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Pathology of the Anal Canal
Anal Anatomic and Histologic Landmarks
The anal canal encompasses the distal most 3 to 4 cm of the most distal intestinal tract. It is defined proximally by the palpable upper border of the internal sphincter muscle, which is a continuation of the muscularis propria of the rectum. Distally, the anal canal is limited by the anal verge, an imaginary line where the squamous mucosa of the anal canal meets the perianal skin. The perianus extends 5 cm laterally from the anal verge and is characterized by the presence of adnexal structures, such as hair and sebaceous glands. The horizontal circular dentate line, located equidistant from the anal canal borders, is the main anal canal landmark and is formed by the bases of vertical mucosal folds called anal columns and by anal valves that connect the bases of anal columns. Behind the valves are small spaces called anal sinuses. Anal papillae are seen as small excrescences of squamous mucosa at the dentate line starting from the base of anal columns or valves. Below the dentate line, the anal canal is lined by nonkeratinizing squamous mucosa. Above the dentate line lies the anal transition zone, measuring a few millimeters to 1 cm in width and lined by stratified epithelium similar to the urothelial mucosa of the bladder. The anal transition zone may be covered by squamous epithelium in some cases and may have islands of colorectal crypts. The most proximal part of the anal canal has colorectal mucosa. Melanocytes are an integral part of the transition zone mucosa and of the squamous zone of the anal canal. The anal sinuses of the transition zone serve as openings for anal glands, which are formed by simple or branching ducts, ramifying in the submucosa. Anal glands may extend into or through the internal anal sphincter and are lined by urothelium-like epithelium at the point of origin and by two cell thick epithelium distally. In both locations, the luminal cell layer is cytokeratin (CK) 7–positive and mucin-producing cells. The basal and intermediate cell layers are p63 and CK5/6 positive, similar to squamous epithelium.
The anal canal is the source of multiple types of primary malignant neoplasms. Whereas the colorectal zone or islands of colorectal mucosa in the transition zone can give rise to adenocarcinoma of colorectal type, intramural adenocarcinoma without a luminal component may originate in anal glands or fistulae. Anal transition zone and the squamous zone are the source of several histologic subtypes of squamous cell carcinoma (SCC) and of melanoma.
Inflammatory And Non-Neoplastic
A number of inflammatory and infectious processes may affect the anal canal; however, the histologic findings of anal fissures, ulcers, abscesses, and fistulas are nonspecific and are discussed only briefly. Infectious agents that can affect the anal canal include human papillomavirus (HPV), herpes simplex virus, Treponema pallidum , Chlamydia spp., Neisseria spp., and Enterobius vermicularis . These infections are described in detail in Chapter 9 .
Anal fissure is a vertical tear or defect in the squamous mucosa of the anal canal distal to the dentate line. The vast majority of fissures are primary, with 90% located in the posterior midline and 10% in the anterior midline. The tear is thought to result from local trauma caused by passage of hard stools, prolonged diarrhea, vaginal delivery, and other injuries, that trigger spasm of the internal anal sphincter, leading to ischemia, necrosis, and poor healing. Secondary fissures are seen in fewer than 1% of patients and are located laterally or are multiple. They are seen in patients with Crohn’s disease other granulomatous diseases, such as tuberculosis and sarcoidosis, infections and malignancy. The typical symptoms of anal fissure include severe pain during defecation and passage of small amount of bright red blood. An acute anal fissure is a fresh laceration, which usually heals within 6 to 8 weeks of conservative treatment with sitz baths and diet modification to increase fiber consumption. Some fissures persist and progress to chronic stage, sometimes called anal ulcer. Typical features of chronic anal fissure include exposure of the internal anal sphincter muscle, indurated and raised fissure edges, and development of an external skin tag (sentinel pile) at the distal end of the fissure and of a hypertrophied anal papilla (fibroepithelial polyp) at the proximal end. The treatment of patients with chronic fissure is surgical and is aimed at reducing spasm of the internal anal sphincter. This may be accomplished by lateral internal sphincterotomy or pneumatic balloon dilation.
Biopsies are rarely used in the assessment of acute anal fissures; however, in chronic lesions to exclude inflammatory bowel disease (IBD) or underlying malignancy. Histopathology of a chronic fissure is poorly studied. Scarce studies paucicellular scar at the base of the ulcer and surprisingly minimal inflammation. Secondary fissures warrant a high degree of suspicion of associated.
