalia, is associated with HPV types 16 and 18.
Cryptococcosis Cryptococcosis is the second most common fungal infection in HIV-positive patients. Skin involvement occurs in 6–7% of patients with cryptococcosis.15 The mucocutaneous lesions are polymorphous.16,17 Histopathology: There is diffuse pallor of the dermis because of the abundance of dermal yeasts with mucoid capsules that stain positively with Southgate’s mucicarmine stain (Fig. 4). Inflammation is often minimal.
Fungal infections Although mucocutaneous fungal infections (FI) may occur at any stage of HIV disease as disseminated or localised disorders, they may serve as the initial marker of HIV infection, being diagnosed in approximately 10% and 20% of HIV-positive patients with cryptococcosis and histoplasmosis respectively.4 Sporotrichosis, blastomycosis, paracoccidiodomycosis and coccidiodomycosis are reported infrequently. The morphological spectrum is clinically non-diagnostic.
Histoplasmosis Approximately 17% of reported HIV-infected patients with disseminated histoplasmosis have histological and/
Figure 3 Histoplasmosis: Histiocytic palisade (asterisks) bordering aggregates of Histoplasma capsulatum. Inset: Oval yeast forms of H. capsulatum [Grocott X 120].
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CURRENT DIAGNOSTIC PATHOLOGY
ing exudate which, on silver staining, highlights numerous pneumocystis microorganisms.
Penicillium marneffei infection Cutaneous manifestations include generalised, crusted or necrotic papules, ulcers, molluscum-like lesions, abscesses and subcutaneous nodules.20 Histopathology: Non-caseative, necrotising granulomatous inflammation is present in which intracellular and extracellular round to oval, blunt-ended yeastlike microorganisms, 2–8 µm in diameter are seen.
Other fungal infections Chronic mucocutaneous and disseminated cutaneous candidiasis are common in AIDS patients.21 The histopathological features of disseminated cutaneous candidiasis include dermal microabscesses and associated leucocytoclastic vasculitis. Aggregates of candidal hyphae and spores are found within microabscesses or in areas of vascular damage. Blastomycosis is an uncommon fungal infection in AIDS patients, occurring in the advanced stage of the disease. In addition to 8–15 µm, thick-walled multinucleate yeast forms, 2 µm microforms, 30 µm macroforms and filamentous forms are described.22 Figure 4 Dermal pallor and replacement by infiltrate of Cryptococcus neoformans. Inset: Carminophilic mucoid capsule of C. Neoformans [Mucicarmine 3 240].
Sporotrichosis Sporotrichosis in HIV-infected individuals occurs as a result of haematogenous dissemination of the fungus rather than from local cutaneous inoculation.18 Skin lesions range from papules, pustules, ulcers and erythematous violaceous nodules to plaques.4,17 Histopathology: Although granulomatous inflammation with micro-abscesses and few oval or ‘cigar-shaped’ spores may be present, fungal spores may also be identified within histiocytes and giant cells or may be lying free in the dermis.
Pneumocystosis Cutaneous pneumocystosis is unusual and occurs as a consequence of the use of Pentamidine sprays in patients with prior pneumocystis pneumonia, or in patients receiving prophylaxis because of CD4+ lymphocyte counts less than 200 cells / mm3. Although these sprays sterilise the respiratory tract, they do not offer systemic protection against Pneumocystis carinii. Cutaneous lesions manifest as molluscum-like plaques, bluish cellulitic plaques and deep-seated abscesses.19 Histopathology: There is diffuse infiltration of the dermis and subcutaneous tissue with pale-staining foamy-appear-
Arthropod reactions Demodicosis Demodex mites are 1–5 mm cutaneous parasites that usually inhabit the hair follicles and sebaceous glands. Demodex folliculorum and Demodex brevis are the species that usually inhabit human skin.4 A range of pruritic and follicular lesions occur in HIV-infected patients.23 Histopathology: Follicular mites and a dense lymphoeosinophilic inflammatory infiltrate in the papillary and mid-reticular dermis and perifollicular area are present (Fig. 5).
