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Epidermoid cancers of the anal canal
Author's Accepted Manuscript
Epidermoid Cancers of the anal canal Shawn Webb MD
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www.elsevier.com/locate/yscrs S1043-1489(15)00011-1 http://dx.doi.org/10.1053/j.scrs.2015.01.004 YSCRS501
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Seminars in Colon and Rectal Surgery
Cite this article as: Shawn Webb MD, Epidermoid Cancers of the anal canal, Seminars in Colon and Rectal Surgery, http://dx.doi.org/10.1053/j.scrs.2015.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Epidermoid Cancers of the Anal Canal Shawn Webb, MD Shawn Webb, MD Henry Ford Hospital [email protected]
Key Words Epidermoid Anal canal cancer HPV HSIL
Abstract Squamous cell cancer of the anal canal continues to be a rare cancer. Recently, the incidence has been slowly rising in part due to longer term HIV survivors and in part due to high prevalence of HPV. Early detection and treatment in these high risk groups is imperative to increasing the survival of the disease. Chemoradiation remains the standard of care for primary therapy reserving surgical resection for salvage.
Incidence Anal cancer is an uncommon malignancy and accounts for 2.4% of all GI malignancies (1) and 4% of all lower GI tract malignancies(2) . The current incidence, in the last decade, compared to the incidence in the 1980’s and early 90’s has increased with a relative risk of 2.2. (3)
This has been attributed to multiple factors including increased screening regimens, increased
spread of HIV disease and increased survival of HIV disease in the era of HAART. (4) In 2014, there are an estimated 7,210 new cases with 950 resulting deaths. (5) This is an increase from 2013's estimates of 7060 new cases and 880 deaths. (1) The number of new cases of anal cancer was 1.8 per 100,000 men and women per year. The number of deaths was 0.2 per 100,000 men and women per year from 2007-2011. (6) Anatomy The major anatomical distinction in treatment of lesions in the area are that of the primary location, either anal canal versus the anal margin. The anal margin is that part of the anus that can be seen with gentle retraction of the buttocks. This is covered of squamous epithelium and contains appendages such as hair follicles. Cancers of this area will be covered under a separate section. The surgical anal canal is the area defined from the anorectal ring proximally to the anal verge distally. This area contains columnar epithelium of the rectal mucosa proximally, squamous epithelium distally, and an area of transition that can extend from 0 to 1.2-cm. This mucosa resembles urothelium. In addition to the anatomic landmarks, an area of transformation has been defined in within the last decade. The distal boundary of this is the dentate line and can extend with finger
like projections 6-10-cm inside the rectum. This area is susceptible to metaplastic changes when exposed to HPV. (7) Terminology Squamous carcinoma of the anal canal has been known to arise from precursor lesions of carcinoma in situ. Since the advent of this terminology by Bowen in 1912, these precursor lesions have been described with multiple nomenclatures. The most current terminology of anal squamous intra-epithelial lesions(ASIL) ranges from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) (which includes carcinoma in situ, high grade dysplasia, and anal intraepithelial neoplasm grade II and III, and high grade intraepithelial neoplasm HGAIN). Although these precursor lesions give rise to anal squamous carcinoma, the incidence of progression ranges from 1% in the general population (8) to 7.5%13% in the HIV positive population. (9,10) Epidemiology The median age at diagnosis of anal canal cancer in the US is 60 years old. Fifty-three percent of patients are between 45-65. (6) The incidence trend has been toward a younger population as HPV and HIV have become more common. There has been an increase in incidence rates of both genders aged 30 to 54 years since the era of antiretroviral therapy. (11) Eighty percent of anal cancers are squamous cell in origin. Some specific risk factors for anal cancer that have been shown in the literature are female gender, HPV infection, history of STDs, number of sexual partners greater than 10, genital warts, cigarette smoking, anal receptive intercourse, and HIV infection or other immunosuppression. (12, 13, 14)
The association of HPV and cancer was first observed in patients with epidermodysplasia verruciformis which can progress to squamous cell cancer in sun exposed areas. Since then, at least 13 serotypes of HPV have been shown to have potential oncogenic effects. The most well established serotypes being HPV 16 and 18. (13) In a meta-analysis by Hoots et al. HPV prevalence was found to be 71%, 91%, and 88% in anal cancer, HSIL, and LSIL, respectively. HPV types 16 and/or 18, the most common high-risk HPV viral types, were detected in 72% of anal cancers. (15) HPV is transmitted by both vaginal and anal intercourse, and has been shown to infect the anal region without having direct anal intercourse. Prevention Abstinence from high risk behaviors is the best prevention for infection from HPV and other risk factors for anal cancer. In 2011, the FDA approved the use of quadrivalent HPV vaccine for prevention of anal cancer to be used in patients aged 9 through 26. This was based on the findings that in a large sample size including MSM, the vaccine prevented any form of ASIL or anal cancer in 78% of this high risk population. (16) Although the initial approval and study of HPV vaccine was for HPV naïve patients, there has been some suggestion of clinical efficacy of the HPV vaccine in patients that have been exposed to HPV and have had HSIL that has been treated. In a nonrandomized study of MSM who were HIV negative and diagnosed with HSIL, the arm of the study that received the HPV vaccination showed a reduced recurrence of HSIL over at least 2 years compared to those that did not take the vaccine. (17)
