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13 Epidemiology, Pathology, Diagnosis,
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Prevention, and Management of
Anal Cancer
Mohamed Rabie & James Wheeler
Cambridge Colorectal Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
[Aspects of stoma management are cover in Chapter 12].
Introduction
Anal cancer is considered a relatively uncommon malignancy
and accounts for 3–4% of gastrointestinal tract cancers, with an
estimated incidence rate of 0.54 per 100,000. The estimated
number of worldwide new cases of anal cancer in 2020 was
50,865, with 19,293 deaths related to anal cancer in the same
year. More patients were diagnosed in women with a female-tomale ratio of 3:2 (GLOBOCAN 2020). The incidence of anal
cancer has also increased in recent years, especially in highincome countries. Infection with high-risk subtypes of human
papillomaviruses (HPV), untreated human immunodeficiency
virus (HIV), men who have sex with men, and females with a
history of HPV-induced cervical, vaginal or vulvar cancer, and
those who are immunocompromised are at higher risk of developing anal cancer (Wieland and Kreuter 2019).
The current standard treatment for anal cancer is
synchronous chemoradiotherapy (CRT). Surgical resection in
the form of abdominoperineal resection (APR) of the anal
canal and rectum with the formation of a permanent colostomy is reserved for residual or recurrent disease after primary
CRT. Overall, survival from anal cancer now approaches 80%
at five years.
While we may see more cases of anal cancer in the short-term
future, this may be ultimately balanced by preventative measures including HPV vaccination, more accurate characterization and treatment of early (in situ) disease, and the optimization
of chemoradiation regimens.
Aetiology
• Risk factors
Human papillomavirus (HPV) infection is considered the most
important etiologic agent for anal cancer. Similar to cervical
intraepithelial neoplasia, HPV can cause anal intraepithelial
neoplasia (AIN). This may progress to invasive cancer through
a complex interplay between HPV infection and subsequent
DNA integration and stepwise mutations in tumor suppressor
genes (Gervaz et al. 2006). While HPV is the likely causative
agent of anal cancer, the immune status may determine the
time of progression to anal cancer.
While anal cancer is rare in the general population, the incidence rates of anal cancer are higher in some individual groups.
In a meta-analysis of anal cancer incidence by risk groups,
HIV-positive men who have sex with men (MSM) had the
highest incidence rate of anal cancer (85 per 100,000 personyears [py]). This was followed by non-MSM male persons
living with HIV (PLHIV) (35 per 100,000 py) and female
PLHIV (22 per 100,000 py). A substantial variation by age was
also noticed in these groups (from 16.8 to 107.5 in < 30 years
and ≥60 years HIV-positive MSM, respectively). The incidence
rates for anal cancer were also much higher after diagnosis of
vulvar than cervical or vaginal cancer (48 versus 9 and 10 per
100,000 py). The incidence rate was 13 in solid organ transplant
recipients, with the risk increasing as the duration of the transplant increases, reaching 24.5 and 49.6 for males and females
>10 years after transplant. Patients with autoimmune diseases
such as systemic lupus erythematosus, ulcerative colitis, and
Crohn’s disease were also reported to have a slightly increased
incidence rate of anal cancer (10, 6, and 3 per 100,000 py,
respectively) (Clifford etal. 2021).
A unifying anal cancer risk scale was developed based on the
incidence rates of anal cancer among populations considered at
significantly higher risk (Figure 1). The scale represents the
broad spectrum of anal cancer burden among the different
populations and identifies high-risk groups in whom anal cancer screening and secondary prevention.
• Pathology
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
Squamous tumors of the cutaneous anal margin, defined as
the circumferential area of pigmented skin lying outside the
anal verge extending laterally to a radius of 5 cm, can be treated
235
236 2 COLORECTAL AND ANAL CANCER
Anal cancer incidence (per 100,000 person-year)
Males Females
https://t.me/medicina_free
≥60 yrs
100
HIV +
45–59 yrs
75
30–44 yrs
Risk scale
1515 50 10 0
50
pre-cancer
HIV +
25
HIV −
≥30 yrs
0
MSM
Figure 1 Anal cancer risk scale. (Clifford etal. 2021/with permission of John Wiley & Sons).
