Abstract
Anal cancer is an uncommon cancer, representing 2.5% of all GI malignancies, with increased incidence in immunosuppressed individuals and those with risk factors for HPV exposure. Precursor lesions include low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL); treatment of HSIL may prevent progression to cancer.
Anal cancer is subdivided into anal canal cancer or perianal cancer. The standard treatment for non-metastatic anal cancer is concurrent radiation and chemotherapy. Some favorable perianal lesions smaller than 2 cm can be excised. Otherwise, surgery plays a role in diagnosis and as a salvage treatment for persistent or recurrent local disease after chemoradiotherapy treatment. In selected cases negative microscopic surgical resection margins are achieved in up to 90% of cases, often with abdominoperineal resection with en bloc resection of adherent structures. For patients with metastatic disease, systemic therapy is the mainstay of treatment.
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Keywords
- Anal squamous intraepithelial lesion
- Anal cancer
- Anal squamous cell carcinoma
- Anal canal cancer
- Perianal cancer
Introduction
Anal cancer is uncommon, representing 2.5% of all gastrointestinal tract malignancies, with an annual incidence rate of 1.8 per 100,000 in the USA and approximately 500 incident cases yearly in Canada [1,2,3]. Nearly two-thirds of incident cases are in women [2, 3]. Over the past decade, incidence has risen by 2% per year [2, 4]. Squamous cell carcinomas account for most anal cancers and are the focus of this chapter, but other histologic types including adenocarcinoma (mostly from anal glands), melanoma, neuroendocrine, and sarcoma occur in the anus rarely [5]. Annual incidence is higher in those with immunodeficiency: 6–12 per 100,000 after solid organ transplantation, and 50 to 145 per 100,000 in those with HIV infection [6,7,8,9].
Terminology
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Anal canal The anal canal extends from the anorectal ring (the palpable upper border of the anal sphincter at the puborectalis muscles) to the lowermost edge of the sphincter complex corresponding to the anal verge or introitus of the anal orifice (Fig. 3.1) [10]. Anal cancer is classified as anal canal cancer if the lesion cannot be fully visualized with gentle traction of the buttocks [11, 12]. Proximal to distal, the anal canal contains several types of mucosa: glandular/columnar, transitional (anal transition zone), nonkeratinizing squamous (anoderm), keratinizing squamous (the dentate line divides keratinizing and nonkeratinizing), and merges with the hair-bearing perianal skin (true epidermis with epidermal appendages) at the mucocutaneous junction (anal verge). The treatment of anal canal tumors has been standardized for all squamous cell carcinomas irrespective of histological subtype (keratinizing or non-keratinizing, epidermoid, transitional, basaloid, or cloacogenic) due to similar prognosis and response to treatment [13].
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Perianal The perianal skin (previously anal margin) begins at the anal verge and extends over a 5 cm radius (Fig. 3.1). It is further defined by the presence of epidermal appendages, and contains the pigmented skin. Perianal cancers are those that can be fully visualized with gentle traction of the buttocks [11, 12]. Those further than 5 cm from the anal orifice are classified as skin cancers.
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Regional lymph nodes The proximal anal canal (above the dentate line) has lymphatic drainage to the mesorectal, superior rectal, and internal iliac nodes. Distal to the dentate line, drainage is to the inguinal nodes and external iliac nodes.
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Precursor lesions (anal squamous intraepithelial lesions ) The Lower Anogenital Squamous Terminology (LAST) should be used [14, 15]. HPV-related squamous anogenital precursor lesions are divided into low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs) based on mitotic activity, depth of dermal involvement, and abnormalities in squamous cell differentiation. LSIL can then be subclassified into condyloma (raised papillary proliferation with low-grade viral cytopathologic changes), and flat lesions labelled anal intraepithelial neoplasia 1 (AIN1). HSIL can be subclassified into AIN2 and AIN3 based on depth of abnormal cells. Generally, LSIL is observed, and HSIL is treated. Older terms such as high-grade anal intraepithelial neoplasia (HGAIN) and low-grade anal intraepithelial neoplasia (LGAIN), Bowen disease, and carcinoma in situ should not be used. Similarly, these squamous lesions are differentiated from extramammary Paget disease which is an apocrine neoplasm from sweat glands; pagetoid spread, known as secondary extramammary Paget disease, can occur from adjacent colorectal adenocarcinoma, urothelial carcinoma, or melanoma [15].