Screening and diagnosis Screening has been recommended by some in patients with high risk features, such as HIV positivity, history of anoreceptive intercourse, immunosuppression, or cervical dysplasia. The method for screening is with Dacron swab into the anal canal similar to pap smear testing of the cervix. (18) It has been recommended that any abnormal cytology should be followed up by high resolution anoscopy (HRA) to identify early lesions for monitoring. The accuracy of HRA is variable with sensitivities ranging from 50-90%. (19,20) Devaraj published a paper that followed 277 HIV + men who have intercourse with men over 4 years. He found an incidence of 49% of HSIL. Because the HSIL progressed to cancer in only 1% of the population, the purpose of the screening was to identify and eradicate early lesions. (21) Although HSIL can be eradicated in immunocompetent patients, HIV + status has shown a recurrence rate of 80% over 2 years and almost 100% over 4 years. (22) The most common sign of anal cancer is bleeding. There is often a delay in diagnosis with this presentation given that anal outlet bleeding is often attributed firstly to benign disease such as hemorrhoids. Other common signs include itching, fullness, pain, a lump, abnormal rectal discharge, or a change in stool caliber. Patients with such complaints should get a digital rectal exam and evaluation with anoscopy along with tissue biopsy of any abnormality found. The exam should focus on size, fixation and any lymph node involvement, including the inguinal basins. Given that most tumors are treated without complete resection by surgery, they are staged based on size and histologic confirmation. Rectal ultrasound is not routinely used to stage.
Metastatic work up should ensue. Physical exam and CT alone are inadequate in detecting lymph node metastasis, many of which will be positive even at 5-mm in size. (23) Studies have shown improved detection rates of primary tumors with PET imaging (91% vs. 59%) and both pelvic and inguinal lymph nodes (20% missed by CT but picked up by PET) (24,25) . Analysis of the SEER database updated in 2014 showed that 32% of patients were node positive on presentation. (26) Staging The American Join Committee on cancer first proposed the TNM classification for anal canal carcinoma in 1989 (Table 1) The staging system has not needed revisions in the interim. The importance of staging on prognosis was shown in an analysis of the SEER database showing 80% 5-survival of stage I and II, 58% 5 year survival in stage III, and 32% survival in stage IV. (26)
Primary Tumor: Tis-Carcinoma in situ, T1-tumor 2cm or less, T2-tumor between 2-5 cm, T3Tumor >5cm, T4-any size tumor that invades nearby organs(ie vagina, urethra, bladder) Lymph Nodes: N0-No regional lymph node metastasis, N1-Metastasis to perirectal lymph nodes, N2-Metastasis in unilateral internal iliac and/or inguinal lymph node(s), N3-Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes Distant Metastasis: M0-No distant metastasis, M1- Distant metastasis Although T and N stage has been shown several times over to have bearing on prognosis, several other factors have been evaluated. In the European Organization for Research and Treatment of Cancer (EORTC) phase III trial, they found that the presence of lymph node involvement
decreased local control and survival, but the number and size of lymph nodes involved had no bearing on these factors. (27) A study by MD Anderson supported that both T-stage and N-stage independently predicted local failure and N stage predicted distant failure and decreased overall survival. (28) A recent revisit of the EORTC data revealed that patients with T3-T4 N+ disease have the worst disease free, colostomy free and overall survival. (29) Other possible prognostic factors such gender, histologic grade and race have been suggested by some studies but not supported by others. Treatment HSIL As mentioned above, (21) only 1% of HSIL progress to invasive cancer. Surveillance versus ablation with topical agents has been advocated by some. Topical agents, such as Imiquimod or 5-FU, or ablative therapy under HRA have both been evaluated. Imiquimod has been used successfully for eradication of HSIL in populations including HIV + patients. One study showed a 61% eradication of HPV and 77% resolution of any ASIL. (30) Studies have shown a sustained absence of HSIL ranging from 61% to 74% in 36-month follow up after obliteration. (31, 32) Topical 5-FU has also been studied to treat HSIL. In one study, 39% of patients had clearance of HSIL with 50% recurrence at 6 months.