Scabies Scabies, reported in 20% of HIV infected individuals, comprises a papulosquamous eruption mimicking atopic dermatitis or seborrheic dermatitis, crusted plaques or scattered pruritic papules.21 Histopathology: There is epidermal crusting, acanthosis and hyperkeratosis with myriads of mites visible within the cornified layer of the hyperplastic epidermis. A superficial and mid-to-deep perivascular and interstitial infiltrate of lymphocytes and a predominance of eosinophils is present. In nodular scabies, the dermal infiltrate may resemble pseudolymphoma with large numbers of eosinophils and a dearth of identifiable mites.
Bacterial infections The commoner bacterial infections are those caused by
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pleomorphic, ulceronodular form of the disease that responds well to Penicillin therapy.26,27 Histopathology: Lues maligna comprises a dense lymphocytic infiltrate in the upper and mid-dermis, in addition to a pronounced perivascular inflammatory cell infiltrate involving superficial and deep vessels. Endothelial cell swelling, proliferation and fibrinoid necrosis of the vessel walls resulting in necrotising vasculitis are noted. The number of spirochaetes is variable. Plasma cells are a consistent finding, especially in perineurial and intraneurial locations. The pathogenesis of lues maligna is not dependent on inoculum size or strain virulence but on host resistance.
Bacillary angiomatosis (BA) The cutaneous lesions are red to violaceous domeshaped papules, nodules, polyps, ulcers or cellulitis.4,21
Figure 5 Demodex mite in follicular infundibulum (arrow), follicular spongiosis and inflammation and dermal inflammation (asterisks).
Staphylococcus aureus and Streptococcus pyogenes, the former being the most common cutaneous and systemic bacterial pathogen encountered in HIV-infected individuals.4,21 A variety of lesions occur, none of which is HIV-disease specific. Banal manifestations such as impetigo and folliculitis are common, especially in more immunocompetent individuals. Fatal cellulitis, abscesses and necrotising fasciitis may also occur.
Mycobacterial infections
Histopathology: There is lobular vascular proliferation containing a dense proliferation of capillary-calibre vessels with plump endothelial cells. Neutrophils are seen in association with intervening interstitial granular amphophilic debris in which clusters of organisms are identified on silver staining (Fig. 6). These organisms have been identified as Bartonella henselae or quintana. The course of BA is variable with spontaneous regression, resolution following antibiotic therapy and haematogenous dissemination to other organs being possible outcomes.
DERMATOSES Papulosquamous disorders Seborrheic dermatitis (SD) SD is a benign dermatosis of unknown aetiology with a prevalence of 1–3% in the general population. An incidence of 46–83.3% has been reported with AIDS.8,28 In addition to being more severe, a predominance of inflammatory and papular facial lesions has been seen in contrast to the mild erythematous scaling plaques that are seen on the scalp and face of HIV-negative patients.
HIV-associated mycobacterial infection may have unusual modes of presentation including macules, acneiform papules, indurated crusted plaques, and draining sinuses.24 Mycobacteria, especially Mycobacterium avium-intracellulare and M. haemophilum, may induce cutaneous lesions in up to 10% of patients with systemic mycobacterial infection. Other mycobacteria causing disease in HIV-infected individuals include M. marinum, M. chelonae, M. bovis following BCG immunisation and M. thermoresistible.
Syphilis The advent of AIDS has resulted in an increased incidence of syphilis, which pursues a more aggressive course in HIV seropositive patients.25 There is an increase in the number of reported cases of lues maligna, a
Figure 6 Bacillary angiomatosis: Vascular channels lined by plump endothelial cells. Interstitial neutrophils and granular debris (arrows). Inset: Aggregates of organisms [Warthin Starry 3 480].
