(Chronic Hypertrophic Herpes) in a Patient with HIV ...

Pathology (2001 ) 33, pp. 532– 535

ATYPICAL PRESENTATION OF HERPES SIMPLEX (CHRONIC HYPERTROPHIC HERPES) IN A PATIENT WITH HIV INFECTION HEM AM ALI SAM ARATUNGA , DAV ID WEEDON *, NICHOLAS MUSGRAV E NAOM I MCCALLUM

AND

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Anatomical Pathology, Royal Brisbane Hospital and *Sullivan Nicolaides Pathology, Brisbane, Qld, Australia

SUMMARY A 46-year-old man with HIV infection and AIDS presented with a large perianal ulcerated vegetative lesion that developed over a 1-year period. He had a past history of recurrent genital herpes infection, treated successfully each time with acyclovir. The perianal lesion developed while he was taking prophylactic acyclovir. Clinically, there were features suspicious of a carcinoma and a biopsy was reported as showing dysplasia. Therefore, the lesion was resected in its entirety. Histologically, there were prominent pseudo-epitheliomatou s hyperplasia and chronic ulceration associated with herpesvirus infection. There was no evidence of dysplasia or malignancy. It is important to be aware of chronic vegetant herpesvirus infection, as clinical appearances are unusual and some methods of identification, such as smears or biopsy, may not be sufficient for diagnosis. Viral culture or PCR may need to be performed for a definite diagnosis to alleviate prolonged discomfort and avoid unnecessary radical surgery.

infection in 1985 and with AIDS in 1997. He had an AIDS-defining illness of cryptococcal meningitis. His HIV infection was thought to have been acquired through drug addiction. HIV infection was well controlled on triple anti-retroviral therapy of Abacovir 300 mg twice daily, nevirapine 200 mg twice daily and stavudine 40 mg twice daily. On this admission he had a CD4-positive lymphocyte count of 400/mm3 and an undetectable HIV load. Over the preceding 2.5 years, he had repeated episodes of genital herpes treated successfully with oral acyclovir 800 mg five times daily for 7–10 days followed by a prophylactic dose of acyclovir 400 mg twice daily. During this time, he also had anal and perianal condylomata treated with liquid nitrogen cryosurgery and podophyllotoxin .

Key words: Chronic herpes simplex, pseudo-epitheliomatous hyperplasia, HIV. Received 22 January 2001; revised 18 May 2001; accepted 21 May 2001

INTRODUCTION Unusual manifestations of herpes infection are common in AIDS patients and other immunocompromised individuals.1,2 However, only rare cases of chronic vegetant herpes simplex3 and chronic varicella zoster4 have been reported in the literature. Perianal or genital squamoproliferative lesions in immunocompromised patients are most likely to be neoplastic or infective in nature and small biopsies may be inconclusive or provide misleading information. Appropriate investigations must be undertaken for a definitive diagnosis. We present the case of a 46-year-old HIV-positive man with AIDS who had a chronic perianal indurated lesion which clinically mimicked carcinoma, but was found to be a squamoproliferative lesion caused by HSV.

CASE REPORT A 46-year-old man with HIV infection and AIDS presented with a large ulcerated, hyperkeratotic and exophytic lesion of the perianal region that had grown over a period of about 1 year. He had been diagnosed with HIV

Fig. 1 Chronic hypertrophic perianal herpes: foci of necrosis and ulceration with marked pseudoepitheliomatous hyperplasia of the intervening epidermis ( H&E, original magnification, ´ 7).

ISSN 0031–3025 printed/ISSN 1465– 3931 online/01/040532 – 04 © 2001 Royal College of Pathologists of Australasia DOI:10.1080/00313020120083322


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Fig. 2 Ulcer edge showing multinucleate keratinocytes with moulded ground glass nuclei and eosinophilic inclusions typical of herpes ( H&E, original magnification, ´ 600 ).

Fig. 3 Immunohistochemical staining shows strong positive staining for HSV2 in nuclei and cytoplasm of affected keratinocytes ( original magnification, ´ 600 ).