Suppurative disease of the anal canal is thought to derive from nonspecific infection of an anal duct or gland, beginning as an abscess, with infection following the least resistant path, determining the location of the abscess (perianal, ischiorectal, or intersphincteric). Less frequently, perianal abscess is associated with Crohn’s disease; or with infections such as actinomycosis, tuberculosis, or lymphogranuloma venereum; and in other instances with incontinence, chronic diarrhea, irradiation, and malignancy. The formation of fistula tract leading to the surface of the perianal skin is the chronic phase of suppurative disease. Histologic features of the perianal abscess and fistula are nonspecific and include acute and chronic inflammation, granulation tissue, fibrosis, and foreign body giant cell granulomas ( Fig. 14.1 ). The latter should be distinguished from the compact epithelioid granulomas of Crohn’s disease. The presence of multiple lymphoid aggregates and more typical sarcoid-type granulomas should raise suspicion for Crohn’s disease.
The treatment of patients with the suppurative disease is surgical and focuses on curing the fistula, preventing or minimizing recurrence, and retaining continence. Long-standing (decades) fistulas are associated with an increased risk of perianal mucinous adenocarcinomas.
Crohn’s Disease
Inflammatory bowel disease is discussed in detail in Chapter 10 . However, anal involvement by Crohn’s disease is described in more detail next.
Clinical Features
Perianal Crohn’s disease may manifest at any age, but most patients are diagnosed in the third or fourth decade of life. Anal involvement in Crohn’s disease is seen in 14% to 38% of the patients. It is present in approximately 15% of patients with ileocolic disease and in 90% of patients with Crohn’s disease involving the colon and rectum. Although intestinal inflammation precedes perianal involvement in the majority of cases, perianal disease maybe the first manifestation of Crohn’s disease. The lesions in perianal Crohn’s disease include fissures, deep anal ulcers, abscesses, fistulas, anal tags, strictures, SCC, and adenocarcinoma. The clinical presentation depends on the type of perianal lesion and may include perianal pain, blood admixed with stool, incontinence, and sepsis. Patients with perianal disease also have more extraintestinal manifestations and increased resistance to steroids.
Crohn’s Disease—Fact Sheet
Definition
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A chronic idiopathic inflammatory process that may involve any portion of the gastrointestinal tract, along with extraintestinal manifestations
Incidence and Location
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Anal involvement in 14% to 38% of patients with Crohn’s disease
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In 15% of patients with ileocolic disease
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In 92% of patients with Crohn’s disease involving the colon and rectum
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Location in anal canal and perianal skin
Morbidity and Mortality
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High morbidity with high relapse rate after therapy
Gender, Race, and Age Distribution
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No gender predominance
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Whites of Anglo-Saxon descent most often affected
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Most common in third and fourth decades of life, but individuals of any age may be affected
Clinical Features
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Perianal pain, blood in stool, sepsis, incontinence
Prognosis and Therapy
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Anal lesions are poorly responsive to usual medical therapy for intestinal Crohn’s disease, such as steroids and aminosalicylates
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Antibiotics and immunomodulators (e.g., cyclosporin A, azathioprine) are useful in managing fistulas
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Surgery: drainage of abscesses, fistulotomy, flap or graft repair of fistulas, proctectomy
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Prognosis is guarded; high relapse rate regardless of therapeutic modality
Crohn’s Disease—Pathologic Features
Gross Findings
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Spectrum of lesions include fissure, ulcer, abscess, fistula, stricture
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Thickened perianal skin; may have fistulous openings
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Anal tag (a fibroepithelial polyp)
Microscopic Findings
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Abscesses and fistulas show acute and chronic inflammation with granulation tissue
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Sarcoid-like granuloma are characteristic
Differential Diagnosis
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Idiopathic abscess and fistula
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Tuberculosis
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Granuloma inguinale
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Sarcoidosis
Pathologic Features
Gross Findings
Gross findings include ulcers and fissures, fistulous openings in or around the anal canal, thickened and discolored perianal skin, and prominent anal tags. Multiplicity of lesions is common ( Fig. 14.2A ).
