Normal Anatomy of the Anus

The anal canal is the terminal part of the large intestine and is slightly longer in male than in female patients. It measures approximately 4 cm and extends from the rectal ampulla (pelvic floor level) to the anal verge, which is defined as the outer opening of the gastrointestinal tract. The anal verge is at the level of the squamous-mucocutaneous junction with the perianal skin.

The dentate line (also called pectinate) consists of the anal valves and bases of the anal columns. It represents the anatomic division of the rectum from the anal canal. The dentate line originates from the embryonic union of the ectoderm with the endoderm. The anal canal epithelium can be divided into three zones ( Fig. 1 ). The upper part consists of colorectal mucosal type, followed by an anal transition zone (ATZ) that is composed of specialized epithelium that starts at the dentate line and extends from 0.5-1 cm. Finally, the distal anal canal consists of squamous epithelium, which may be partially keratinized. The anatomic distribution is clinically significant because it is related to lymphatic drainage and different types of precursor epithelium.

Normal epithelium. ( A ) Squamous epithelium. ( B ) Anal transition zone epithelium showing in the left cuboidal or polygonal surface cells. In the right can be viewed colonic mucosa with an underlying crypt.

The tumor can be accessed for biopsy using anoscopy, rectoscopy, or direct examination of anal and perineal exophytic lesions.

Histology Classification

Tumors of the anal canal were classified by the World Health Organization (WHO) in three main groups: epithelial, mesenchymal, and secondary tumors. Epithelial tumors were subdivided into malignant and premalignant lesions ( Box 1 ).

Human Papilloma Virus Infection

Evidence indicates an association between oncogenic HPV infection with premalignant and malignant lesions of the genital tract, including the anus. The presence of HPV in anal cancer is variable and may be influenced by the methodology used for virus identification and by population characteristics. The HPV infection can be detected in tumor tissue using different techniques, including in situ hybridization ( Fig. 2 ) and polymerase chain reaction (PCR).

In situ hybridization. ( A ) Note the positivity for high-risk HPV probe. ( B ) Diffuse staining with condensed and uniform signs in the nuclei of the cancer cells.

Currently, 88% of anal SCC tumor samples are usually HPV positive, with different rates according to geographic location. HPV16 infection is the most common, present in 86% of cases. In some cases, coinfection was found with multiple HPV types.

HPV is a nonenveloped virus with double-stranded DNA in circular form, containing a genome of around 8000 base pairs. HPV can remain housed in the nuclei of basal epithelial cells for decades after initial infection of the mucosa, which usually occurs through sexual contact. There are more than 240 types described and the alpha human papillomavirus is usually related to mucosal infection. The high-risk HPV genotypes (16 and 18) encode at least 3 oncoproteins with stimulatory properties: E5, E6, and E7. Integration of the viral DNA in the genome of the host cell is important for the progression of preneoplastic lesions to invasive carcinoma. During HPV integration, breakage of the E2 region of the viral genome occurs in the DNA of the infected cells, which causes the loss of suppressor function of the E2 protein. This results in an increased expression of the E6 and E7 proteins and their stimulation promotes invasiveness and keratinocyte immortalization. E6 and E7 expression is required for the induction and maintenance of the transformed state of HPV-related neoplasm. The protein E7 interacts with Rb protein (pRb) and E6 is able to bind and inactivate P53.

Normal Anatomy of the Anus

The anal canal is the terminal part of the large intestine and is slightly longer in male than in female patients. It measures approximately 4 cm and extends from the rectal ampulla (pelvic floor level) to the anal verge, which is defined as the outer opening of the gastrointestinal tract. The anal verge is at the level of the squamous-mucocutaneous junction with the perianal skin.

The dentate line (also called pectinate) consists of the anal valves and bases of the anal columns. It represents the anatomic division of the rectum from the anal canal. The dentate line originates from the embryonic union of the ectoderm with the endoderm. The anal canal epithelium can be divided into three zones ( Fig. 1 ). The upper part consists of colorectal mucosal type, followed by an anal transition zone (ATZ) that is composed of specialized epithelium that starts at the dentate line and extends from 0.5-1 cm. Finally, the distal anal canal consists of squamous epithelium, which may be partially keratinized. The anatomic distribution is clinically significant because it is related to lymphatic drainage and different types of precursor epithelium.

