Neoplasms of the Anus

Elizabeth C. Wick , Jonathan E. Efron , in Shackelford's Surgery of the Alimentary Tract (Seventh Edition), 2013

Anal dysplasia

Anal dysplasia is becoming a more common condition that can occur both in the anal canal and at the anal margin. The terms Bowen disease, anal intraepithelial neoplasia (AIN) I, II, and III, and squamous carcinoma cell in situ have all been used to describe anal dysplasia. The recent edition of the American Joint Committee on Cancer manual has recommended simplifying the classification scheme to either low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL). 1 Differentiation between LSIL and HSIL is based on specific histologic features: nuclear-to-cytoplasmic ratio and relationship of atypical cells with respect to the basement membrane. The definition of LSIL includes AIN I and HSIL includes Bowen disease, AIN II, and AIN III. In the past, Bowen disease or squamous cell carcinoma in situ was usually diagnosed as an incidental finding by pathologists after another anorectal procedure, commonly excisional hemorrhoidectomy. The recommended treatment for Bowen disease was detailed mapping of the anal canal followed by wide local excision and skin grafting. 24 This procedure was associated with very high morbidity as well as high recurrence rates (23% in one report). Recent detailed pathologic studies of patients with Bowen disease demonstrated that these lesions were indistinguishable from HSIL and all had histologic evidence of HPV infection. 25

Anal squamous intraepithelial lesion (SIL) is associated with the human papillomavirus (HPV) infection and anal condyloma. HPV is the cause of almost all cervical cancers and the majority of anal cancers. In a population-based study using the SEER database, 77.9% of anal cancers and 65.5% of anal dysplasia were considered HPV-associated. 26 HPV types can be further classified based on their potential for malignant transformation. In general, low-risk types (6, 11, 16, and 39) are associated with anal warts and high-risk types (16, 18, 58, and 45) are associated with LSIL, HSIL, and anal cancer. 25 HPV is the most common sexually transmitted disease and infection is associated with sexual promiscuity and the presence of other venereal diseases. Anoreceptive intercourse is not necessary for transmission. In heterosexual patients, anal and perianal infection occurs because the virus pools in the vagina or at the base of the penis and from there it can spread to the perianal region. Patients with a compromised cellular immune system are at higher risk of developing chronic infection. This includes patients with human immunodeficiency virus (HIV), solid organ transplant recipients, and those with autoimmune diseases. 27,28

The incidence of SIL in HIV-positive males who engage in anal receptive intercourse has been documented to be as high as 52% in some series. 29 Indeed, the overall incidence of SIL in males engaging in anal receptive intercourse is thought to be 35 per 100,000, and this figure doubles in the same population that is also HIV positive. 29,30 A study by Palefsky et al found that in patients who are HIV positive, engage in anoreceptive intercourse, and are taking highly active antiviral therapy, 81% had some form of anal dysplasia and 52% had HSIL. 30 The clinical features of SIL are not well defined, and most patients are asymptomatic with the diagnosis made during the diagnosis and/or treatment of anal condyloma. The rate of detection of SIL in patients who undergo resection of anal condyloma ranges from 28% to 35%. This figure can rise as high as 60% in HIV-positive individuals. 31-33 Novel screening techniques, such as anal cytology and high-resolution anoscopy, have been investigated over the past 20 years in high-risk populations. 34 Such screening has been prompted by the high incidence of SIL in HIV-positive patients and the fact that SIL is essentially asymptomatic and undetectable to the naked eye. Anal cytologic examination uses techniques similar to cervical Pap smears and requires brushing of the anal canal and verge. Palefsky et al demonstrated a 69% sensitivity of detecting dysplasia in HIV-positive patients versus a 47% sensitivity in HIV-negative patients. Increasing the number of visits and screening procedures enhanced the sensitivity of the test. 35 A diagnosis of SIL should be followed up with a detailed evaluation of the perianal and anal region.

High-resolution anoscopy requires an operating microscope, acetic acid, and Lugol's iodine. First, the anal margin and anal canal are coated with 3% acetic acid and then examined using the microscope. Areas infected with HPV will be white and have characteristic vascular markings. Lugol's iodine is then applied; areas of HSIL do not absorb the Lugol's iodine and will remain pale. Areas of LSIL and normal tissue will turn brown/black from the Lugol's iodine (Figure 172-5). The areas of suspected HSIL should be biopsied to confirm the diagnosis and then ablated with either electrocautery or infrared coagulation. The goal is to achieve a superficial burn in the areas of HSIL while preserving uninvolved regions. Using this technique, HSIL can be eradicated from immunocompetent patients. Recurrence is common in HIV-positive patients; thus, close followup is important. After treatment, patients should be followed with anal Pap smears at 3-month intervals. 25,36-38

An alternative treatment for HSIL is immunomodulation. Reports on the use of immunotherapy, which involves the application of 5% imiquimod (Aldara) cream, topical 5% 5-fluorouracil (5-FU), or a combination of the two to the anal area are limited to small case series. Imiquimod is an immunomodulator that enhances interferon's activity. Several case reports have documented complete resolution of HSIL when treated with imiquimod cream or both imiquimod and 5-FU. 39,40 Kreuter et al reported on 10 HIV-positive patients who were also infected with HPV serotype 16, had various grades of AIN, and were treated with 5% imiquimod cream. The cream was applied three times a week for 4 months; side effects included erythema and burning at the initiation of therapy. Most patients had complete resolution or downgrading of the AIN. 41

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Gynecologic Cytopathology

In Diagnostic Pathology: Cytopathology (Second Edition), 2018

CLINICAL ISSUES

Epidemiology

•

Anal squamous cell carcinoma is uncommon but has been increasing in recent years

Presentation

•

Anal dysplasia is more prevalent in AIDS patients, men who have sex with men, transplant recipients, and women with cervicovaginal or vulvar dysplasia

