Anal Cancer

Related Summaries

● Condyloma acuminatum (anogenital wart)

● Human papillomavirus DNA testing

● Human papillomavirus (HPV) vaccine

● Anal ssure

● Fistula in ano and anorectal abscess

General Information

Description

● malignant neoplasm of anal canal

Also called

● anal canal cancer

● anal carcinoma

● anal squamous carcinoma

● cancer of anal canal

● squamous cancer of anal canal

● carcinoma of anal canal

Definitions

● anal canal 5

⚬ begins at anorectal junction at upper portion of pelvic oor (upper border of anal sphincter is the
puborectalis muscle), passes through anal ring, and ends at merging of skin and anal margin
⚬ anatomic anal canal is region from dentate line to anal verge
⚬ surgical anal canal is area from anorectal junction extending to anal verge

● anal margin is area from anal verge that extends 5 cm onto perineum 5

● anal verge - junction of anal canal and hair-bearing skin 5 , see Squamous cell carcinoma for cancer of

perianal skin

● dentate line - line separating simple columnar epithelium of rectum from strati ed squamous

epithelium of anal canal 5

Types
● squamous cell carcinoma makes up majority of anal carcinomas 5

● anal adenocarcinoma makes up small minority of anal carcinoma 5

● rare tumors that should be di erentiated from squamous cell carcinoma 1 , 5

⚬ poorly di erentiated squamous cell carcinoma

⚬ undi erentiated carcinoma
⚬ poorly di erentiated adenocarcinoma
⚬ malignant melanoma
⚬ sarcoma
⚬ sarcomatoid carcinoma
⚬ small cell neuroendocrine carcinoma
⚬ cloacogenic carcinoma
⚬ lymphoma (rare unless immunocompromised)
⚬ metastases from other local or distant sites
⚬ large cell neuroendocrine carcinoma
⚬ CK20-positive neuroendocrine carcinoma (rare)
⚬ perianal Paget’s disease (rare)

Epidemiology

Who is most affected

● women

⚬ estimated 2,750 new cases in women vs. 1,910 in men in United States in 2006
⚬ Reference - CA Cancer J Clin 2006 Mar-Apr;56(2):106 full-text

● persons who practice anoreceptive intercourse 2

● patients with HIV infection 5

Incidence/Prevalence

● age-adjusted incidence of anal cancer in persons ≥ 20 years old 1.5 per 100,000 in United States from
2000-2004
⚬ based on data from Surveillance, Epidemiology, and End Results (SEER) program
⚬ Reference - National Cancer Institute Fact Sheet on Cancer of Anus, Anal Canal and Anorectum

● age-adjusted incidence of anal cancer in persons ≥ 20 years old 1.7 per 100,000 person-years in
United States from 1973-2000
⚬ based on data from Surveillance, Epidemiology, and End Results (SEER) program
⚬ incidence increased during this period in men and women (p < 0.01 for both)
⚬ incidence of invasive disease increased over time in men and women, but women had higher
annual rates
⚬ incidence of in situ disease increased more over time in men than women
⚬ higher incidence of anal cancer in women ≥ 65 years old than men ≥ 65 years old
⚬ Reference - Cancer 2004 Jul 15;101(2):281 PDF
● up to 35 per 100,000 population per year for men who practice anoreceptive sexual intercourse 6

● 1.5% of all gastrointestinal tract cancers in United States (CA Cancer J Clin 2000 Jan-Feb;50(1):7 full-
text )

Likely risk factors

● anal intraepithelial neoplasia (Gastroenterol Clin North Am 2007 Dec;36(4):969 )

STUDY
● SUMMARY
HIV infection associated with increased risk of anal cancer

COHORT STUDY: Ann Intern Med 2015 Oct 6;163(7):507

Details
⚬ based on cohort study
⚬ 86,620 persons with HIV and 196,987 uninfected adults from the United States and Canada
followed between 1996 and 2009
⚬ cumulative incidence of anal cancer by age 75 years 1.5% for persons with HIV infection vs. 0.05%
for uninfected persons (p < 0.05)
⚬ Reference - Ann Intern Med 2015 Oct 6;163(7):507

● HIV associated with increased risk of squamous cell carcinoma of the anus (World J Gastroenterol
2011 Jul 7;17(25):2987 full-text )

STUDY
● SUMMARY
risk factors for anal cancer

CASE-CONTROL STUDY: Cancer 2004 Jul 15;101(2):270 | PDF

Details
⚬ based on case-control study with 306 men and women diagnosed with anal cancer 1986-1998 and
1,700 population-based controls in Seattle, Washington
⚬ men not being exclusively heterosexual (adjusted odds ratio [OR] 17.3, 95% CI 8.2-36.1)
⚬ history of ≥ 15 lifetime sexual partners

– OR 3.9 (95% CI 1.4-10.7) in heterosexual men

– OR 6.6 (95% CI 0.9-47.1) in men not exclusively heterosexual
– OR 11 (95% CI 5.5-22.1) in women

⚬ anoreceptive intercourse

– OR 6.8 (95% CI 1.4-33.8) in men not exclusively heterosexual

– OR 2.2 (95% CI 1.4-3.3) in women

⚬ cigarette smoking

– OR 3.9 (95% CI 1.9-8) in men

– OR 3.8 (95% CI 2.4-6.2) in women

⚬ history of genital warts (OR 7.4, 95% CI 3.2-17.1)

⚬ corticosteroid use

– OR 3.2 (95% CI 1.4-7.2) in men

– OR 2.3 (95% CI 1.4-3.7) in women
 ⚬ Reference - Cancer 2004 Jul 15;101(2):270 PDF

STUDY
● SUMMARY
receptive anal intercourse, other sexually transmitted disease, and higher numbers of sexual
partners appear to be risk factors for anal cancer

CASE-CONTROL STUDY: N Engl J Med 1997 Nov 6;337(19):1350

Details
⚬ based on case-control study with 324 women and 93 men with invasive or in situ anal cancer 1991-
1994 compared to 534 controls with rectal adenocarcinoma and 554 population controls in
Denmark and Sweden
⚬ Reference - N Engl J Med 1997 Nov 6;337(19):1350 , editorial can be found in N Engl J Med 1997
Nov 6;337(19):1386 , commentary can be found in N Engl J Med 1998 Mar 26;338(13):921

STUDY
● SUMMARY
risk factors for anal and rectal squamous cell carcinoma

CASE-CONTROL STUDY: J Natl Cancer Inst 1989 Nov 15;81(22):1726

Details
⚬ based on case-control study with 126 patients and 372 controls in San Francisco, California
⚬ history of homosexual activity in men (relative risk [RR] 12.4, p < 0.001) but not signi cant in
adjusted analysis
⚬ history of genital warts

– RR 12.6 in men who have sex with men (p = 0.03)

– RR 4.4 in heterosexual men and women (p = 0.003)

⚬ history of anal ssure or stula

– RR 9.1 in men who have sex with men (p = 0.05)

– RR 2.4 in heterosexual men and women (p = 0.03)

⚬ history of > 12 episodes of hemorrhoids (RR 2.6 in heterosexual men and women, p < 0.001)
⚬ cigarette smoking in men who have sex with men

– RR 1.9 for 20 pack-years, p < 0.001

– RR 5.2 for 50 pack-years, p < 0.001

⚬ Reference - J Natl Cancer Inst 1989 Nov 15;81(22):1726

STUDY
● SUMMARY
history of lower genital tract neoplasia may increase risk for abnormal anal cytology, high-risk
HPV in anal canal, and anal intraepithelial neoplasia

CROSS-SECTIONAL STUDY: Obstet Gynecol 2015 Dec;126(6):1294 | Full Text

Details
⚬ based on cross-sectional cohort study
⚬ 273 HIV-negative women ≥ 18 years old evaluated for history of HPV-related genital neoplasia and
had anal cytologic testing
⚬ 190 women (70%) had history of high-grade cervical, vulvar, or vaginal cytology, dysplasia, or cancer
(high-risk group)
 ⚬ women in high-risk group were younger than those in low-risk group (median 47 years vs. 57 years,
p < 0.001) and more likely to be current smokers (30% vs. 12%, p = 0.002)
⚬ comparing high-risk group vs. women with no history of high-grade anogenital dysplasia or cancer

– abnormal anal cytology in 41.2% vs. 21.7% (p = 0.006)

– high-risk HPV in anal canal in 20.8% vs. 1.2% (p < 0.001)
– anal intraepithelial neoplasia in 13.4% vs. 0% in women with anoscopy (p < 0.001)

⚬ Reference - Obstet Gynecol 2015 Dec;126(6):1294 full-text

STUDY
● SUMMARY
higher incidence of anal cancer reported in women with history of cervical cancer or cervical
intraepithelial neoplasia 3 and in women with HIV infection

SYSTEMATIC REVIEW: Am J Obstet Gynecol 2015 Sep;213(3):278 | Full Text

Details
⚬ based on systematic review of observational studies
⚬ systematic review of 60 observational studies evaluating epidemiology of anal HPV infection, anal
intraepithelial neoplasia, and anal cancer in women
⚬ meta-analyses not performed due to heterogeneity in HPV testing and study types
⚬ incidence of anal cancer (per 100,000 person-years)

– 0.8-63.8 in women with history of cervical cancer or cervical intraepithelial neoplasia 3 (the study
reporting 63.8 per 100,000 person-years included rectal and anal cancers)
– 3.9-30 in women with HIV infection
– 0.55-2.4 in general female population

⚬ Reference - Am J Obstet Gynecol 2015 Sep;213(3):278 full-text

STUDY
● SUMMARY
risk of anal HPV infection in women associated with cervical HPV infection

