Clinical Features

Grossly, high-grade perianal AIN or Bowen’s disease appears as discrete, erythematous, occasionally pigmented, noninfiltrating, scaly, or crusted plaques, which sometimes have a moist surface. Foci of ulceration indicate that an invasive carcinoma has developed. Patients may complain of itching, which often is intense, burning, or spotted bleeding, but only a biopsy will confirm the diagnosis. In a series by Marchesa et al, ⁴⁰ 25.5% of the cases of perianal Bowen’s disease were incidental findings, diagnosed after pathologic evaluation of tissue removed from different perianal diseases. The histologic picture is that of in situ squamous cell carcinoma that may have characteristic bowenoid cells, which are multinucleated giant cells with some vacuolization, giving a “halo” effect (▶ Fig. 17.1).

Diagnosis

Perianal high-grade AIN can involve perianal skin, anal verge, anoderm, and vulva. A circumferential involvement of the disease is common. ⁴¹ Although the gross lesions can be biopsied, their boundary and extent cannot be ascertained. This problem can be overcome by painting the anal canal and perianal region, and in women, including the vulva, with 3 or 5% acetic acid. The abnormal skin and mucosa will be demarcated by whitening of the tissue that should be biopsied. Chang and Welton ²⁷ performed the examination in the operating room under sedation and perianal block. They examined the painted tissue through the operating microscope attached to a real-time video display. Changes in the vascular pattern suggestive of high-grade dysplasia are identified. The same tissue is then painted with Lugol’s solution (10% iodine). High-grade AIN does not take up the iodine solution because of the lack of glycogen in the dysplastic cells and they appear yellow or tan, whereas normal tissue or low-grade AIN appears dark brown or black. Lesions suspicious for high-grade AIN are biopsied. As discussed later, this technique is currently referred to as high-resolution anoscopy or HRA.

Treatment

Treatment of Bowen’s disease or high-grade AIN has changed dramatically. Although the natural history of high-grade AIN is still not known, recent information has played an important role in the current management. High-grade AIN is pre-invasive and requires further management. At the time of surgical treatment, 2 to 28% of patients already have an invasive squamous cell carcinoma. ^{32 , 40 , 41} It is well known that the extent of the disease is usually beyond the gross demarcation of the lesion and can only be detected microscopically. Preoperative mappings were used in the past but were plagued with residual disease. ^{31 , 40 , 41} Currently, the biopsies are performed with the aid of staining the perianal skin, perineum, and anal canal with 3 or 5% acetic acid. ^{27 , 42} For low-grade AIN, treatment is not necessary if it is asymptomatic, but the patients should be followed periodically. There are several options on the treatment of high-grade AIN.

Summary

The management of perianal high-grade AIN or perianal Bowen’s disease has changed from the standard, “surgical excision of high-grade AIN remains the treatment of choice” ⁵⁰ to a more conservative, “close observation with regular biopsy of any suspicious areas to exclude invasive malignancy may be a better treatment option and is the policy currently advocated in this unit.” ³² Unless there is an invasive carcinoma, it is reasonable to apply imiquimod ⁴⁵ or topical 5-FU ⁴⁶ as an initial treatment. An alternative option may be cautery ablation. Surgical excision, especially an extensive one, should be reserved for patients with symptomatic disease such as untreatable itching, burning, or crusting of the skin. ⁴⁵ A long-term follow-up is essential because the skin may harbor the virus that perpetuates the disease. Subsequent development of malignancies in other organs should be kept in mind.

Screening for Anal Carcinoma Precursors

Prevention of cervical carcinoma has relied on the identification and treatment of cervical intraepithelial neoplasia before its progression to invasive carcinoma. Typically, women are screened at regular intervals using cervical cytology. Women with abnormal results are referred for colposcopy, to permit visualization of the lesion, and biopsy, to precisely ascertain the level of the disease. Based on the biologic similarity between anal and cervical carcinomas and their respective precursors, similar methods might be used to identify the potential anal carcinoma precursors. ⁵⁵

Screening should be considered in the high-risk group: (1) a history of homosexual activity in men and/or a history of receptive anal intercourse; (2) all HIV-positive women, regardless of whether or not they have engaged in anal intercourse; (3) all women with high-grade cervical or vulvar lesions or carcinoma. ³⁵ In homosexual and bisexual men, Goldie et al ⁵⁶ found that screening every 2 or 3 years for anal squamous intraepithelial lesions with anal cytology would provide life-expectancy benefits comparable to other accepted preventive health measures, and would be cost effective.