○

Anal cancer incidence in HIV patients is 30x higher than the general population

•

No clear screening guidelines exist, but some centers do screen high-risk groups

○

Percentage of positive cases is therefore higher than in typical gynecologic screening

•

Positive cytology is followed by anoscopy (similar to colposcopy) and biopsy

Laboratory Tests

•

Sampling is performed with moistened swab, from distal rectum outward with lateral pressure on anal canal mucosa

○

Dacron or flocked nylon swabs preferred to cotton

•

Liquid-based cytology preferred for better adequacy; human papillomavirus testing can be performed

Natural History

•

Poorly studied but thought to be slowly progressive to malignancy

Treatment

•

Topical agents or ablation for nonsurgical treatment

•

Excision limited by stenosis complications and recurrence

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Diseases of the Rectum and Anus

Robert D. Madoff , in Goldman's Cecil Medicine (Twenty Fourth Edition), 2012

Epidemiology and Pathobiology

Human papillomavirus (HPV, Chapter 381 ), which is the most common sexually transmitted infection, is a cause of anal dysplasia and cancer. The approximately 40 HPV subtypes that can cause anogenital infections are divided into low-risk types (e.g., types 6 and 11) that cause anal warts (condyloma acuminata) and high-risk types (e.g., types 16, 18, and 33) that can cause anal dysplasia and cancer. HPV infection is associated with cervical, vulvar, vaginal, and penile cancers, and some patients have HPV-related dysplasia or cancer in multiple sites. Approximately 90% of anal cancers are attributable to HPV infection.

The incidence of anal cancer has been steadily increasing, from 0.6 per 100,000 in 1973 to 1.0 per 100,000 in 2001; the female-male ratio decreased from 1.6 : 1 to 1.2 : 1 over the same period. These epidemiologic trends have been attributed to a particularly rapid increase in anal cancers among men who have sex with men, especially men infected with HIV. Anal HPV, including the high-risk types, is highly prevalent in at-risk populations (sex workers, intravenous drug users, transplant recipients, men who have sex with men, and HIV-positive men and women). Furthermore, anal dysplasia is common in at-risk populations; indeed, the prevalence rates of high-grade anal dysplasia are reportedly 40 to 60% among HIV-positive men who have sex with men seen in specialty clinics in New York and San Francisco.

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Neoplasms of the Anus

Mark Lane Welton , Imran Hassan , in Shackelford's Surgery of the Alimentary Tract, 2 Volume Set (Eighth Edition), 2019

Squamous Intraepithelial Lesions

The lesions under this term have been previously known as Bowen disease, anal intraepithelial neoplasia (AIN) I, II, and III, anal dysplasia, and SCC in situ. 30 Based on current guidelines, 30 it has been recommended that these should be classified as either (1) low-grade squamous intraepithelial lesions (LSILs) or (2) high-grade squamous intraepithelial lesions (HSILs). The difference between LSIL and HSIL is based on histologic features, including nuclear-to-cytoplasmic ratio and relationship of the atypical cells with the basement membrane. Based on its current definition, LSIL includes AIN I, as well as anal and perianal condylomas, and HSIL includes Bowen disease, AIN II, and AIN III, as well as SCC in situ. The exact prevalence of HSIL is not known and is considered to be less than 1%, but its incidence appears to be increasing. Certain factors are associated with a high risk of HSIL and include HIV, systemic immunosuppression, long-term steroid use, a history of cervical and vulvar intraepithelial neoplasia (CIN and VIN), and extensive condylomatous disease. The incidence of HSIL in MSM is 35 per 100,000, and this doubles in the same population that is HIV positive. The prevalence of HSIL in nonimmunocompromised patients, such as women with VIN and CIN, is approximately 5%, whereas it is reported to be approximately 3% to 5% in renal allograft patients. 31

The natural history of HSIL is not clearly established, with progression to invasive cancer reported to be approximately 10% in 5 years, with several factors impacting this rate, including the immune status of the patient and how HSIL is managed. 31 The incidence of progression in HIV-positive and immunocompromised patients is probably higher, based on the fact that there is a higher incidence of anal SCC in these patient groups. The theoretical progression of HSIL to anal SCC is considered to be approximately 1 in 600 per year in HIV-positive MSM and 1 in 4000 per year in HIV-negative MSM. 32

The clinical features of HSIL are relatively non specific, and most patients are asymptomatic with the diagnosis being made during surgical excision of perianal lesions, including anal condylomas. The incidence of HSIL in patients who undergo excision of condylomas is between 28% and 35% but can be as high as 60% in HIV-positive patients. In symptomatic patients, HSIL of the perianus can be associated with plaques, erythema, and/or pigmentation and may present with perianal irritation or pain.

The primary objective of treating HSIL is to prevent its progression to anal SCC, preserve anorectal function, and minimize treatment-related morbidity. There are several treatment modalities available for treating HSIL, including surgical excision, electrocautery ablation, topical imiquimod, and topical 5-FU. However, the efficacy and benefit of any one therapy over the other is limited by the lack of high-quality data. Although surgery involving wide local excision with negative margins was considered the standard treatment, it is associated with significant wound morbidity, adverse functional outcomes (incontinence, anal stenosis), and high rates of local recurrence. There also does not appear to be a significant impact on decreasing the progression to invasive disease. As a result, less radical approaches have been considered and available evidence suggests that high-resolution anoscopy (HRA) is the optimal treatment approach. This technique allows for targeted destruction of HSIL, with minimal wound and functional morbidity with lower rates of progression to invasive disease than other reported approaches.