Microscopic Findings
Acute and chronic inflammation, necrosis, presence of granulation tissue, and fibrosis are usually present, but are nonspecific. However, the presence of well-defined sarcoid-like granulomas with associated multinucleated giant cells, particularly in close proximity to the anal mucosa, is suggestive of Crohn’s disease ( Figs. 14.2B and C ). In many patients with perianal Crohn’s disease, the histologic findings are nonspecific.
Differential Diagnosis
Idiopathic anal abscesses, fistulas, and primary fissures may be difficult to distinguish from anal Crohn’s disease if granulomas are not present and the diagnosis of IBD is not established. The differential diagnosis of granulomatous inflammation includes foreign body reaction, tuberculosis, sarcoidosis, and granuloma inguinale. Perianal tuberculosis is rare but should be suspected in high-risk populations, such as HIV-infected individuals, low-income patients, homeless people, and people with alcoholism. Tuberculous granulomas are usually characterized by caseation, acid-fast bacilli, and positive mycobacterial cultures. The diagnosis of granuloma inguinale is supported by identification of intracellular Donovan bodies using silver-based stains (e.g., Warthin-Starry stain). Sarcoidosis is another potential cause of perianal granulomatous inflammation, but is extremely rare.
Prognosis and Therapy
Medical treatment of patients with perianal Crohn’s disease includes antibiotics; steroids and immunomodulators, such as mercaptopurine, azathioprine, or methotrexate; anti–tumor necrosis factor-α agents; and cyclosporin A. Relapse is common after cessation of therapy. Fistulas may require placement of drains or diversion of the fecal stream to allow clearing of the underlying infection. Operative procedures include fistulotomy, placement of flaps or grafts to repair the defect, resection of proximal intestinal disease, a permanent diverting colostomy, and as a measure of last resort, proctectomy. The prognosis for patients with perianal Crohn’s disease is guarded because of the high incidence of recurrence. Approximately 20% of patients eventually require proctectomy. In addition, the incidence of anal SCC and adenocarcinoma is significantly increased in patients with perianal Crohn’s disease.
Hemorrhoids And Anal Tags
Symptomatic hemorrhoids have a prevalence of 4.4% to 12.8% in the general population. In a recent study of screening colonoscopy, weighted toward individuals older than 50 years of age, hemorrhoids were found in 39% with approximately half having symptoms. In both sexes, peak prevalence of symptomatic hemorrhoids appears to be between the ages of 45 and 65 years. Whites are affected more frequently than Blacks, and increased prevalence rates are associated with higher socioeconomic status. Pregnancy is also associated with an increased risk of hemorrhoids. There is no established association between hemorrhoids and chronic constipation or portal hypertension.
Current evidence suggests that hemorrhoids represent “sagging” or “slippage” of the thickened submucosal tissue of the anal canal called cushions. The cushions carry the superior (above the dentate line) and inferior (below the dentate line) hemorrhoidal vascular plexus that have direct arteriovenous communication. With aging, the supportive connective tissue of the cushions may weaken, causing distal displacement of the cushions, which in turn leads to venous distention, erosion, bleeding, and thrombosis. “Internal” hemorrhoids arise above the dentate line and are subclassified on the basis of whether they prolapse out of the canal and on the persistence of the prolapse. Hemorrhoids that are permanently prolapsed are prone to thrombosis and infarction. External hemorrhoids, arising below the dentate line, are prone to thrombosis.
Clinical Features
The main complaint is minor painless bleeding, which is associated mostly with internal hemorrhoids. They rarely show thrombosis and are not painful. In contrast, pain is usually associated with thrombosed external hemorrhoids.
Pathologic Features
Gross Findings
Hemorrhoids are fragments of dark purple connective tissue covered by mucosa. They may be firm when thrombosed, and sectioning typically reveals dilated vascular spaces.
Microscopic Findings
The overlying mucosa of hemorrhoid specimens may be columnar, transitional, or nonkeratinizing squamous. The submucosa contains dilated thick-walled vessels and thin sinusoidal spaces in a loose and often edematous fibrous tissue, which may show variable chronic inflammation ( Fig. 14.3A ). Thrombosis is common, and hemosiderin deposits indicate previous trauma and hemorrhage. Organization of intravascular thrombi may produce cellular masses of granulation tissue that may obliterate the vascular lumen. Excised hemorrhoidal tissue should always be carefully examined microscopically to exclude an inflammatory or infectious condition, or associated squamous neoplasia or melanoma.
