Schematic representation of squamous intraepithelial lesions (From The PRN Notebook vol. 10, no. 4, December 2005 (available at www.prn.org; reprinted without permission). Koilocytes are a typical representation of human papillomavirus–infected cells. Koilocytes may show the following cellular changes: nuclear enlaregment, hyperchromasia, irregular contour of the nuclear membrane, and a clear area around the nucleus, known as a perinuclear halo. As illustrated, the proportion of the epithelium that is replaced by dysplastic cells (presenting a large nucleus-to-cytoplasm ratio) increases with increasing severity of the dysplasia. In anal intraepithelial neoplasia (AIN) I, dysplastic cells are found in the basal third of the epithelium, in AIN II in the basal two thirds, and in AIN III throughout the whole epithelium
Little is known about the progression rate from high-grade AIN to anal carcinoma. In a small study, three of six immunosuppressed patients developed anal carcinoma within 5 years . Another study observed 72 patients with high-grade dysplasia, among whom 13 % (8 patients) progressed to anal carcinoma . Interestingly, no development of anal carcinoma was seen in a group of 446 human immunodeficiency virus (HIV)–positive homosexual patients in whom a high-grade dysplasia was treated. However, five patients who refused dysplasia treatment progressed to anal carcinoma .
As mentioned before, HPV infections (especially HPV-16 and -18) are strongly associated with the appearance of squamous cell carcinoma of the anus. In particular, persisting HPV infections caused by anal intercourse and a high number of sexual partners over a lifetime increase the risk of developing anal carcinoma. In addition to HPV infection, other important risk factors are
Immune suppression after transplant or long-term use of corticosteroids
A history of other HPV-related cancers
Anal cancer is subdivided into two categories:
Cancer of the anal canal
Cancer of the anal margin
The anal canal extends from the anorectal junction to the anal margin. The pigmented skin immediately surrounding the anal orifice is considered the anal margin, which extends laterally to a radius of ∼5 cm (Fig. 27.2). Lymphatic drainage of the proximal anal canal flows to perirectal nodes along the inferior mesenteric artery. Close to the dentate line, lymphatic vessels drain to internal pudendal nodes and to the internal iliac system. The region below the dentate line and the perianal region drain to the femoral, inguinal, and external iliac nodes.
Clinical presentation of endoanal dysplasia using high-resolution anoscopy (HRA) (From Kreuter et al. ; reprinted without permission) (a) Normal squamocolumnar junction without any signs of human papillomavirus–associated lesions. (b) Anal dysplasia (AIN 2). The lesion bleeds easily and is slightly thickened. Opaque areas with characteristic punctuation and mosaic structure are seen. (c) Anal dysplasia (AIN 2). Homogenous, well-demarcated, hyperkeratotic area with a granular surface. (d) Anal dysplasia (AIN 3). Large hyperkeratotic area with satellite lesions. The surface of the lesion is focally spiked and granular
Approximately 20 % of HIV-negative MSM suffer from anal dysplasia, 5–10 % of whom already exhibit severe epithelial dysplasia (AIN 2–3). In HIV-positive MSM, the prevalence of severe AIN reaches up to 50 % . In a study investigating 448 HIV-positive MSM, anal cancer was already present in 2.5 % of the patients .
There has not been much research on the prevalence of anal dysplasia among women, despite the fact that 6 % of HIV-negative and 21 % of HIV-positive women were found to suffer from anal dysplasia .
Anal cancer has gained particular attention since the late twentieth century as a result of its rapidly increasing incidence. Since the 1970s the incidence of 1 in 100,000 has doubled, and the sex distribution has changed from more women being affected to now having both sexes equally affected . Since the beginning of the AIDS epidemic in 1982, the incidence has especially been increasing among MSM, in whom the incidence of anal carcinoma has increased from 3.7 (1973–1978) to 20.6 in 100,000 people (1996–1999) . Cervical carcinoma had reached the same level of incidence before standardized screening tests were introduced, after which it dropped dramatically . Meanwhile, the incidence of anal carcinoma in HIV-positive MSM has reached 137–225 in 100,000 [12, 13], and the incidence is 10–100 times higher among immunosuppressed patients . The increasing incidence of anal cancer was not influenced by the introduction of highly active antiretroviral treatment.
The increasing incidence of anal cancer was not influenced by the introduction of HAART (Highly Active Anti Retroviral Treatment).
Approximately 80 % of sexually active adults will contract a genital HPV-infection at some point in their lives.
Approximately 80 % of sexually active adults will contract a genital HPV infection at some point in their lives. Infection with a specific HPV subtype typically lasts 6 months to 2 years, and it is assumed that 90 % of patients spontaneously eradicate the virus within this time period .