In HRA the anal canal and perianus is coated with 3% acetic acid and then examined using an operating microscope. Areas that are affected by HPV turn white and have characteristic vascular patterns. Lugol iodine may then be applied to areas of concern that may lack the classic vascular changes; areas of HSIL do not absorb the Lugol iodine and turn yellow, whereas areas of LSIL and normal tissue turn brown/black. The area of suspected HSIL should be biopsied to confirm the diagnosis and then ablated with either electrocautery or infrared coagulation, with the goal of achieving a superficial burn in the areas of HSIL and preserving uninvolved regions. Using this approach, HSIL can be eradicated, even in immunocompromised patients, although multiple treatments may be required initially. 33,34

An alternative treatment for HSIL is immunomodulators such as 5% imiquimod (Aldara) cream, topical 5% 5-FU, or a combination of the two. In a randomized trial, 388 HIV-positive MSM were screened for HSIL by HRA, of which 246 patients who were diagnosed with HSIL were randomly assigned to receive imiquimod, topical 5-FU, or ablation with electrocautery. Although electrocautery was superior to the other two regimens, more than half of the patients recurred regardless of the treatment agent. 35 These finding are similar to those from a large retrospective cohort analysis of 456 HIV-positive and 271 HIV-negative MSM treated for HSIL with ablation. After a follow-up of 3 years, 77% of the HIV- positive and 66% of the HIV-negative patients developed recurrent HSIL. 36 Despite the high risk of recurrence and regardless of the treatment strategy, HIV-positive patients and/or MSM should be closely monitored for recurrent HSIL and be treated as this approach minimizes the risk of progression to anal SCC.

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Therapeutic Areas II: Cancer, Infectious Diseases, Inflammation & Immunology and Dermatology

E. De Clercq , in Comprehensive Medicinal Chemistry II, 2007

7.10.4 Papillomaviruses

As for polyomaviruses, no antivirals have been licensed for the treatment of human papillomavirus-associated diseases, including warts, condylomata acuminata, papillomas, and cervical, vulvar, penile, and (peri)anal dysplasia (evolving to carcinoma). Cidofovir has been used 'off label,' with success, in the topical and, occasionally, systemic treatment of HPV-associated papillomatous lesions. 2 In many instances, a virtually complete and durable resolution of the lesions was achieved following topical application of cidofovir as a 1% gel or cream. In addition to cidofovir, other acyclic nucleoside phosphonates, such as cPrPMEDAP (N6-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine, 2), are being explored for their potential in the treatment of HPV-associated papillomas and dysplasias. 2,3 These compounds have been shown to specifically induce apoptosis in HPV-infected cells, which, in turn, may be related to their ability to restore the function of the tumor suppressor proteins p53 and pRb (which are neutralized by the oncoproteins E6 and E7, respectively, in HPV-infected cells).

Recently, biphenylsulfonacetic acid derivatives have been described as inhibitors of HPV E1 helicase-associated ATP hydrolysis. 4,5 Although these novel ATPase inhibitors can hardly be considered to be good drug candidates, they may serve as leads for further optimization as potential antiviral agents active against multiple HPV types. 5

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Vulva, Vagina, and Anus

Fadi W. Abdul-Karim , ... Bin Yang , in Comprehensive Cytopathology (Third Edition), 2008

Anal Cytologic Screening Guidelines

Currently there is no official guideline regarding anal cytology as screening for anal SIL. The following is based on the approach used by the group at the University of California at San Francisco, which is spearheading the clinical research on anal dysplasia. 96,114,115

1.

HIV-negative men with history of receptive anal intercourse or anal warts. If the first anal Pap is negative, it should be repeated in 6 months. If the second Pap is negative, then repeat Pap should be obtained in 3 to 5 years.

2.

HIV-positive men with history of anal intercourse or anal warts. If the first anal Pap is negative, it should be repeated in 6 months. If the second Pap is negative, then repeat cytology should be obtained in one year. It has been suggested that patients with CD4 counts 500 mm should be screened more frequently.

3.

HIV-negative women with history of anal warts, cervicovaginal HSIL, VIN, or invasive cervical cancer. If the first anal Pap is negative, it should be repeated in 6 months. If the second Pap is negative, then repeat Pap should be obtained in 3 to 5 years.

4.

HIV-positive women. If the first anal Pap is negative, it should be repeated in 6 months. If the second Pap is negative, then repeat cytology should be obtained in one year. Some clinicians screen patients with CD4 counts < 500 mm more frequently.

5.

Consider screening patients with organ transplants on chronic immunosuppressive agents.

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SEXUALLY TRANSMITTED DISEASES OF THE ANUS AND RECTUM

In Surgery of the Anus, Rectum & Colon (Third Edition), 2008

HUMAN PAPILLOMA VIRUS (HPV)

HPV is highly prevalent, occurring in 20–40% of sexually active adults (Stanley, 2003). It has an estimated incidence of 5.5 million cases/year, and a prevalence of 20 million cases in the United States (Cates, 1999). HPV of the cervix is more delineated, although the incidence of perianal HPV is reported to be higher in MSM (60% HIV-negative versus 93% HIV-positive) (Palefsky et al, 1998b) and in high-risk women (42% HIV-negative versus 76% HIV-positive) (Palefsky, 2000). Patients with HIV tend to present with more clinical manifestations of HPV, although it is unknown if HIV augments HPV (Vernon et al, 1993).

HPV is a nonenveloped, double-stranded DNA. There are more than 30 types of HPV that can infect the genital tract, and more than one-third cause anogenital warts. HPV enters the body through abrasions in the continuity of skin or epithelium, and direct anal sex is not necessary for anal disease to occur. Upon entry it resides in the basal epithelium, avoiding the normal immune surveillance of the anus. HPV typically infects and replicates in the lower levels of stratified epithelium, causing infected keratinocytes to proliferate in an abnormal fashion, and producing genital warts (Beutner et al, 1998, 1999 ). HPV-6 and -11 are the most common low-risk HPV subtypes, and generally reside in the cytoplasm of the host cell. HPV-16, -18, -31, -33 and -35 subtypes are associated with an increase in anal dysplasia and neoplasia ( Wiley et al, 2002a). The oncogenic HPV types generally reside in the nucleus and fuse with the host genome. It is believed that, with oncogenic HPV types, the E2 protein loses its ability to make keratinized warts and thus produces softer warts on the inside of the anus. It is common for patients to be infected with multiple HPV types (Sobhani et al, 2001; Stebbing et al, 2003).