(30)
Surgical treatment has varied from wide local excision with anal mapping to focal obliteration with HRA guidance. Historic results of wide local excision with mapping revealed a local recurrence rate of 23%. (33) One study utilizing HRA mapping and directed surgical cauterization of HSIL and LSIL found no long term anal dysfunction with no progression to cancer in the follow up period (12-50 months) regardless of HIV status. (34)
There is currently a trial to compare topical versus ablative therapy to prevent anal cancer with HIV and HSIL that is in the recruitment phase. (35) Invasive carcinoma Until the late 1970’s and early 1980’s, anal canal cancer was treated primarily with surgical intervention by APR and end colostomy. The overall 5 year survival of this was reported from 40-70%. (36-39) In 1974, Nigro introduced the concept of chemotherapy and radiation as definitive treatment for anal squamous cell carcinoma. He published his results in 1983 quoting an 86% clinical response with an 80% disease free survival. (40) His study focused on 5-fluorouracil, mitomycin C, and radiation therapy. Several studies have assessed the necessity and benefit of each of these individual factors. The superiority of chemotherapy combined with radiation therapy over radiation alone was demonstrated in the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) (41)
and the European Organization for Research and Treatment of Cancer (EORTC) (27) . Both
studies showed a reduced local failure rate from 50-60% with radiation alone to 32-39% radiation with chemotherapy. Neither study showed a survival advantage. Mitomycin has a side effect of hematologic toxicity such as thrombocytopenia and leukocytopenia. These side effects have been prohibitive in completion of therapy in several patients. The Radiation Therapy Oncology Group (RTOG)87-04 and the Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial comparing radiation therapy with 5-FU alone versus combined with mitomycin. (42,43) They demonstrated both a reduced need for colostomy (9% down from 22%) along with an increased disease free survival (73% vs. 51%) with the use of mitomycin.
To avoid the potential toxicity of mitomycin, alternative therapies have been evaluated. Cisplatin showed some potential in the 1990’s as an alternative chemoradiotherapy for anal cancer with some studies showing a 94% response rate. (44) Multiple studies have evaluated cisplatin as an alternative to mitomycin which have revealed no difference in overall or disease free survival. Earlier studies have showed increased need for colostomy with cisplatin with no difference in colostomy free survival seen in more recent studies. Some studies have shown increased toxicity of cisplatin while others have shown no difference in toxicity. (42,43, 45,46) Early studies suggest Capecitabine as a reasonable alternative for IV 5-FU with 93% disease free survival at 20 months. (47) Further investigation is required to fully compare the long term outcomes. Radiation Nigro originally used 30 Gy of radiation in his study. Since then, dose escalation has been evaluated and shown to have improved locoregional control. Escalating doses of radiation up to 55 Gy in T1 and T2 and up to 60 Gy in T3 and T4 have shown good locoregional control at 5 years. (up to 90% at 5 years). (48) Radiation toxicity at above 65 Gy has resulted in anal canal necrosis. (49) Prophylactic inguinal lymph node basin treatment is debated due to the complications and side effects of radiation to those basins. Prophylactic inguinal basin irradiation with 45-50 Gy has been shown to reduce inguinal node recurrence rate from 16% to 2%. This reduction was largest in T3-T4 tumors (30% recurrence with no prophylactic irradiation.) (50) Radiotherapy is fractionated over 6 weeks. Breaks or prolongation of this therapy have shown worse rates of local control. (51) To combat breaks in therapy, dose-painted intensity modulated
radiation therapy utilizes computer-controlled linear accelerators to deliver precise radiation doses to a malignant tumor using a 3-D model of the tumor. The goal is to reduce radiation to normal tissues while increasing radiation to the tumor. This has been shown to decrease acute radiation toxicity and increase completion of therapy without breaks. (52) HIV patients HIV-positive patients were excluded from the early major randomized trials which left questions about how to treat them. Studies focusing on these populations have been mostly small but suggest a similar long term survival with increased toxicity. Hematologic toxicity ranged from 52%-80% leading to delay or breaks in therapy. (53-55) These breaks did not lead to disease specific survival differences. Overall patient survival correlated with CD4 counts <200cells/ml. The chemoradiotherapy did result in an overall decrease in CD 4 count of these patients. (56) Some advocate initiation of HAART prior to initiation of CRT. Elderly Although some have had concern over the ability to tolerate full dose chemotherapy and radiation side effects, this should not preclude therapy. One single institution retrospective study of 278 patients showed 8.6% of patients over 70 either stopped or had a break in therapy due to toxicity versus 2.6% of patients under 70. This did not result in any survival disadvantage. (57) Complications of radiation Long term side effects of radiation therapy to the pelvis include fibrosis of the rectum or anal canal, skin dryness, vaginal shrinkage, erectile dysfunction and radiation proctitis. The impact on quality of life from skin toxicity and sexual dysfunction has more significant impact on younger