COHORT STUDY: J Infect Dis 2008 Apr 1;197(7):957 | PDF

Details
⚬ based on a cohort of 431 women followed for mean 1.3 years
⚬ 70% were positive for anal HPV
⚬ incidence of high-risk anal HPV infections 19.5 per 1,000 woman-months (95% CI 16-23.6)
⚬ risk of incident high-risk anal HPV infection associated with high-risk cervical HPV infection at
baseline (odds ratio 1.81, 95% CI 1.09-3.02)
⚬ Reference - J Infect Dis 2008 Apr 1;197(7):957 PDF

STUDY
● SUMMARY
high-risk cervical HPV associated with increased high-risk anal HPV, and high-risk anal HPV
associated with increased risk of abnormal anal cytology

COHORT STUDY: Obstet Gynecol 2014 Aug;124(2 Pt 1):242

Details
⚬ based on prospective cohort study
 ⚬ 196 women ≥ 21 years old with 1 of the following conditions had standard colposcopy with possible
biopsy and cervical human papillomavirus (HPV) testing as well as anal swab testing for anal HPV
and anal cytology
– atypical squamous cells of undetermined signi cance with HPV
– atypical squamous cells, cannot rule out high-grade dysplasia
– low-grade squamous intraepithelial lesions
– high-grade squamous intraepithelial lesions

⚬ 32.5% had anal HPV

⚬ 17.6% had abnormal anal cytology
⚬ high-risk cervical HPV associated with increased high-risk anal HPV (odds ratio [OR] 3.6, 95% CI
1.19-10.77)
⚬ high-risk anal HPV associated with increased risk of abnormal anal cytology (OR 6.5, 95% CI 2.74-
15.6)
⚬ Reference - Obstet Gynecol 2014 Aug;124(2 Pt 1):242

● additional risk factors for anal cancer 2 , 4

⚬ history of high-risk genotype HPV infection

⚬ infection with multiple HPV genotypes
⚬ history of cervical dysplasia
⚬ history of cervical, vulvar or vaginal cancer
⚬ low CD4 count
⚬ history of sexually transmitted disease

● organ transplant associated with increased risk of anal cancer (incidence 11.6/100,000 person-years,
excess absolute risk 9.6/100,000 person-years [95% CI 7.3-12.3]) based on cohort study of 175,732
patients with solid organ transplants (JAMA 2011 Nov 2;306(17):1891 full-text )

Possible risk factors

STUDY
● SUMMARY
benign anal lesions may be associated with increased risk for anal cancer

COHORT STUDY: N Engl J Med 1994 Aug 4;331(5):300

COHORT STUDY: Gut 2006 May;55(5):703 | Full Text

Details
⚬ based on 2 retrospective cohort studies
⚬ 68,549 patients hospitalized with benign anal lesions between 1977-1989 were followed for median
6.2 years (427,922 person-years of follow-up)
– 23 patients developed anal cancer

● higher than expected 5.25 cases of anal cancer for general population
● standardized incidence ratio (SIR) 4.4 (95% CI 2.8-6.6)

– standardized incidence ratios for speci c anal lesions

● 5.4 (95% CI 2-11.7) for anal ssure (based on 6 cases of anal cancer)
● 8.1 (95% CI 2.2-20.8) for anal stula (based on 4 cases of anal cancer)
● 6.4 (95% CI 2.1-14.8) for perianal abscess (based on 5 cases of anal cancer)
● 3.8 (95% CI 2-6.5) for hemorrhoids (based on 13 cases of anal cancer)
 – Reference - N Engl J Med 1994 Aug 4;331(5):300 , commentary can be found in N Engl J Med
1995 Jan 19;332(3):190
⚬ 45,186 patients hospitalized for in ammatory anal lesions (anal ssures, stulas, or perianal
abscesses) and 79,808 hemorrhoid patients from 1965 to 2002 were evaluated
– anal squamous cell carcinoma determined from medical record linkages through 2002
– patients with in ammatory anal lesions had higher than expected incidence of anal squamous
cell carcinoma
● 6 cases in rst year (13.3 per 100,000) or standardized incidence ratio (SIR) 24 (95% CI 8.8 -
52.3)
● 4 cases in second year (8.85 per 100,000) or SIR 16.3 (95% CI 4.4 - 41.7)
● 13 cases during 3-37 years of follow-up (28.7 per 100,000) or SIR 3.3 (95% CI 1.8 - 5.7)

– hemorrhoids associated with increased risk in rst year (SIR 14.9) and no signi cant increased
risk in subsequent years
– colorectal cancer only associated with in increased risk in rst year after hospitalization for both
patients with in ammatory anal lesions and patients with hemorrhoids
– Reference - Gut 2006 May;55(5):703 full-text

Associated conditions

● HIV infection 2

● condyloma acuminatum 2

STUDY
● SUMMARY
model with 3 risk factors may help to predict anal intraepithelial neoplasia in women with
genital dysplasia

COHORT STUDY: Obstet Gynecol 2013 Aug;122(2 Pt 1):218

Details
⚬ based on cohort study without independent validation
⚬ 327 women with biopsy-con rmed diagnosis of genital intraepithelial neoplasia (vulvar, vaginal, or
cervical) had both anal cytology and anoscopy
⚬ 19.6% had anal intraepithelial neoplasia
⚬ 3 risk factors associated with anal intraepithelial neoplasia

– vulvar intraepithelial neoplasia (VIN)

– immunosuppression
– history of anal sex

⚬ for predicting anal intraepithelial neoplasia, presence of 2 of 3 risk factors had

– sensitivity 47%
– speci city 86.2%
– positive predictive value 43.1%
– negative predictive value 88.2%

⚬ Reference - Obstet Gynecol 2013 Aug;122(2 Pt 1):218 , commentary can be found in Obstet
Gynecol 2014 Jan;123(1):183
⚬ prevalence of anal intraepithelial neoplasia 12.2% in women with genital intraepithelial
neoplasia
 – based on cohort study
– 205 women aged 14-83 years (mean 40 years) with con rmed genital intraepithelial neoplasia
had anal cytology and high-resolution anoscopy
– biopsy-proven anal intraepithelial neoplasia in 12.2%

● abnormal anal cytology in 5.9% (8% sensitive, 94% speci c for anal intraepithelial neoplasia)
● abnormal anoscopy ndings in 38% (100% sensitive, 71% speci c for anal intraepithelial
neoplasia)
– comparing anal cytology vs. anoscopy

● sensitivity for anal intraepithelial neoplasia 8% vs. 100%

● speci city for anal intraepithelial neoplasia 94% vs. 71%

– Reference - Obstet Gynecol 2010 Sep;116(3):578 , editorial can be found in Obstet Gynecol
2010 Sep;116(3):566
⚬ presence of human papillomavirus-related gynecologic neoplasms associated with increased
risk of anal cancer
– based on retrospective cohort study
– 189,206 cases of in situ or invasive cervical, vulvar, or vaginal neoplasm followed for 138,553,519
person-years for development of primary anal cancer compared with expected ratios in
una ected matched controls from the general population
– anal cancer developed in 255 women with gynecologic neoplasm (aggregate standardized
incidence ratio 13.6, 95% CI 11.9-15.3)
– standardized incidence ratio for anal cancer among women with

● in situ vulvar cancer 22.2 (95% CI 16.7-28.4)

● invasive vulvar cancer 17.4 (95% CI 11.5-24.4)
● in situ cervical cancer 16.4 (95% CI 13.7-19.2)
● invasive cervical cancer 6.2 (95% CI 4.1-8.7)
● in situ vaginal cancer 7.6 (95% CI 2.4-15.6)
● invasive vaginal cancer 1.8 (95% CI 0.2-5.3)

– Reference - Obstet Gynecol 2011 Mar;117(3):643

STUDY
● SUMMARY
previous HPV-related cancers associated with increased risk of primary HPV-related anal cancer

SYSTEMATIC REVIEW: Br J Cancer 2018 Nov 28 early online

Details
⚬ based on systematic review of observational studies
⚬ systematic review of 32 cohort studies evaluating incidence of second HPV-related cancer in
3,759,726 patients with previous preinvasive or invasive HPV-related cancer
⚬ increased risk of primary HPV-related anal cancer associated with previous HPV-related

– anal cancer (standardized incidence ratio [SIR] 30.81, 95% CI 23.5-40.39) in analysis of 2 studies
– vaginovulval cancer (SIR 13.69, 95% CI 8.56-21.89) in analysis of 6 studies, results limited by
signi cant heterogeneity
– cervical intraepithelial neoplasia (SIR 4.47, 95% CI 2.66-7.51) in analysis of 9 studies, results
limited by signi cant heterogeneity
– cervical cancer (SIR 3.82, 95% CI 2.35-6.2) in analysis of 8 studies, results limited by signi cant
heterogeneity
– oropharyngeal cancer (SIR 2.7, 95% CI 1.17-6.23) in analysis of 5 studies
 ⚬ Reference - Br J Cancer 2018 Nov 28 early online

Etiology and Pathogenesis

Causes

● human papillomavirus (HPV) infection most important causative agent 2 , 4 , 6

⚬ low-risk HPV subtypes associated with low-grade dysplasia

⚬ high-risk HPV subtypes (16, 18, 31, 33, 35, 39, 45, 50, 51, 53, 56, 58, 59, 68) more often associated
with high-grade dysplasia or invasive carcinoma
⚬ high-risk HPV-16 may be most frequently associated with anal cancer

STUDY
● SUMMARY
high-risk HPV detected in anal carcinomas in 90% of women and 63% of men