HPV causes a spectrum of anal diseases, ranging from asymptomatic infections to warts, precancerous changes and malignancy (Beutner et al, 1999). Although not a prerequisite, patients typically have a history of ano-receptive intercourse. Warts may be identified in asymptomatic individuals. Alternatively, patients may present with growths, bleeding, pruritus and/or chronic discharge. Examination reveals growths that can range from small, flesh-colored lesions or plaques to cauliflower-like abnormalities that grow singularly, in clusters or in plaques (Wiley et al, 2002a). Anoscopic examination is critical, and reveals lesions up to the dentate line. Examination of the perineum should include the genitalia, skin folds and a vaginal exam in women. Histologically dysplastic changes range from koilocytes to precancerous abnormalities. Pathologic confirmation is usually not necessary, but should be used in instances where the lesions are atypical.

The presence of perianal and/or anal canal warts can cause physical and emotional symptoms, and may lead to anal dysplasia. The role of vaccination against HPV is now being explored in the protection of cervical malignancy, but the role of vaccination in the protection of anal disease is at present unknown. Therefore, eradication is recommended. Although this has not been rigorously studied, it is generally believed that the infectivity rate is decreased after the eradication of visible warts. There are no data to indicate whether treatment for warts eliminates infectivity (Wiley et al, 2002a), although it is hypothesized that destroying the virus-laden cells, most commonly seen superficially, decreases shedding of the virus (Stanley, 2003). Current sexual partners of the infected individual should also be examined and standard STD evaluation undertaken, although the virus may be latent for years, and therefore patients may have been infected years prior to showing clinical manifestations of condyloma. Prior to treatment, patients should be advised of the possibility of transmitting HPV, especially when clinically apparent warts are present. Several methods have been advocated for treatment, and a combination of therapies is sometimes necessary to eradicate anal warts.

Patient-applied therapies are advocated by many primary care physicians. Topical agents such as podofilox (podophyllin) 0.5% (twice a day for 3 days, nil × 4 days and repeat for up to 4 cycles) or imiquimod 5% cream (nightly 3 times/week for up to 16 weeks) are the most common. Podofilox has been reported to eradicate warts in 45–82% of patients (Beutner et al, 1999). However, recurrence rates may be high, and patients may develop adverse outcomes such as skin ulcerations and erosions, erythema and irritation (Beutner et al, 1999). Imiquimod activates macrophages and dendritic cells to release interferon-α and other pro-inflammatory cytokines (Stanley, 2003). A recent case series reported very low recurrence in patients treated with either imiquimod alone (15%) or with imiquimod for 16 weeks followed by surgery (20%) (Carrasco et al, 2002); although several larger studies suggest that imiquimod is usually not effective in isolation (Stanley, 2003). In addition, no patient-applied therapy has been approved for the treatment of anal canal warts.

The preferred treatment method for managing perianal and anal warts involves fulguration of small lesions or excision of large lesions. Depending on the extent of disease and patient preference, treatment may be done in the office with local anaesthetic or as a same-day procedure with either spinal or general anaesthesia. Patients are placed in the prone jack-knife position with buttocks taped apart. Acetic acid staining of the perineum and/or anal canal is done if necessary. Careful examinations of the perineal area and the anal canal are repeated. Fulguration of each growth is done until the tissue can be wiped away with gauze. After fulguration or excision, repeat examination is undertaken to ensure that all lesions have been removed and that haemostasis has been achieved. Patients are advised to take oral analgesics, sit in warm water, avoid soap and cleanse the perineum with warm water and/or a perineal cleansing cream until symptom resolution.

After surgical eradication of warts, the local recurrence rates vary from 20 to 30% (Wiley et al, 2002a). Patients with HIV are more likely to recur (Manzione et al, 2003). A recent study demonstrated that patients with anal HPV warts were frequently not able to detect recurrences by self examination (Wiley et al, 2002b). Therefore, patients with HPV-associated warts need to be followed clinically. It is our practice to examine patients every three months for the first year after treatment. There are some data to suggest that use of imiquimod after fulguration decreases the incidence of local recurrence (Kaspari et al, 2002). However, imiquimod is expensive, painful and cumbersome to use, and is reserved for patients with multiple recurrences. In patients who develop recurrences, fulguration is repeated; and in patients with multiple recurrences imiquimod is offered after fulguration. If patients do not develop any additional warts in the year following treatment, then surveillance is decreased to once every six months. After two years without recurrence, patients should be followed on a yearly basis.

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Diseases of the Anorectum

Peter W. Marcello , in Sleisenger and Fordtran's Gastrointestinal and Liver Disease (Ninth Edition), 2010

PRURITUS ANI

Pruritus ani is an itch localized to the anus and perianal skin. Most patients presenting with pruritus ani believe their symptoms are from hemorrhoids, but most often this is not the case. Pruritus ani is categorized as either idiopathic (primary) or secondary. Idiopathic pruritus ani is diagnosed when no underlying etiology is found. Secondary pruritus ani results from an underlying disorder, and specific treatment leads to resolution of symptoms. Because pruritus ani is poorly understood, and an underlying premalignant lesion such as Bowen's disease or Paget's disease may be the cause of symptoms, all patients with pruritus ani deserve a thorough investigation.