patients than the elderly. (58) Dose-related radiation side effects, such as anal ulcers, stenosis, and necrosis, can necessitate a subsequent colostomy in 6% to 12% of patients. (59) Side effects of inguinal node basin irradiation include the risk of inguinal fibrosis, epidermolysis, necrosis of the femoral head, and stenosis of iliac artery. Salvage Although overall response rates to chemoradiation therapy have been 80%, local failure rate and recurrence rate have been 20-25% (41, 42) Salvage chemoradiation therapy has shown 5-year survival rates from 19%-50% (60,61) . Two-year survival has been shown to be 25% in HIV patients with recurrence. (62) Abdomino-perineal resection is the mainstay of salvage treatment with survival rates ranging from 29-60%. (63-66) Perineal wound complications occur in 66 to 80% of these patients even with reconstruction flaps. (66,67) Metastatic treatment options Metastasis is present in 5% of patients upon initial presentation and despite treatment with chemoradiation, distant metastasis develop in 10 to 17% of patients. (27,41) The rarity of the disease and metastatic presentation prevents the ability to create a standardized treatment regimen. A response rate of 66% has been shown using 5-FU and cisplatin in 18 patients. (68) . Another study showed 60% response rate with paclitaxel alone in 5 patients(69) . In one study of metastatic squamous cell cancer from any site (of which 4 patients were anal canal primary) there was a 90% response rate using Carboplatin, paclitaxel and 5-FU (70) . These patient populations are small and any patient with metastatic squamous cell carcinoma of the anal canal should be encouraged to enroll in a clinical trial.
Follow up Follow up should begin 6-12 weeks after completion of treatment. If the patient shows persistence of the disease without progression, they should be reassessed 4 weeks after prior to labeling them as non-responders. Examinations should be done every 3 to 6 months with digital rectal exam, anoscopy with biopsy of any questionable lesions, and palpation of the inguinal lymph node basins for 5 years. Very few recurrences occur after 3 years. Adjunctive endorectal US has not been shown to have any predictive benefit in recurrence. (71, 72) Annual CT scans of chest, abdomen, and pelvis for the first 3 years for locally advanced tumors has been advocated. FDG-PET/CT has been shown to be more sensitive, 90-100% , than CT alone in detecting lymph node recurrence. This comes with a price of decreased specificity of 83% and a PPV of 43%. (73) In one study, the increased sensitivity, specificity, and negative predictive value of PET/CT was suggested to have an impact on management of disease in 20% of patients. (74) Conclusion Squamous cell carcinoma of the anal canal is a rare malignancy. The patient population has become younger over time largely to do with the increased prevalence of HPV. There appears to be a preventative role in prophylactic HPV vaccination and a possible benefit to reduction in progression for those who have already been exposed to HPV. Earlier detection with closer monitoring of high risk groups offers a higher chance for survival. Close follow up after therapy is important for early detection of recurrence.
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65. Mullen JT, Rodriguez-Bigas MA, Chang GJ, et al. Results of surgical salvage after failed chemoradiation therapy for epidermoid carcinoma of the anal canal. Ann Surg Oncol 2007;14: 478–83. 66. Schiller DE, Cummings BJ, Rai S, Le LW, Last L, Davey P, Easson A, Smith AJ, Swallow CJ. Outcomes of salvage surgery for squamous cell carcinoma of the anal canal. Annals of Surgical Oncology. Oct 2007. 14(10):2780-9. 67. Papaconstantinou HT, Bullard KM, Rothenberger DA, Madoff RD. Salvage abdominoperineal resection after failed Nigro protocol: Modest success, major morbidity. Colorectal Dis 2006;8: 124–9. 68. Faivre C, Rougier P, Ducreux M, et al. 5-Fluorouracil and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer. Bull Cancer 1999, 86(10):861– 865. 69. Alcindor T: Activity of paclitaxel in metastatic squamous anal carcinoma. Int J Colorectal Dis 2008, 23(7):717. 70. Hainsworth JD, Burris HA III, Meluch AA, et al. Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial. Cancer 2001, 92(3):642–649. 71. Martelluci J, Naldini, G, Colosimo C, Cionini L, Rossi M. Accuracy of endoanal ultrasound in the follow-up assessment for squamous cell carcinoma of the anal canal treated with radiochemotherapy. Surg Endosc (2009), 23:1054-1057
72. Lund JA, Sundstrom SH, Haaverstad R, Wibe A, Svinsaas M, Myrvold HE (2004) Endoanal ultrasound is of little value in follow-up of anal carcinomas. Dis Colon Rectum 47:839–842 73. Mistrangelo, M., E. Pelosi, Bell, et al. Comparison of positron emission tomography scanning and sentinel node biopsy in the detection of inguinal node metastases in patients with anal cancer. Int J of Rad Oncol Bio Phys. 2010. 77(1): 73-78. 74. Vercellino L, Montravers F, de Parades V, et al. Impact of FDG PET/CT in the staging and the follow-up of anal carcinoma. Int J Colorectal Dis. 2011. 26:201–210