CASE-CONTROL STUDY: Cancer Res 1999 Feb 1;59(3):753 | Full Text

Details
⚬ based on histologic evaluation of tumor tissue from 331 patients with invasive anal cancer
⚬ polymerase chain reaction assay used to test for HPV type 16 and 13 other high-risk HPV types
⚬ high-risk HPV detected in anal carcinomas in 90% of women and 63% of men
⚬ among high-risk HPVs identi ed

– 87% HPV-16
– 7% HPV-18
– 6% HPV-33
– 1% HPV-31
– 2% untyped high-risk HPV
– 7 patients had HPV infection with 2 subtypes

⚬ 100% of men reporting homosexual activity vs. 58% without homosexual activity had high-risk HPV
types identi ed (p = 0.006)
⚬ Reference - Cancer Res 1999 Feb 1;59(3):753 full-text

● HPV DNA detected in 88% of tumors from 306 men and women diagnosed with anal cancer 1986-
1998
⚬ HPV-16 detected in 73% of all tumors
⚬ HPV-18 detected in 6.9% of all tumors
⚬ HPV detected in tumors from 89% of women and 86% of men (98% men who were not exclusively
heterosexual, 78% of exclusively heterosexual men)
⚬ Reference - Cancer 2004 Jul 15;101(2):270 PDF

Pathogenesis

● HPV infection associated with development of premalignant anal squamous intraepithelial lesions

(both low and high grade) 2 , 4

● progression of squamous intraepithelial lesions to anal cancer in uenced by risk factors 2 , 4

History and Physical

History

Chief concern (CC)

● anal symptoms may include 2 , 3 , 6

⚬ rectal bleeding (common)

⚬ pain (common)
⚬ sensation of mass (common)
⚬ mucus discharge from anus
⚬ itching
⚬ tenesmus and fecal incontinence may result from anal sphincter invasion

● advanced disease may present with 3

⚬ weight loss
⚬ constipation
⚬ change in stool caliber
⚬ inguinal adenopathy
⚬ rectovaginal stula

Past medical history (PMH)

● risk factors may include 2 , 3

⚬ HIV infection
⚬ human papillomavirus (HPV) infection
⚬ tobacco use
⚬ hemorrhoids
⚬ anal ssures (based on weak evidence)
⚬ organ transplant

Physical

Lungs

● common site of metastatic disease 3

Abdomen

● look for liver enlargement or masses due to metastatic disease 3

Extremities

● inguinal or femoral lymph nodes may be palpable 2 , 6

Rectal

● digital rectal exam (NCCN Category 2A) 7

● anorectal exam may nd

⚬ mass, lesions 2

⚬ enlarged perirectal lymph nodes on digital exam 6

⚬ genital warts 5
● metastatic colorectal carcinoma within thrombosed hemorrhoids in case report (J Med Case Reports
2008 Apr 28;2:128 full-text )

Pelvic

● inguinal region lymphadenopathy 3

● gynecological examination - look for vaginal involvement, vaginal stula 6

Diagnosis and staging

Making the diagnosis

● cytological or histological exam 6

Differential diagnosis

● causes of anal pain

⚬ thrombosed external hemorrhoid - acute onset of pain with a palpable mass

⚬ anal ssure
⚬ proctalgia fugax - episodic severe spasm-like pain with urgency to defecate

● palpable masses

⚬ condyloma
⚬ molluscum contagiosum
⚬ hemorrhoids
⚬ polyps

● causes of rectal bleeding

⚬ anal ssure
⚬ hemorrhoids
⚬ regional enteritis (Crohn disease)
⚬ ulcerative colitis
⚬ infectious colitis
⚬ polyps
⚬ arteriovenous malformation
⚬ intussusception
⚬ stula
⚬ chronic ulcer

Testing overview

● biopsy and pathological exam of anal lesion (NCCN Category 2A) 7

● anoscopy, particularly high resolution anoscopy (NCCN Category 2A) 7

● proctosigmoidoscopy 5

● ne-needle aspiration and cytology for suspicious palpable lymphadenopathy (NCCN Category 2A) 7
● imaging studies for staging

⚬ endoanal ultrasound 5 , 6

⚬ either of the following are recommended options 7

– computed tomography (CT) of pelvis, abdomen and chest (NCCN Category 2A)
– magnetic resonance imaging (MRI) of pelvis and abdomen (NCCN Category 2A)

⚬ consider positron emission tomography (PET) for 7

– stage II-IV disease without lymph node involvement (NCCN Category 2A)
– any stage disease with lymph node involvement (NCCN Category 2A)

⚬ chest x-ray for metastases 5 , 6

● consider the following 7

⚬ HIV test and CD4+ level (NCCN Category 2A)

⚬ gynecological exam for women, including cervical cancer screening (NCCN Category 2A)

Staging system

● American Joint Committee on Cancer (AJCC) staging for anal cancer, eighth edition

Table 1. Clinical Staging

Stage T N M

0 Tis N0 M0

I T1 N0 M0

IIA T2 N0 M0

IIB T3 N0 M0

IIIA T1 N1 M0

T2 N1 M0

IIIB T4 N0 M0

IIIC T3 N1 M0

T4 N1 M0

IV Any T Any N M1
● de nitions of staging abbreviations

⚬ primary tumor (T)

– TX - primary tumor cannot be assessed

– T0 - no evidence of primary tumor
– Tis - high-grade squamous intraepithelial lesion (HSIL) (previously termed carcinoma in situ,
Bowen disease, anal intraepithelial neoplasia [AIN] II-III, high-grade anal intraepithelial
neoplasia)
– T1 - tumor ≤ 2 cm
– T2 - tumor > 2 cm but ≤ 5 cm
– T3 - tumor > 5 cm
– T4 - tumor of any size invading adjacent organ(s), for example, vagina, urethra, bladder

⚬ regional lymph nodes (N)

– NX - regional lymph nodes cannot be assessed

– N0 - no regional lymph node metastasis
– N1 - metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes

● N1a - metastasis in inguinal, mesorectal, internal iliac lymph nodes

● N1b - metastasis in external iliac lymph nodes

● N1c - metastasis in external iliac with any N1a nodes

⚬ distant metastasis (M)

– M0 - no distant metastasis
– M1 - distant metastasis

● Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this
information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International
Publishing.

Imaging studies

● endoanal ultrasound may improve tumor staging

⚬ anorectal endosonography reported to be better for staging of anal carcinoma than classical TNM
classi cation alone (Scand J Gastroenterol Suppl 2006 May;(243):165 )
⚬ 3-dimensional anal endosonography more sensitive than 2-dimensional anal endosonography in
prospective study of 38 patients with history of anal carcinoma being evaluated for recurrent anal
cancer (Dis Colon Rectum 2006 Oct;49(10):1527 )
⚬ review of endoanal ultrasound for evaluation of anorectal disease can be found in Eur J Radiol
2007 Mar;61(3):480
⚬ retrospective series of 30 patients who had endoscopic ultrasound for squamous cell carcinoma of
anal canal can be found in Endoscopy 1999 Jun;31(5):359

● magnetic resonance imaging (MRI)

⚬ MRI may be more accurate than CT in di erentiating tumor from normal pelvic structures 6

⚬ retrospective series of MRI imaging in 27 cases of primary or recurrent anal carcinoma can be
found in Clin Radiol 2005 Oct;60(10):1111
⚬ review of postoperative anatomic and pathologic ndings on pelvic MRI can be found in
Radiographics 2006 Sep-Oct;26(5):1391 full-text

STUDY
● SUMMARY
FDG-PET scanning may be more sensitive than CT in identification of disease DynaMed Level 2

COHORT STUDY: Int J Radiat Oncol Biol Phys 2006 Jul 1;65(3):720
COHORT STUDY: Mol Imaging Biol 2005 Jul;7(4):309

Details
⚬ based on 2 small cohort studies
⚬ 41 consecutive patients with anal carcinoma had staging evaluation including physical examination,
CT, and 2-FDG-PET/CT
– PET detected 91% and CT detected 59% of nonexcised primary tumors
– PET identi ed abnormal nodal uptake in 17% of groins not identi ed by either CT or physical
examination
– Reference - Int J Radiat Oncol Biol Phys 2006 Jul 1;65(3):720

⚬ 21 patients with anal cancer had pre-treatment and follow-up PET and CT scanning

– PET identi ed metastases (lymphoid and omental) not observed by CT scan in 24% (5 of 21)
patients
– post treatment PET may not be accurate for prognosis

● 3 of 9 patients (33%) with minimal residual activity at primary site had recurrence
● 3 of 6 patients (50%) with negative post treatment PETs had recurrence

– Reference - Mol Imaging Biol 2005 Jul;7(4):309

● review of imaging for investigating perianal pain of uncertain cause can be found in BMJ 2008 Feb
16;336(7640):387 full-text

● American College of Radiology (ACR) Appropriateness Criteria for anal cancer can be found at ACR
2013 PDF

Biopsy and pathology

● special stains and immunohistochemical markers for poorly di erentiated neoplasms include 1

⚬ mucin
⚬ S100
⚬ CK7/20
⚬ NSE/chromogranin/synaptophysin
⚬ CD20/EBV
⚬ CK5/6 and p63
⚬ keratin AE1/AE3

● limited evidence regarding use of sentinel lymph node biopsy to guide treatment (Ann Surg Oncol
2010 Oct;17(10):2656 full-text )

● survivin expression in immunohistochemical staining reportedly associated with some survival

outcomes in 62 patients (Radiat Oncol 2012 Jun 14;7:88 full-text )

● intraepithelial neoplasia 8

⚬ precursor lesion to squamous cell carcinoma

⚬ terminology evolving
⚬ 3 grades
 – anal intraepithelial neoplasia (AIN) I, corresponding to low-grade dysplasia, also called low grade
squamous intraepithelial lesion (LSIL)
– anal intraepithelial neoplasia (AIN) II corresponding to moderate-grade dysplasia, also called
high grade squamous intraepithelial lesion (HSIL)
– anal intraepithelial neoplasia (AIN) III corresponding to high-grade dysplasia, also called high
grade squamous intraepithelial lesion (HSIL)
⚬ Bowen disease is older term for HSIL (AIN II and AIN III)
⚬ newer terminology

