Anal Condyloma And Hiv

Surg Clin N Am 82 (2002) 1199–1211

Anal condyloma and HIV-associated anal disease Petar Vukasin, MD* Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Suite 5400, Los Angeles, CA 90033, USA

In the United States, improved understanding and therapy against the HIV virus since 1996 has been accompanied by a substantial decrease in those diagnosed with acquired immunodeficiency syndrome (AIDS); 41,113 new cases were diagnosed during the year 2000 [1,2]. A concurrent decrease in AIDS-related deaths, however, has increased the number of persons living with the disease to an estimated 337,731 in the year 2000 [1]. Although it is more difficult to estimate, more than 900,000 people may be infected with the HIV virus [3]. Anorectal disorders occur in 5.9% to 34% of the HIV population [4–6] and are often the initial reason to seek medical attention [7]. Although there are a large variety of anal diagnoses associated with the HIV population, anal condyloma and anal ulcerations make up the vast majority (Table 1) [4,5,8,9]. A large percentage of individuals having multiple concurrent pathologies should also be noted [5,8]. Thus, this review will concentrate on anal condyloma, anal ulceration, HIV, and making note of other significant issues. Anal condyloma Anogenital warts are among the most common sexually transmitted diseases [10] seen in surgical practices, found in up to 1.7% of the population [5,11]. Even in the pre-HIV era, increased rates were documented in males with homosexual contact [12]. More recent investigations report that 3% to 24.9% of HIV positive individuals have anal warts [4,5,13], with Beck reporting that 18% of military recruits newly diagnosed with HIV had the anal lesions [13]. * Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Suite 5400, Los Angeles, CA 90033. E-mail address: [email protected] 0039-6109/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 3 9 - 6 1 0 9 ( 0 2 ) 0 0 0 8 5 - 3

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Table 1 Incidence of anal pathology in HIV infected individuals as a percentage of those treated for anorectal disorders

Miles et al 1990 [4] Nadal et al 1999 [5] Orkin et al 1992 [8] Yuhan et al 1998 [9]

Anal condyloma

Anal ulcers

Multiple pathology

38% 24.9% 52% 43%

26% 21.8% 32% 32%

– 17.2% 63% 16%

Clinical manifestations of anal warts are variable, with some patients that are otherwise asymptomatic presenting with only perianal masses, whereas others may complain of bleeding, itching, or discomfort. Significant pain is unusual and should prompt a search for other concurrent etiologies, such as anal ulcers, fissures, malignancy, or abscesses. It is not uncommon for the initial diagnosis to be made at a routine physical examination. Diagnosis is usually obvious to the physician by visualization of multiple white, pink, or gray papillary hyperkeratotic lesions covering variable extents of the anoderm. External anal condyloma should always prompt an anoscopic examination, because up to 78% of such patients will have internal lesions as well [14]. Because this is an infection of squamous epithelium, warts are unlikely to be found significantly proximal to the dentate line. A great number of treatments for anal condyloma have been described (Table 2) [15]. Those in common usage today are discussed below. Eradication of condyloma Podophyllin is a chemical that is cytotoxic to warts and was first described in clinical use by Kaplan in 1942 [16]. The solution is applied directly to external anal condyloma. It is often quite irritating to the surrounding normal anoderm, with reported local and systemic toxicity, as well as having theoretical oncogenic potential [17]. These features limit its use for internal anal condyloma. Application of petroleum-based gel to the normal anoderm surrounding the warts before podophyllin application may limit its local toxicity (R.W. Beart, personal communication, 2000). Success is limited, with one study showing only 22% of patients free of warts after three months of use [18]. Another report finds that at 42 weeks, condyloma had recurred in 68% of those treated with podophyllin, but in only 28% of those undergoing surgical excision [19]. Imiquimod is a new topical agent, approved for use in 1997, whose application locally releases endogenous cytokines such as interferon [20]. This immunomodulator applied as a 5% cream (Aldara) has been shown to have activity against genital condyloma [20,21]. Up to 50% of patients had complete eradication of their anogenital warts after three times weekly application for 16 weeks, with minimal anodermal irritation and erythema [22]. Bichloroacetic acid causes a chemical burn, destroying the keratin layers and subsequently exposed tissues underneath. It shares many of the limita-

