Classification and epidemiology of anal cancer

Authors: David P Ryan, MD, Christopher G Willett, MD

Section Editor: Richard M Goldberg, MD
Deputy Editor: Diane MF Savarese, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2017. | This topic last updated: Nov 20, 2017.

INTRODUCTION — Anal cancer is uncommon. It comprises only 2.5 percent of all digestive

system malignancies in the United States; only 8200 new cases are diagnosed annually [1].

The incidence of anal cancer in the general population has increased over the last 30 years,
both in the United States and elsewhere [2-6]. An increased incidence has been associated
with female gender, infection with human papillomavirus (HPV), lifetime number of sexual
partners, genital warts, cigarette smoking, receptive anal intercourse, and infection with
human immunodeficiency virus (HIV) [7]. Thus, from an etiologic standpoint, anal cancer is
more similar to genital malignancies than it is to gastrointestinal tract cancers.

Substantial progress has been made in the pathophysiology and treatment of anal cancer [8].
In the 1960s, this malignancy was thought to be due to chronic perianal inflammation and
was treated routinely by abdominoperineal resection, necessitating a permanent colostomy
[9]. As a result of carefully conducted epidemiologic and clinical studies, it is now known that
anal cancer is associated with HPV infection and that cure of anal cancer is possible in the
majority of patients with preservation of the anal sphincter.

The pathology and epidemiology of anal cancer will be reviewed here. The clinical features,
diagnosis, and treatment are discussed separately. (See "Clinical features, staging, and
treatment of anal cancer".)

ANATOMY AND HISTOLOGY — The anal canal is 2.5 to 3.5 cm long. It begins where the
rectum enters the puborectalis sling at the apex of the anal sphincter complex (palpable as
the anorectal ring on digital rectal examination and approximately 1 to 2 cm proximal to the
dentate line) and ends where the squamous mucosa blends with the perianal skin, which
roughly coincides with the palpable intersphincteric groove or the outermost boundary of the
internal sphincter muscle (figure 1). Externally, the anal canal is surrounded by the internal
and external anal sphincter muscles (figure 1) [10]. The anal canal is divided by the dentate
(pectinate) line, a macroscopically visible landmark that overlies the transition from
glandular to squamous mucosa; immediately proximal to the dentate line, a narrow zone of
transitional mucosa that is similar to urothelium is variably present.
The proximal region of the anus encompasses mucosa of three different histologic types:
glandular, transitional, and nonkeratinizing squamous (proximal to distal, respectively).
Distally, the squamous mucosa (which is devoid of epidermal appendages, such as hair
follicles, apocrine glands, and sweat glands) merges with the perianal skin (true epidermis).
This mucocutaneous junction has been referred to as the anal "verge" or margin. This
boundary is indistinct on macroscopic examination, and anatomically, its location may vary
with the patient's body habitus.

As a result, four distinct categories of tumors arise in the anal region:

● Tumors that develop from any of the three types of mucosa, which cannot be visualized
in their entirety while gentle traction is placed on the buttocks, are termed anal cancers
[10]:

• Tumors arising in the transitional or squamous mucosa are squamous cell cancers
(SCCs) and appear to behave similarly, despite their sometimes variable
morphologic appearance. By convention, most series that report outcomes of "anal
cancer" refer exclusively to these tumors. The term "anal cancer," by common
definition, refers to SCCs arising within the mucosa of the anus, and the two terms
will be used interchangeably throughout this review.

• Basaloid (also termed junctional or cloacogenic) carcinoma is a variant of SCC that

arises from the epithelial transitional zone. However, these terms have largely been
abandoned because these tumors are now recognized as nonkeratinizing types of
SCC. Tumors arising within the anal canal above the dentate line are often
nonkeratinizing SCCs, while those arising within the anal canal distal to the
pectinate (dentate) line are often keratinizing.

• Adenocarcinomas arising from glandular elements within the anal canal are rare,
but they appear to share a similar natural history to rectal adenocarcinomas and are
treated similarly. (See "Clinical features, staging, and treatment of anal cancer",
section on 'Treatment of localized adenocarcinoma of the anal canal'.)

● Tumors arising within the hair-bearing skin at or distal to the squamous mucocutaneous
junction have been referred to as anal margin cancers. However, the most recent
(eighth) edition of the American Joint Committee on Cancer (AJCC) cancer staging
manual defines tumors that arise within the skin at or distal to the squamous
mucocutaneous junction that can be seen in their entirety with gentle traction placed on
the buttocks and are within 5 cm of the anus as perianal skin cancers [10]. In practice,
perianal skin cancers are rare.