In a prospective study, 109 patients were referred over a period of two years to a colorectal clinic with a primary symptom of itching. On evaluation, 26 patients were found to have some form of colorectal or anal dysplasia, 56 had anorectal disease (most commonly fissures or hemorrhoids), and 27 had no identifiable etiologic disorder. 108 After surgical treatment of all patients with colorectal neoplasia, their itching resolved. Of the 56 patients with anorectal disease, six continued to have itching after medical or surgical treatment. All 27 of the patients with no obvious cause for their itching underwent conservative medical treatment, and six continued to have persistent symptoms. 7

A thorough history and physical examination are the starting points for evaluating patients with anal itching. Examination of the rectum and sigmoid colon should be included. The pattern of irritation should be noted, and consideration should be given to biopsy any abnormal skin. Usually, diet-induced pruritus is symmetrical, whereas infectious causes lead to an asymmetrical pattern of anal irritation. Leakage of stool due to fecal incontinence and leakage of mucus are common sources of pruritus ani and may be associated with prolapsing hemorrhoids or true rectal prolapse. Other causes include contact dermatitis, infections (e.g., candidiasis), parasites, systemic diseases (e.g., diabetes mellitus), diet (caffeine in coffee, cola, or chocolate; dairy; citrus; beer; and others), and some medications. It has been said that dietary factors, especially any form of caffeine, may be the most common culprit. 109 The exact mechanism whereby caffeine might act as an irritant to the perianal skin is unclear.

Any underlying disorder should be treated; however, in many patients the cause of pruritus ani cannot be identified. These patients should be advised to modify their cleansing habits and to eliminate potential caffeine-related dietary culprits such as coffee, tea, and chocolate during a trial period. Most important is to convince the patient to stop "polishing" his or her anus. Frequently, the patient feels that the anal area is unclean, and he or she rubs the area vigorously, both for comfort and to try to clean the area more completely. Wiping gently with wet facial tissue or baby wipes is recommended. Avoiding soap and a washcloth in the shower may help. The patient should be instructed to use plain water and his or her hand to wash the perineum in the tub or shower. Creams or emulsifying ointments may be used instead of soap. 110 Perfumed soaps and astringents (such as witch hazel) should be avoided. Tissue paper or a cotton ball placed by the anus and changed several times a day will absorb moisture and create a drier environment. A diet high in fiber with plenty of fluids (similar to the diet described for hemorrhoids) is recommended. A limited amount of 1% hydrocortisone cream can be used. Patients should be warned that chronic use of hydrocortisone will thin the anal skin and can lead to more problems.

Most patients respond to this regimen. Relapse is common and can require re-education of the patient. The physician should be aware that a previously overlooked underlying problem may be the cause of the pruritus and should take a fresh look at a patient who has a relapse. Assistance from a dermatologist also may be helpful and should be considered initially. 110

Intradermal injection of methylene blue has been used successfully for the treatment of intractable idiopathic pruritus ani that has not responded to any other measures. 111

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Sexually transmitted diseases and the anorectum

Lester Gottesman , Josef A. Shehebar , in Colorectal Surgery (Fifth Edition), 2014

Human papillomavirus

Human papillomaviruses (HPVs), which are small DNA viruses, cause benign and malignant changes to the epithelium of the anorectum and genitalia. It is likely the commonest STD worldwide, with an estimated incidence of over 6.2 million cases annually in the USA. 21

There are over 120 types of HPV and approximately half are capable of anogenital infection. 22 Infections may remain subclinical or be active and induce benign, hyperproliferative lesions of the epithelia, called warts, papillomas, or condylomata.

The α-papillomavirus group of HPV types (comprising 15 species distinguished to date) are those that typically infect the anogenital tract. These mucosotropic HPVs are further classified into non-oncogenic or low-risk (LR) types, such as HPV-6 and HPV-11, and potentially oncogenic or high-risk (HR) viruses, including HPV-16, HPV-18, HPV-51 and HPV-53. Lesions induced by the oncogenic types can progress to high-grade dysplasias and cancers. In contrast, the LR HPV-6 and HPV-11 are rarely found in anogenital cancers. 22

The natural host tissue for the infection cycle of all HPVs is the squamous epithelium lining of body openings. A band of rapidly cycling and dividing keratinocytes called the transformation zone establishes a squamo-columnar junction at each body opening. 22 Because this zone is particularly susceptible to papillomavirus infection, if the infecting strain is an HR genotype there is a risk of dysplasia and even progression to carcinoma. The ability to destabilise the tumour suppressors p53 and pRB, as well as other cellular proteins, is what largely accounts for the oncogenic potential of the HR HPVs. 22

HPV infects the squamous epithelium when basal or parabasal cells are exposed by wounding and come into contact with infected skin, mucosa or fluid. Additionally, wounding of an infected surface may cause desquamation, releasing HPV virions and causing more infection. Transmission occurs most commonly via sexual contact with infected individuals, although perianal and genital involvement can occur without anal intercourse via skin-to-skin or skin-to-mucosa contact. 23

Infection can be clinically silent or result in bleeding, pruritus, pain, wetness and/or the feeling of a lump. The lesions can range in appearance from a single, pinkish-white lesion, to multiple large cauliflower-like masses ( Fig. 16.2 ).

Diagnosis is primarily made on physical exam; anoscopy is necessary for complete evaluation because involvement within the anal canal can occur, although lesions above the dentate line are rare. Because associated genital lesions are common, patients with anal condyloma should undergo thorough physical examination, including a vaginal exam and Pap smear in women. Anal canal lesions that are missed on simple visual inspection with anoscopy can be detected with 5% aqueous acetic acid; regions of active HPV mucosal infection briefly turn cloudy white ('aceto-whitening'). Colposcopy of the anus (high-resolution anoscopy) can be used with acetic acid and Lugol's iodine to assess the presence of anal dysplasia and identify high-grade dysplasia from benign condyloma.

Lesions that are confused with anal condylomata include condyloma lata (syphilis), molluscum contagiosum and hypertrophied anal papillae. Histopathology will confirm the diagnosis. The goal of treatment is to destroy all visible disease while minimising morbidity. Because only gross lesions are treated, virus will remain in adjacent epithelium and can lead to recurrence.