Table 1: Adapted from the American Joint Committee on Cancer(AJCC):7th Ed. TNM staging system for Anal Cancer, p. 165
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage II
T2 or T3
N0
M0
Stage IIIA
T1, T2, or T3
N1
M0
T4
N0
M0
T4
N1
M0
Any T
N2 or N3
M0
Any T
Any N
M1
Stage IIIB
Stage IV
Epidermoid Cancers of the anal canal Shawn Webb MD
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www.elsevier.com/locate/yscrs S1043-1489(15)00011-1 http://dx.doi.org/10.1053/j.scrs.2015.01.004 YSCRS501
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Seminars in Colon and Rectal Surgery
Cite this article as: Shawn Webb MD, Epidermoid Cancers of the anal canal, Seminars in Colon and Rectal Surgery, http://dx.doi.org/10.1053/j.scrs.2015.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Epidermoid Cancers of the Anal Canal Shawn Webb, MD Shawn Webb, MD Henry Ford Hospital [email protected]
Key Words Epidermoid Anal canal cancer HPV HSIL
Abstract Squamous cell cancer of the anal canal continues to be a rare cancer. Recently, the incidence has been slowly rising in part due to longer term HIV survivors and in part due to high prevalence of HPV. Early detection and treatment in these high risk groups is imperative to increasing the survival of the disease. Chemoradiation remains the standard of care for primary therapy reserving surgical resection for salvage.
Incidence Anal cancer is an uncommon malignancy and accounts for 2.4% of all GI malignancies (1) and 4% of all lower GI tract malignancies(2) . The current incidence, in the last decade, compared to the incidence in the 1980’s and early 90’s has increased with a relative risk of 2.2. (3)
This has been attributed to multiple factors including increased screening regimens, increased
spread of HIV disease and increased survival of HIV disease in the era of HAART. (4) In 2014, there are an estimated 7,210 new cases with 950 resulting deaths. (5) This is an increase from 2013's estimates of 7060 new cases and 880 deaths. (1) The number of new cases of anal cancer was 1.8 per 100,000 men and women per year. The number of deaths was 0.2 per 100,000 men and women per year from 2007-2011. (6) Anatomy The major anatomical distinction in treatment of lesions in the area are that of the primary location, either anal canal versus the anal margin. The anal margin is that part of the anus that can be seen with gentle retraction of the buttocks. This is covered of squamous epithelium and contains appendages such as hair follicles. Cancers of this area will be covered under a separate section. The surgical anal canal is the area defined from the anorectal ring proximally to the anal verge distally. This area contains columnar epithelium of the rectal mucosa proximally, squamous epithelium distally, and an area of transition that can extend from 0 to 1.2-cm. This mucosa resembles urothelium. In addition to the anatomic landmarks, an area of transformation has been defined in within the last decade. The distal boundary of this is the dentate line and can extend with finger
like projections 6-10-cm inside the rectum. This area is susceptible to metaplastic changes when exposed to HPV. (7) Terminology Squamous carcinoma of the anal canal has been known to arise from precursor lesions of carcinoma in situ. Since the advent of this terminology by Bowen in 1912, these precursor lesions have been described with multiple nomenclatures. The most current terminology of anal squamous intra-epithelial lesions(ASIL) ranges from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) (which includes carcinoma in situ, high grade dysplasia, and anal intraepithelial neoplasm grade II and III, and high grade intraepithelial neoplasm HGAIN). Although these precursor lesions give rise to anal squamous carcinoma, the incidence of progression ranges from 1% in the general population (8) to 7.5%13% in the HIV positive population. (9,10) Epidemiology The median age at diagnosis of anal canal cancer in the US is 60 years old. Fifty-three percent of patients are between 45-65. (6) The incidence trend has been toward a younger population as HPV and HIV have become more common. There has been an increase in incidence rates of both genders aged 30 to 54 years since the era of antiretroviral therapy. (11) Eighty percent of anal cancers are squamous cell in origin. Some specific risk factors for anal cancer that have been shown in the literature are female gender, HPV infection, history of STDs, number of sexual partners greater than 10, genital warts, cigarette smoking, anal receptive intercourse, and HIV infection or other immunosuppression. (12, 13, 14)
The association of HPV and cancer was first observed in patients with epidermodysplasia verruciformis which can progress to squamous cell cancer in sun exposed areas. Since then, at least 13 serotypes of HPV have been shown to have potential oncogenic effects. The most well established serotypes being HPV 16 and 18. (13) In a meta-analysis by Hoots et al. HPV prevalence was found to be 71%, 91%, and 88% in anal cancer, HSIL, and LSIL, respectively. HPV types 16 and/or 18, the most common high-risk HPV viral types, were detected in 72% of anal cancers. (15) HPV is transmitted by both vaginal and anal intercourse, and has been shown to infect the anal region without having direct anal intercourse. Prevention Abstinence from high risk behaviors is the best prevention for infection from HPV and other risk factors for anal cancer. In 2011, the FDA approved the use of quadrivalent HPV vaccine for prevention of anal cancer to be used in patients aged 9 through 26. This was based on the findings that in a large sample size including MSM, the vaccine prevented any form of ASIL or anal cancer in 78% of this high risk population. (16) Although the initial approval and study of HPV vaccine was for HPV naïve patients, there has been some suggestion of clinical efficacy of the HPV vaccine in patients that have been exposed to HPV and have had HSIL that has been treated. In a nonrandomized study of MSM who were HIV negative and diagnosed with HSIL, the arm of the study that received the HPV vaccination showed a reduced recurrence of HSIL over at least 2 years compared to those that did not take the vaccine. (17)