● Primary rectal SCCs, which are very rare, can be difficult to distinguish from anal
cancers, and they should be treated according to the same approach as anal cancer.
 (See "Clinical features, staging, and treatment of anal cancer", section on 'Rectal
squamous cell cancers'.)

Histology — Several histologic types of malignancy arise within the anus, including SCC,
which is most common, adenocarcinoma, melanoma, and rarely, sarcoma (table 1) [11]. Due
to the variation in anatomy (particularly the transition zone), the anal canal can be quite short
in length in some individuals, and the anatomical location as determined by a surgeon or
endoscopist should not determine the classification of a tumor. Rather, the histology and
location of tumors in the anal region guide the appropriate diagnosis and treatment.

Anal canal tumors — There is no easily identifiable landmark between the rectum and the
anus; in addition, the transition zone has a widely variable histologic appearance. As a result,
the pathologic classification of tumors arising in this area may be difficult.

● Squamous cell cancer – Tumors arising in the transitional or squamous mucosa are
SCCs and appear to behave similarly, despite their sometimes variable morphologic
appearance [12,13]. By convention, most series that report outcomes of "anal cancer"
refer exclusively to these tumors. The term "anal cancer," by common definition, refers to
SCCs arising within the mucosa of the anus, and the two terms will be used
interchangeably throughout this review.

Basaloid features are identified in approximately 25 percent of SCCs of the anal canal
and must be distinguished from basal cell carcinomas of the perianal skin, which as
noted below, are classified as skin cancers. Basaloid (also termed junctional or
cloacogenic) carcinoma is a variant of SCC that arises from epithelial transitional zone.
However, these terms have largely been abandoned because these tumors are now
recognized as nonkeratinizing types of SCC. Tumors arising within the anal canal above
the dentate line are termed nonkeratinizing SCCs, while those arising within the anal
canal distal to the dentate line are termed keratinizing SCCs.

● Adenocarcinomas – Adenocarcinomas arising from glandular elements within the anal

canal are rare, but they appear to share a similar natural history to rectal
adenocarcinomas and are treated similarly.

Determination of the anatomic site of origin of carcinomas that overlap the anorectal
junction can be problematic, particularly since the rectal mucosa may extend to within 1 to 2
cm of the anal verge.

Perianal skin cancers — The clinical distinction between tumors of the anal canal and
those that involve the anal "margin" or perianal skin can also be difficult. As noted above,
SCCs that arise on any mucosal surface of the anus are treated as anal canal cancers, even
if they are located distally at the perianal margin. In contrast, tumors arising within the hair-
bearing skin at or distal to the squamous mucocutaneous junction have been termed anal
margin cancers. However, the preferred term is perianal skin cancer, since with the exception
of melanomas, tumors arising within the perianal skin behave biologically like skin cancers.
Although there are essentially no prospective data validating this practice, these tumors had
been classified and staged as skin cancers, rather than anal canal cancers, until more
recently [14]. The most recent (eighth) edition of the AJCC cancer staging manual departs
from this practice and stages perianal skin cancers the same as anal cancers (table 2) [10].

Most clinicians treat SCC lesions of the perianal skin similarly to anal canal cancers, using
radiation therapy and concurrent chemotherapy. Local treatment (surgery, or local RT
[electrons]) is appropriate when the lesion is very separate from the anal verge and is a
discrete skin lesion. However, it can be very difficult to distinguish between tumors arising on
the hair-bearing skin or within the anus/anal cancer. In practice, the distinction between
perianal skin cancers and anal canal/margin cancers can be difficult, and the default
management by most clinicians is to assume that these are anal margin/canal cancers if
there is any doubt, and to treat with initial chemoradiotherapy rather than local therapy alone.

Tumors of the perianal skin are most often SCCs, but other types of cutaneous malignancies
(eg, basal cell carcinoma, melanoma, Bowen disease, extramammary Paget disease) can
arise within this region.

● Bowen disease (SCC in situ) can occur within the perianal skin as it can in other areas of
non-sun-exposed skin. (See "Clinical features and diagnosis of cutaneous squamous
cell carcinoma (SCC)".)

● Melanomas that arise in either the anal canal or perianal skin should be treated
according to the same principles commonly applied to this tumor at other sites. (See
"Initial surgical management of melanoma of the skin and unusual sites".)