Differential Diagnosis
The most common differential diagnosis is with an anal skin tag. If an organizing thrombus results in florid intravascular granulation tissue, a question of a vascular neoplasm can be raised, but the intravascular distribution and residual thrombus with recanalization allow easy distinction in most cases.
Hemorrhoids—Fact Sheet
Definition
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Enlarged and edematous soft tissue lesions associated with the anal mucosa that result from slippage or sagging of the normal soft tissue in this region
Incidence and Location
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Reported incidence varies from 4.4% to 12.8%
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Location above and below the dentate line
Morbidity and Mortality
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Not a significant cause of mortality but a common cause of discomfort and morbidity
Gender, Race, and Age Distribution
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Males equal to females; males more likely to seek medical attention
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Wide age and ethnicity range, peaking in middle age and declining thereafter
Clinical Features
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Painless bleeding most common symptom; also anal discomfort on defecation
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Acute pain exacerbations with thrombosis and infarction
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Commonly symptomatic during pregnancy
Prognosis and Therapy
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Medical therapy is mainstay of therapy: increases in dietary fiber, injection sclerotherapy, banding, ablative photocoagulation, electrocoagulation, laser ablation, and cryotherapy
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Surgical therapy is reserved for the 5% to 10% of those who fail conservative measures
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Surgical excision should include only symptomatic hemorrhoidal tissue to protect continence
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Recurrence rate is high
Hemorrhoids—Pathologic Features
Gross Findings
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Usually 1 to 3 cm in diameter
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Pale connective tissue covered by thin gray to tan mucosa
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Infarcted or thrombosed hemorrhoids are dark purple and firm
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Cut surface with dilated vascular spaces, some with thrombi
Microscopic Findings
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Epithelium: columnar, transitional, or squamous
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Submucosa with edematous stroma and dilated vessels
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Vessels may contain thrombi, with intravascular and perivascular hemosiderin deposits, often with marked reactive changes
Differential Diagnosis
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Gross differential diagnosis includes melanoma and carcinoma
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Histologic differential diagnosis of a thrombosed hemorrhoid with organization includes angiosarcoma and Kaposi’s sarcoma
Prognosis and Therapy
Treatment options for patients with mild symptoms include analgesics, sitz baths, increased dietary fiber, and stool softeners. In those with more severe symptoms or failed therapy, sclerotherapy and banding to induce fibrosis and fixation of the sagging tissue is used. Surgical excision or ablative techniques such as photocoagulation, electrocoagulation, laser ablation, and cryotherapy are also widely used in patient management.
Anal Tags
Anal tag, also known as hypertrophied anal papilla or anal fibroepithelial polyp, is a polypoid excrescence of anal squamous mucosa and underlying tissue caused by enlargement of an anal papilla. Anal tags can be idiopathic, associated with fissures or fistulas, or associated with Crohn’s disease. The gross appearance may be similar to hemorrhoids, but the dilated blood vessels of hemorrhoidal tissue are lacking. Anal tags resemble cutaneous fibroepithelial polyps, with a squamous epithelial lining over loose fibrovascular tissue ( Fig. 14.3B ). The stroma contains a variably cellular fibroblastic proliferation, which may show small spindle cells or, if the tissue was traumatized, enlarged stellate multinucleated cells with bizarre nuclei. Such stellate cells are evenly distributed within the collagenous stroma and are of no clinical significance. Anal tags are easily removed by a snare or snip excision.