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Munoz-Perez et al also reported frequent genital localisation.29 Severe SD is associated with involvement of more than two anatomical sites, occurrence in the late stage of HIV disease with low CD4+ lymphocyte counts and greater resistance to therapy. Histopathology: In addition to the usual features of seborrheic dermatitis, there is keratinocyte necrosis, dermal perivascular neutrophils with leucocytoclasis and leucoexocytosis. Malassezia furfur is implicated in the pathogenesis of HIV-associated SD.4,8
Psoriasis vulgaris HIV infection can trigger proriasis or exacerbate preexisting disease.2,4,8 Although the incidence of 1.3–2.0% in HIV-positive patients is not greater than that in the general population, the disease manifests in a more severe form as the degree of immunodeficiency increases.4 Histopathology: Although the features may be similar to PV in HIV-negative patients, it may differ by displaying acanthosis without supra-papillary thinning, slight spongiosis, necrotic keratinocytes, more dermal plasma cells, fewer T lymphocytes, and decreased epidermal Langerhans cells (Fig. 7). The decrease in epidermal Langerhans cells is postulated to parallel the deterioration in the clinical state. The role of Langerhans cells in PV is unclear, but a postulate is that either a direct HIV-induced cytotoxic effect results in their decrease, or, HIV stimulates autoreactivity resulting in an auto-immune process similar to graft versus host reaction, resulting in a decrease in Langerhans cells.
CURRENT DIAGNOSTIC PATHOLOGY
perivascular lymphocytic infiltrate. There are associated melanophages in the papillary dermis, indicative of pigmentary incontinence. Civatte bodies are seen at the dermo-epidermal junction. There is hyperkeratosis, marked acanthosis and hypergranulosis of the epidermis (Fig. 8). The immunohistochemical features of the cellular infiltrate reveals a predominance of T lymphocytes in the lichenoid and perivascular components and in the epidermis.30 CD68+ macrophages are present in the lichenoid and dermal components. In the dermal component there is an approximately equal number of T-helper and T-suppressor lymphocytes. The T-suppressor lymphocytes closely approximate and hug the dermoepidermal junction while T-helper cells are present in the papillary dermis. Epidermal lymphocytes are almost entirely of T-suppressor phenotype. Langerhans cells are present within the stratum spinosum and in the papillary and superficial reticular dermis. HLA-DR antigen is also identified on the surface of basal and spinous layer keratinocytes. Lymphocytes aggregate around Langerhans cells in the epidermis. NK cells, monocytes and lymphocytes expressing IL-2 receptor are also a component of the dermal infiltrate. LP in the immunocompromised host differs in its distribution, being confined to the extremities in immunocompetent patients and being more widely distributed
Hypertrophic lichen planus (LP) HIV-associated LP presents with a generalised hypertrophic form of the disease on the trunk, face and extremities, which may have been previously involved by a photosensitivity eruption.30 Histopathology: A band-like lymphocytic infiltrate is present at the dermo-epidermal junction together with a
Figure 7 Psoriasis vulgaris: Psoriasiform epidermal hyperplasia, Munro microabscess, spongiosis and dermal inflammation.
Figure 8 Hypertrophic lichen planus: Extensive epidermal hyperkeratosis, acathosis, hypergranulosis and a dense lichenoid inflamatory infiltrate.
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on the face and extremities in AIDS. There is no definite histological difference in the density and nature of the lymphocytic infiltrate or the severity of basal keratinocyte destruction. The immunohistochemical features of the lichenoid and dermal infiltrate are similar in both groups of patients, but in contrast to findings in HIVnegative patients, the intra-epidermal lymphocytes are predominantly of T-suppressor phenotype in AIDS. This may represent either differences in antigen presentation and response by immunocompromised patients to immune stimuli or may be a secondary phenomenon to the systemic depression of circulating T-helper lymphocytes.
Gianotti-Crosti syndrome (GCS) This is a distinctive self limiting acral papular or papulovesicular eruption associated with an underlying viral illness.31 Histopathology: There are focal parakeratotic mounds, scattered necrotic keratinocytes, exocytosis, a moderate perivascular lymphocytic infiltrate and extravasated erythrocytes. Diagnosis of HIV-GCS is dependent on the exclusion of other viral causes of GCS since there are no histopathological distinguishing features.