● Paget disease of the anus, an intraepithelial adenocarcinoma, can be one of two types: a
primary cutaneous malignancy in which the tumor cells show sweat gland
differentiation, and a lesion in which there is involvement of adjacent squamous
epithelium by lateral intramucosal/intraepithelial spread from an underlying
adenocarcinoma of the rectum or perianal glands.

Lymphatic drainage — Lymphatic drainage of anal canal and perianal skin cancers is

dependent upon the anatomic site of origin (figure 1) [15-17]. Tumors originating above the
dentate line, similar to rectal cancers, drain to the mesorectal and internal iliac nodes. In
contrast, tumors arising below the dentate line may also spread to the superficial inguinal
and external iliac (deep inguinal) nodes. In contrast to earlier editions, in the eighth edition of
the AJCC/Union for International Cancer Control (UICC) staging system, metastases in the
inguinal, mesorectal, internal, or external iliac are all considered N1 nodes (table 2).
EPIDEMIOLOGY AND RISK FACTORS — Although it remains an uncommon cancer, the
incidence of anal cancer is increasing in the United States and other countries [2,18-21]. In
data from the Surveillance, Epidemiology, and End Results (SEER) program of the National
Cancer Institute, between 1973 to 1996 and 1997 to 2009, United States incidence rates for
anal squamous cell cancer (SCC) increased threefold in men (from 1 to 3 per 100,000
person-years) and 1.7-fold in women (from 1.4 to 2.4 per 100,000 person-years) [22].

In certain populations, such as men who have sex with other men (MSM) and human
immunodeficiency virus (HIV)-infected patients, there is an especially high incidence of anal
cancer. The rate of anal cancer was estimated to be as high as 37 per 100,000 among MSM
prior to the HIV epidemic [23], rendering its incidence in this population similar to that of
cervical cancer in women prior to the introduction of cervical Papanicolaou (Pap) smear
screening [13]. The incidence of anal cancer among HIV positive MSM has been estimated to
be approximately twice that of HIV negative MSM [24,25].

In contrast to other common malignancies affecting HIV positive individuals (eg, Kaposi
sarcoma and non-Hodgkin lymphoma), the incidence of anal cancer has not declined in the
era of potent antiretroviral therapy (formerly referred to as highly active antiretroviral therapy
[HAART]) [26,27]. This was demonstrated in a study in San Francisco County, in which the
age-adjusted incidence of anal cancer in men 40 to 64 years of age (regardless of sexual
orientation) more than quadrupled from the pre-HIV period (1973 to 1978) to the present era
(1996 to 1999) following the widespread availability of potent antiretroviral therapy [28]. (See
"HIV infection and malignancy: Management considerations".)

Risk factors — In the past, anal cancer was thought to develop in areas of chronic local
inflammation or irritation associated with benign anal and perianal conditions, such as
hemorrhoids, fissures, and fistulae [29,30]. Case reports of anal cancer developing in the
setting of inflammatory bowel disease (IBD) led to the conclusion that this tumor resulted
from chronic inflammation in a manner similar to the development of colorectal neoplasia in
patients with underlying IBD [31,32]. (See "Surveillance and management of dysplasia in
patients with inflammatory bowel disease".)

However, subsequent case-control studies found little to no impact of a history of

hemorrhoids, fistulae, and fissures on the development of anal cancer [33,34]. Furthermore,
in a large Danish series, none of the 1160 patients with IBD developed anal cancer [35].

Sexual activity — Initial reports suggesting an increased incidence of the disease in

homosexual men provided a link between sexual activity and the development of anal cancer
[23,36]. This relationship has been confirmed in subsequent reports, as illustrated by the
following observations:
 ● In a population-based case-control study of anal cancer, women with anal cancer were
more likely than controls to have a history of genital warts (relative risk [RR] 32.5),
herpes simplex 2 (RR 4.1), or chlamydia trachomatis (RR 2.3), while men with anal
cancer were more likely than controls to have never been married (RR 8.6), to have
engaged in homosexual sexual activity (RR 50), to have practiced receptive anal
intercourse (RR 33), and to have a history of genital warts (RR 27) or gonorrhea (RR 17)
[37]. Subsequent studies confirmed the relationship between anal cancer and receptive
anal intercourse in men [33,34,38-40].