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Superficially invasive squamous cell carcinoma (SISCCA) Invasive squamous carcinoma that invades ≤3 mm from the basement membrane has a horizontal spread ≤7 mm, and must have been completely excised to confirm limited extent of the tumor [14]. These are classified as T1 anal carcinomas by AJCC [11]. SISCCA are typically identified by high-resolution anoscopy (HRA) and ongoing studies are investigating the role of excision alone as treatment for these lesions [16].
Risk Factors and Precursor Lesions
Anal cancer is an human papillomavirus (HPV)-associated cancer, like cervical, vaginal, penile, and oropharyngeal cancers, with 80–90% attributable to HPV [4, 17,18,19]. High-risk HPV types include HPV 16 and HPV 18 in 80–90% of cases, as well as HPV 31, 33, 45, 52, and 58 in a lesser proportion [17, 18, 20]. Oncogenesis is associated with persistent infection with high-risk HPV producing oncoproteins E6 and E7 which bind cellular proteins, including p53 and pRb from the tumor suppressor genes TP53 and retinoblastoma, deregulating DNA repair and apoptosis, and stimulating cell-cycle progression [21].
Risk factors for anal cancer largely relate to HPV exposure and immunodeficiency enabling persistence of HPV infection (Table 3.1) [22, 23]. Benign anal conditions such as hemorrhoids and fissures, and inflammatory bowel diseases, are not associated with an increased risk of anal cancer [24, 25].
HPV-related precursor lesions can be (1) clinically apparent raised condylomata, (2) incidentally found in anorectal surgical specimens, or (3) subclinical flat lesions seen on HRA or as subtle plaques, erythema, pigmentation, or pruritis. Histologically they are classified as LSIL or HSIL. LSIL represents morphologic features of HPV infection, while HSIL is a non-obligate precancerous lesion [14]. Typically, condylomata are LSIL, and flat lesions can be LSIL or HSIL.
Anal condyloma acuminata (anal warts) are the most common HPV-related anogenital lesions, and present as exophytic, soft, cauliflower-like masses [15]. Typically associated with low-risk HPV types 6 and 11, condylomata are low-risk lesions that may recur but have little, if any, risk of progression to carcinoma [12]. A small proportion of condylomata, more so anal canal lesions, may be associated with high-risk HPV and may progress to HSIL and invasive carcinoma, but this association is not fully clear [15]. A condyloma is distinguished from skin stags and hemorrhoids clinically. Flat LSIL (AIN1) are typically within the anal canal. They should be differentiated from seborrheic keratosis and psoriasiform dermatitis, and can be histologically similar to reactive changes [14, 15]. HSIL can arise in a condyloma, but typically are a flat lesion. Because the morphologic features of AIN2 fall between HPV infection (LSIL) and precancer (HSIL), immunohistochemical staining for p16, a biomarker for HPV-related cell proliferation is used to confirm HSIL when morphological features of AIN2 are present [14]. AIN2 that is p16 negative is classified as LSIL. Use of the LAST criteria limits inter-rater discordance in pathology interpretation [14, 15].
LSIL may spontaneously regress or progress to HSIL. HSIL is less likely to regress, and may progress to anal cancer. Population-based estimates of the rate of progression from HSIL to anal cancer may be as high as 2% per year (10% at 5 years), and may be higher in those with HIV [16, 35,36,37,38,39,40]. Spontaneous regression of HSIL may occur in some [36, 41]. There is no conclusive evidence that treatment of HSIL effectively prevents incident anal cancer; retrospective studies show variable results comparing treatment of HSIL to watchful waiting [16, 42,43,44,45]. Two ongoing randomized clinical trials (ANCHOR and HPV-SAVE) aim to investigate this question [46, 47]. The management of anal squamous intraepithelial lesions is detailed in Table 3.2
Anal Cancer
Almost half of patients present with bleeding; a third with mass sensation; some may have pain, irritation, or pruritis; and a fifth are asymptomatic [51, 68]. Diagnostic delay may occur if nonspecific anorectal symptoms are attributed to benign anorectal pathology such as hemorrhoids [51]. Pain and itching should be treated seriously even if invasion cannot be confirmed on biopsy. The onset of pain and symptoms is a key indicator of possible recurrence.