Folliculitis Apart from bacterial and fungal folliculitis, HIVassociated necrotising and eosinophilic folliculitis have been reported.32–33
Figure 9 Eosinophilic folliculitis: Follicular spongiosis and infiltration by eosinophils and lymphocytes (asterisk). Eosinophil degranulation in dermis. Inset: Flame figure in adjacent dermis.
enhances eosinophil and macrophage migration. Interleukin 5 increases eosinophil survival. Papulopruritic eruption:34–35 Smith et al described variably pruritic, skin-coloured, 2–5 mm diameter, papules on the head, neck and upper trunk with a waxing and waning chronic course.35 It occurs in 20% of HIVpositive patients in any stage of HIV infection. PPE has been speculated to be part of the spectrum of HIV-EF.35 Histopathology: The histopathological features are those of perivascular lymphocytes and histiocytes and variable eosinophils, folliculitis and granuloma formation. Epidermal excoriation may be present.
HIV-associated photosensitivity Eosinophilic folliculitis (EF) HIV-associated eosinophilic folliculitis manifests in the late stage of HIV disease. Multiple discrete, erythematous, crusted, follicular papules on the head, neck and trunk, measuring 3–5 mm in diameter are described.33–34 HIV-EF is associated with pruritus, variable decrease in leucocytes, relative or true eosinophilia and a CD4 cell count 5–80 cells / mm3. IgE levels may be raised. Histopathology: The histopathological features are those of a follicular and perifollicular infiltrate of lymphocytes and eosinophils together with spongiosis of the follicular infundibulum or sebaceous gland (Fig. 9). The adjacent dermis contains large numbers of eosinophils and mast cells and eosinophil degranulation and ‘flame figures’ may be prominent (Fig. 9). The pathogenesis of HIV-EF is not known, but contributory roles for mast cells, sebum and a hypersensitivity reaction to dermatophytes have been implicated. Innocuous follicular antigens such as Pityrosporum yeasts, Demodex mites and bacteria may become antigenic in a Th2-dominant environment and produce interleukins-4 and 5. The former results in isotype switching of antibodies from IgG to IgE with resultant enhanced local and systemic IgE levels. In addition, interleukin-4 causes the production of vascular cell adhesion molecule, which
Valerie and Rosenberg have shown that ultraviolet light (UVL) can activate the HIV promoter, the gene sequence responsible for driving viral gene expression. It is not clear how UVL activates HIV.36 It has been speculated that during the repair of UVL-damaged DNA, viral genes that are incorporated into host cells are stimulated, undergo replication and host cells are subsequently destroyed. HIV-induced photosensitivity reactions include porphyria cutanea tarda, pseudoporphyria cutanea tarda, chronic actinic dermatitis, photosensitive granuloma annulare and photodistributed hyperpigmentation.37,38,39
Chronic actinic dermatitis (CAD) The diagnostic criteria for CAD include a chronic photodermatitis in the absence of continued exposure to photosensitisers, abnormal phototest responses and histological changes consistent with photodermatosis.39 It may be the presenting marker of HIV infection and advanced disease. Histopathology: There is psoariasiform epidermal hyperplasia and variable interface dermatitis. A lichenoid inflammatory cell infiltrate and a variable number of necrotic keratinocytes and eosinophils are identified.
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CURRENT DIAGNOSTIC PATHOLOGY
The pathogenesis and prognosis of CAD is unknown. HIV infected individuals are susceptible to CAD because they often require treatment with multiple medications which act as photosensitising agents and because they are known to have non-specific elevation of polyclonal immunoglobulins and circulating immune complexes with defective removal of these complexes by the reticuloendothelial system. Heightened awareness of the clinicopathological manifestations of CAD is necessary, since phototherapy, which is a treatment modality for a range of HIV dermatoses, is also a known cause of CAD.
Photosensitive granuloma annulare (PGA)
A
The presentation of PGA includes that of a generalised or localised eruption. Circulating lymphokines are detected in these patients, hence, T-helper cells are implicated in the pathogenesis of PGA. Th-1 cells, producing interleukin-2 and involved in delayed hypersensitivity reactions, interact with macrophages in the skin. PGA occurs in the early stages of the disease when Th-1 cells are still retained.