The perianal lesion clinically resembled a malignancy and was biopsied. The biopsy showed koilocytosis indicating human papilloma virus ( HPV) infection and a focus of squamous epithelial atypia interpreted as dysplasia. No ulceration was evident in the biopsy and there was no evidence of in situ or invasive squamous cell carcinoma. However, a histological diagnosis of dysplasia in the presence of a macroscopic appearanc e suggesting carcinoma led to a complete excision of the lesion. This resulted in a large defect that had to be repaired with a skin flap. The resected tissue was an elliptical piece of skin measuring 17 cm in length. There was a central hyperkeratotic, indurated plaque-like and nodular lesion measuring 5 cm in diameter and elevated 5–10 mm above the surface. Twelve blocks, to include the entire lesion and to represent margins, were examined. Histologically, there were foci of necrosis and ulceration with marked pseudo-epitheliomatous hyperplasia of the intervening epidermis ( Fig. 1) giving rise to a nodular and undulating surface. There was also prominent hyperkeratosis but no koilocytosis or papillomatosis in the proliferative areas. A small focus of koilocytosis was noted only at a distance from the hyperplastic foci. At the depth of the ulcers, there was dense fibrosis and a moderately heavy infiltrate of lymphocytes, plasma cells and eosinophils. At the periphery of some ulcers, there were large clusters of multinucleate keratinocytes with ground glass nuclei. These nuclei were slate grey and showed moulding and intranuclear eosinophilic inclusions typical of herpes ( Fig. 2). Herpesvirus changes were found in < 1% of the tissue examined. While there was epithelial reparative/inflammatory atypia resulting from chronic ulceration, there was no evidence of epithelial dysplasia or squamous cell carcinoma. No Donovan bodies or protozoal parasites were noted and stains for bacteria, mycobacteria, fungi and spirochaetes were negative.

Immunohistochemical staining for HSV2 was strongly positive in the nuclei and cytoplasm of the affected multinucleate keratinocytes ( Fig. 3). Electron microscopy showed parallel arrays of virus particles with central cores measuring 40 nm and capsid measuring 100 nm in diameter, the size and morphology consistent with HSV ( Fig. 4). Most of the viral particles were intranuclear but some cytoplasmic virus was also noted. Surprisingly, PCR amplification on tissue retrieved from paraffin blocks was negative for HSV1, HSV2 and varicella zoster DNA as well as for DNA of other viruses including HPV. Review of the previous biopsy revealed that there was only inflammatory/reparative atypia and not dysplasia. Following resection of the perianal lesion, the patient remains clinically well 11 months later with no recurrence of the perianal lesion, a CD4-positive lymphocyte count of 470/ml and an undetectable HIV load. He is currently on valacyclovir for prophylaxis against herpes simplex.

DISCUSSION Cutaneous disease is common in HIV-infected patients.5 Perianal squamoproliferative lesions in AIDS and other immunocompromised patients are most likely to be neoplastic or infective in nature6,7 although pyoderma gangrenosum, cutaneous Crohn’s disease and chronic irritant-associated lesions (due to heat, urine, faeces, etc.) need also to be considered in the differential diagnosis.8 –10 We report the case of a patient with AIDS who presented with a perianal squamoproliferative lesion which was found

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bacteria ( granuloma inguinale), mycobacteria, spirochaetes ( yaws), protozoa ( amoebiasis, toxoplasmosis, leishmaniasis), trematodes ( schistosomiasis ), fungi and other viruses ( HPV, varicella zoster).14 Recognition of the characteristic

Fig. 4 Ultrastructurally, there are parallel arrays of virus particles with central cores measuring 40 nm and capsid measuring 100 nm in diameter ( original magnification, ´ 100 000 ).