Cytology remains the screening test of choice as it is easy to perform and is relatively inexpensive. A Cytette brush (▶ Fig. 10.9) is moistened in saline solution or tap water and is rotated on the perianal skin for 10 to 20 revolutions with firm pressure abrading cells from the area. In the anal canal, very few high-grade squamous intraepithelial lesions (HSIL) occur solely in the transitional zone. The cytological preparation should be taken from the anal verge and lower anal canal only, to avoid fecal contamination in the smears. The brush is then smeared across a glass slide and the smear is fixed for standard fixative for Papanicolaou staining. Another option is to use a wooden spatula. When properly performed, the sensitivity and specificity is over 95% on the presence or absence of abnormal cells. ³¹

Abnormal anal cytologic results (LSIL or HSIL) should prompt anoscopic assessment, preferably with magnification and after application of 3 or 5% acetic acid. If one or more well-demarcated lesions are identified (by their white appearance after the application of 3 or 5% acetic acid, and by demonstrating features of vascular punctuation, leukoplakia, papillations, or other topographric irregularities), they should be biopsied if ^{31 , 32} there is no contraindication, such as a bleeding disorder. ^{29 , 30}

Patients with high-grade AIN should be treated with electrocautery or excisional biopsy. Low-grade AIN should be followed by a repeat screening cytology in 3 to 6 months. ⁵⁶

Screening HIV-positive homosexual and bisexual men for anal intraepithelial lesions and squamous cell carcinoma with anal Pap tests offers quality-adjusted life-expectancy benefits at a cost comparable with other accepted clinical preventive interventions. ⁵⁷

Human Papilloma Virus Vaccine

Vaccination against HPV types will require universal immunization as opposed to the targeting of “high-risk” persons. Because these are sexually acquired pathogens, immunizing persons before they become sexually experienced will afford the greatest benefit. ^{58 , 59} A vaccine against four types of HPV (GARDASIL; Merc & Co, Whitehouse, NJ) is currently available. In girls and young women ages 9 to 26, GARDASIL helps protect against two types of HPV that cause 70% of cervical cancer cases, and two more types that cause approximately 90% of genital warts cases. In boys and young men ages 9 to 26, GARDASIL helps protect against approximately 90% of genital warts cases. GARDASIL also helps protect girls and young women ages 9 to 26 against about 70% of vaginal cancer cases and up to 50% of vulvar cancer cases. In males and females ages 9 to 26, GARDASIL helps protect against about 80% of anal cancer cases. GARDASIL is not intended to be used for treatment of active genital lesions, AIN, or anal cancers. GARDASIL should be administered intramuscularly as a 0.5-mL dose at the following schedule: 0, 2, and 6 months. ⁶⁰ It is currently recommended that this vaccine be administered to all persons between the ages of 9 and 26. Future experience will demonstrate the impact on the incidence of HPV-related lesions.

General Considerations

Squamous cell carcinomas of the perianal skin resemble those occurring in skin elsewhere in the body. Grossly, they typically have rolled, everted edges with central ulceration (▶ Fig. 17.2). Any chronic unhealed ulcer should be considered a potential squamous cell carcinoma until proven otherwise by biopsy. Squamous cell carcinomas vary in size from as small as < 1 cm to large masses that completely surround and obstruct the anal orifice. The average age of the patient is between 62 and 70 years with a male-to-female ratio approximately equal. ^{61 , 62}

Clinical Features

Despite their surface location, squamous cell carcinomas are usually diagnosed late; more than 50% of cases are detected more than 24 months after the onset of symptoms. ⁶³ The carcinoma is often discovered at a late stage measuring 5 cm or larger in diameter. ⁶² The usual presentations are a lump, bleeding, pain, discharge, and itching. ⁶¹ On rare occasions, squamous cell carcinoma presents as a perianal abscess. ⁶⁴ Up to 28% of patients with perianal squamous cell carcinoma are misdiagnosed as having hemorrhoids, an anal fissure, an anal fistula, atopic eczema, an anorectal abscess, or a benign neoplasm. ⁴

Histologically, these carcinomas are usually well differentiated, with well-developed patterns of keratinization (▶ Fig. 17.3). Local invasion occurs, but the carcinoma is typically slow growing. Lymphatic spread from these carcinomas is directed mainly to the inguinal lymph nodes.