For small (1–3   mm) external and accessible lesions on the perianal skin, a topical patient-applied agent such as podofilox, imiquimod, cidofovir or green-tea extract (sinecatechins) is first-line therapy, although all have shown substantial failure and recurrence rates. The patient needs to be compliant and able to identify and reach all lesions. Patient-applied topical therapies are approved for external lesions only. If one type of topical therapy fails, another may be initiated. 3

Podophyllin is a non-standardised resin from the may-apple plant (Podophyllum peltatum) that is cytotoxic. A 15–25% solution is applied once or twice weekly and washed off 4 hours later. It is not intended for use in the anal canal. Concerns about systemic side-effects when applied to larger lesions and inferior efficacy compared to podophyllotoxin have led experts to no longer recommend its use. 24

Podofilox (podophyllotoxin) is the purified active antimitotic compound from Podophyllum spp., which is available as 0.5% solution or 0.15% cream. Both have demonstrated clinical superiority to podophyllin. 25 Podophyllotoxin can be self-administered twice daily for 3 days, followed by 4 days off, repeated for four cycles. The total volume used per day should not exceed 0.5   mL. 3 Resolution of warts has been reported in 20–50%, with recurrence rates of almost 50% at 1 year. 26 Ulceration occurs in 10–20% but other side-effects can occur if it is applied to areas greater than 10   cm2 or to skin surfaces that allow systemic absorption, such as the mucosal surface of the anal canal. 27

Imiquimod (Aldara) is an immune response modifier that induces α-interferon, tumour necrosis factor-α and other cytokines. It has the potential to eradicate HPV from mucocutaneous surfaces adjacent to gross lesions following excision/ destruction; 5% cream is applied nightly three times a week and washed off after 8 hours. This can be continued for up to 16 weeks. Local skin reactions are common but only about 5% of patients cease treatment because of them. Complete resolution of external lesions occurs in over 50% and additional patients experience a substantial reduction of wart volume. 28, 29 Recurrence rates have been reported to be between 19% and 23% at 3–6 months. 30 This agent is emerging as a safe, effective topical treatment, even in HIV-positive patients.

Imiquimod can be used as initial treatment with electrodessication reserved for an incomplete response, although the authors use imiquimod to treat early recurrences after surgical treatment, or as adjuvant treatment after surgery in patients who have a tendency for recurrence. 30

Cidofovir 1% gel is an acyclic nucleoside phosphonate with broad-spectrum antiviral activity. It has activity against vulval, vaginal and perianal intraepithelial neoplasia. When used for up to 6 weeks it has been shown to be more effective than electrosurgery in the treatment of anogenital warts in HIV-positive patients. 31 Cidofovir alone cleared all low-risk HPV and 57% of high-risk HPV, with a 35% relapse rate compared with 74% in the surgery-alone group at 6 months, although combined electrocautery and cidofovir gave the best results (100% complete response). While these studies are of great interest, the follow-up is short. 32

A newer treatment for HPV is sinecatechin (Polyphenon E) ointment, a mixture of polyphenols from green-tea extracts, which has an antioxidative, anti-inflammatory and anti-cancer effect. Three trials have demonstrated eradication of anogenital warts in over 50% of patients using Polyphenon E ointment versus 35.4% using placebo. This ointment seems to be better tolerated than imiquimod. It is for external lesions only, and is applied by patients three times daily, for 16 weeks. 3 Sinecatechins are not recommended for immunocompromised patients or patients with genital herpes. 3

Lesions inside the anal canal require provider-administered therapies including trichloracetic acid, cryotherapy and surgery. Trichloracetic acid as a 60–90% solution can be applied directly to perianal and anal canal lesions. Destruction of the lesion is by protein coagulation with tissue sloughing, so adjacent skin should be protected or cleaned immediately. Care is taken to apply the solution only on the warts and allow the solution to dry before the patient moves. It is applied weekly and numerous treatments are usually required. It is best reserved for lesions that are small (1–4   mm) and few. Multiple lesions can be treated simultaneously. The recurrence rate is about 25%. 33

Cryotherapy is listed in the Centers for Disease Control (CDC) treatment guideline for anal warts. 3 Freeze–thaw cycles can be produced with a cryoprobe, application of liquid nitrogen with a cotton-tipped applicator or with aerosolised liquid nitrogen. The procedure is inexact and it is difficult to gauge depth of tissue destruction. Painful local reaction is common, and some may experience ulceration and foul-smelling discharge. The provider can repeat treatment of the warts every 1–2 weeks until the lesion has resolved. Studies have found the success rate to be about 75%, with a recurrence rate as high as 25–39%. 34

Tangential excision or fulguration of small internal and external lesions (smaller than 5   mm) can be performed in the office with local anaesthetic after a circumferential anal block. Larger and broad-based lesions, which would require excision of a substantial portion of perianal skin, are treated by electrodessication, usually with a spinal anaesthetic, local anaesthetic, deep sedation or a combination thereof. The superficial-most layer of the condyloma is fulgurated with the cautery tip until it takes on a grey–white appearance. This is followed by curettage or simply abrading the fulgurated tissue with forceps or gauze. Treatment is repeated until the condylomata are completely removed without burning into the deep dermis. Pedunculated warts can be transected at their base. Tissue from HIV-positive patients, flat, recurrent or suspicious lesions that may be ulcerated, friable or hypervascular should be sent for histopathology, and it may be useful to send tissue for HPV typing too. Daily wound care with soap and water is usually adequate; however, in the USA mupirocin or sulfadiazine is given if evidence of infection develops.

Compared to patient-applied and provider-applied therapies, surgical excision has the greatest success in treating anal condyloma, with clearance rates of 71–93%, and recurrence rates between 4% and 29%. 35, 36

Laser destruction has been advocated as less painful and associated with fewer recurrences than other destructive techniques. No prospective, randomised data support these claims. A risk of laser is the problem of aerosolised viral particles in the plume. Viable viral particles have been recovered from this smoke and cases of medical providers developing condylomata in their respiratory tract after using a laser to treat warts have been reported. Masks and smoke evacuators are recommended. Transmission of viral particles appears to be less of a problem with the larger-particle smoke from electrocautery. Finally, the laser is vastly more expensive than electrocautery and requires special training.