Screening and diagnosis Screening has been recommended by some in patients with high risk features, such as HIV positivity, history of anoreceptive intercourse, immunosuppression, or cervical dysplasia. The method for screening is with Dacron swab into the anal canal similar to pap smear testing of the cervix. (18) It has been recommended that any abnormal cytology should be followed up by high resolution anoscopy (HRA) to identify early lesions for monitoring. The accuracy of HRA is variable with sensitivities ranging from 50-90%. (19,20) Devaraj published a paper that followed 277 HIV + men who have intercourse with men over 4 years. He found an incidence of 49% of HSIL. Because the HSIL progressed to cancer in only 1% of the population, the purpose of the screening was to identify and eradicate early lesions. (21) Although HSIL can be eradicated in immunocompetent patients, HIV + status has shown a recurrence rate of 80% over 2 years and almost 100% over 4 years. (22) The most common sign of anal cancer is bleeding. There is often a delay in diagnosis with this presentation given that anal outlet bleeding is often attributed firstly to benign disease such as hemorrhoids. Other common signs include itching, fullness, pain, a lump, abnormal rectal discharge, or a change in stool caliber. Patients with such complaints should get a digital rectal exam and evaluation with anoscopy along with tissue biopsy of any abnormality found. The exam should focus on size, fixation and any lymph node involvement, including the inguinal basins. Given that most tumors are treated without complete resection by surgery, they are staged based on size and histologic confirmation. Rectal ultrasound is not routinely used to stage.
Metastatic work up should ensue. Physical exam and CT alone are inadequate in detecting lymph node metastasis, many of which will be positive even at 5-mm in size. (23) Studies have shown improved detection rates of primary tumors with PET imaging (91% vs. 59%) and both pelvic and inguinal lymph nodes (20% missed by CT but picked up by PET) (24,25) . Analysis of the SEER database updated in 2014 showed that 32% of patients were node positive on presentation. (26) Staging The American Join Committee on cancer first proposed the TNM classification for anal canal carcinoma in 1989 (Table 1) The staging system has not needed revisions in the interim. The importance of staging on prognosis was shown in an analysis of the SEER database showing 80% 5-survival of stage I and II, 58% 5 year survival in stage III, and 32% survival in stage IV. (26)
Primary Tumor: Tis-Carcinoma in situ, T1-tumor 2cm or less, T2-tumor between 2-5 cm, T3Tumor >5cm, T4-any size tumor that invades nearby organs(ie vagina, urethra, bladder) Lymph Nodes: N0-No regional lymph node metastasis, N1-Metastasis to perirectal lymph nodes, N2-Metastasis in unilateral internal iliac and/or inguinal lymph node(s), N3-Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes Distant Metastasis: M0-No distant metastasis, M1- Distant metastasis Although T and N stage has been shown several times over to have bearing on prognosis, several other factors have been evaluated. In the European Organization for Research and Treatment of Cancer (EORTC) phase III trial, they found that the presence of lymph node involvement
decreased local control and survival, but the number and size of lymph nodes involved had no bearing on these factors. (27) A study by MD Anderson supported that both T-stage and N-stage independently predicted local failure and N stage predicted distant failure and decreased overall survival. (28) A recent revisit of the EORTC data revealed that patients with T3-T4 N+ disease have the worst disease free, colostomy free and overall survival. (29) Other possible prognostic factors such gender, histologic grade and race have been suggested by some studies but not supported by others. Treatment HSIL As mentioned above, (21) only 1% of HSIL progress to invasive cancer. Surveillance versus ablation with topical agents has been advocated by some. Topical agents, such as Imiquimod or 5-FU, or ablative therapy under HRA have both been evaluated. Imiquimod has been used successfully for eradication of HSIL in populations including HIV + patients. One study showed a 61% eradication of HPV and 77% resolution of any ASIL. (30) Studies have shown a sustained absence of HSIL ranging from 61% to 74% in 36-month follow up after obliteration. (31, 32) Topical 5-FU has also been studied to treat HSIL. In one study, 39% of patients had clearance of HSIL with 50% recurrence at 6 months.