● A second case-control study in heterosexuals compared 417 patients with anal cancer,
534 patients with rectal cancer, and 554 normal controls [41]. In multivariate analysis,
the strongest risk factors for anal cancer in women were 10 or more lifetime sexual
partners (RR 4.5) and a history of anal warts (RR 11.7), genital warts (RR 4.6), gonorrhea
(RR 3.3), cervical dysplasia (RR 2.3), or sexual partners with a history of a sexually
transmitted disease (RR 2.4). A history of engaging in receptive anal intercourse before
the age of 30 and at least two anal intercourse partners were also significant risk factors
in women. Among heterosexual men, multivariate analysis revealed significantly
elevated risks of anal cancer with 10 or more lifetime sexual partners (RR 2.5), a history
of anal warts (RR 4.9), or a history of syphilis or hepatitis (RR 4.0).

● Anal cancer and cervical cancer in women – Further support for the role of sexual
activity in the development of anal cancers derives from reports demonstrating a strong
relationship between cervical cancer and anal cancer in women [42-45]. In data from the
Danish Cancer Registry, the odds ratio for developing anal cancer following a diagnosis
of cervical cancer was significantly higher than the risk of developing either stomach or
colon cancer [43]. In addition, women with anal cancer had a greater likelihood of prior
vulvar, vaginal, or cervical cancers [44].

● In the SEER database, in the United States, the RR of developing anal or vaginal cancer
following a diagnosis of invasive cervical cancer were 4.6 and 5.6, respectively [45].

Human papillomavirus infection — Human papillomavirus (HPV) infection is the most

commonly diagnosed sexually transmitted disease in the United States and provides as least
part of the link between sexual activity and anal cancer. A close association exists between
infection by oncogenic HPV strains and many premalignant and malignant lesions of the
genital tract, anus, and rectum [41,46]. Furthermore, HPV infection is the common link that
explains the association between index and second primary anogenital cancers and oral
cavity/pharyngeal cancers. (See "Virology of human papillomavirus infections and the link to
cancer" and "Human papillomavirus associated head and neck cancer", section on
'Epidemiology' and "Second primary malignancies in patients with head and neck cancers",
section on 'Incidence'.)
HPV DNA has been isolated from 46 to 100 percent of in situ and invasive SCCs of the anus
[41,47-49], and epidemiologic studies have shown that up to 93 percent of anal SCCs are
associated with HPV infection. Women are more likely to have HPV associated anal cancer
than are men [50]. HPV 16 presence is also associated with a worse prognosis [51].

While a number of HPV types can be found in the anogenital tract, only a few have been
associated with cancer. The spectrum of HPV types in the anal canal is similar to that
described in the cervix and is associated with the same "risk" phenotypes. As in cervical
cancer, HPV 16 is the most frequently isolated type in anal malignancies [41,49,52,53], and
its presence predicts for preinvasive as well as invasive cancer. HPV 16 associated anal SCC
can be identified histologically by immunohistochemical expression of p16 [51]. In contrast,
low-grade in situ lesions frequently are associated with other HPV subtypes [40,53,54].

The premalignant condition of cervical intraepithelial neoplasia (CIN or squamous

intraepithelial lesions) associated with HPV infection also occurs with HPV infections
involving the anus (termed anal intraepithelial neoplasia [AIN], also known as anal squamous
intraepithelial lesions [ASIL]). As in CIN, AIN can be morphologically low grade or high grade.
(See "Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and
treatment".)

HPV infection in the anal canal and perianal region may be subclinical or clinically apparent
as condylomata. AIN, particularly high-grade AIN, is considered to be the precursor of anal
cancer. Progression of AIN to invasive anal SCC is related to many factors, including HIV
seropositivity, a lower CD4 count, the type of HPV infection, and higher levels of DNA of high-
risk HPV types in the anal canal [55].

The prevalence of HPV infection in MSM, a group at high risk for both AIN and invasive anal
cancer, is higher in the presence of HIV infection [56]. (See 'HIV infection' below.).

A substantial minority of anal cancers are not associated with HPV infection. No difference
has been noted between HPV positive and HPV negative tumors in regards to patient age,
the presence of adjacent dysplasia, ductal differentiation, or prognosis [57].

Vaccines directed against the HPV types associated with cervical and anal neoplasia in
women and anal lesions in males have been developed, and their utility for prevention of anal
neoplasia is beginning to be studied. As an example, in a randomized trial involving 4065
males, a quadrivalent HPV vaccine was effective in preventing infection with HPV types 6, 11,
16, and 18 and preventing the development of external genital lesions.