Anal And Perianal Squamous Neoplasia Terminology
A unified lower anogenital squamous terminology (LAST) for HPV-associated lesions was proposed by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology in 2012 and includes updated nomenclature for squamous neoplasia of both the anal canal and perianal skin. LAST is based on the assumption of similar biology and morphologic equivalence of HPV-related squamous lesions across lower anogenital sites is an attempt to standardize diagnostic categories to improve interdisciplinary communication and patient management. The recommended nomenclature uses a two-tiered system for premalignant squamous lesions: low-grade squamous intraepithelial lesion (LSIL) and high-grade SIL (HSIL). Reported reproducibility is superior to prior three-tiered systems, and in addition, a two-tiered classification system is supported by our current understanding of the biology of HPV infection. LSIL is usually associated with transient extrachromosomal HPV replication, whereas HSIL is associated with genomically integrated HPV DNA. Because LSIL and HSIL terminology does not distinguish between different anogenital sites, a site-specific classification using two-tiered intraepithelial neoplasia (IN) terminology (e.g., AIN; see later) has been proposed for clarity of communication. It was acknowledged, however, that currently used clinical guidelines may stratify management of HPV-related lesion according to a three-tiered (AIN1–3) classification. The latter can therefore be used in parenthesis when necessary. Comparison of the LAST terminology with the three- and two-tiered anal and perianal IN terminology is presented in Table 14.1 .
Table 14.1
Terminology for Intraepithelial Neoplasia (Dysplasia) of the Anal Canal and Perianal Skin
| AIN (Three-Tiered System) | ASIN (Two-Tiered System, WHO) | Anal SIL (LAST) |
|---|---|---|
| I | ASIN-L | LSIL (AIN 1 or ASIN-L) |
| II | ASIN-H | HSIL (AIN 2 or ASIN-H) |
| III | ASIN-H | HSIL (AIN 3 or ASIN-H) |
| Condyloma acuminatum | Condyloma acuminatum | LSIL (condyloma acuminatum) |
| Bowen’s disease | Bowen’s disease/PSIN | HSIL (PAIN 3, PSIN-H) |
AIN , anal intraepithelial neoplasia; ASIN-H , high-grade anal squamous intraepithelial neoplasia; ASIN-L , low-grade anal squamous intraepithelial neoplasia; LSIL , low-grade squamous intraepithelial lesion; PAIN , perianal intraepithelial neoplasia; PSIN-H , high-grade perianal squamous intraepithelial neoplasia.
Tumors And Precursor Lesions Of The Anal Canal
Low-Grade Squamous Intraepithelial Lesion (Condyloma Acuminatum) of the Anal Canal
Condyloma acuminatum is more common in the perianal skin and is associated with low-risk HPV genotypes 6 and 11. This is described in greater detail in the section on perianal lesions.
Anal Canal Squamous Intraepithelial Lesion
Clinical Features
Anal canal SIL (ASIL) has been also termed anal (canal) intraepithelial neoplasia (AIN), anal squamous intraepithelial neoplasia, and anal squamous dysplasia. It is considered to be a precursor of SCC of the anal canal and frequently accompanies SIL of the perianal skin, cervix, and vulvar and other lower genital sites. There is a strong association of ASIL with HPV infection. Low-grade lesions, in general, are associated with low-risk HPV genotypes, whereas high-grade lesions occur in association with high-risk HPV genotypes, particularly 16 and 18. ASIL is most common in HIV-positive homosexual men and is rare in heterosexual men. About 5% to 20% of ASIL cases occur in HIV-negative homosexual men. In women, ASIL is also linked to anal intercourse and HIV-positive status. Immunosuppression from causes other than HIV, such as solid organ transplantation, also increases the risk for high-grade ASIL. ASIL is more likely to occur in the transition zone and can be identified as acetowhite epithelium similar to lesions of cervical SIL.
Pathologic Features
Gross Findings
Anal precursor lesions may be macroscopically invisible or present as plaque-like or warty lesions or as mass lesions mimicking malignancy.