(30)
Surgical treatment has varied from wide local excision with anal mapping to focal obliteration with HRA guidance. Historic results of wide local excision with mapping revealed a local recurrence rate of 23%. (33) One study utilizing HRA mapping and directed surgical cauterization of HSIL and LSIL found no long term anal dysfunction with no progression to cancer in the follow up period (12-50 months) regardless of HIV status. (34)
There is currently a trial to compare topical versus ablative therapy to prevent anal cancer with HIV and HSIL that is in the recruitment phase. (35) Invasive carcinoma Until the late 1970’s and early 1980’s, anal canal cancer was treated primarily with surgical intervention by APR and end colostomy. The overall 5 year survival of this was reported from 40-70%. (36-39) In 1974, Nigro introduced the concept of chemotherapy and radiation as definitive treatment for anal squamous cell carcinoma. He published his results in 1983 quoting an 86% clinical response with an 80% disease free survival. (40) His study focused on 5-fluorouracil, mitomycin C, and radiation therapy. Several studies have assessed the necessity and benefit of each of these individual factors. The superiority of chemotherapy combined with radiation therapy over radiation alone was demonstrated in the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) (41)
and the European Organization for Research and Treatment of Cancer (EORTC) (27) . Both
studies showed a reduced local failure rate from 50-60% with radiation alone to 32-39% radiation with chemotherapy. Neither study showed a survival advantage. Mitomycin has a side effect of hematologic toxicity such as thrombocytopenia and leukocytopenia. These side effects have been prohibitive in completion of therapy in several patients. The Radiation Therapy Oncology Group (RTOG)87-04 and the Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial comparing radiation therapy with 5-FU alone versus combined with mitomycin. (42,43) They demonstrated both a reduced need for colostomy (9% down from 22%) along with an increased disease free survival (73% vs. 51%) with the use of mitomycin.
To avoid the potential toxicity of mitomycin, alternative therapies have been evaluated. Cisplatin showed some potential in the 1990’s as an alternative chemoradiotherapy for anal cancer with some studies showing a 94% response rate. (44) Multiple studies have evaluated cisplatin as an alternative to mitomycin which have revealed no difference in overall or disease free survival. Earlier studies have showed increased need for colostomy with cisplatin with no difference in colostomy free survival seen in more recent studies. Some studies have shown increased toxicity of cisplatin while others have shown no difference in toxicity. (42,43, 45,46) Early studies suggest Capecitabine as a reasonable alternative for IV 5-FU with 93% disease free survival at 20 months. (47) Further investigation is required to fully compare the long term outcomes. Radiation Nigro originally used 30 Gy of radiation in his study. Since then, dose escalation has been evaluated and shown to have improved locoregional control. Escalating doses of radiation up to 55 Gy in T1 and T2 and up to 60 Gy in T3 and T4 have shown good locoregional control at 5 years. (up to 90% at 5 years). (48) Radiation toxicity at above 65 Gy has resulted in anal canal necrosis. (49) Prophylactic inguinal lymph node basin treatment is debated due to the complications and side effects of radiation to those basins. Prophylactic inguinal basin irradiation with 45-50 Gy has been shown to reduce inguinal node recurrence rate from 16% to 2%. This reduction was largest in T3-T4 tumors (30% recurrence with no prophylactic irradiation.) (50) Radiotherapy is fractionated over 6 weeks. Breaks or prolongation of this therapy have shown worse rates of local control. (51) To combat breaks in therapy, dose-painted intensity modulated