to be caused by herpesvirus. Typical herpes cytopathic changes and inclusions were present only focally at the healing edge of ulcers in regenerative squamous epithelium. The biopsy taken prior to the excision had been superficial, unrepresentative of the main lesion and misinterpreted as showing dysplasia. This case demonstrates the difficulty of laboratory diagnosis of chronic herpes. Although skin scrapings and Tszank smears are useful in diagnosing acute herpes, this has been shown to be unsuitable for diagnosing chronic herpes.11 Since clinical features are highly unusual and overlap with other diseases such as pyoderma gangrenosum, 12 it is important to be aware of this condition. Although appropriate clinical information and a biopsy from the ulcer edge may point to the diagnosis, several methods of identification of herpes may need to be employed in suspicious cases. Although PCR was not positive for virus in paraffin-embedded tissue in this case, it is very likely to be useful when fresh tissue is available.13 Paraffin processing may have denatured the virus beyond recognition in this case. Given the perianal location of the lesion, the virus was most likely to be HSV type 2. Immunoperoxidase staining for HSV2 confirmed this. Viral culture and repeat biopsies are indicated in negative cases. Electron microscopy and immunohistochemistry are useful only when diagnostic areas are sampled. Other infective agents to be considered in the differential diagnosis of perianal squamoproliferative lesions include

morphology of these lesions together with identification of the infective agents are necessary for diagnosis. The possibility of a coexistent infection contributing to squamous proliferation was considered in our case and ruled out. Although HPV was present in this case, it was found at a distance from the squamous proliferation and therefore not likely to be causing it. Logan et al.5 were the first to report chronic cutaneous herpes simplex characterised by “a chronically active, smouldering destructive skin lesion without dissemination”. Prior to this, some cases of herpes simplex persistent for prolonged periods but without the characteristic morphology of hyperplastic lesions had been reported.16,17 All of these cases occurred in immunocompromised patients. Since then, there have been a few case reports describing chronic cutaneous hypertrophic lesions with both herpes simplex and varicella zoster viruses. Brown and Callen12 reported a patient with chronic lymphocytic leukaemia who had a chronic perianal lesion for several years before viral culture identified HSV2. Beasley et al.18 reported a 27-year-old pregnant woman with common variable immunodeficiency ( CVI) who had recurrent vegetations covering the entire vulva, the lesions resembling verrucous carcinoma. HSV type 2 was isolated from the lesions. Another case report was of a 28-year-old HIV-infected woman with AIDS who developed chronic ulcerating lesions on a finger and lower leg. Varicella zoster was found in these lesions.4 As with our case, the patients described in these last two case reports4,18 were already taking prophylactic acyclovir when they developed chronic squamoproliferative lesions due to herpesvirus. Their lesions were found to be resistant to high-dose intravenous acyclovir, but resolved with intravenous foscarnet. Acyclovir resistance of the viral isolates may influence the unusual presentation of these cases. Since these cases occur in immunocompromised patients, the inability to mount an effective cell-mediated immune response also contributes to a large viral load which is implicated in prolongation of the course. 18 The proliferative nature of the lesion is thought to be a reflection of the duration of the disease rather than any inherent change in the pathogenecity of the herpesvirus.18 The influence of herpesvirus on the recruitment of T cells and the production of many cytokines is probably important as well. Interleukin-6 increases the expression of two cellular genes ( My D116 and GA DD 34) that prevent apoptosis.19 Overproduction of tumour necrosis factor by dermal dendritic cells in HIV-infected patients may also result in enhanced proliferation of keratinocytes.19 Address for correspondence: Dr H. Samaratunga, Department of Anatomical Pathology, Royal Brisbane Hospital, Herston Road, Brisbane, QLD 4069, Australia.

References 1. Langtry JAA, Ostlere LS, Hawkins DA, et al. The difficulty in diagnosis of cutaneous herpes simplex virus infection in patients with AIDS. Clin Exp Dermatol 1994; 19: 224–6. 2. Burgoyne M, Burke W. Atypical herpes simplex infection in patients with acute myelogenous leukemia recovering from chemotherapy. J Am Acad Dermatol 1989; 20: 1125–7.


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