Anal Squamous Intraepithelial Lesion—Fact Sheet
Definition
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A precursor of invasive squamous cell carcinoma, also known as anal intraepithelial neoplasia
Incidence and Location
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True incidence of anal squamous intraepithelial lesion in the general public is unknown because only high-risk populations are screened for dysplasia
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The incidence of high-grade squamous intraepithelial lesion (HSIL)in HIV-negative men who have sex with men (MSM) is 17% to 21%, whereas HIV-infected MSM have a rate of 29% to 52%
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The prevalences of anal HSIL are 0% to 3% and 0% to 9% in HIV-negative women without and with known HPV-related pathology of the lower genital tract, respectively, and in 3% to 26% of HIV-positive women
Morbidity and Mortality
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Little or no morbidity and no mortality
Gender, Race, and Age Distribution
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Males more than females
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Men who have sex with men (MSM) have a higher incidence of anal SIL
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The rate of anal SIL does not decrease with age in MSM
Clinical Features
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Anal SIL is asymptomatic
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Detection by anal cytology and by anoscopy with biopsy
Prognosis and Therapy
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Progression rates of HSIL to anal cancer are 0.17% per year for HIV-positive MSM and 0.03% for HIV-negative MSM
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Topical treatment: fluorouracil, imiquimod, cidofovir, trichloroacetic acid and lopinavir
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Ablative treatment: laser, infrared coagulation, and electrocautery
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High recurrence rate in high-risk populations
Microscopic Findings
ASIL is characterized by nuclear atypia, abnormal maturation, and abrupt transition from uninvolved epithelium to SIL. Nuclear atypia is characterized by hyperchromasia, pleomorphism, irregular nuclear borders, coarse chromatin, and loss of nuclear polarity. Abnormal maturation refers to a delay in cytoplasm accumulation, which normally begins from the second or third basal cell layer. LSIL is defined by mild cytologic atypia and minimal maturation in the lower third of the epithelium. Cells appear basaloid and immature because of high nuclear-to-cytoplasmic ratio, and mitotic figures are increased but limited to the lower third of the epithelium. Koilocytic change may be seen in the superficial epithelial layers and is diagnostic of HPV cytopathic effect. Koilocytes characteristically have enlarged hyperchromatic nuclei with irregular nuclear borders and perinuclear clear halo and may show binucleation ( Fig. 14.4A ). HSIL is characterized by prominent nuclear atypia and lack of maturation involving more than one-third of the epithelium. Mitotic figures, including atypical forms, may be present ( Figs. 14.4B and C ). In the previous three-tiered grading system, AIN I (mild dysplasia) is characterized by nuclear atypia and lack of maturation in the lower third of the epithelium; AIN II (moderate dysplasia) involves the lower two-thirds of the epithelium; and AIN III (severe dysplasia) is diagnosed when dysmaturation involves the full thickness of the epithelium.
Anal Squamous Intraepithelial Lesion—Pathologic Features
Gross Findings
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No distinctive features
Microscopic Findings
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Nuclear atypia, delayed maturation, and abrupt transition from uninvolved epithelium to squamous intraepithelial lesion
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Low-grade squamous intraepithelial lesion (LSIL): lack of maturation involves the lower third of the epithelium
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High-grade squamous intraepithelial lesion (HSIL): lack of maturation in at least the lower two-thirds or the epithelium; prominent nuclear atypia
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Koilocytotic change is common in upper epithelial layers, especially in LSIL but can also be seen in HSIL
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Mitotic figures are limited to basal layers in LSIL and throughout the full thickness of the epithelium in HSIL
Molecular Studies
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Polymerase chain reaction and fluorescent in situ hybridization are frequently positive for human papillomavirus (HPV) types 6 and 11 in LSIL and 16 and 18 in HSIL
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Risk for developing invasive carcinoma is higher with HPV 16 and 18
Immunohistochemistry
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p16 immunohistochemistry is helpful in selected situations
Differential Diagnosis
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Reactive epithelial proliferation
Ancillary Studies
Immunohistochemistry
A broad array of biomarkers that includes p16, Ki-67 (Mib1), ProEx C, telomerase/TERC, HPV genotyping, and HPV16/18 mRNA levels is available for ancillary testing in anal neoplasia. However, LAST guidelines recommend only p16 immunohistochemistry (IHC) as a surrogate assay for HPV infection in biopsies. Positive p16 IHC is defined as continuous and strong nuclear or nuclear and cytoplasmic staining involving at least the basal third of the epithelial thickness ( Fig. 14.4D ). Focal or patchy nuclear staining can be seen in both reactive squamous metaplasia and in LSIL and is therefore nonspecific. Other staining patterns, such as cytoplasmic only, single cell, and blob-like positivity, are considered negative. LAST guidelines propose to limit p16 IHC to the following scenarios: (1) differential diagnosis between HSIL and a neoplastic mimic, such as immature squamous metaplasia, atrophy, reparative change, or tangential cutting; (2) differentiation of HSIL from LSIL when it is not clear whether hematoxylin and eosin morphology is that of AIN 2 or AIN 1 in the older three-tiered nomenclature. (block-positive strong staining supports the diagnosis of HSIL); or (3) there is a difference of opinion regarding the presence of HSIL. P16 IHC is currently not recommended for the diagnosis of LSIL, which should be definitely established morphologically, or for the differential diagnosis of LSIL versus non–HPV-associated abnormalities.