Photodistributed hyperpigmentation Photodistributed hyperpigmentation is associated with advanced HIV infection. The exact cause of this solarinduced melanogenesisis is not known, but hormonal, endocrine and drug related interactions do not appear to be related. Skin biopsies reveal pigmentary incontinence and increased melanin along the dermo-epidermal junction and within keratinocytes.
Lichenoid photo-eruptions Lichenoid photoeruptions are frequently seen as the CD4 cell count decreases. They may be related to photosensitising drugs, some of which may be used in the treatment of HIV related disease.
Cutaneous drug eruptions
B
Cutaneous drug eruptions are the most common manifestation of drug hypersensitivity in HIV-infected individuals.21 Trimethoprim-sulphamethoxazole is the most commonly implicated drug causing adverse skin eruptions in 50–60% of HIV positive individuals.21,40 A variably desquamative maculopapular eruption is seen in addition to Stevens–Johnson syndrome and toxic epidermal necrolysis. Lichenoid papular and severe exanthematous eruptions may occur in patients on zidovudine.
Histopathology Maculopapular lesions demonstrate variable vacuolar alteration of the basal layer of the epidermis, exocytosis, pigmentary incontinence and dermal inflammation (Figs. 10A–C). Individual necrotic keratinocytes are seen. The superficial dermis contains a variable number of mononuclear cells, including eosinophils. Toxic epidermal
C Figure 10 Cutaneous drug reactions: (To Trimethoprimsulphamethoxazole). A) Interface change with necrotic keratinocytes (arrows) and exocytosis. B) Interface change and denser inflammatory component. C) Marked epidermal hyperkeratosis and pigmentary incontinence.
HIV-ASSOCIATED SKIN PATHOLOGY
necrolysis, Stevens–Johnson syndrome and erythema multiforme are characterised by more pronounced interface changes and extensive keratinocyte necrosis. In toxic epidermal necrolysis, confluent epidermal necrosis is seen in the absence of dermal inflammation.21
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lular immunity is compromised because of a decrease in the number and functional capacity of T-helper lymphocytes and relative increase in T-suppressor and cytotoxic cells. Aberrations in the ratio and function of T-helper lymphocytes and T-suppressor lymphocytes may play an important role in the development of HIV-ID.
Miscellaneous inflammatory conditions Acute HIV exanthem This occurs in approximately 23% of patients and represents an acute seroconversion reaction.41 The eruption may be macular over the trunk with roseolalike features on the extremities, or, maculopapular with scattered haemorrhagic and necrotic blisters. The macular lesions are 3–11 mm in diameter and erythematous with darker centres. Histopathology: Early lesions reveal a perivascular lymphohistiocytic infiltrate and little or no epidermal changes. Advanced lesions demonstrate spongiosis, intra-epidermal vesiculation and ballooning degeneration and epidermal necrosis. Inflammatory cells are of T-helper/T-inducer and T-suppressor immunophenotype. Confirmation of the diagnosis necessitates proof of seroconversion.
Unusual chronic maculopapular rash associated with HIV This is associated with conversion from the PGL stage to overt AIDS with a decrease in circulating lymphocytes and T-helper cells.42 It comprises 5–15 mm dark brown macules and papules, mainly on extensor surfaces of arms and legs. Histopathology: There are perivascular mononuclear cells, with a predominance of lymphocytes, especially around superficial and deep dermal blood vessels. This rash is differentiated from PPE by the absence of eosinophils.