<30 yrs
HIV −
Non-MSM All Gynaecological
≥45 yrs
30–44 yrs
HIV +
HIV −
<30 yrs
like skin lesions with wide excision, which can result in 80%
≥45 yrs
30–44 yrs
<30 yrs
• Screening and prevention
five-year survival. True anal canal cancer arises from the
squamous epithelium lining the distal anal canal, which
changes to a transitional epithelium near the dentate line and
ultimately to the non-squamous rectal mucosa. Distal anal
tumors tend to have a keratinizing squamous morphology. In
contrast, more proximal tumors are less likely to be keratinized (cloacogenic or basaloid) (Williams and Talbot 1994), yet
this distinction is of little clinical relevance. Rare anal canal
There is an increased risk of malignant transformation for
some HPV subtypes. Immunization against HPV type 16 has
been shown to reduce the incidence of cervical neoplasms, and
several nations are exploring making this practice more widely
available. Additionally, this might help prevent the development
of anal cancer. Smoking is likely to raise the risk of anal
cancer.
tumors include adenocarcinomas of the anal ducts or glands
(which behave almost identically to rectal adenocarcinoma)
and anal melanoma.
Anatomy
Anal cancer typically spreads initially through the lymphatic
system. Inguinal and femoral lymph nodes are more frequently
• The anal canal, anal verge, and anal margin
affected below the dentate line, whereas the proximal anal canal
drains to perirectal nodes. About 10% of individuals initially
exhibit synchronous groin nodal illness. In 10–20% of patients
receiving treatment for anal cancer, distant metastases (often to
the liver and lungs) manifest.
The anal canal starts at the anorectal junction at the level of the
puborectalis sling and extends to the anal verge, which coincides with the inter-sphincteric groove. The anal margin is the
circumferential area of pigmented skin lying outside the anal
Vulvar
cancer
Vulvar
Vaginal
pre-cancer
Vaginal
cancer
Cervical
cancer
Cervical
pre-cancer
(pre)cancers
≥60 yrs
Ulcerative
40–59 yrs
<40 yrs
SOTR
Lupus
Colitis
Crohn’s
disease
Non-HIV
immuno-
suppressed
≥10 yrs
(female)
≥10 yrs
(male)
5–10 yrs
(female)
<5 yrs
(female)
5–10 yrs
(male)
<5 yrs
(male)
13 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF ANAL CANCER 237
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verge extending laterally to a radius of 5 cm. Cancers of the anal
margin are considered anal cancers, while cancers outside the
anal margin are classified as skin cancers. The columnar epithelium of the rectum extends to cover the upper part of the
anal canal above the anal transition zone, which lies about 1 cm
above the dentate line. The anal canal distal to the dentate line
is covered by squamous epithelium.
• Lymphatic drainage
The lymphatic drainage of the proximal anal canal follows the
rectal lymphatic drainage to perirectal paravertebral lymph
nodes. In contrast, the area just proximal to the dentate line
drains into the internal pudendal and internal iliac lymphatics,
while the anal canal below the dentate line and the anal margin is
drained by the inguinal, femoral, and external iliac lymph nodes.
Diagnosis
• Symptoms
Anal cancer symptoms are often nonspecific, with the most
typical symptom being fresh rectal bleeding. This is often
misattributed to other benign anal conditions such as hemorrhoids leading to the often-delayed diagnosis of anal cancer.
Anal cancer may also present as anal pain, itching, discharge,
mass, non-healing ulcer, and incontinence. Perianal pain, painful defecation, and weight loss are common features of advanced
(T3/T4) disease (Sauter etal. 2016). Rarely may patients present with enlarged inguinal lymph nodes, and a minority of
patients are asymptomatic. The patient assessment also includes
discussing sexual activity, previous history of sexually transmitted diseases, and the risk of immunosuppression.
• Examination and clinical findings
Digital rectal examination (DRE) is essential in assessing anal
cancer. A mass is usually identified. The size and position of the
mass and fixity to the surrounding structure should be evaluated and documented. Enlarged perirectal lymph nodes are
evident on digital examination of the rectum in some patients.
A gynecological exam is performed in women to assess if vaginal involvement or a fistula is present. Synchronous vulvar,
vaginal or cervical neoplasia may coexist. Draining nodal
basins are checked, and a general examination for distant
metastases is performed.
When a clinically suspicious lesion is found, a diagnosis of
anal cancer depends on cytologic or histologic confirmation.