Intralesional interferon-α (IFN-α) has been used with good results in recurrent condyloma or condyloma that have been resistant to other therapy. It is administered as an injection of 1   ×   106 IU under a maximum of five lesions, three times a week for 3–8 weeks. 32 IFN-α blocks viral reproduction and is an integral part of natural antiviral defences. Efficacy as primary treatment is no better than other modalities and systemic side-effects such as fever, myalgia, headache and leucopenia occur. When IFN-α is used in combination with surgery for resistant anal condyloma the recurrence rate is 12% at 4 months, compared with a 39% recurrence in a placebo group. 37, 38

Vaccination against HPV (Gardisil) was approved in the USA in 2006. The evidence for its use in preventing cervical intraepithelial neoplasia and cervical malignancies as part of a population immunisation programme is well established. The quadrivalent vaccine (against HPV-6, -11, -16 and -18) is delivered through a series of three intramuscular injections. Currently, the CDC recommends routine administration of the vaccine to girls and women from ages 9 to 26. 39 The vaccine has also shown efficacy against anogenital warts in Phase II/III trials. In a recent randomised trial performed on over 4000 healthy males aged 16–26, it was demonstrated to prevent infection with HPV-6, -11, -16 and -18 and the development of related external genital lesions with an efficacy of 65.5%. 40 A newer study has shown that the quadrivalent HPV vaccine is effective in preventing anal intraepithelial neoplasia (AIN) among MSM, although the study was limited to those who were HIV negative at enrolment. 41 Clarification of some uncertainties, notably vaccine efficacy in men and HIV-infected individuals, is required to establish the benefits of HPV vaccines for the prevention of malignant and premalignant anal lesions. 41 Although sexually active patients may have already been infected with one or more of the vaccine HPV serotypes, they may still derive partial benefit by getting vaccinated against those serotypes to which they have not yet been exposed. 42

Immunotherapy with weekly injections of 0.5   mL of an autologous vaccine has been described, 43 with no adverse reactions. Disappearance of warts occurred in 84% of patients. Vaccine preparation and treatment time prevented this from more widespread use.

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Skin Manifestations in Patients with Human Immunodeficiency Virus Infection

Toby Maurer , in Goldman's Cecil Medicine (Twenty Fourth Edition), 2012

Infectious Manifestations

HIV Seroconversion Exanthem

Frequently observed in acute HIV infection is an infectious mononucleosis–like illness that precedes seroconversion by 2 to 6 weeks. The rash is characterized by erythematous macules and papules ranging from 2 mm to a few centimeters, particularly on the upper part of the trunk and face with relative sparing of peripheral regions. It is commonly accompanied by aphthous or penile ulceration, or both. There is evidence that very early after infection, HIV goes to dendritic cells in skin and causes an inflammatory response, which may explain the rash. At this stage the viral load may be very high and is suggestive of acute HIV seroconversion, although the HIV antibody test is likely to be negative.

Viruses

Herpes Zoster

Herpes zoster (Chapter 383) is often observed even at relatively normal CD4+ counts and may therefore be the first feature of HIV infection. The mouth may also be affected. In any patient younger than 50 years with zoster, risk factors for HIV should be explored and consideration given to HIV testing. Zoster infection may be multidermatomal or disseminated even in patients with relatively high CD4+ counts, and if it involves the eye, treatment with intravenous acyclovir should be considered. Antiviral treatment should be started at any time during the disease course (not only within the first 48 hours, as with zoster not associated with HIV). Less severe disease normally responds to standard treatment. There have been a few reports of a verrucous chronic form of zoster occurring in more severely immunosuppressed patients; this form of zoster is usually associated with acyclovir resistance. Zoster has been one of the more commonly reported diseases in patients with immune reconstitution inflammatory syndrome (IRIS) (Chapter 402) and has been noted to appear in the second phase of IRIS, that is, later than the initial 3 months of ART.

Herpes Simplex Virus

Infection with herpes simplex virus (HSV) (Chapter 382) should always be considered in patients with HIV who have mucocutaneous ulcerations (Fig. 399-1), particularly in the anogenital area. Patients with CD4+ counts lower than 200 cells/µL may require higher doses of acyclovir to treat the infection. (See Table 399-1 for skin conditions occurring at CD4+ counts lower than 200 cells/µL in patients not receiving ART.) Patients who fail to respond may have HSV with acyclovir resistance, and alternative agents such as foscarnet or cidofovir may be required. The presence of HSV clinically or subclinically increases the likelihood of transmission of HIV. There also appears to be synergy between HSV and HIV, which may mean faster progression of HIV disease. Daily acyclovir therapy to suppress coinfection with HSV-2 has recently been found not to reduce the risk for transmission of HIV. 1

Human Papillomavirus

Human papillomavirus infection (Chapter 381) is very common in all stages of HIV infection. Common, flat, genital, and plantar warts are all seen with increased frequency. Patients with significant immunosuppression may have particularly extensive warts that are recalcitrant to standard treatment. Most patients commencing ART often notice considerable improvement or resolution of the warts. However, some patients receiving ART will not clear their warts despite improvement in the CD4+ count, suppressed viral load, and resolution of all other opportunistic infections. The reasons for this observation remain obscure. Treatment modalities include cryotherapy, surgery, laser, topical salicylic acid preparations, podophyllin, intralesional bleomycin, and contact sensitization immunotherapy. Imiquimod has proved to be a useful modality for genital warts but appears to be less effective in the HIV setting. Anal carcinoma and anal intraepithelial neoplasia are frequent in HIV-infected patients (men and women), and screening anal Papanicolaou smears may be helpful in identifying anal dysplasia.