Interface dermatitis (ID) The age range of HIV-ID is 4 months to 48 years.43 Clinically, there are widespread erythematous macules, papules or plaques or localised 2 cm diameter acral papules. Histopathology: There is vacuolar interface change, aggregated necrotic keratinocytes and a superficial lymphocytic infiltrate. The basal layer changes are more intense than those seen in drug reactions. Eosinophils and neutrophils are absent. The aetiopathogenesis of ID in AIDS patients is not known but specific immunological changes initiated by HIV are implicated, including polyclonal B lymphocyte activation with circulating immune complexes, T-helper lymphocyte decrease and dysfunction, and Langerhans cell depletion. Langerhans cells play an important role in clearing antigen from the epidermis or may serve as target sites in immune mediated reactions, in addition to their role in antigen processing and presentation. Cel-
Papular neutrophilic xanthomas Papular neutrophilic xanthomas are distinctive papular facial xanthomas that may mimic folliculitis clinically.44 They may serve as a marker of HIV infection and represent a pattern of immunodysregulation, immunodeficiency and immunoproliferation seen in HIV disease. Histopathology: Lipid-laden macrophages, neutrophils, nuclear dust and histiocytes with phagocytosed nuclear debris are present in the papillary and mid-reticular dermis. Hyalinisation with areas of hyaline necrosis of collagen fibres are also seen.
AIDS trichopathy The majority of hair and scalp disorders occur when the CD4+ lymphocyte count is less than 150 mm3.45 Seborrheic dermatitis and psoriasis are the most common lesions followed by disorders of cell growth cycle regulation and trichokeratinisation. Staphylococcal furunculosis is seen in adults and children. Syphilitic involvement manifests as patchy hair loss and papulosquamous eruptions. In biopsies of Tinea capitis Trichophyton tonsurans and mentagrophytes are seen. Alopecia areata, alopecia totalis and universalis, are known to occur in association with HIV infection.46 Skin biopsies reveal a perifollicular lymphocytic infiltrate with infiltration of the hair bulb and miniaturisation of hair follicles.
MALIGNANCIES Malignant cutaneous neoplasms associated with HIV infection are Kaposi’s sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease and anorectal squamous carcinoma.4,21,47–51 As with other immunocompromised states, basal and squamous cell carcinomas occur with increased frequency. The risk factors for development of these tumours are similar, and include fair skin type and excessive sun exposure. Maurer et al suggested that p53 overexpression and not HPV infection played a role in the oncogenesis of these tumours.47 Cloacogenic carcinoma occurs with increased frequency in HIV-positive homosexual males. They tend to be more aggressive, are associated with increased morbidity and mortality and respond poorly to treatment.
Kaposi’s sarcoma (KS) In contrast to the original description of KS in 1872 of a rare, slowly-growing tumour that was confined to the skin of the lower extremities of elderly men, HIVassociated KS is the commonest HIV associated malig-
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nancy and presents in younger individuals as multiple skin lesions, which may cause cosmetic disfigurement. In the USA, it is 20 000 times more common in HIV seropositive patients than in the general population. The clinical lesions manifest as macules, plaques and nodules in varied dermatological patterns, including follicular and pityriasis-rosea-like patterns. In addition, oedema is a common associated finding. Common sites of cutaneous involvement include the trunk, legs, arms and face. Koebnerisation of KS may occur. The histopathological spectrum of KS is well described.21 Macular lesions may simulate granulation tissue. Histologically aggressive forms of Kaposi’s sarcoma have been described, especially in Africa. They are characterised by cellular pleomorphism and brisk mitotic activity and may possess dilated vascular channels. Angiosarcoma is simulated when these vascular channels are lined by atypical endothelial cells. The aetiopathogenesis of KS is multifactorial, and encompasses the roles of Human Herpesvirus Type 8 (HHV-8), genetic and HIV-associated factors.21 The sexual transmission of HHV-8 accounts for the high occurrence of KS in homosexual American males and heterosexual females in Africa, and, its rare occurrence in intravenous drug users and haemophiliacs. Vascular proliferation may also occur as a result of the release of cytokines such as interleukin-6 and fibroblast growth factor by HIV.21 Indirect evidence of the role of HIV in the induction of KS stems from the stimulated growth of AIDS-associated KS cells in vitro by HIV-tat protein, a phenomenon that can be blocked by an anti-tat antibody.21 The prognosis of KS is related to disease activity and the state of immunosuppression rather than to the tumour itself. With advanced immunodeficiency and opportunistic infections, the outcome is poor.