– high-grade anal intraepithelial neoplasia (HGAIN), corresponds to AIN III

– low-grade anal intraepithelial neoplasia (LGAIN), corresponds to AIN I/II

Management

Management overview

● for patients with well-di erentiated stage I anal margin lesion without lymph node involvement 7

⚬ local excision is recommended (NCCN Category 2A)

⚬ if inadequate margins after initial excision, consider either re-excision (preferred) or local radiation
therapy with or without 5- uorouracil (5-FU) or capecitabine-based chemotherapy (NCCN Category
2A)

● for patients with anal margin lesion that is T2-T4, N0 or any T N-positive disease, or in patients with
nonmetastatic anal canal cancer, consider concurrent chemoradiation (NCCN Category 2A; ASCRS
Grade 1A [ASCRS Grade 1C for lymph node disease]) 7 , 8
⚬ for radiation therapy

– consider intensity-modulated radiation therapy-based chemoradiation (IMRT) to reduce

treatment-related toxicity (ASCRS Grade 2B)
– higher dose radiation therapy (such as 56-60 Gy [up to 65 Gy for T3/T4 tumors]) preferred if
tolerable without prolonged breaks in treatment (ASCRS Grade 2B)
⚬ for chemotherapy, consider either mitomycin plus 5-FU (NCCN Category 2A; ASCRS Grade 1A) or
mitomycin plus capecitabine (NCCN Category 2A)
⚬ addition of 5-FU plus mitomycin to radiation therapy may reduce local failure and colostomy rates
DynaMed Level 2

⚬ addition of mitomycin to chemoradiation with 5-FU may improve colostomy-free survival

DynaMed Level 2

● for patients with metastatic anal margin lesion or anal canal cancer, consider systemic chemotherapy

(NCCN Category 2A; ASCRS Grade 1C for extrapelvic metastases) 7 , 8

⚬ cisplatin plus 5- uroruracil with or without radiation therapy recommended (NCCN Category 2A)
⚬ cisplatin may be associated with less hematologic toxicity than mitomycin as part of
chemoradiation but increased risk for colostomy and lower 5-year overall survival
DynaMed Level 2

● for patients with HIV infection, consider basing treatment approach on CD4 counts (ASCRS Grade

2C) 8
⚬ if CD4 counts > 200 cells/mL, use similar approach as in patients without HIV infection
 ⚬ if CD4 counts < 200 cells/mL, individualize treatment (may require lower doses of chemoradiation
and/or may have wound healing de ciencies after surgery)

● three-dimensional conformal radiation therapy (3D-CRT) may improve survival and freedom from
relapse compared to conventional radiation therapy DynaMed Level 2

● pelvic irradiation associated with increased risk of pelvic fracture in older women DynaMed Level 2

● assessment of response to chemoradiation recommended at 8-12 weeks (NCCN Category 2A)

Medications

● recommended chemotherapy or chemoradiation regimens 7

⚬ for patients with localized disease, options include

– 5-FU plus mitomycin plus concurrent radiation therapy

– capecitabine plus mitomycin plus concurrent radiation therapy

⚬ for patients with metastatic disease, recommended regimen is 5-FU plus cisplatin

STUDY
● SUMMARY
addition of 5-FU plus mitomycin to radiation therapy may reduce local failure and colostomy
rates DynaMed Level 2

RANDOMIZED TRIAL: Lancet 1996 Oct 19;348(9034):1049

RANDOMIZED TRIAL: J Clin Oncol 1997 May;15(5):2040

Details
⚬ based on 2 randomized trials without blinding
⚬ UKCCCR trial

– 585 patients aged 26-88 years with epidermoid anal cancer were randomized to chemoradiation
(radiation plus mitomycin plus 5-FU) vs. radiation therapy alone and followed for median 42
months
● external beam radiation with 45 Gy as central axis dose given for 4-5 weeks
● chemotherapy given with rst course of radiation therapy

⚬ initial chemotherapy was 5-FU (1,000 mg/m2 IV for 4 days or 750 mg/m2 for 5 days) plus

mitomycin (12 mg/m2 IV given on day 1 of rst course of radiation therapy)

⚬ subsequent chemotherapy was 5-FU (same dose) without mitomycin during nal week of
rst radiation therapy course
– 562 (96%) patients who had ≥ 6 weeks of treatment were analyzed
– comparing chemoradiation vs. radiation alone at 3 years

● 39% vs. 61% local failure (p < 0.0001, NNT 5)

● 65% vs. 58% overall survival (not signi cant)

– Reference - Lancet 1996 Oct 19;348(9034):1049

– similar results in 13-year follow-up of UKCCR trial Br J Cancer 2010 Mar 30;102(7):1123 full-
text
⚬ EORTC trial

– 110 patients with locally advanced anal cancer were randomized to chemoradiation (5-FU plus
mitomycin plus radiation) vs. radiation alone and followed for median 42 months
 ● radiation therapy consisted of 45 Gy given in 5 weeks (daily dose 1.8 Gy), additional
treatment given at 6 weeks if partial (20 Gy) or complete (15 Gy) response
● chemotherapy (given with rst course of radiation therapy) consisted of uorouracil 750
mg/m2 IV continuously on days 1-5 and 29-33 plus mitomycin 15 mg/m2 as single dose on
day 1
– comparing chemoradiation vs. radiation alone

● 80% vs. 54% had complete remission

● 68% vs. 50% estimated locoregional control at 5 years (p = 0.02, NNT 6)
● 72% vs. 40% estimated colostomy-free rate (p = 0.002, NNT 3)
● 58% vs. 54% overall survival (not signi cant)

– no signi cant di erences in severe side e ects but anal ulcers more frequent with combination
therapy
– Reference - J Clin Oncol 1997 May;15(5):2040 , commentary can be found in J Clin Oncol 1998
Feb;16(2):802

STUDY
● SUMMARY
addition of mitomycin to chemoradiation with 5-FU may improve colostomy-free survival
DynaMed Level 2

RANDOMIZED TRIAL: J Clin Oncol 1996 Sep;14(9):2527

Details
⚬ based on randomized trial with allocation concealment and blinding not stated
⚬ 310 patients with anal canal cancer were given chemoradiation with 5-FU (1,000 mg/m2 on days 1
and 29) plus radiation therapy (45-50 Gy over 5 weeks) and then randomized to mitomycin (10
mg/m2 on days 1 and 29) vs. no additional treatment and followed for median 3 years
⚬ patients with residual tumor had salvage treatment with radiation 9 Gy, 5-FU, and cisplatin 100
mg/m2
⚬ 291 patients (94%) were analyzed
⚬ comparing chemoradiation with vs. without mitomycin at 4 years

– 9% vs. 22% colostomy rate (p = 0.002, NNT 8)

– 71% vs. 59% colostomy-free survival (p = 0.014, NNT 9)
– 73% vs. 51% disease-free survival (p = 0.0003, NNT 5)
– no signi cant di erences in overall survival

⚬ grade 4-5 toxicity occurred in 23% of patients with mitomycin vs. 7% without (p < 0.001, NNH 7)
⚬ Reference - RTOG 87-04 trial (J Clin Oncol 1996 Sep;14(9):2527 )

STUDY
● SUMMARY
chemoradiation with mitomycin associated with higher 5-year survival but greater hematologic
toxicity than chemoradiation with cisplatin for patients with anal cancer DynaMed Level 2

RANDOMIZED TRIAL: JAMA 2008 Apr 23;299(16):1914

Details
⚬ based on randomized trial without blinding
⚬ 682 patients with anal cancer were given radiation and were randomized to 5-FU plus mitomycin
vs. 5-FU plus cisplatin
 – 5-FU plus mitomycin group treated with

● 5-FU 1,000 mg/m2 (days 1-4, 29-32)

● mitomycin 10 mg/m2 bolus (days 1, 29)
● radiation 45-59 Gy

– 5-FU plus cisplatin group treated with

● 5-FU 1,000 mg/m2 (days 1-4, 29-32, 57-60, 85-88)

● cisplatin 75 mg/m2 (days 1, 29, 57, 85)
● radiation 45-59 Gy starting on day 57

⚬ 649 patients (95%) were included in analyses at 5-year follow-up

⚬ 5-year outcomes comparing chemoradiation with mitomycin vs. chemoradiation with cisplatin

– overall survival 78.3% vs. 70.7% (p = 0.026, NNT 14)

– disease-free survival 67.8%% vs. 57.8 (p = 0.006, NNT 10)
– colostomy-free survival 71.9% vs. 65% (p = 0.05)
– locoregional failure in 20% vs. 26.4%(p = 0.087)
– grade 3-4 hematologic toxicity in 61.8% vs. 42% (p < 0.001, NNH 5)

⚬ 644 (94.4%) patients were analyzed at median follow-up 2.5 years in original publication
⚬ 3-year outcomes comparing chemoradiation with mitomycin vs. chemoradiation with cisplatin

– grade 3-4 hematologic toxicity in 61% vs. 42% (p = 0.001, NNH 5)

– colostomy at 3 years in 10% vs. 16% (p = 0.02, NNT 17)
– overall survival 84% vs. 76% (not signi cant)
– disease-free survival 67% vs. 61% (not signi cant)

⚬ References - RTOG 98-11 trial (JAMA 2008 Apr 23;299(16):1914 ), commentary can be found in
JAMA 2008 Sep 24;300(12):1410
⚬ follow-up study (J Clin Oncol 2012 Dec 10;30(35):4344 full-text )