Examination under anesthesia provides an optimum assessment
of the tumor and involvement of nearby structures and facilitates biopsy to confirm the diagnosis. Appropriate biopsies
with accompanying clinical information should allow the
pathologist to diagnose anal cancer confidently.
• Staging and other investigations MRI, CT CAP, PET CT
The TNM (tumor-node-metastasis) staging system is based on
tumor size and nodal status (Tables 1 & 2) (Brierley etal. 2017)
The Tumor (T) staging depends on the tumor size and invasion
of adjacent organs. This can be assessed by clinical examination; however, magnetic resonance imaging (MRI) is considered the mainstay of local staging and provides a more detailed
assessment of the tumor extent.
Endoanal ultrasound scan is highly sensitive in detecting
anal cancer and can detect up to 100% of cases and is superior
to MRI scans for T1 tumors (Tumor size less than 2 cm) (Sauter
etal. 2016); however, it is user-dependent and less sensitive for
nodal involvement.
The MRI scanning techniques for anal cancer are similar to
rectal cancer and consist of 3 T2-weighted sequences in sagittal, axial, and coronal planes, which are angled perpendicular
or parallel to the anal canal. A T1-weighted sequence covering
the whole pelvis is required to image nodal disease. The tumor
will have a relatively high signal intensity compared to the low
signal intensity of the surrounding muscle (Maas etal. 2020)
user-dependent than endoanal ultrasound. Many clinicians
find the ability to project and compare images (especially follow-up images in questions of recurrence) in a multidisciplinary review extremely useful.
The MRI report should include the relationship of the lower
edge of the tumor to the anal margin, the tumor extent with
quadrant involvement of the anal canal or rectum, the craniocaudal tumor length, and its depth of invasion. Any evidence of
adjacent organ infiltration such as vagina, prostate, urethra, or
bladder wall should also be reported. The MRI scan should also
report on draining lymph nodes sites and should include both
inguinal regions, the pelvic sidewalls, and the top of the mesorectum up to the L5 level (Rao etal. 2021).
CT of the pelvis is often obtained during staging for distant
disease. Still, as for rectal cancer, it does not reveal the layers of
the anorectal region nor differentiate between tumor and
normal pelvic tissues as clearly as MRI.
• LN
Unlike rectal cancer, the nodal (N) staging of anal cancer
depends on the site rather than the number of involved lymph
nodes (Table 1). The presence of nodal disease has important
implications for prognosis and may require alterations in
treatment. Involvement of perirectal lymph nodes may be more
frequent but are clinically less important as such nodes are
included in the radiotherapy fields of the primary tumor. In
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UICC TNM (8th edition) clinical classification for anal cancer.
Table 1
Primary tumor (T)
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ (Bowen disease, HSIL, AIN II-III)
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3 Tumors more than 5 cm in greatest dimension
T4 Tumor of any size invades adjacent organ(s), e.g., vagina, urethra, bladder (direct invasion of the rectal wall, perirectal
skin, subcutaneous tissue, or the sphincter muscle(s) is not classified as T4)
Regional lymph nodes (N)
Nx Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis
N1 Metastasis in regional lymph node(s)
N1a Metastases in inguinal, mesorectal, and/or internal iliac lymph nodes
N1b Metastasis in external iliac lymph nodes
N1c Metastases in external iliac and in inguinal, mesorectal and/or internal iliac lymph nodes
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
AIN, anal intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesion; TNM, tumor–node–metastasis; UICC, Union for International Cancer
Control (Brierley etal. 2017).
Table 2 UICC pTNM (8th edition) stage classification of anal cancer.
involving the midline of the anal canal commonly spread to
both inguinal lymphatic basins. It has been suggested that
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T2 N0 M0
Stage IIB T3 N0 M0
Stage IIIA T1-T2 N1 M0
Stage IIIB T4 N0 M0
Stage IIIC T3-T4 N1 M0
Stage IV Any T Any N M1
TNM, tumor node metastasis; UICC, Union for International Cancer
Control (Brierley etal. 2017).
patients without inguinal node involvement may be able to
avoid the risks of prophylactic inguinal irradiation thanks to
sentinel lymph node biopsy. Around 20% of patients were
found to have subclinical lymph node disease at sentinel node
biopsy in some reported studies (Damin etal. 2006).