In a planned substudy of that trial evaluating the impact of the quadrivalent vaccine on the
development of AIN in 602 MSM, there was a 78 percent decrease in the incidence of AIN
associated with HPV types 6, 11, 16, and 18 among men who received all three vaccine
doses compared with placebo [58]. The results of this trial and recommendations for the use
of HPV vaccines are discussed separately. (See "Anal squamous intraepithelial lesions:
Diagnosis, screening, prevention, and treatment", section on 'Prevention' and "Human
papillomavirus vaccination".)

HIV infection — It is unclear whether HIV infection itself has a direct effect on the
development of anal cancer or if this is mediated through HPV. The data supporting a
relationship between HIV, HPV, and anal cancer include the following observations:

● Epidemiologic data indicate that the increasing anal cancer rates in the United States
between 1980 and 2005 were strongly influenced by the HIV epidemic in males but were
independent of HIV infection in females [19]. Among men, the incidence rates increased
by 3.4 percent annually overall and by 1.7 percent annually in men without HIV infection.
Among women, incidence rates of anal cancer increased 3.3 percent annually overall
and by 3.3 percent annually in those without HIV infection.

● There is a markedly higher incidence of AIN and anal cancer in HIV infected men,
particularly MSM [56,59-62]. In a report of data from 13 cohorts (11 clinic-based,
including 34,189 HIV infected and 114,260 HIV uninfected individuals) that were
included in the North American AIDS Cohort Collaboration on Research and Design (NA-
ACCORD) for the years 1996 to 2007, the unadjusted anal cancer incidence rates per
100,000 person-years were 131 for HIV infected MSM, 46 for other HIV infected men,
and 2 for HIV uninfected men [62].

● The incidence of HPV infection and HPV associated preinvasive and invasive
malignancy is increased in HIV infected patients, regardless of sexual practice [40,63-
67].

● Among HPV infected individuals, the prevalence of high-grade AIN and anal carcinoma
is higher in those with concomitant HIV infection compared with those who are HIV
negative [68].

● In a meta-analysis of 53 studies, the prevalence of both high-risk anal HPV subtypes (74
versus 34 percent) and anal cancer (45.9 versus 5.1 per 100,000 men) was significantly
higher among HIV positive as compared with HIV negative MSM [56].

Despite these observations, the overall impact of HIV infection on incidence rates of anal
cancer remains unclear, since population-based studies have produced conflicting results
[4,19,24,25,69,70]. The following observations illustrate the range of findings:

● An increased incidence of anal cancer was noted in some reports during the peak of the
acquired immunodeficiency syndrome (AIDS) epidemic [69]. In New York City, for
example, there was a 10-fold increase in the incidence of anal cancer among men aged
20 to 49 from 1979 to 1985, concurrent with the onset of the AIDS epidemic and a
 marked rise in Kaposi sarcoma and non-Hodgkin lymphoma in this population [69]. In
contrast, case-control studies of single men living in San Francisco did not find a
significant rise in the incidence of anal cancer from before the appearance of AIDS in
about 1980 to the late 1980s, a period in which there was an increased incidence of both
Kaposi sarcoma and non-Hodgkin lymphoma [39,71,72]. (See "HIV infection and
malignancy: Management considerations" and "HIV infection and malignancy:
Epidemiology and pathogenesis".)

● In an American series linking registries reporting both AIDS and cancer, the RR of
developing anal cancer in patients with HIV infection was much higher than that in the
general population (standardized incidence ratio 19.1, 95% CI 18.1-20.0) [73]. The anal
cancer incidence was highest among MSM, increased with age, and was higher in those
with AIDS compared with those with HIV infection alone (adjusted incidence rate ratio
3.82).

● Patients with a longer duration of HIV infection have a substantially higher rate of anal
cancer, but in contrast to other AIDS-associated cancers, the use of potent antiretroviral
therapy has not led to a decline in the incidence of anal cancer [74,75].

Without controlling for receptive anal intercourse and prior HPV infection, it is difficult to
discern the true effect of HIV on the incidence of anal cancer. It is possible that HIV infection
interacts with HPV to predispose to anal cancer. In a cohort of 346 HIV infected and 262 HIV
negative homosexual men, infection with multiple anal HPV types was more common in the
HIV infected patients (73 versus 23 percent) and was associated with significant
immunosuppression (CD4 count below 200/microL) [76]. This finding could reflect increased
HPV replication in patients with AIDS, which would allow more HPV types to reach a
detectable concentration. Infection with more than one type of HPV is associated with an
increased risk of abnormal anal cytology [59,77]. (See "Virology of human papillomavirus
infections and the link to cancer".)