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Table 2 Treatments for condyloma acuminata [15] Folklore Charming Hypnosis Lime water Lemon juice Rubbing with raw potato, then burying this during the full moon Chemical Methods Podophyllin Podpphyllotoxin Imiquimod Dinitrochlorobenzene Fowler’s solution Phenol Colchicine Bichloroacetic acid Trichloroacetic acid Dimethyl sulfoxide 5-Fluorouracil Tetracycline ointment Bismuth sodium triglycollamate Thiotepa Sulfonamide cream Ammoniated mercury Idoxuridine Bleomycin Cantharidin Solcoderm Immunologic methods Autovaccine Bacille Calmette-Guerin Vaccinia Inerferon Cryotherapy Liquid nitrogen Carbon dioxide snow Liquid air Electrocautery Laser Surgical excision alone

tions of podophyllin in its local irritation, but is not believed to have systemic effects. 5-Fluorouracil as an antimetabolite chemotherapeutic agent has been has been used in the treatment of anal warts with some success [23,24]. Three- to seven-day treatments topically have eradicated anogenital warts in up to 60% of cases, but as von Krough points out, this treatment ‘‘often causes intolerable discomfort to the patients’’ [24]. He and others recommend reserving this treatment for warts refractory to other methods. Cryotherapy, most commonly using liquid nitrogen, has been used to treat anal condyloma. Direct application of this chemical by either spray or cotton

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applicator is relatively easy and inexpensive, and has become a very common practice, especially by dermatologists, who have the equipment and liquid nitrogen readily at hand. Although the technique has been reported in the literature [25,26], there are no strong data as to its efficacy. Clearly, however, there is significant discomfort to the patient, even though this therapy is usually reserved for those with limited numbers of condyloma. Interferon, through its antiproliferative properties toward viruses, has been shown to be effective treatment for anal condyloma [27,28]. Systemic use has not been helpful, with studies reporting some decrease in condyloma burden, but rare eradication [29]. One report found a 36% clearance of condyloma after intralesional injection of up to three warts, three times a week, for three weeks. Interestingly, 17% of the warts in the same study cleared with simply placebo injection [27]. Another report showed a similar protocol achieving condyloma resolution in 62% of patients [28]. The most reliable means of eradicating all condyloma concurrently is by use of scissor excision and electrocoagulation. These techniques continue to be avoided in preference to the nonsurgical methods because of the significant associated pain and the cost of anesthesia. Electrocoagulation is accomplished by creating first and second degree burns of the condyloma-bearing anoderm using a diathermy electrode. With both techniques, damage to clinically uninvolved anoderm should be minimized. Again, little information exists regarding the efficacy of this treatment, but Thomson et al [30] report complete clearance of condyloma at a single session in 80% of patients, with recurrence, however, approaching 50% at 3 months. Khawaja [19], on the other hand, found only 28% recurrence at 10 months after excision, compared with 68% recurrence after treatment with podophyllin. The advent of laser surgery has seen its application to condyloma eradication with success rates similar to those of traditional surgical excision [31]. Two comparative studies [32,33] of laser versus conventional surgical excision found no differences in postoperative pain, healing time, or scar formation. Bilingham and Lewis [33] do report a somewhat higher recurrence rate using laser surgery for excision. Due to the expense of equipment and lack of clinical advantage, the use of lasers in condyloma surgery has been limited. In addition, some concern has been raised over the human papilloma virus (HPV) viral particles known to be aerosolized in the laser plume [34,35], and at least one case of HPV laryngeal papillomatosis contracted by a laser surgeon is reported [36]. Whether similar risks exist for diathermy smoke is unknown; however, general recommendations include wearing of specialized surgical masks and evacuating the surgical ‘‘smoke’’ through a micropore filter. Condyloma recurrence The great variability in success of treatment and recurrence of all the above techniques is likely partly attributable to the extent of disease before