The Union for International Cancer Control’s (UICC)/American Joint Committee on Cancer (AJCC) eighth edition is the recommended anal cancer staging system [11]. This is based on tumor size, invasion of adjacent structures, regional nodal involvement, and distant metastases. Notable changes from UICC/AJCC seventh edition include staging perianal cancers such as anal canal cancers rather than squamous cell skin cancers as previously done; removal of N2 and N3 categories and defining N1a, N1b, and N1c; and revision of stage groupings including subclassification of stage II into IIA and IIB with differing prognosis [69]. Tumor size determines T-category: ≤2 cm (T1), >2 to ≤5 cm (T2), >5 cm (T3), and T4 can be any size but invades adjacent organ (e.g., vagina, urethra, bladder) [11]. Any regional nodal involvement is staged N1; this is subclassified into N1a (mesorectal, internal iliac, or inguinal), N1b (external iliac only), N1c (any N1a with external iliac) [11]. Regarding stage classifications, any distant metastasis is stage IV, any regional nodal metastasis or T4 category are stage III, larger tumors (>2 cm) without nodal involvement is stage II, and small tumors without nodal involvement (≤2 cm) are stage I.
At presentation, 50% are localized, 30% regional, and 15% distant, with population-based overall survival at 5 years of 82%, 64%, and 30%, respectively [2]. Tumor size >5 cm, regional nodal and extrapelvic metastases are the most important prognostic features influencing overall survival [69, 70]. Tumor >5 cm and tumor invasion to other organs are frequently identified as risk factors for colostomy [70,71,72]. Currently, there are no other prognostic or predictive biomarkers established for routine clinical use [73].
Historically, anal cancers were treated with radical surgery by abdominoperineal resection; however, in a few centers radical radiation without chemotherapy was used to facilitate sphincter preservation. In 1974, Nigro et al. first described preoperative combined chemoradiotherapy in an attempt to reduce recurrence rates after abdominoperineal resection and observed complete clinical response in the first three patients and complete pathological response in the two that underwent surgery [74]. This led to the investigation of what has now become the standard treatment – concurrent radiation and chemotherapy without surgery as primary treatment, reserving surgery for treatment salvage of persistent or recurrent disease. Concurrent radiation and chemotherapy results in sphincter preservation in the majority of cases and allows prophylactic treatment to uninvolved nodes reducing of nodal recurrence [75, 76]. The management of anal cancer is detailed in Tables 3.3, and 3.4. Table 3.5 summarizes landmark studies in anal cancer treatment.
Prevention and Screening
Vaccination should be routinely administered to everyone between ages 9–13 to prevent initial HPV infection, and later if not previously immunized including MSM and those with immunodeficiency [13, 20, 114, 115]. HPV-9 nonvalent vaccine targets high-risk HPV types 16, 18, 31, 33, 45, 52, and 58, as well as low-risk HPV 6 and 11, accounting for nearly all causes of HPV-associated cancers and condyloma [20, 116]. Efficacy for preventing persistent infection is over 90% [117,118,119]. The prior quadrivalent vaccine targeted HPV 16, 18, 6, 11 [117]. Safer sex practices including routine condom use, as well as smoking cessation should also be advocated [8].