Molecular Pathology
Although not necessary for histologic diagnosis of ASIL, in situ hybridization and polymerase chain reaction (PCR) techniques have been used in epidemiologic studies. In one systematic meta-analysis, crude prevalences of HPV in LSIL and HSIL were 88% and 91%, respectively. In order of prevalence, HPV genotypes 11, 6, 16, 70, and 31 were detected in LSIL and genotypes 16, 18, 6, 33, 31, and 11 in HSIL. The combined prevalences of genotypes 16 and 18 were 27% in LSIL and 69% in HSIL, supporting the view that LSIL and HSIL are associated with different HPV subtypes.
Differential Diagnosis
One of the main challenges in the diagnosis of ASIL is its distinction from reactive squamous proliferation. There is significant interobserver variability in the diagnosis of LSIL because of mild cytologic abnormalities and because delayed maturation in regenerative epithelium is difficult to distinguish from the dysmaturation seen in LSIL. An abrupt transition from normal epithelium to an atypical area and koilocytes in the upper epithelium are the hallmarks of LSIL. Even though a subset of LSIL cases show strong diffuse p16 immunostaining, the use of p16 IHC is not recommended for diagnosis. Positive staining may lead to overinterpretation and inappropriate upgrade to HSIL. Similarly, negative p16 in an otherwise unequivocal HSIL should not be used to downgrade the lesion to LSIL. ASIL can be encountered in specimens from benign anal disease, such as hemorrhoids, fissures, and fistulas. The prevalence of incidental HSIL in surgical specimens varies from 0.25% to 2.5%.
Prognosis and Therapy
Low-grade squamous intraepithelial lesion is mainly caused by transient HPV infection and is self-limited. The estimates from a meta-analysis showed that progression rate from HSIL to anal cancer in men who have sex with men (MSM) is 0.17% per year for HIV-positive MSM and 0.03% for HIV-negative MSM, suggesting that immunologic status plays an important role in progression to cancer.
Cytopathologic techniques similar to those used for the cervix have been used for screening high-risk populations for anal SIL. Reflex testing for HPV is often performed on specimens with atypical cytology, and patients with positive results are referred for high-resolution anoscopy and biopsy.
The quadrivalent HPV vaccine, now administered to prevent cervical cancer, offers protection against HPV 6, 11, 16, and 18 and has demonstrated high efficacy against anogenital warts and may also prevent anal SIL.
Options available for treatment of anal SIL can be divided into topical and ablative. Topically applied agents include fluorouracil, imiquimod, cidofovir, trichloroacetic acid, and lopinavir. Ablation methods include laser, infrared coagulation, and electrocautery. Ablative methods are more effective than self-applied topical treatments, but the recurrence rates are high. One recent study of HSIL ablation in MSM demonstrated recurrence rate of 68% at 2 years for HIV-positive patients and 57% for HIV-negative patients.
Squamous Cell Carcinoma
Clinical Features
Squamous cell carcinoma comprises 75% to 80% of all malignant tumors of the anal canal. The overall incidence of the disease, although still rare at 0.2 to 4.4 per 100,000, has increased dramatically in recent decades. There has been also a demographic shift of the affected individuals with an increase in young adults, particularly in patients with HIV and other immune deficiencies, and in transplant patients on immunosuppression. The average age of diagnosis in HIV-infected individuals is in the fourth decade of life. The risk is higher in urban populations and in Blacks. In contrast, the risk is particularly low among Asians and Pacific Islanders. The incidence in MSM is 35 per 100,000, which doubles in those infected with HIV to approximately 70 per 100,000. Other associated risk factors include multiple sexual partners, receptive anal intercourse, and presence of other sexually transmitted diseases. HPV is detected in the majority of anal SCCs. A strong link to tobacco smoking has been noted in women but is less definitive in men. Hemorrhoids, fissures, fistulas, abscesses, and IBD are not associated with increased incidence of SCC.