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treatment. At my institution (The Los Angeles County and University of Southern California Medical Center HIV Clinic in Los Angeles) we prospectively examined 74 HIV positive patients undergoing surgical excision of warts, and found that those with less than 25% of their anoderm replaced by condyloma had a recurrence rate of 38% at four months, whereas those with more than 25% anodermal replacement experienced a 62% recurrence rate in the same time interval [37]. Although there is great variability of time to recurrence of condyloma, the majority recur early, usually within months [18,19,24,28,30]. This is most likely due to residual virus in the anoderm, rather than reinfection. Ferenczy et al [38] biopsied normal appearing anodermal margins after laser excision of anal condyloma and found HPV in 45%. Condyloma recurred in 67% of patients with biopsies showing HPV, but only in 9% of those without residual virus. The belief that condyloma recurrence is due to persistent anodermal HPV virus after local wart destruction has led to adjuvant HPV treatment in hopes of reducing this recurrence. Vance et al [39] found a 38.2% condyloma recurrence after 13 weeks using laser excision alone. When the sites of excision were injected with interferon, however, the rate of return of warts fell to 18.5%. In 1994, Fleshner and Freilich [40] reported similar results after diathermy excision of anal condyloma followed by injection of 2 million units of interferon into surrounding anoderm. They found that at 3.8 months, 12% of those receiving interferon recurred, versus 39% of those receiving placebo. At our institution, we recently also found benefit to injecting 4 million units of interferon after surgical resection of extensive anal condyloma in HIV positive patients. The recurrence rate at four months decreased from 55% to 31% [37]. Other agents, such as imiquimod, are yet to be studied as adjuncts to eradicative methods in hopes of preventing recurrence of anal condyloma. HPV, HIV, and neoplasia As noted in the beginning of this article, there is an increased incidence of anal condyloma in the HIV population [4,5,13]. There is also evidence that condyloma in HIV patients is a more aggressive disease in terms of recurrence and dysplasia. Sobhani et al [41] recently showed a higher rate of recurrence after destruction of anal condyloma in their HIV positive patients (75%) when compared with those who were HIV negative (6%). They also demonstrated a higher risk of dysplasia in condyloma from HIV positive patients. Metcalf and Dean [42] similarly found decreased risk of dysplasia in warts from heterosexual males (6%) versus homosexual or bisexual males (28%), although both had an equal risk of squamous cell carcinoma at 3%. These authors also found an independently increased risk of dysplasia with HIV positivity and condyloma located above the dentate line. These data raise the possibility of more virulent condyloma subtypes predominating in homosexual and HIV positive populations.

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The incidence of anal squamous cell carcinoma among all men in the United States is 0.7 per 100,000, but the incidence in homosexual men has been estimated to be between 25 and 37 per 100,000 [43]. Moreover, the incidence in homosexual men with AIDS may be as high as 84 times that of the general population [44]. An epidemiologic link between anal condyloma and anal carcinoma was demonstrated by Byars [45], who reported on 275 patients. He found that 12.2% of those with squamous cell carcinoma had concurrent condyloma, and that 3.5% of those with condyloma had invasive carcinoma. Of particular interest is an article published by Frisch et al [46] in 1997, in which his group applied infectious disease principles to anal squamous cell carcinoma, effectively demonstrating that this neoplasm fits the criteria of sexually transmitted diseases (STD). They suggest that practices to control STDs would reduce the incidence of this anal malignancy. The infective agent of anal condyloma is the human papilloma virus, a DNA papovavirus [47], over 100 genotypes of which have been identified, with more than 30 linked to anogenital warts. However, anal HPV is associated with a spectrum of anal pathology including asymptomatic infection, benign warts, dysplasia, and invasive anal squamous cell carcinoma [48]. Although perfect correlation seems to be lacking, several groups have noted increased association of subtypes 16 and 18 with anodermal and condyloma dysplasia, whereas subtypes 6 and 11 correlate with a lack of dysplasia [49–51]. In one study, 54% of males attending an HIV clinic were found to have HPV in their anoderm [51]. Further evidence of the association of condyloma and anal squamous cell carcinoma is given by DNA studies that have identified the HPV genome within squamous cell carcinomas [46,49,52]. Gal et al [52] reported HPV genome present in 63% of squamous cell carcinomas from homosexual patients, whereas those from heterosexual patients were found with HPV only 33% of the time, again indicating a more aggressive disease in the homosexual population. Frisch et al [46] identified HPV in 84% of the squamous carcinomas in their mostly HIV negative population. Direct causality between HPV virus and malignant transformation has not been demonstrated, however, and the above observations may be due to a cofactor effect of HPV on other malignancy promoters. This view is supported by Dreau et al [53], who report that 58% of melanoma biopsies contained HPV DNA, and those that did contain it acted more aggressively. Goldstone et al [54] recently reported that 54% of homosexual men who were referred to them for surgical treatment of other pathology were found to have high grade dysplasia in the anal canal. Following the precedent set by female cervical HPV association of dysplasia, routine cytology followed by colposcopy, biopsy, and eradication of clinically nonevident anal intraepithelial neoplasia (AIN) was reported [13,51]. Palefsky et al [51] found AIN by cytology in 14% of their HIV positive population. Although the rate of progression of AIN to invasive squamous cell carcinoma is not known, the above practice is supported by the observation that anal carcinoma may arise from