Screening is proposed for well-established high-risk groups including persons living with HIV, men who have sex with men (MSM), and MSM with HIV infection who have even greater risk [9, 28, 30, 40, 51, 120, 121]. Screening may allow early detection of HPV-related precursor lesions which can be treated to prevent anal cancer. However, evidence is not yet available to demonstrate reduced anal cancer incidence, mortality benefit, cost-effectiveness, or optimal screening approach and follow-up [43, 120, 122]. Ongoing studies will inform screening strategies [46, 47, 123]. At least, for those in high-risk populations, discussion of the risk of anal cancer and symptoms that should prompt clinical assessment and routine digital anorectal examination is appropriate [124]. Screening methods include anal cytology, HPV testing, high-resolution anoscopy, and directed biopsies [120,121,122, 125, 126]. A strategy analogous to cervical cancer screening includes anal cytology or HPV testing to triage use of HRA and directed biopsy. Anal cytology is categorized using the Bethesda system into negative, atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL); atypical squamous cells, cannot exclude HSIL (ASC-H); or HSIL [127]. Those with any abnormal cytology (ACS-US or more) are then screened with HRA and directed biopsies [51, 120, 128]. Anal cytology testing and interpretation, HRA, and follow-up strategies require expertise, and use of screening strategies should not be done without local expertise [48, 51, 129,130,131].
Referring to Medical Oncology
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1.
All patients with a biopsy-proven diagnosis of anal canal carcinoma should be referred to a medical oncologist for consideration of primary combined-modality chemoradiotherapy.
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2.
All patients with a biopsy-proven diagnosis of perianal carcinoma not suitable for local excision should be referred to a medical oncologist for consideration of primary combined-modality chemoradiotherapy.
Referring to Radiation Oncology
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1.
All patients with a biopsy-proven diagnosis of anal canal carcinoma should be referred to a radiation oncologist for consideration of primary combined-modality chemoradiotherapy.
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2.
All patients with a biopsy-proven diagnosis of perianal carcinoma not suitable for local excision should be referred to radiation oncologist for consideration of primary combined-modality chemoradiotherapy.
Referring to Multidisciplinary Cancer Conference
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1.
All patients with clinically suspected or biopsy -proven persistent or recurrent anal carcinoma following primary combined-modality or surgical treatment should be discussed at a Multidisciplinary Cancer Conference (MCC).
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2.
Patients not suitable for combined-modality chemoradiotherapy as the primary treatment of an anal carcinoma (due to patient comorbidities or tumor-related factors such as prior pelvic radiation, incontinence, fistula) should be discussed at an MCC, and considered for radical radiation alone or radical surgery (possibly with adjuvant preoperative or postoperative radiation with/without chemotherapy).
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3.
Patients presenting with metastatic disease should be discussed at MCC.
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4.
All patients with a biopsy-proven diagnosis of adenocarcinoma of the anal canal or perianal area should be discussed at MCC. Standard of care remains multimodality treatment including surgery as well as chemotherapy and radiation, like that in rectal adenocarcinoma. Several small series (including the Toronto experience) have found that local control can be achieved in about 50% of cases with adenocarcinomas, less than about 3 cm in size using combination chemoradiation alone. Treatment plans should be individualized on a case-by-case basis.
Toronto Pearls
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For patients undergoing chemoradiotherapy, the use of intensity modulated radiation therapy is associated with less treatment toxicity and better quality of life [132, 133].
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For patients undergoing radical salvage surgery, the use of a myocutaneous flap for perineal reconstruction is recommended.
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In order to achieve an R0 resection in locally advanced or recurrent disease, a multidisciplinary surgical team (including uro-oncology, plastic surgery, and/or orthopedic surgery) should be used in the context of multivisceral pelvic resections.
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HIV-positive patients should be managed similarly to non-HIV-infected patients. The risk of excessive reaction to radiation and/or chemotherapy is low. Treatment should be adjusted on an individual basis based on toxicity and side-effect profile.
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Previous pelvic radiation is a relative, but not an absolute, contraindication to radiation and chemotherapy for anal cancer. Such patients should be referred to a radiation oncologist for assessment and discussed at an MCC.
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Chesney, T.R., Weiss, E., Krzyzanowska, M.K., Hosni, A., Brierley, J., Easson, A.M. (2020). Anal Cancer. In: Wright, F., Escallon, J., Cukier, M., Tsang, M., Hameed, U. (eds) Surgical Oncology Manual. Springer, Cham. https://doi.org/10.1007/978-3-030-48363-0_3
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