Normal epithelium. ( A ) Squamous epithelium. ( B ) Anal transition zone epithelium showing in the left cuboidal or polygonal surface cells. In the right can be viewed colonic mucosa with an underlying crypt.

The tumor can be accessed for biopsy using anoscopy, rectoscopy, or direct examination of anal and perineal exophytic lesions.

Histology Classification

Tumors of the anal canal were classified by the World Health Organization (WHO) in three main groups: epithelial, mesenchymal, and secondary tumors. Epithelial tumors were subdivided into malignant and premalignant lesions ( Box 1 ).

Human Papilloma Virus Infection

Evidence indicates an association between oncogenic HPV infection with premalignant and malignant lesions of the genital tract, including the anus. The presence of HPV in anal cancer is variable and may be influenced by the methodology used for virus identification and by population characteristics. The HPV infection can be detected in tumor tissue using different techniques, including in situ hybridization ( Fig. 2 ) and polymerase chain reaction (PCR).

In situ hybridization. ( A ) Note the positivity for high-risk HPV probe. ( B ) Diffuse staining with condensed and uniform signs in the nuclei of the cancer cells.

Currently, 88% of anal SCC tumor samples are usually HPV positive, with different rates according to geographic location. HPV16 infection is the most common, present in 86% of cases. In some cases, coinfection was found with multiple HPV types.

HPV is a nonenveloped virus with double-stranded DNA in circular form, containing a genome of around 8000 base pairs. HPV can remain housed in the nuclei of basal epithelial cells for decades after initial infection of the mucosa, which usually occurs through sexual contact. There are more than 240 types described and the alpha human papillomavirus is usually related to mucosal infection. The high-risk HPV genotypes (16 and 18) encode at least 3 oncoproteins with stimulatory properties: E5, E6, and E7. Integration of the viral DNA in the genome of the host cell is important for the progression of preneoplastic lesions to invasive carcinoma. During HPV integration, breakage of the E2 region of the viral genome occurs in the DNA of the infected cells, which causes the loss of suppressor function of the E2 protein. This results in an increased expression of the E6 and E7 proteins and their stimulation promotes invasiveness and keratinocyte immortalization. E6 and E7 expression is required for the induction and maintenance of the transformed state of HPV-related neoplasm. The protein E7 interacts with Rb protein (pRb) and E6 is able to bind and inactivate P53.

Squamous Intraepithelial Lesions

Because HPV plays a causal role in perianal and anal neoplasia, anal squamous precancerous lesions should now be classified according to the same criteria and terminology as their cervical counterparts using the Lower Anogenital Squamous Terminology (LAST) system.

A consensus process was organized by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology to recommend terminology unified across lower anogenital sites. The aim of this system of standardization was to create uniformity in histologic nomenclature for HPV-associated tumors that occurred in the anogenital tract. This permits a better use of current biomarkers and enables an efficient communication between specialties that establish the diagnosis and treatment of these lesions. The recommendation for classifying preinvasive lesions in the anal canal was similar to the cervical site. Hence, the same two-tiered nomenclature of intraepithelial lesion could be applied: low-grade squamous intraepithelial lesion (LSIL) and HSIL. The lesions are located above the basement membrane and may originate from the transitional or squamous epithelium of the anal canal. In the LAST system, condyloma is located with LSIL in the same category and Bowenoid papulosis is considered a special form of HSIL. Besides this, it does not discriminate cytologic from tissue specimens. Therefore, the terms LSIL and HSIL can be used in both materials. However, for histopathological diagnosis, the suffix AIN can be used; therefore, the lesion in the anal canal can be subcategorized as: LSIL-AIN 1 and HSIL-AIN 2–3.

LSIL-AIN 1 can be defined as a proliferation of metaplastic squamous cells with nuclear atypia in the lower third of the epithelium or demonstrating koilocytotic changes in a papillary lesion ( Fig. 3 ). The histologic findings of HSIL-AIN 2-3 consist of a thickened proliferating epithelium containing atypical cells showing abnormal nuclear polarity, nuclear pleomorphism, and high nuclear hyperchromatism: cytoplasmic ratio and increased mitotic activity ( Fig. 4 ).

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