In HIV-negative MSM the prevalence of HPV is 50-–60 %  whereas in HIV-positive MSM it is almost 100 % .
In HIV-negative MSM, the prevalence of HPV is 50–60 % , whereas among HIV-positive MSM it is almost 100 % . The prevalence of anal HPV infections among heterosexual men was found to be 12 %. In 7 % of the patients examined, an oncogenic HPV subtype was present in the anal canal . In women, the prevalence of anal HPV infections lies between 13 and 29 % and is comparable to that of cervical infections . The prevalence of anal HPV infections in men seems to remain stable with age , contrasting with the age-specific prevalence of cervical HPV infections in women, which decreases after the age of 30.
The prevalence of anal HPV infections in men seems to remain stable with age .
As the symptoms of AIN are unspecific and similar to common benign anorectal diseases, it is important that all patients are properly clinically assessed to avoid delays in diagnosis. This is especially true for high-risk patients. It is mandatory to take biopsies of all unclear anal lesions to exclude anal dysplasia and cancer. Occasionally, AIN presents with symptoms such as itching or mild bleeding, but the majority of patients with anal dysplasia are asymptomatic.
High-resolution anoscopy (HRA) facilitates examination of the anal region and canal with 20× magnification and as such has proven itself superior to conventional proctoscopy. It enables the detection and targeted treatment of subclinical dysplasia, and in most cases it eliminates the need for a standard biopsy (anal mapping). A traditional proctoscopy without HRA misses 50 % of anal dysplasias . However, HRA was only used to diagnose anal dysplasia by 23 % of responders in a survey targeting over 6,000 surgeons and dermatologists in the field of coloproctology in Europe and Australia .
Polymerase chain reaction and in situ hybridization are used to type HPV upon a diagnosis of anal HPV infection, although the importance of this typification is questioned.
Patients with anal cancer present with perianal lesions that can be wartlike, ulcerative, or both. Although local pain is often missing, approximately one-third of patients with anal cancer experience pain caused by the invasion of the tumor into the anoderm and the sphincter complex. Incontinence or tenesmus may also result from sphincter involvement. A localized inguinal lymphadenopathy can also be a symptom of metastatic disease. Rectal bleeding is usually the first symptom of anal cancer and occurs in over half of patients .
Since the implementation of standardized screening tests, the incidence of cervical carcinoma has decreased by 70 % in developed countries. The effectiveness of regular gynecological checkups to prevent cervical cancer is no longer questioned. However, there are currently no general recommendations for screening tests for anal carcinoma in high-risk patients.
Regular screening tests are now starting to be recommended. For example, the Department of Public Health of the State of New York currently recommends yearly screening tests for all HIV-positive MSM, HIV-negative MSM with a history of genital condyloma, and women with abnormal gynecological cytology . Available data indicate that these recommendations should also include HIV-positive women.
In hypothetical models, regular anal smears were cost-effective for both HIV-positive and HIV-negative MSM [23, 24]. Prospective studies of cost efficiency are currently still outstanding.
Screening on a yearly basis in HIV-positive MSM provides clinical benefit and increases quality-adjusted life expectancy. Screening performed every 2–3 years is sufficient for HIV-negative MSM [23, 24]. The screening test should consist of a digital rectal examination (DRE) and anal brush cytology. Anal cytology has a sensitivity of 60–80 % and is similar to that of cervical cytology. If there is abnormal brush cytology, HRA is recommended .
Anal cytology has a sensitivity of 60-–80 % and is similar to that of cervical cytology. If there is abnormal brush cytology, a high resolution anoscopy (HRA) is recommended 
The seventh edition of the American Joint Committee on Cancer’s Cancer Staging System (2010) is used internationally to classify anal cancer  (Table 27.1). After confirming a diagnosis, further investigation includes computed tomography (CT) of the chest, abdomen, and pelvis to assess the size of the primary tumor and rule out metastatic disease. Magnetic resonance imaging (MRI) of the pelvis allows more accurate local staging of a primary tumor and reveals the extent of tumor invasion into the external sphincter and perirectal tissue. It is therefore advantageous over CT because it differentiates between soft tissues and outlines structures more clearly.
TNM classification of anal cancer
Primary tumor (T)
Carcinoma in situ
Tumor invades ≤2 cm at the largest dimension
Tumor >2 cm but not >5 cm at the largest dimension
Tumor >5 cm at the largest dimension
Tumor of any size invades an adjacent organ (e.g., the vagina, urethra, bladder – but not the anal sphincter, perirectal skin, or subcutaneous tissue)
Regional lymph nodes (N)
No regional lymph node metastasis
Metastasis in perirectal lymph nodes
Metastasis in unilateral internal iliac and/or inguinal lymph nodes
Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes
Distant metastasis (M)
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