• PET CT
The majority (90%) of anal cancers are avid on positron
emission tomography (PET) CT with 18-fluorodeoxyglucose
(FDG–PET-CT). The metanalysis by Mahmud etal. on the role
contrast, the diagnosis of involved inguinal or iliac nodes may
demand additional radiation to these fields.
MRI features that will suggest lymph node involvement
include enlargement of the lymph node (largest short-axis
diameter > 1 cm for mesorectal nodes and > 1.5 cm for other
nodes), heterogeneity, necrosis, irregular contours, and strong
enhancement. However, these radiological criteria for lymph
node metastasis have not been validated due to the scarcity of
surgical specimens (Durot etal. 2017).
It is technically possible to perform a sentinel lymph node
biopsy utilizing lymphoscintigraphy with patent blue dye
injected near the tumor site. The presence of microscopic disease can then be examined in this sentinel node. Tumors
of PET scan in anal cancer recommended that (FDG–PET-CT)
adds value to conventional imaging in the initial staging of
T2-T4 anal cancer with a change in the treatment plan; mainly
in the term of radiotherapy dosage or field changes, in a
significant number of patients (12.5–59.3%) to justify the routine use of PET-CT in the staging of locally advanced anal cancer (Mahmud etal. 2017). While achieving a complete response
to treatment on PET-CT is a good prognostic factor for overall
and progression-free survival, insufficient evidence was found
to recommend routine PET-CT in assessing treatment response
(Mahmud etal. 2017).
PET-CT is beneficial in cases with enlarged lymph nodes
which lack other radiological features of disease involvement.
13 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF ANAL CANCER 239
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Around 50% of enlarged inguinal lymph nodes in patients with
anal cancer are reactionary lymph nodes. Further characterization of these lymph nodes through an ultrasound-guided fineneedle aspiration (FNA) is recommended when radiological
features of disease involvement are absent on MRI and PET-CT
to avoid morbidity from irradiation of the inguinal regions
(Rao etal. 2021).
• Distant spread
Hematogenous spread of anal cancer typically affects the liver
and lungs. The imaging modalities most frequently utilized to
identify metastases to these areas are contrast-enhanced CT
and MRI. CT scans of the chest, abdomen, and pelvis are generally used for the staging of distant disease, and MRI for local
staging due to cost and time efficiency.
Figure 2 summaries a diagnostic algorithm for anal cancer as
recommended by the European society of medical oncology
(ESMO) (Rao etal. 2021).
Treatment
• CRT
The main aim of anal cancer treatment is to cure locoregional
disease while preserving anal function and quality of life. Since
Nigro’s 1974 publication (Nigro et al. 1974) of pathologic
complete responses in two of three anal cancer patients following low-dose radiotherapy and synchronous mitomycin C
(MMC) and 5-fluorouracil (5-FU) given before abdominoperineal resection, numerous additional studies (Table 3) have
established that primary CRT is suitable for the majority of
patients, with the significant benefit of preserved anal sphincter
function without an apparent adverse effect on overall survival.
The treatment protocol used by Nigro was a combination of
radiotherapy as 3000 rad (30 Gy) over three weeks (200 rad per
day, 5 days a week) with a combination of Chemotherapy in the
form of 5-fluorouracil infusion (1g/m2 on days 1–4 and
repeated on days 29–32) and a single dose of Mitomycin C
intravenous bolus (15 mg/m2) on day 1. Surgery was done at
4–6 weeks intervals from the end of radiation therapy (Nigro
etal. 1983). About 80% of anal cancer patients will be treated
initially with CRT.
Two studies in the 1980s compared the outcomes of CRT
with those of historical controls who had only had radiotherapy, pointing to enhanced local control with the addition
of chemotherapy (Cummings 1984; Papillon and Montbarbon
1987). Two randomized trials later supported these results in
the 1990s, the EORTC and UKCCCR ACT I study, concluding
the superiority of combined CRT with 5-FU and MMC over
radiotherapy alone (Bartelink et al. 1997; Northover et al.
Figure 2 Diagnostic algorithm for anal cancer.
CT, computed tomography; HIV, human immunodeficiency virus; HPV,
human papillomavirus; MRI, magnetic resonance imaging; PET, positron
emission tomography; SCCA, squamous-cell carcinoma of the anus (Rao
etal. 2021/with permission of Elsevier).