The initial presentation of SCC may be nonspecific, resulting in delayed diagnosis. Minor anal bleeding, pain, discharge, altered bowel habits, pelvic pain, discomfort in the sitting position, anal fissure or fistula, and incontinence from the involvement of the anal sphincter may be noted. A mass lesion is often evident on digital examination. Clinical evaluation typically includes rigid proctoscopy for biopsy, assessment for inguinal lymphadenopathy, computed tomography or magnetic resonance imaging to evaluate other lymph node groups (inferior mesenteric, inferior rectal, and internal iliac), colonoscopy to exclude extension from a primary rectal tumor, and ultrasonography to assess depth of invasion.
Pathologic Features
Gross Findings
Anal canal SCCs are typically ulcerated, with raised borders and may extend into the distal rectum and perianal skin ( Fig. 14.5A ). It is uncommon to see an intact lesion from the anal canal because most patients are treated with neoadjuvant therapy. In such specimens, the tumor may not be grossly evident. Careful and extensive sampling may be necessary to demonstrate the lesion; areas of induration or mucosal thickening are of particular concern and should be selected for histologic examination.
Microscopic Findings
Although SCC of the anal canal may demonstrate one predominant pattern, the majority of tumors are characterized by a varied histologic appearance. The tumors above the dentate line often show basaloid pattern, characterized by small cells with high nuclear-to-cytoplasmic ratio and nuclear palisading at the periphery of tumor islands. The tumor islands may have necrotic centers and small mucinous microcysts ( Figs. 14.5B and C ). The tumors below the dentate line may have predominance of large cells with pale eosinophilic cytoplasm without keratinization or keratinization of lamellar or single-cell type or ( Figs. 14.5D and E ). There is frequently a transition from one pattern to another with a spectrum of intermediate variations.
Squamous Cell Carcinoma Of The Anal Canal—Fact Sheet
Definition
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Invasive malignant neoplasm demonstrating squamous differentiation
Incidence and Location
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75% to 80% of anal cancers
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Incidence: 3400 new cases annually
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Worldwide incidence is increasing, especially among HIV-positive individuals
Morbidity and Mortality
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Anal canal lesions: 5-year survival rate is 60% to 86%
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Survival has increased with the advent of combined chemoradiation, eliminating the need for abdominoperineal resection
Gender, Race, and Age Distribution
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Females more than males, 2 to 1
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Increase in young males over past two decades, especially HIV-positive men who have sex with men
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Higher incidence among urban populations
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More common in Blacks than in Whites; very low incidence in Asians and Pacific Islanders
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Demographic shift in progress from older women to young men
Clinical Features
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Symptoms include pain, itching, bleeding, nonhealing ulcer, anal discharge, altered bowel habits, anal fissure, fistula, and incontinence
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Risk factors: multiple sexual partners, anal-receptive intercourse, presence of other sexually transmitted diseases, tobacco smoking in women, immunosuppression, HIV seropositivity
Prognosis and Therapy
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May metastasize to perirectal, iliac, or inguinal lymph nodes
- ■
Chemoradiation therapy usually eliminates the need for radical resection and yields 5-year survival rates of 60% to 86%
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Abdominoperineal resection is used as salvage procedure for recurrence or persistence after chemoradiation therapy; the 3– to 5-year survival rates are 44% to 100%
In the past, anal canal tumors were subclassified into large-cell keratinizing, large-cell nonkeratinizing, and basaloid types. However, the majority of tumors demonstrate a mixture of histologic patterns, and no definite association between histologic patterns and prognosis has been established. In addition, the diagnosis is usually based on a small biopsy specimen that may not be representative of the entire tumor. Therapy has also shifted from radical surgery to combined modality chemoradiation, which is not dependent on the histologic subtype. Therefore, the current World Health Organization (WHO) classification suggests that the broader term SCC be used for these tumors. It may be accompanied by a comment describing additional histologic features, such as basaloid features, degree of keratinization, presence of mucinous microcysts, or adjacent SIL.
Squamous Cell Carcinoma Of The Anal Canal—Pathologic Features
Gross Findings
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Mass, ulcer, or stricture may be seen
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In salvage surgery cases, carcinoma may not be grossly evident; diagnosed by biopsy of the area of induration or mucosal thickening
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