Chronic immunosuppression in HIV infection is also associated with a higher risk of anal
cancer and of progression from low-grade AIN to high-grade AIN or invasive cancer
[40,55,78]. As an example, within a nested case-control study in the Swiss HIV cohort study,
low CD4 counts were significantly associated with anal cancer, both at nadir and at the time
of cancer diagnosis [78]. The influence of CD4 counts appeared to be strongest six to seven
years prior to the diagnosis of anal cancer (odds ratio for <200 versus ≥500 cells/microL
14.0, 95% CI 3.85-50.9).

Chronic immunosuppression not due to HIV — Other causes of chronic

immunosuppression, such as solid organ transplantation, also may be associated with the
development of high-grade AIN and invasive anal carcinoma [79]. Among renal transplant
recipients, for example, the risk of anogenital cancer may be increased as much as 100-fold;
this risk has been associated with persistent HPV infection [80,81]. Similarly, chronic
glucocorticoid therapy for the treatment of autoimmune disease may predispose to both
HPV infection and HPV related invasive anal cancer [82,83]. (See "Major side effects of
systemic glucocorticoids".)

Cigarette smoking — Several case-control studies have noted a statistically significant

risk of anal cancer in smokers, especially current smokers [33,45,49,78,84-86]. In one series,
compared with controls without anal cancer, cigarette smoking was associated with a
significantly increased risk of anal cancer (RR 1.9 for 20 pack-years, RR 5.2 for 50 pack-
years) [33]. Cigarette smoking is highly associated with cervical neoplasia and is thought to
act as a cocarcinogen [87]. (See "Cervical cancer screening tests: Techniques for cervical
cytology and human papillomavirus testing".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in
plain language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for patients
who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Anal cancer (The Basics)")

SUMMARY

● Four distinct categories of tumors arise in the anal region (see 'Anatomy and histology'
above):

• Tumors that develop from any of the three types of lining mucosa (glandular,
transitional, and squamous) that cannot be visualized in their entirety while gentle
traction is placed on the buttocks are termed anal canal cancers [10], and are
staged and treated similarly. The vast majority are squamous cell cancers (SCCs).
(See "Clinical features, staging, and treatment of anal cancer", section on
'Introduction'.)

• Tumors arising within the hair-bearing skin at or distal to the squamous

mucocutaneous junction have been referred to as anal margin cancers. However,
the most recent (eighth) edition of the American Joint Committee on Cancer (AJCC)
 cancer staging manual defines tumors that arise within the skin at or distal to the
squamous mucocutaneous junction that can be seen in their entirety with gentle
traction placed on the buttocks and are within 5 cm of the anus as perianal skin
cancers [10]. (See "Clinical features, staging, and treatment of anal cancer", section
on 'Anal canal versus perianal skin cancers'.)

• Adenocarcinomas arising from glandular elements within the anal canal are rare,
but they appear to share a similar natural history to rectal adenocarcinomas and are
treated similarly. (See "Clinical features, staging, and treatment of anal cancer",
section on 'Treatment of localized adenocarcinoma of the anal canal'.)

• Primary rectal SCCs, which are very rare, can be difficult to distinguish from anal
cancers, and they should be treated according to the same approach as anal
cancer.

● Most clinicians treat SCC lesions of the perianal skin as anal canal cancers, using
radiation therapy (RT) and concurrent chemotherapy. Local treatment, surgery, or local
RT (electrons) is used only when the lesion is very separate from the anal verge and is a
discrete skin lesion. (See "Clinical features, staging, and treatment of anal cancer",
section on 'Anal canal versus perianal skin cancers'.)

● The majority of tumors arising in the transitional or squamous mucosa of the anal canal
are SCCs. The term "anal cancer," by common definition, refers to SCCs arising within the
mucosa of the anal canal. In contrast, adenocarcinomas arising from glandular
elements within the anal canal are rare but appear to share a similar natural history to
rectal adenocarcinomas. They are treated in a manner that is similar to rectal carcinoma
rather than anal cancer. (See 'Anal canal tumors' above.)

● Although it remains an uncommon cancer, the incidence of anal cancer is increasing in

the United States and other countries. (See 'Epidemiology and risk factors' above.)

● An increased incidence has been associated with female gender, infection with human
papillomavirus (HPV), lifetime number of sexual partners, genital warts, cigarette
smoking, receptive anal intercourse, infection with human immunodeficiency virus (HIV),
and other causes of chronic immunosuppression. Thus, from an etiologic standpoint,
anal cancer is more similar to genital malignancies than it is to gastrointestinal tract
cancers. (See 'Risk factors' above.)

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