radiation therapy utilizes computer-controlled linear accelerators to deliver precise radiation doses to a malignant tumor using a 3-D model of the tumor. The goal is to reduce radiation to normal tissues while increasing radiation to the tumor. This has been shown to decrease acute radiation toxicity and increase completion of therapy without breaks. (52) HIV patients HIV-positive patients were excluded from the early major randomized trials which left questions about how to treat them. Studies focusing on these populations have been mostly small but suggest a similar long term survival with increased toxicity. Hematologic toxicity ranged from 52%-80% leading to delay or breaks in therapy. (53-55) These breaks did not lead to disease specific survival differences. Overall patient survival correlated with CD4 counts <200cells/ml. The chemoradiotherapy did result in an overall decrease in CD 4 count of these patients. (56) Some advocate initiation of HAART prior to initiation of CRT. Elderly Although some have had concern over the ability to tolerate full dose chemotherapy and radiation side effects, this should not preclude therapy. One single institution retrospective study of 278 patients showed 8.6% of patients over 70 either stopped or had a break in therapy due to toxicity versus 2.6% of patients under 70. This did not result in any survival disadvantage. (57) Complications of radiation Long term side effects of radiation therapy to the pelvis include fibrosis of the rectum or anal canal, skin dryness, vaginal shrinkage, erectile dysfunction and radiation proctitis. The impact on quality of life from skin toxicity and sexual dysfunction has more significant impact on younger
patients than the elderly. (58) Dose-related radiation side effects, such as anal ulcers, stenosis, and necrosis, can necessitate a subsequent colostomy in 6% to 12% of patients. (59) Side effects of inguinal node basin irradiation include the risk of inguinal fibrosis, epidermolysis, necrosis of the femoral head, and stenosis of iliac artery. Salvage Although overall response rates to chemoradiation therapy have been 80%, local failure rate and recurrence rate have been 20-25% (41, 42) Salvage chemoradiation therapy has shown 5-year survival rates from 19%-50% (60,61) . Two-year survival has been shown to be 25% in HIV patients with recurrence. (62) Abdomino-perineal resection is the mainstay of salvage treatment with survival rates ranging from 29-60%. (63-66) Perineal wound complications occur in 66 to 80% of these patients even with reconstruction flaps. (66,67) Metastatic treatment options Metastasis is present in 5% of patients upon initial presentation and despite treatment with chemoradiation, distant metastasis develop in 10 to 17% of patients. (27,41) The rarity of the disease and metastatic presentation prevents the ability to create a standardized treatment regimen. A response rate of 66% has been shown using 5-FU and cisplatin in 18 patients. (68) . Another study showed 60% response rate with paclitaxel alone in 5 patients(69) . In one study of metastatic squamous cell cancer from any site (of which 4 patients were anal canal primary) there was a 90% response rate using Carboplatin, paclitaxel and 5-FU (70) . These patient populations are small and any patient with metastatic squamous cell carcinoma of the anal canal should be encouraged to enroll in a clinical trial.
Follow up Follow up should begin 6-12 weeks after completion of treatment. If the patient shows persistence of the disease without progression, they should be reassessed 4 weeks after prior to labeling them as non-responders. Examinations should be done every 3 to 6 months with digital rectal exam, anoscopy with biopsy of any questionable lesions, and palpation of the inguinal lymph node basins for 5 years. Very few recurrences occur after 3 years. Adjunctive endorectal US has not been shown to have any predictive benefit in recurrence. (71, 72) Annual CT scans of chest, abdomen, and pelvis for the first 3 years for locally advanced tumors has been advocated. FDG-PET/CT has been shown to be more sensitive, 90-100% , than CT alone in detecting lymph node recurrence. This comes with a price of decreased specificity of 83% and a PPV of 43%. (73) In one study, the increased sensitivity, specificity, and negative predictive value of PET/CT was suggested to have an impact on management of disease in 20% of patients. (74) Conclusion Squamous cell carcinoma of the anal canal is a rare malignancy. The patient population has become younger over time largely to do with the increased prevalence of HPV. There appears to be a preventative role in prophylactic HPV vaccination and a possible benefit to reduction in progression for those who have already been exposed to HPV. Earlier detection with closer monitoring of high risk groups offers a higher chance for survival. Close follow up after therapy is important for early detection of recurrence.
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Table 1: Adapted from the American Joint Committee on Cancer(AJCC):7th Ed. TNM staging system for Anal Cancer, p. 165
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage II
T2 or T3
N0
M0
Stage IIIA
T1, T2, or T3
N1
M0
T4
N0
M0
T4
N1
M0
Any T
N2 or N3
M0
Any T
Any N
M1
Stage IIIB
Stage IV