Molluscum Contagiosum

Molluscum contagiosum is a poxvirus (Chapter 380) that causes a self-limited papular umbilicated eruption commonly seen in children. It is rarer in adults and, when present on the face, persistent, or severe, raises the possibility of HIV coinfection. It tends to occur when the CD4+ count falls below 200 cells/µL. First-line treatment is ART because molluscum contagiosum is invariably cleared with rising CD4+ counts. Ablative treatments such as cryotherapy or curettage will treat individual lesions more expeditiously but can leave scarring; however, without ART the lesions are likely to recur.

Epstein-Barr Virus (Oral Hairy Leukoplakia)

Oral hairy leukoplakia (OHL) is characterized by nonpainful white plaques with a feathered edge, particularly on the lateral border of the tongue. It is associated with Epstein-Barr virus (Chapter 385) and is very rare in immunocompetent hosts. OHL can occur at any CD4+ count and may therefore be the initial feature of HIV infection. (See Table 399-2 for skin diseases not affected by the CD4+ count.) The appearance of OHL was a poor prognostic indicator before ART. There is no specific treatment of OHL, although it tends to resolve when patients are receiving ART. Superinfection with Candida spp should be considered if the lesions are painful.

Bacteria

Staphylococcus aureus

Infections with Staphylococcus aureus (Chapter 296) are commonly seen in HIV disease. Staphylococcal folliculitis (Fig. 399-2) tends to be more severe or refractory to treatment in HIV-infected patients than in those who are HIV negative. Other cutaneous manifestations of staphylococcal infection include cellulitis, ecthyma (necrotic plaques), or, rarely, botryomycosis. Treatment of folliculitis includes antiseptic washes such as chlorhexidine solution, eradication of nasal carriage with mupirocin ointment, and, occasionally, systemic antibiotics. More severe infections may require intravenous antibiotics. There has been concern that patients infected with HIV are at increased risk for the development of infections, particularly recurrent infections with methicillin-resistant S. aureus (MRSA). Rifampicin is often used to clear MRSA, but caution should be used in patients receiving ART because rifampicin is a potent inducer of cytochrome P-450 and will therefore interfere with protease inhibitors. Risk factors for infection, including colonization with S. aureus, are being explored.

Bartonella

Bacillary angiomatosis is caused by Bartonella species (most commonly Bartonella henselae and Bartonella quintana) (Chapter 323). Occult infection with Bartonella should be considered in any HIV-infected patient with fever of unknown origin. The cutaneous lesions appear as purple papules, nodules, or ulcers in HIV-positive individuals. Clinically, they may resemble lesions of Kaposi's sarcoma (KS) and may also be confused with pyogenic granuloma or cutaneous lymphoma. These lesions should always undergo biopsy with tissue sent for culture. Bacillary angiomatosis responds to antibiotics such as macrolides, which will be needed for at least a 2-month course of treatment. Bacillary angiomatosis can be associated with visceral disease; in particular, the liver and spleen may be affected.

Syphilis

Syphilis (Chapter 327) is frequently seen in patients with HIV infection. Its cutaneous manifestations are protean, and therefore syphilis should be considered in any patient infected with HIV who has a new cutaneous eruption. An example of a secondary syphilis exanthem is shown in Figure 399-3. Primary, secondary, and tertiary forms of syphilis may be manifested clinically as they are in HIV-negative individuals, although atypical findings are not uncommon. Serology is not as reliable in patients with HIV infection, and skin biopsy may be useful in establishing the diagnosis. First-line treatment is still with penicillin. Azithromycin resistance has been reported. Follow-up titers of syphilis serology should be documented to ensure adequate treatment and central nervous system (CNS) clearance.

Fungi

Candida

Oral candidiasis (Chapter 346) is commonly seen in patients with immunodeficiency, including HIV infection. It is characterized by white, cheesy plaques and papules loosely adherent to the tongue and oropharynx. Topical therapies include clotrimazole troches and nystatin oral suspension. First-line oral treatment is with fluconazole, although there is emerging resistance in Candida species, including Candida albicans, the most common species associated with thrush. Second-line treatment consists of oral itraconazole, although it is unclear whether pulsed therapy is preferable.

Dermatophytes

The prevalence of dermatophyte infection (Chapter 446) is not higher in HIV-infected patients than in control groups. However, increased severity and variability in the manifestations of dermatophyte infection are seen in HIV coinfection. Tinea corporis and tinea cruris can occur at all stages of immunosuppression and may be treated successfully with topical antidermatophytic preparations such as ketoconazole or terbinafine. Treatment of onychomycosis is systemic therapy with oral antifungals, although onychomycosis recurrence rates have not been studied.

Other Fungi

Cryptococcus neoformans is a yeast that tends to cause clinical problems when patients are profoundly immunosuppressed (CD4+ count <100 cells/µL). It commonly affects the CNS and causes meningitis, but it can affect the skin and give rise to papules indistinguishable from molluscum contagiosum. Histoplasma capsulatum and Penicillium marneffei may morphologically resemble molluscum. Patients who have had these diseases need long-term suppressive doses of antifungal medications.

Infestations

Scabies

Scabies (Chapter 367) is caused by infestation with the mite Sarcoptes scabiei and is commonly seen in HIV-infected individuals. It can be manifested as the classic rash of scabies with burrows affecting the finger and toe webs and widespread excoriated papules with a predilection for the axillae, nipples, and genitalia. It can also appear as crusted scabies with hyperkeratotic plaques that tend not to be pruritic. Combination treatment with a topical agent such as permethrin or benzoyl benzoate and systemic treatment with ivermectin tablets is recommended for crusted scabies. Topical agents may be sufficient for classic scabies. Lindane lotion is often used to treat scabies, but there have been reports of lindane-resistant scabies and neurologic side effects attributed to this treatment.

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