STUDY
● SUMMARY
chemoradiation with mitomycin associated with similar rates of complete response but
increased hematologic toxicity compared to chemoradiation with cisplatin; addition of
maintenance therapy to either chemoradiation regimen does not appear to improve
progression-free survival DynaMed Level 2

RANDOMIZED TRIAL: Lancet Oncol 2013 May;14(6):516

Details
⚬ based on randomized trial without blinding
⚬ 940 patients (median age 58 years) with squamous cell carcinoma of anus without metastasis
randomized to
– uorouracil 1,000 mg/m2/day IV on days 1-4 and 29-32 plus radiotherapy 50.4 Gy in 28 fractions
plus mitomycin 12 mg/m2 IV on day 1 vs. cisplatin 60 mg/m2 IV on days 1 and 29
– maintenance chemotherapy with uorouracil plus cisplatin on days 71-74 and days 92-95 vs. no
maintenance chemotherapy
⚬ median follow-up 5.1 years
⚬ complete response de ned as disappearance of clinically or radiologically overt disease
⚬ comparing mitomycin vs. cisplatin

– complete response at 26 weeks in 90.5% vs. 89.6% (not signi cant)

– grade 3-4 hematologic adverse events in 26% vs. 16% (p < 0.001, NNH 10)
 – any grade 3-4 adverse event in 71% vs. 72% (not signi cant)

⚬ 3-year progression-free survival 74% with maintenance chemotherapy vs. 73% with no
maintenance chemotherapy (not signi cant)
⚬ no signi cant di erences in overall survival among groups
⚬ Reference - ACT II trial (Lancet Oncol 2013 May;14(6):516 ), editorial can be found in Lancet Oncol
2013 May;14(6):443 , commentary can be found in Nat Rev Clin Oncol 2013 Jun;10(6):306

STUDY
● SUMMARY
longer treatment duration associated with increased local failure in patients with anal cancer
treated with radiation therapy (RT) plus fluorouracil (FU) and mitomycin or cisplatin
DynaMed Level 2

RANDOMIZED TRIAL: J Clin Oncol 2010 Dec 1;28(34):5061 | Full Text

Details
⚬ based on post hoc analysis of 2 randomized trials (RTOG 98-11 and RTOG 87-04) above
⚬ 937 patients receiving any combination of treatment (RT plus FU plus mitomycin vs. RT plus FU plus
cisplatin vs. RT plus FU) evaluated for total duration of treatment
⚬ longer overall total treatment duration associated with

– local failure (p = 0.0006)

– trend toward colostomy failure (p = 0.06)

⚬ Reference - J Clin Oncol 2010 Dec 1;28(34):5061 full-text

STUDY
● SUMMARY
addition of induction chemotherapy to radiochemotherapy may not improve survival in patients
with locally advanced anal canal carcinoma DynaMed Level 2

RANDOMIZED TRIAL: J Clin Oncol 2012 Jun 1;30(16):1941

Details
⚬ based on randomized trial without blinding
⚬ 307 patients aged 18-80 years with locally advanced anal canal carcinoma randomized to 1 of 4
treatments and followed for median 50 months
– induction chemotherapy of uorouracil 800 mg/m2 IV on days 1-4 and 29-32 plus cisplatin 80

mg/m2 IV on days 1 and 29 for 2 cycles, radiochemotherapy of 45 Gy in 25 fractions over weeks

9-13 plus uorouracil plus cisplatin, and standard boost of 15 Gy in responders
– induction chemotherapy plus radiochemotherapy over weeks 9-13 plus high-dose boost of 20-
25 Gy in responders
– radiochemotherapy over weeks 1-5 plus standard boost
– radiochemotherapy over weeks 1-5 plus high-dose boost

⚬ overall survival

– 74.5% with induction chemotherapy plus radiochemotherapy vs. 71% with radiochemotherapy
(not signi cant)
– 71% with standard boost vs. 74% with high-dose boost (not signi cant)

⚬ Reference - UNICANCER ACCORD 03 trial (J Clin Oncol 2012 Jun 1;30(16):1941 )

Surgery and procedures

● abdominoperineal resection (APR) 3

⚬ results in permanent end colostomy

⚬ current recommended role is salvage therapy for persistent or recurrent disease following
chemoradiation in patients who are not candidates for salvage chemoradiation

Radiation therapy

STUDY
● SUMMARY
three-dimensional conformal radiation therapy (3D-CRT) may improve survival and freedom
from relapse compared to conventional radiation therapy DynaMed Level 2

COHORT STUDY: Int J Radiat Oncol Biol Phys 2007 Apr 1;67(5):1394

Details
⚬ based on prospective cohort study
⚬ 62 consecutive patients with anal cancer had 3D-CRT 54 Gy in 30 fractions continuously and were
compared to 60 historical controls having conventional radiation therapy with median 54 Gy in split
course
⚬ all patients had concurrent chemotherapy with 5- uorouracil plus either mitomycin-C or cis-
platinum
⚬ comparing 3D-CRT vs. conventional radiation at 5 years

– 80.7% vs. 53.9% overall survival (p = 0.017, NNT 4)

– 70.2% vs. 46.1% freedom from relapse (p = 0.016, NNT 4)
– 85.1% vs. 61.1% actuarial local control (p = 0.005, NNT 5)

⚬ Reference - Int J Radiat Oncol Biol Phys 2007 Apr 1;67(5):1394

STUDY
● SUMMARY
external radiation therapy without chemotherapy reported to be effective for T1 and T2 lesions
DynaMed Level 3

CASE SERIES: Int J Radiat Oncol Biol Phys 2003 Aug 1;56(5):1259
CASE SERIES: Radiother Oncol 1992 Nov;25(3):196
CASE SERIES: Cancer 1993 Mar 1;71(5):1736

Details
⚬ based on 3 case series
⚬ case series of 305 patients with cancer of anal canal

– 305 patients with anal cancer had curative-intent radiation therapy (median dose 45 Gy) and
were followed for mean 103 months
● 279 patients had EBRT 20 Gy boost after rest period of 4-6 weeks
● 17 had interstitial (192)Ir brachytherapy boost after rest period of 4-6 weeks
● 7 patients had only 1 course of EBRT
● 2 patients had interstitial (192)Ir brachytherapy only
● 19 patients had concomitant chemotherapy with 5-FU plus either cisplatin or mitomycin-C

– local tumor clinical response rates at end of radiation therapy

● 96% for T1 tumors

● 87% for T2 tumors
79% for T3 tumors
 ● 44% for T4 tumors
●

– 74% disease-free survival at 10 years

– factors associated with disease-free survival were

● interval between 2 courses of radiation therapy

● pretreatment anal function score
● clinical compete response after radiation therapy

– Reference - Int J Radiat Oncol Biol Phys 2003 Aug 1;56(5):1259

⚬ case series of 72 patients with cancer of anal canal

– all patients treated with external beam radiation (commonly 5,000 centigray over 4 weeks)
– 5-year outcomes

● 66% actuarial survival

● 78% disease-speci c survival (71% T1, 88% T2, 41% T3, 42% T4)

– 17 patients (24%) had local recurrence

– 53 patients (74%) retained anal function
– 6 patients (8%) had severe late complications
– Reference - Radiother Oncol 1992 Nov;25(3):196

⚬ case series of 18 patients with cancer of anal canal

– all had radiation 45-50 Gy in 25-28 fractions, 16 had additional radiation increasing total dose to
55-67 Gy
– follow-up ranged from 2.5-11.2 years
– 94% projected survival at 5 years
– 100% projected freedom from local recurrence at 5 years
– no patient required permanent colostomy or had permanent sphincter function loss
– Reference - Cancer 1993 Mar 1;71(5):1736

STUDY
● SUMMARY
chemotherapy plus external beam radiation followed by interstitial implant reported to have
84% loco-regional control in patients with T3 and T4 anal cancer DynaMed Level 3

CASE SERIES: Brachytherapy 2004;3(2):95

Details
⚬ based on case series
⚬ 31 patients with T3 or T4 anal cancer had external beam radiation 30 Gy plus 5-FU plus mitomycin-
C followed by interstitial (192)Ir implant boost (median implant dose 31.3 Gy at 0.5 cm delivered at
mean 0.52 Gy/hour)
⚬ 6 patients had local persistence
⚬ 4 developed local recurrence
⚬ 8 patients had abdominoperineal resection (APR)
⚬ 84% local regional control after initial treatment and APR
⚬ Reference - Brachytherapy 2004;3(2):95

STUDY
● SUMMARY
pelvic irradiation associated with increased risk of pelvic fracture in older women
DynaMed Level 2

COHORT STUDY: JAMA 2005 Nov 23-30;294(20):2587

 Details
⚬ based on retrospective cohort study
⚬ 6,428 women > 65 years old with pelvic malignancies included 556 women with anal cancer, 1,605
with cervical cancer and 4,267 with rectal cancer
⚬ rates of pelvic fracture in women who had pelvic irradiation vs. women who did not have pelvic
irradiation
– 14% vs. 5% in women with anal cancer
– 7% vs. 5% in women with cervical cancer
– 9% vs. 9% in women with rectal cancer

⚬ cumulative 5-year fracture rate (after adjusting for length of follow-up) in women who had pelvic
irradiation vs. women who did not have pelvic irradiation
– 14% vs. 7.5% in women with anal cancer
– 8.2% vs. 5.9% in women with cervical cancer
– 11.2% vs. 8.7% in women with rectal cancer

⚬ Reference - JAMA 2005 Nov 23-30;294(20):2587 , editorial can be found in JAMA 2005 Nov 23-
30;294(20):2635