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high grade dysplasia in visually normal anoderm in homosexual men [55]. In 2002, however, Chang et al [56] reported that after surgical eradication of all high grade AIN lesions in 29 HIV positive patients, 23 had recurrent high grade AIN lesions by 12 months. Lack of data concerning incidence of progression of AIN to invasive carcinoma, coupled with poor options for treatment of this lesion, have kept the screening for and treatment of clinically nonevident anal dysplasia in HIV positive patients controversial. HIV-associated anal ulcer disease In 1981, Siegal and coworkers [57] were the first to appreciate an association of anal ulcerative disease with HIV when they reported four immunodeficient homosexuals with large perianal ulcers due to herpes simplex virus (HSV) infection. Their writing that this association was ‘‘part of a nationwide epidemic of immunodeficiency among male homosexuals’’ now seems prophetic. Ulcerations remain as one of the two most common anal pathologies in HIV patients [4,5,8,9]. Possible ulcer etiologies are listed in Table 3 [58,59]; however, in many cases a specific cause can not be found and the ulcer is termed idiopathic [57,59,60]. In any case, these ulcers can become chronic and quite debilitating [6,58], with the most common presenting symptoms being pain, purulent discharge, and bleeding [61]. Nonsurgical management Aggressive work-up to identify the etiology of ulcers is usually unsuccessful, with the exception of biopsy in cases clinically suspicious for neoplasm [60]. Goldberg [61] reported cytomegalovirus isolated by culture from 8% of his anal ulcer patients, but it is not clear whether this was a concomitant infection or causative, as subsequent antiviral treatment was not particularly Table 3 Causes of ulcerations in HIV (+) patients [58,59] Benign Anal fissure Trauma Infectious Herpes simplex virus Cytomegalovirus Chancroid Tuberculosis Cryptococcosis Actinomycosis Neoplastic Lymphoma Anal carcinoma KS Idiopathic HIV anal ulcers

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successful. Fifty per cent of anoderm adjacent to ulcerations is found to contain HPV infection [62], but the association was not thought to be causal. Nonoperative management with antibacterial and antiviral agents showed variable results, but generally poor success [63,64]. Newer strategies include anecdotal reports of intralesional steroid injections of nonhealing ulcers [6,65], and use of thalidomide [66]. Broader experience is needed before assessing the true efficacy of these agents. Idiopathic HIV-associated anal ulcers can be reliably clinically differentiated from anal fissures and other ulcerative diseases by a set of characteristic features described by Viamonte et al [58]. These include noting the lesion’s location, associated sphincter tone, sphincter or postanal space invasion, associated skin tags and mucosal bridging, and the width of the ulcer base (Table 4). Additional experience at our institution shows that HSV ulcers tend to be multiple, more superficial, and quite a bit more tender to palpation than idiopathic ulcers. Surgical management Three of four of Siegel et al’s original patients died with their anal ulcerations [57]. Wexner and colleagues then reported their early experience in 1986 of surgical management of AIDS-associated anorectal disorders [67], noting a 16% major complication rate, a 43% death rate at six months, and only a 12% healing rate at 30 days after surgical treatment of anal ulcers. These initial reports set a foreboding environment for surgical approaches to HIV-associated anorectal diseases, but subsequent reports became more positive. In 1991, Miles et al [63] reported 11 of 12 HIV positive patients healing within 10 weeks after excision of perianal ulcerations. In the same year, Burke et al [68] reported a 94% healing rate after anorectal surgery in a similar population. Also in 1991, Savavi’s group [6] showed significant improvement or resolution in symptoms of 87% of postoperative patients, despite a wound healing rate of only 53%. Similarly, Nadal in 1999 [59] reported relief of symptoms in all 33 HIV positive patients undergoing ulcer excision, but with variable healing.

Table 4 Characteristic features of HIV-associated anal ulcers [58]

Location Sphincter Invasion Sentinel tag Mucosal bridging Width AIDS

Benign anal fissure

Idiopathic anal ulcer

Low Normal to hypertonic ÿ + ÿ Narrow +/ÿ (50%)

High Lax + ÿ + Broad-based + (100%)