Treatment

Perianal squamous cell carcinoma is five times less common than squamous cell carcinoma of the anal canal. ⁶² There is limited information in the literature, few authors clearly define the perianal region according to the WHO and the AJCC standards, and the treatment varies widely among different institutions. However, in advanced cases, local excision and abdominoperineal resection (APR) have high failure rates because of local recurrence and inguinal node and distant metastasis. ^{62 , 65 , 66} In properly selected cases, wide local excision remains the cornerstone of the treatment of perianal squamous cell carcinoma. For in situ or microinvasive carcinoma, local excision has a 100% cure rate. ^{61 , 67} For superficial well-differentiated or moderately well-differentiated squamous cell carcinoma up to 3 to 4 cm in diameter, Cummings ³ of Princess Margaret Hospital in Toronto has shifted away from radiation therapy toward local excision, supplemented with a skin graft when necessary, provided that the operation is not anticipated to interfere with anal sphincter function. Cummings reasons, “Although severe damage is infrequent following radiation, chronic irritation of the perianal skin and varying degrees of dysfunction of the anal region are common and can be troublesome.” ³ For other less favorable lesions, he recommends chemoradiation. Most authors deliver 40 to 70 Gy. ^{62 , 65 , 66 , 68} Chemoradiation has also been shown to be superior to radiation alone in nonrandomized studies. ³ Residual or recurrent carcinoma after radiation can be treated with local excision or an APR. Prophylactic radiation to the groin is also recommended, particularly for T2 and T3 lesions. ^{62 , 66}

In a series of 54 patients who received radiation with or without chemotherapy, Papillon and Chassard ⁶² achieved a cancer-specific 5-year survival rate of 80%. The 5- and 10-year cancer-specific survival rates of 86 and 77%, respectively, were reported by Touboul et al ⁶⁶ in a series of 17 patients. The size of the carcinoma determined the patient’s survival. In that study, 5- and 10-year survival rates for T1 lesions were 100 and 100%, respectively, compared to 60 and 40% for T2 lesions, respectively. ⁴ With proper technique, serious complications from radiation therapy are uncommon. Radionecrosis and fecal incontinence have been claimed to occur only in a few patients. ⁶⁶

General Considerations

Perianal Paget’s disease is an intraepithelial neoplasm of the perianal skin. In 1874, Sir James Paget first described this disease in relation to the nipple of the female breast. ⁶⁹ George Thin, in 1881, was the first to describe the cytologic features of Paget’s cells, which appeared microscopically as large rounded cells with abundant pale-staining cytoplasm and a large nucleus that is often displaced to the periphery of the cell. ⁷⁰ The first case of perianal Paget’s disease was reported by Darier and Couillaud in 1893. ⁷¹ Extramammary Paget’s disease may be found in the axilla and the anogenital region (labia majora, penis, scrotum, groin, pubic area, perineum, perianal region, thigh, and buttock).

The histogenesis of perianal Paget’s disease is not fully understood, but ultrastructural and immunohistochemical studies have helped to clarify the debate. In contrast to Paget’s disease of the nipple, which is invariably associated with an underlying invasive or in situ ductal adenocarcinoma, perianal Paget’s disease starts out as a benign neoplasm. It may eventually become invasive and give rise to an adenocarcinoma. The immunohistochemical studies show that, in general, Paget’s cells stain positive for apocrine cells and in most cases stain negative for colorectal goblet cells. ⁷² Unfortunately, many of the markers expressed by perianal Paget’s cells are also expressed by signet ring cell carcinoma of the anorectum. ⁷² However, staining that is negative for all except a marker for anorectal goblet cells almost certainly indicates a spread of Paget’s cells from an anorectal mucinous adenocarcinoma. Most authors agree with the concept that Paget’s cells are of glandular and probably of apocrine origin. ^{73 , 74 , 75} An alternative hypothesis implicating pluripotential intraepidermal cells cannot be excluded, but the evidence for such a histogenesis is lacking. ⁷³