Consultation and referral

● gynecologist for women, especially if 6

⚬ anterior tumor
⚬ perineum involvement
⚬ vaginal-mucosal involvement (may indicate risk for rectovaginal stula with chemoradiation)

Follow-up

● assessment of response to chemoradiation recommended at 8-12 weeks (NCCN Category 2A) 7

⚬ if locally recurrent progressive disease, abdominoperineal resection (APR) recommended (NCCN

Category 2A; ASCRS Grade 1B) 7 , 8

⚬ if persistent disease without progression, reevaluate patient in 4-6 weeks and again in 3 months

(NCCN Category 2A) 7

⚬ if complete remission 7

– perform every 3-6 months for 5 years

● digital rectal exam (NCCN Category 2A)

● anoscopy (NCCN Category 2A)
● inguinal node palpation (NCCN Category 2A)

– perform annually for 3 years if stage III-IV or inguinal node positive

● computed tomography (CT) of pelvis, abdomen and chest (NCCN Category 2A)
● magnetic resonance imaging (MRI) of pelvis and abdomen (NCCN Category 2A)

⚬ if local recurrence, APR with groin dissection if positive inguinal lymph nodes (NCCN Category 2A) 7

⚬ if inguinal node recurrence 7

– groin dissection recommended (NCCN Category 2A)

– consider radiation therapy if no prior radiation therapy to groin with or without chemotherapy
(NCCN Category 2A)
 ⚬ if distant metastases, consider 5- uorouracil plus cisplatin or enrollment into clinical trial (NCCN

Category 2A) 7

Surveillance

● National Comprehensive Cancer Network (NCCN) recommendations for surveillance 7

⚬ after abdominoperineal resection (APR), the following are recommended

– inguinal node palpation every 3-6 months for 5 years (NCCN Category 2A)
– annual chest/abdominal/pelvic CT or MRI for 3 years (NCCN Category 2A)

⚬ if no APR due to no progression or regression of disease, the following are recommended

– every 3-6 months for 5 years (NCCN Category 2A)

● digital rectal exam

● anoscopy
● inguinal node palpation

– annual chest/abdominal/pelvic CT or MRI for 3 years (NCCN Category 2A)

● American Society of Colon and Rectal Surgeons (ASCRS) recommendations on surveillance 8

⚬ perform examination (digital rectal exam, anoscopy, and inguinal palpation) (ASCRS Grade 1C)

– 6-12 weeks after completion of treatment

– every 3-6 months until 2 years
– every 6-12 months until 5 years
– annually after 5 years (or more frequently if clinical ndings indicate)

⚬ consider imaging (such as endoanal ultrasound, computed tomography [CT], magnetic resonance
imaging, and FDG-PET/CT) to assess for persistent or recurrent disease (ASCRS Grade 1C)

Complications and Prognosis

Complications

● about 10% incidence of metastasis at presentation

⚬ about 10% incidence of nodal metastases reported at presentation, but may be higher (20-60%) for

T4 lesions (Dis Colon Rectum 1986 May;29(5):336 as referenced in 2 )

⚬ 10% incidence of visceral metastases reported at diagnosis (liver and lung most common sites) 3

⚬ up to 25% incidence of distant metastases reported in patients with inguinal adenopathy or with

lesions > 5 cm 3

● complications of chemoradiation 2

⚬ acute complications of chemoradiation

– diarrhea
– mucositis
– skin erythema and desquamation
– myelosuppression

⚬ late complications of chemoradiation

– anal ulcers
– stricture/stenosis
 – stulae
– necrosis

● patients with CD4 count < 200 cells/mm3 had increased risk for complications in cohort of 17 patients

with HIV infection with anal canal cancer (Int J Radiat Oncol Biol Phys 1999 Apr 1;44(1):127 )

Prognosis

● tumor size reported to be most important prognostic factor 2 , 4

⚬ 80%-90% 5-year survival rates reported for T1-T2 lesions

⚬ < 50% survival rate for T4 lesions

● tumor size > 5 cm associated with increased risk of colostomy (J Clin Oncol 2009 Mar 1;27(7):1116
full-text )

● poor prognosis for patients with distant metastases 3

STUDY
● SUMMARY
relative 5-year survival improving for women but worsening for black men in United States

POPULATION-BASED SURVEILLANCE: Cancer 2004 Jul 15;101(2):281 | PDF

Details
⚬ based on data from Surveillance, Epidemiology, and End Results (SEER) program from 1973-2000
⚬ relative 5-year survival rates

– 58% overall for men (relatively unchanged from 60% [1973-1979] to 61% [1994-2000])
– 64% overall for women (increased from 59% [1973-1979] to 73% [1994-2000])
– 38% overall for black men (decreased from 45% [1973-1979] to 27% [1994-2000])

⚬ later disease stage associated with decreased 5-year survival

– 78% for local-stage disease

– 56% for regional-stage disease
– 18% for distant disease
– stage-speci c survival poorer in black patients than white patients

⚬ age ≥ 65 years at diagnosis associated with poorer survival in men and women
⚬ Reference - Cancer 2004 Jul 15;101(2):281 PDF

STUDY
● SUMMARY
larger tumor size and poor response to first course of radiation associated with worse 5-year
prognosis

COHORT STUDY: Cancer Radiother 2007 Jun;11(4):169

Details
⚬ based on cohort study with full-text in English not available
⚬ 286 patients with anal cancer were treated at one institution 1976-2005 and followed for mean 65
months (range 1.3-250 months)
– 180 had radiation therapy
– 106 had chemoradiation
 – 233 had brachytherapy boost following either radiation therapy or chemoradiation
– 24 had external beam radiation therapy boost following either radiation therapy or
chemoradiation
⚬ staging on presentation

– 43 stage I
– 154 stage II
– 31 stage IIIA
– 53 stage IIIB

⚬ 66.4% overall survival at 5 years

⚬ 78.1% disease-speci c survival at 5 years
⚬ poor prognosis for disease-speci c survival associated with

– tumor size ≥ 40 mm
– node involvement
– poor response (< 75%) to rst course of irradiation
– local relapse
– distant metastases

⚬ 71.5% overall loco-regional control at 5 years

– 88% for stage I

– 69% for stage II
– 77% for stage IIIA
– 60% for stage IIIB
– prognosis associated with tumor size and response to rst course of radiation

⚬ 71% overall sphincter conservation at 5 years, prognosis associated with tumor size and response
to rst course of radiation
⚬ Reference - Cancer Radiother 2007 Jun;11(4):169 [French]

STUDY
● SUMMARY
more advanced tumor node category associated with decreased 5-year overall survival in
patients with nonmetastatic anal cancer who received chemoradiation

COHORT STUDY: Int J Radiat Oncol Biol Phys 2013 Nov 15;87(4):638

Details
⚬ based on cohort analysis of data from RTOG 98-11 trial
⚬ 620 patients with nonmetastatic anal cancer who received chemoradiation were analyzed by tumor
node (TN) category
⚬ 5-year overall survival

– 82% in 323 patients with T2N0 disease

– 74% in 96 patients with T3N0 disease
– 57% in 31 patients with T4N0 disease
– 70% in 99 patients with T2N1-3 disease
– 57% in 46 patients with T3N1-3 disease
– 42% in 25 patients with T4N1-3 disease

⚬ compared to patients with T2-3N0 disease, T4N0/T2-4N+ disease associated with decreased overall
and disease-free survival, and higher rates of local-regional failure and distant metastasis at 5 years
(p < 0.0001 for each)
⚬ Reference - Int J Radiat Oncol Biol Phys 2013 Nov 15;87(4):638
STUDY
● SUMMARY
well-differentiated tumors have higher 5-year survival than poorly differentiated tumors

COHORT STUDY: Dis Colon Rectum 1987 Jun;30(6):444

Details
⚬ based on small cohort study
⚬ 47 patients with anal squamous cell carcinoma had specimens evaluated for stage (43), grade (41)
and DNA content (31) and were followed 4-7 years (median 5.5 years)
⚬ 5-year survival 75% for well-di erentiated vs. 24% for poorly-di erentiated tumors
⚬ signi cant increase in mortality with higher grade and more advanced stage lesions
⚬ Reference - Dis Colon Rectum 1987 Jun;30(6):444 as referenced in 6

STUDY
● SUMMARY
local failure rates about 35% with chemoradiation and 53% with radiation therapy alone

COHORT STUDY: Br J Surg 2005 May;92(5):605

Details
⚬ based on retrospective cohort study
⚬ 254 patients with non-metastatic epidermoid anal cancer were treated with radiation alone (127
patients) or chemoradiation (127 patients)
⚬ 99 patients (39%) had local disease failure

– median time to local failure 20.4 months

– most local failures occurred within 3 years of initial treatment
– 5-year rates of local failure 52.5% with radiation alone, 35.3% with chemoradiation

⚬ overall survival after local failure 46% at 3 years, 29% at 5 years

⚬ risk factors for local failure

– higher T stage
– increased age
– total radiation dose < 50 Gy

⚬ Reference - Br J Surg 2005 May;92(5):605 as referenced in 2

STUDY
● SUMMARY
adenocarcinoma associated with lower survival and higher recurrence rate compared to
epidermoid carcinoma

COHORT STUDY: Int J Radiat Oncol Biol Phys 2003 Mar 1;55(3):669

Details
⚬ based on retrospective cohort study comparing

– 16 patients with localized adenocarcinoma of anal canal had radiation therapy (median dose 55
Gy) with curative intent, 11 patients had concurrent 5-FU-based chemotherapy
– 92 patients with epidermoid cancer treated with chemoradiation (radiation median dose 55 Gy,
5-FU plus cisplatin)
⚬ median follow-up 44-45 months
⚬ 5-year actuarial outcomes comparing adenocarcinoma vs. epidermoid lesions