CURRENT DIAGNOSTIC PATHOLOGY
tumours were primary CNHLs that were characterised by frequent CD4+ T-lymphocyte origin, CD30 +/ALKphenotype and p53 protein overexpression. Nonepidermotropic B-cell CNHLs may also express CD30 positivity, and those bearing EBV sequences together with p53 overexpression occur mostly, if not solely, in HIV-infected patients.53
IMPACT OF HIGHLY ACTIVE ANTI-RETROVIRAL THERAPY (HAART) The use of combination drug regimens that include protease inhibitors, known also as highly active antiretroviral therapy, in the management of HIV-infected patients, suppresses viral replication and results in repletion of CD4+ lymphocyte counts.21 This has altered the trend of HIV-induced cutaneous pathology in countries where such regimens are employed, with a decrease in the incidence of diseases associated with advanced AIDS being reported. Many of the skin disorders in patients receiving HAART are similar to those in immunocompetent patients because of the rise in CD4 levels.
CONCLUSION The impact of HIV and AIDS on the skin has far-reaching consequences. Although the HIV-induced skin lesions are not life-threatening, they may be the most debilitating element of the patient’s condition, seriously affecting their quality of life. Not only do skin lesions serve as a marker of HIV disease, but they also predict stage of HIV infection and disease activity. This is crucial in planning optimal management protocols of HIV-infected patients.
Cutaneous lymphoreticular malignancies Although patients infected with HIV are at increased risk for the development of Non-Hodgkin’s lymphomas (NHLs), cutaneous localisation of AIDS-NHL is a rare event. Cutaneous NHL (CNHL) manifests as papules or nodules on any site. A predominance of CNHLs of T-cell origin contrasts with that of B-cell origin in other organs. The pathogenesis of CNHL includes a combination of disrupted immunosurveillance mechanisms, chronic B-lymphocyte stimulation and an accumulation of multiple genetic abnormalities. Mycosis fungoides is rare during HIV infection and its occurrence may be co-incidental. Documented cases of mycosis fungoides are characterised by immunophenotypic heterogeneity (CD4+/CD8+ or CD4–/CD8–) and genotypic inconsistency.49,50 The diagnosis of mycosis fungoides in an HIV-positive patient must be made with caution, as CD8 T-cell predominant dermatoses may serve as a histological mimic.51 Beylot–Barry et al reported non-epidermotropic CNHLs, that developed at an advanced stage of immunosuppression, to be the most frequent in their series.52 The majority of these
PRACTICE POINTS
• Viral, fungal, bacterial and parasitic infections occur alone or in combination with each other • The histopathological spectrum of HSV and VZV is • • • • • •
identical—type-specific polymerase chain reaction based assays differentiate the two viruses Giant and warty verrucous mollusca contagiosa are markers of advanced HIV infection Disseminated candidiasis, histoplasmosis and cryptococcosis are the commoner deep fungal infections with skin involvement Nodular scabies may resemble a pseudolymphoma Biopsies of seborrheic dermatitis may display keratinocyte necrosis, and dermal perivascular neutrophils and leucocytoclasis In psoriasis vulgaris, acanthosis without suprapapillary thinning may be present Lichen planus manifests as a generalised hypertrophic form of the disease
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PRACTICE POINTS (cont)
• Extensive sectioning of pruritic, papular lesions may unmask eosinophilic folliculitis • HIV-induced photosensitivity reactions may be a • • •
side effect of treatment modalities employed in the management of HIV infected patients Cutaneous drug reactions are the most common manifestation of drug hypersensitivity in HIVinfected patients Aggressive Kaposi’s sarcoma may simulate angiosarcoma CD8 T-cell predominant dermatoses may mimic mycosis fungoides
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RESEARCH DIRECTIONS
• The immunopathogenesis of eosinophilic folliculitis • The cutaneous immunological abnormalities in pruritic HIV associated lesions • The role of Langerhans cells in HIV-associated interface dermatitis • The spectrum and pathogenesis of HIV associated drug reactions at different stages of HIV infection • The effect of HAART on cutaneous drug reactions • The immunopathogenesis of HIV associated cutaneous tuberculous reactions • The relationship between HIV subtype and cutaneous manifestations
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