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Several authors have reported relief of HIV anal ulceration associated symptoms after surgical excision, despite poor healing and persistent wounds [6,59,69,70]. The etiology of this phenomenon is not known, nor is the healing rate for each individual patient reliably predictable. However, Safavi et al [6] reported healing after anorectal surgery in 69% of those who were HIV positive, but in only 26% of those with AIDS. Nadal’s group [69] reported fistulotomy in their patients followed by healing in an average of 44.8 days for HIV negative patients, versus 60.8 days in those who were HIV positive. 22% of their patients with advanced AIDS did not heal. Another study found that poor anal ulcer healing was associated with low T4-cell counts [70]. It seems prudent to advise patients with AIDS who are about to undergo surgery for anal ulcerations and other anorectal disorders that there is the possibility of poor wound healing, but that symptomatic relief is nonetheless highly likely. Treatment algorithm Based on available data at the time, in 1993 our institution established an algorithm for the treatment of HIV-associated perianal ulcerations [71]. Initially, cultures for HSV were positive in about 50% of our patients. These were treated with oral acyclovir at 800 mg three times daily for 14 days. Those who returned HSV culture negative were treated with metronidazole at 500 mg. three times daily for 14 days. This antibiotic choice was based on its known benefits in Crohn’s anal ulcerations [72,73] and analgesic effects after hemorrhoidectomy [74], both of which were thought to have clinical similarities to HIV-associated anal ulcers. Treatment success was defined as relief of anal symptoms, which was often seen before healing of the ulcerations, as has been reported by others after surgical ulcer excision [6, 59,69,70]. Antimicrobial failures then underwent additional intervention, such as change of antiviral therapy, intralesional steroid injection, or surgical

Fig. 1. Algorithm for management of HIV-associated anal ulcers.

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excision. Under this algorithm, 85% of cases resolved after antimicrobial treatment, and only 9% required surgical intervention, all of whom healed. The algorithm was simplified in 1997 to that seen in Fig. 1. and was used for all HIV related ulcerations not associated with mass suspicious for malignancy or prior history of anal malignancy in that patient. Antimicrobial therapy for all patients consisted of concurrent treatment with acyclovir and metronidazole at the same doses and time period as above. 76% of patients responded to initial treatment, and 21% subsequently went on to surgical excision, all of whom attained symptomatic relief and complete wound healing within 5.3  4.6 weeks. 21 ulcerations recurred at a mean of 17.1  13.1 weeks. These were treated again with antimicrobials, achieving an 82% success rate, and the 18% of these that persisted responded to surgical excision. We feel that the success of this treatment protocol has been very helpful in the management of our HIV infected population. References [1] Anonymous. Update: AIDS–United States, 2000. MMWR Morb Mortal Wkly Rep 2002;51(27):592–5. [2] Karon JM, Fleming PL, Steketee RW, et al. HIV in the United States at the turn of the century; an epidemic in transition. Am J Public Health 2001;91:1060–8. [3] Karon JM, Rosenburg PS, McQuillan G, et al. Prevalence of HIV infection in the United States, 1984 to 1992. JAMA 1996;276:126–31. [4] Miles AJ, Mellor CH, Gazzard B, et al. Surgical management of anorectal disease in HIVpositive homosexuals. Br J Surg 1990;77(8):869–71. [5] Nadal SR, Menzione CR, Galvao VdM, et al. Perianal diseases in HIV-positive patients compared with a seronegative population. Dis Colon Rectum 1999;42:649–54. [6] Safavi A, Gottesman L, Dailey T. Anorectal surgery in the HIV+ patient: update. Dis Colon Rectum 1991;34:299–304. [7] Gelb A, Miller S. AIDS and gastroenterology. Am J Gastroenterol 1986;81:619–22. [8] Orkin BA, Smith LE. Perineal manifistations of HIV infection. Dis Colon Rectum 1992;35: 310–4. [9] Yuhan R, Orsay C, DelPino A, et al. Anorectal disease in HIV-infected patients. Dis Colon Rectum 1998;41(11):1367–70. [10] Barrett TJ, Silbar JD, McGinley JP, et al. Genital warts – a venereal disease. JAMA 1954;154:333–4. [11] Koutsky LA, Galloway DA, Holmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122–63. [12] Marino AWM. Proctologic lesions observed in male homosexuals. Dis Colon Rectum 1964; 7:121. [13] Beck DE, Jaso RG, Zajic RA. Surgical management of anal condylomata in the HIVpositive patient. Dis Colon Rectum 1990;33:180–3. [14] Petersen IM, Rao R. Genital warts. Newly discovered consequences of an acient disease. Postgrad Med 1989;86:197–204. [15] Billingham R. Condyloma acuminata. In: Mazier WP, Levien DH, et al, editors. Surgery of the colon, rectum, and anus. Philadelphia: W.B. Saunders Company; 1995. p. 315. [16] Kaplan IW. Candyloma acuminata. New Orleans Med Surg J 1942;94:388–90. [17] Oriel JD. Genital warts. Sex Transm Dis 1977;4:153–9.

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