– 54% vs. 18% recurrence rate (p = 0.004)

 – 66% vs. 10% distant disease rate (p < 0.001)
– 19% vs. 77% disease-free survival (p < 0.0001)
– 64% vs. 85% overall survival (p = 0.017)

⚬ Reference - Int J Radiat Oncol Biol Phys 2003 Mar 1;55(3):669

STUDY
● SUMMARY
primary anorectal melanoma associated with poor 5-year survival

COHORT STUDY: Br J Surg 2004 Sep;91(9):1183

Details
⚬ based on retrospective cohort study
⚬ 40 patients (mean age 58 years, 70% women) with primary anorectal melanoma were assessed
⚬ median overall survival 17 months, 5-year overall survival 17%
⚬ median disease-free survival 10 months, 5-year disease-free survival 14%
⚬ 5-year survival 24% for stage I and 0% for stage II or III disease
⚬ Reference - Br J Surg 2004 Sep;91(9):1183

Prevention and Screening

Prevention

● preventive measures for HPV infection

⚬ avoid unsafe sexual practices

⚬ vaccinate against human papillomavirus (HPV) infection (see also Human papillomavirus (HPV)
vaccine)

● intraepithelial neoplasia

⚬ American Society of Colon and Rectal Surgeons (ASCRS) guideline-recommended treatment

options for anal intraepithelial neoplasia (AIN) include 8

– observation alone (ASCRS Grade 2C)

● follow-up with surveillance every 4 to 6 months

● for women, refer also to gynecology to evaluate for cervical intraepithelial neoplasia (CIN)

– topical 5% imiquimod cream with close follow-up (ASCRS Grade 1C)

● clinical response reported in 77%-86%

● adverse e ects may include irritation, burning, and erosions

– topical 5% 5-FU cream with close follow-up (ASCRS Grade 1C)

● clinical response reported in up to 90%, but recurrence reported in up to 50%

● local adverse e ects, such as skin irritation or hypopigmentation in 85%

– targeted destruction guided by high resolution anoscopy (ASCRS Grade 1C)

– photodynamic therapy with close follow-up (ASCRS Grade 2C)

⚬ monitor AIN on-going follow-up at 3- to 6-month intervals with (ASCRS Grade 2C) 8

– digital rectal examination, anoscopic exam, with or without magni cation or topical acetic acid
and Lugol solution
– anorectal cytology and/or biopsy for suspicious areas

STUDY
● SUMMARY
electrocautery may be more effective in clearing anal intraepithelial neoplasia (AIN) than
fluorouracil, and imiquimod and electrocautery appear similarly effective for clearing AIN
DynaMed Level 2

RANDOMIZED TRIAL: Lancet Oncol 2013 Apr;14(4):346

Details
⚬ based on randomized trial without blinding
⚬ 156 men who have sex with men (MSM), HIV positivity, and anal intraintraepithelial neoplasia (AIN)
randomized to 1 of following treatments
– imiquimod 6.25 mg topical 3 times weekly for 16 weeks
– uorouracil 2% topical applied once in morning and once in evening twice weekly for 16 weeks
– electrocautery of AIN monthly for 4 months (up to 5 sessions)

⚬ 57% with high-grade AIN

⚬ complete response at 4 weeks after end of treatment in

– 39% with electrocautery (p = 0.008 compared to uorouracil, p = 0.10 compared to imiquimod)

– 24% with imiquimod
– 17% with uorouracil

⚬ no signi cant di erence in incidence of adverse e ects (mostly pain, irritation, or bleeding)
between groups
⚬ Reference - Lancet Oncol 2013 Apr;14(4):346

STUDY
● SUMMARY
imiquimod might clear anal canal high-grade anal intraepithelial neoplasia DynaMed Level 2

RANDOMIZED TRIAL: AIDS 2010 Sep 24;24(15):2331

Details
⚬ based on small randomized trial
⚬ 53 patients with HIV positivity and anal canal high-grade anal intraepithelial neoplasia (AIN)
randomized to imiquimod topically 3 times weekly for 4 months
⚬ resolution of AIN in 4 (14%) with imiquimod vs. 1 (4%) with placebo
⚬ AIN downgraded to low-grade squamous intraepithelial lesion (LSIL) in 8 (29%) with imiquimod vs. 0
with placebo
⚬ Reference - AIDS 2010 Sep 24;24(15):2331
⚬ no additional randomized trials evaluating treatment for AIN identi ed in systematic review in
Cochrane Database Syst Rev 2012 Dec 12;12:CD009244

Screening

● recommendations

⚬ United States Preventive Services Task Force (USPSTF), American Cancer Society (ACS), Centers for
Disease Control and Prevention, and the Infectious Diseases Society of America (IDSA) make no
recommendations regarding screening for anal cancer (Managing HPV: A New Era in Patient Care
)
⚬ New York State Department of Health AIDS Institute recommends

– at baseline and as part of annual physical exam for all adults with HIV infection, regardless of
age, clinicians should
 ● inquire about anal symptoms, such as itching, bleeding, diarrhea, or pain
● perform a visual inspection of the perianal region
● perform a digital rectal examination

– clinicians should refer women with cervical high-grade squamous intraepithelial lesion (HSIL)
and any patient with abnormal anal physical ndings, such as warts, hypopigmented or
hyperpigmented plaques/lesions, lesions that bleed, or any other lesions of uncertain etiology,
for high-resolution anoscopy and/or examination with biopsy of abnormal tissue
– clinicians should obtain anal cytology at baseline and annually in the following HIV-infected
populations
● men who have sex with men
● any patient with a history of anogenital condylomas
● women with abnormal cervical and/or vulvar histology

– Reference - New York State Department of Health AIDS Institute 2007 Jul

⚬ screening for anal cancer in high-risk population with HIV infection may not be cost-e ective
(Health Technol Assess 2010 Nov;14(53):iii PDF )
⚬ American Society of Colon and Rectal Surgeons (ASCRS) recommends anal Papanicolaou smear
may be useful for detection and follow-up of low-grade anal intraepithelial neoplasia (LGAIN) and
high-grade anal intraepithelial neoplasia (HGAIN) (ASCRS Grade 1C) 8

STUDY
● SUMMARY
anal cytology may not rule out anal cancer or precursor lesions DynaMed Level 2

SYSTEMATIC REVIEW: PLoS One 2012;7(7):e38956 | Full Text

Details
⚬ based on systematic review of mostly moderate quality studies
⚬ systematic review of 44 studies comparing cytologic sampling of cervical or anal tissues with
histology on magni cation-directed punch biopsy for detection of high-grade squamous
intraepithelial lesions
⚬ 11 studies comparing anal cytology to histology (reference standard) in 2,384 patients
⚬ anal cytology criteria for detection of histopathology-con rmed high-grade squamous
intraepithelial lesions included
– high-grade squamous intraepithelial lesion (HSIL)
– atypical squamous cells, cannot rule out high grade (ASC-H)
– low-grade squamous intraepithelial lesion (LSIL)
– atypical squamous cells of uncertain signi cance (ASCUS)
– no atypical or malignant cells (normal)

⚬ diagnostic performance of cytology for detection of histopathology-con rmed high-grade

squamous intraepithelial lesion or carcinoma
– with cytology cuto of HSIL or ASC-H
● sensitivity 30%
● speci city 93%
● negative likelihood ratio 0.65

– with cytology cuto of LSIL

● sensitivity 73%
● speci city 55%
● negative likelihood ratio 0.49
 – with cytology cuto of ASCUS
● sensitivity 90%
● speci city 33%
● negative likelihood ratio 0.3

⚬ Reference - PLoS One 2012;7(7):e38956 full-text

● anorectal cytology appears to have high sensitivity but low speci city for anal squamous
intraepithelial lesions DynaMed Level 2

⚬ based on 2 cohort studies with limited use of reference standards

⚬ anal Pap smear reported to have high (98%) sensitivity but low (50%) speci city for anal squamous
intraepithelial lesions in series of 181 patients, but only 71 (39%) had follow-up biopsy or smears to
apply as reference standard (Cytojournal 2005 Feb 16;2(1):4 full-text ), editorial can be found
in Cytojournal 2005 Feb 16;2(1):5 full-text

STUDY
⚬ SUMMARY
anorectal cytology reported to have 92% sensitivity and 50% specificity for detecting anal
squamous lesions

COHORT STUDY: Cancer 2004 Feb 25;102(1):19 | Full Text

Details
– based on retrospective cohort study with limited use of reference standard
– 78 consecutive anorectal cytology specimens (75 ThinPrep, 3 conventional smears) from 51
patients were stained with Pap stain
● 32 patients also had anoscopy
● 30 patients with anoscopy also had anorectal biopsy specimens

– 6 cytology specimens not evaluable due to lack of squamous cells

– histology as reference standard determined in 26 specimens from 20 patients
– cytology had 92% sensitivity and 50% speci city for distinguishing benign from dysplastic or
malignant lesions
– Reference - Cancer 2004 Feb 25;102(1):19 full-text

STUDY
● SUMMARY
anal HPV infection may occur in men with HIV infection without history of anoreceptive
intercourse

CROSS-SECTIONAL STUDY: Ann Intern Med 2003 Mar 18;138(6):453 | PDF

Details
⚬ based on cross-sectional study of 117 men with HIV infection
⚬ 50 had history of injection drug use but no history of anoreceptive intercourse
⚬ 67 had anoreceptive intercourse
⚬ comparing men with vs. without history of anoreceptive intercourse

– 85% vs. 46% had anal HPV infection

– 49% vs. 16% had low-grade squamous intraepithelial lesions
– 18% vs. 18% had high-grade squamous intraepithelial lesions

⚬ Reference - Ann Intern Med 2003 Mar 18;138(6):453 PDF

● discussion of anal Pap smear can be found in Am Fam Physician 2005 May 15;71(10):1874 full-text

● self-collected anal swab may be almost as adequate as clinician-collected anal swab for liquid-
based cytology
⚬ 222 young men who have sex with men (mostly HIV-1 seronegative) had paired self- and clinician-
collected anorectal Dacron swabs for liquid-based (ThinPrep) cytology
⚬ 83% self-collected specimens vs. 92% clinician-collected specimens were adequate for cytological
evaluation (p < 0.001)
⚬ both groups had 21% rate of detection of cytological abnormalities (with fair agreement, kappa =
0.4) including 5% atypical squamous cells of undetermined signi cance (ASC-US), 13% low-grade
squamous intraepithelial lesions and 3% high-grade squamous intraepithelial lesions
⚬ Reference - Cytojournal 2006 Mar 20;3:4 full-text

STUDY
● SUMMARY
patient-collected anal cytology samples may have lower sensitivity for anal intraepithelial
neoplasia (AIN) than clinician-collected samples

CROSS-SECTIONAL STUDY: Ann Intern Med 2008 Sep 2;149(5):300

Details
⚬ based on cross-sectional study with 126 men who have sex with men
⚬ 38 (30%) were patients with HIV infection (by self-report)
⚬ biopsy-proven AIN in 57% of patients with HIV infection vs. 35% of patients without HIV infection (p
= 0.04)
⚬ patient-collected samples

– sensitivity 75% for patients with HIV infection and 48% for patients without HIV infection
– speci city 50% for patients with HIV infection and 86% for patients without HIV infection

⚬ clinician-collected samples

– sensitivity 90% for patients with HIV infection and 62% for patients without HIV infection
– speci city 64% for patients with HIV infection and 85% for patients without HIV infection

⚬ Reference - Ann Intern Med 2008 Sep 2;149(5):300 , commentary can be found in Ann Intern Med
2009 Feb 17;150(4):283

Guidelines and Resources

Guidelines

United States guidelines

● American College of Radiology (ACR) Appropriateness Criteria for anal cancer can be found at ACR
2013 PDF

● American Society of Colon and Rectal Surgeons (ASCRS) clinical practice guideline on anal squamous
cell cancers can be found in Dis Colon Rectum 2018 Jul;61(7):755 PDF

● American Society of Colon and Rectal Surgeons (ASCRS) clinical practice guideline on ambulatory
anorectal surgery can be found in Dis Colon Rectum 2015 Oct;58(10):915 PDF
● National Comprehensive Cancer Network (NCCN) clinical practice guideline on anal carcinoma be
found at NCCN website (free registration required) or in J Natl Compr Canc Netw 2010 Jan;8(1):106

● College of American Pathologists/American Society for Colposcopy and Cervical Pathology

(CAP/ASCCP) consensus recommendations on lower anogenital squamous terminology
standardization project for HPV-associated lesions can be found in Arch Pathol Lab Med 2012
Oct;136(10):1266 full-text

United Kingdom guidelines

● Association of Coloproctology of Great Britain and Ireland (ACPGBI) position statement on anal cancer
can be found in Colorectal Dis 2011 Feb;13 Suppl 1:1

● Association of Coloproctology of Great Britain and Ireland (ACPGBI) guidelines for management of
anal intraepithelial neoplasia can be found in Colorectal Dis 2011 Feb;13 Suppl 1:3

Canadian guidelines

● Cancer Care Ontario (CCO) guideline on PET imaging in anal canal cancer can be found at CCO 2017
Jan

● Cancer Care Ontario (CCO) evidence-based guideline recommendations on management of

squamous cell cancer of anal canal can be found at CCO 2013 Feb

● Alberta Health Services (AHS) clinical practice guideline on anal canal cancer can be found at AHS 2010
Mar PDF

European guidelines

● European Society for Medical Oncology/European Society of Radiotherapy and Oncology

(ESMO/ESTRO) clinical practice guideline on diagnosis, treatment, and follow-up of anal cancer can be
found in Ann Oncol 2014 Jul 6 early online PDF or in Radiother Oncol 2014 Jun;111(3):330

● German S1 guideline on anal intraepithelial neoplasia (AIN) and perianal intraepithelial neoplasia
(PAIN) can be found in J Dtsch Dermatol Ges 2011 Mar;9(3):256

● Spanish Society for Medical Oncology (SEOM) clinical guideline on treatment of anal cancer can be
found in Clin Transl Oncol 2011 Aug;13(8):525

● Directorate of Health (Helsedirektoratet [DOH]) guideline on diagnosis, treatment, and follow-up of

anal cancer can be found at DOH 2017 May [Norwegian]

● Dutch Country Working Group on Gastrointestinal Tumors (Landelijke Werkgroep Gastro-Intestinale

Tumoren [LWGIT]) guideline on anus carcinoma can be found at LWGIT 2012 [Dutch]

Asian guidelines

● Korean Academy of Medical Sciences (KAMS) guideline on rating system for digestive system
impairments can be found in J Korean Med Sci 2009 May;24 Suppl 2:S271 full-text

Australian and New Zealand guidelines

● Australasian Gastrointestinal Trials Group (AGITG) guidelines on intensity-modulated radiotherapy in
anal cancer can be found in Int J Radiat Oncol Biol Phys 2012 Aug 1;83(5):1455

Review articles

● review of diagnosis and management of anal intraepithelial neoplasia and anal cancer can be found in
BMJ 2011 Nov 4;343:d6818

● review of diagnosis, treatment and prevention of anal cancer can be found in Curr Infect Dis Rep 2012
Feb;14(1):61

● review of treatment for localized anal carcinoma can be found in Curr Opin Oncol 2007 Jul;19(4):396

● review of evaluation and management of common anorectal conditions can be found in Am Fam
Physician 2012 Mar 15;85(6):624 full-text

● review of common anorectal conditions can be found in Am Fam Physician 2001 Jun 15;63(12):2391

full-text and in Am Fam Physician 2001 Jul 1;64(1):77 full-text

● review of intensity-modulated radiotherapy can be found in Lancet Oncol 2008 Apr;9(4):367 ,

correction can be found in Lancet Oncol. 2008 Jun;9(6):513

MEDLINE search

● to search MEDLINE for (Anal cancer) with targeted search (Clinical Queries), click therapy , diagnosis
, or prognosis

Patient Information

● multi-page handout from National Cancer Institute or in Spanish

● multi-page handout from American Cancer Society

● handout from American Society of Colon & Rectal Surgeons

● handout from MacMillan Cancer Support

ICD Codes

ICD-10 codes

● C21 malignant neoplasm of anus and anal canal

⚬ C21.0 anus, unspeci ed

⚬ C21.1 anal canal
⚬ C21.2 cloacogenic zone
⚬ C21.8 overlapping lesion of rectum, anus and anal canal

References
General references used

1. Balachandra B, Marcus V, Jass JR. Poorly di erentiated tumours of the anal canal: a diagnostic strategy
for the surgical pathologist. Histopathology. 2007 Jan;50(1):163-74

2. Uronis HE, Bendell JC. Anal cancer: an overview. Oncologist. 2007 May;12(5):524-34 full-text

3. Rousseau DL Jr, Thomas CR Jr, Petrelli NJ, Kahlenberg MS. Squamous cell carcinoma of the anal canal.
Surg Oncol. 2005 Nov;14(3):121-32

4. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000 Mar 16;342(11):792-
800 , summary can be found in Am Fam Physician 2000 Sep 1;62(5):1173

5. Eng C. Anal cancer: current and future methodology. Cancer Invest. 2006 Aug-Sep;24(5):535-44

6. Clark MA, Hartley A, Geh JI. Cancer of the anal canal. Lancet Oncol. 2004 Mar;5(3):149-57

7. Benson AB, Venook AP, Bekaii-Saab T, et al. Anal Carcinoma. Version 2.2015. In: National
Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines).
NCCN 2014 Dec from NCCN website (free registration required)

8. American Society of Colon and Rectal Surgeons (ASCRS) practice parameter on anal squamous
neoplasms. Dis Colon Rectum 2012 Jul;55(7):735 PDF , commentary can be found in Dis Colon
Rectum 2013 Feb;56(2):e18

Recommendation grading systems used

● American Society of Colon and Rectal Surgeons (ASCRS) grading system for recommendations based
on Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) System
⚬ strength of recommendation grades

– Grade 1 - strong recommendation - bene ts clearly outweigh risks and burdens (or vice versa)
for most, if not all, patients
– Grade 2 - weak recommendation - bene ts and risks closely balanced and/or uncertain

⚬ quality of evidence grades

– Level A - high-quality evidence - randomized trials without factors that reduce quality of
evidence, or well-done observational studies with very large magnitude of e ect
– Level B - moderate-quality evidence - downgraded randomized trials or upgraded observational
studies
– Level C - low- or very low-quality evidence - observational studies or case series

⚬ Reference - ASCRS practice parameter on anal squamous neoplasms (Dis Colon Rectum 2012
Jul;55(7):735 )

● National Comprehensive Cancer Network (NCCN) categories of evidence and consensus

⚬ Category 1 - based on high-level evidence, there is uniform NCCN consensus that intervention is
appropriate
⚬ Category 2A - based on lower-level evidence, there is uniform NCCN consensus that intervention is
appropriate
⚬ Category 2B - based on lower-level evidence, there is NCCN consensus that intervention is
appropriate
 ⚬ Category 3 - based on any level of evidence, there is major NCCN disagreement that intervention is
appropriate
⚬ Reference - NCCN Categories of Evidence and Consensus

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