1996). In 1996, The RTOG 87–04 study compared the radiotherapy combination with 5FU alone against the combination
of 5FU and MMC and reported the superiority of the
combined effect of 5FU and MMC (Flam etal. 2016).
The next cohort of clinical trials focused on comparing cisplatin (CisP) against MMC in combination with 5FU and
radiotherapy in treating SCC of the anal canal. The RTOG 98
–11 (Ajani etal. 2008) and CRUK ACT II (James et al. 2013)
trials concluded that cisplatin did not improve outcomes,
including complete response rate and DFS, when compared
with MMC. The UNICANCER ACCORD 03 trial examined
whether a greater radiation boost or two cycles of induction
chemotherapy before concurrent RCT may improve colostomy-free survival. The study reported that neither induction
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Table 3 Randomized studies of the treatment of anal cancer.
Study and design No. of patients Local failure Colostomy-free
survival
UKCCCR (Northover etal. 1996) 585
5FU/RT 59% 61% 58%
5FU/MMC/RT 36% 72% 65%
P = <0.0001 p = 0.25
EORTC (Bartelink etal. 1997) 110
RT 50% 40% 52%
5FU/MMC/RT 40% 73% 59%
p = 0.02 p = 0.002 NS
ECOG/RTOG (Flam etal. 2016) 310
5FU/RT 59% 51% 42%
5FU/MMC/RT 71% 73% 32%
p = 0.014 p = 0.0003 NS
RTOG 98–11 (Ajani etal. 2008) 644
Two cycles CisP/5FU then MMC/5FU/RT 72% 68% 78%
Two cycles CisP/5FU then CisP/5FU/RT 65% 58% 70%
p = 0.05 p = 0.006 p = 0.026
CRUK ACT II (James etal. 2013) 940
5FU/MMC/RT 68% 69% 79%
5FU/CisP/RT 67% 69% 77%
NS NS NS
No maintenance 66% 69% 79%
Maintenance (5FU/CisP) 69% 70% 76%
NS NS NS
ACCORD 03 (Peiffert etal. 2012) 307
Neoadjuvant 5FU/CisP + 5FU/CisP/RT + LD booster RT 67% 70% 74.5%
Neoadjuvant 5FU/CisP + 5FU/CisP/RT + HD booster RT 82% 78%
5FU/CisP/RT + LD booster RT 77% 67% 71%
5FU/CisP/RT + HD booster RT 72% 68%
Disease-free
survival
Overall
survival
RT = radiotherapy, 5FU=5Fluorouracil, CisP=Cisplatinum, MMC=Mitomycin C, NS= not significant, HD=high-dose, LD=low-dose. All p-values relate to
Hazard Ratios.
chemotherapy nor higher boost radiotherapy improved outcomes (Peiffert etal. 2012).
The commonly used dose of 5-FU is 1gm/m
2
on days 1–4,
and 29–32 of radiotherapy and MMC is either given as 12 mg/m
on days 1 (James etal. 2013) or 10 mg/m
2
on days 1 and 29 (Ajani
etal. 2008) Recently, 5FU has been replaced with oral capecitabin e
(825 mg/m2 twice daily for five days per week) for all days of
radiotherapy (Glynne-Jones etal. 2008).
There is no consensus on the optimal curative radiotherapy dose for anal cancer, and treatment protocols vary
from 45 to 60 Gy, including the boost doses. The radiotherapy dose for locally advanced anal cancer should be more
than 50.4 Gy (James et al. 2013). The initial treatment field
should include the primary tumor, the anal canal, and nodal
regions, including the inguinal canal, followed by a higher
dose to a reduced field that consists of the primary tumor
and sites of possible nodal involvement. Intensity-modulated
radiotherapy (IMRT) allows for precise delivery of radiotherapy to cancer tissues, reduces toxicity to nearby structures, and is the recommended radiotherapy technique
2
for anal cancer (Rao et
al. 2021). The risk of inguinal LN
involvement increases with increased tumor size, tumors
located below the dentate line, or in patients with N1 disease. It is recommended that inguinal LN be included in
the radiotherapy field in most anal cancer patients (Rao
et al. 2021). Elective radiation to inguinal lymph nodes
and nodes superior to the sacroiliac joint can be omitted in
selected patients with early tumors (T1N0) (Ng et al. 2012).
The PLATO (PersonaLizing Anal cancer radioTherapy
dOse) study is an ongoing non-randomized single protocol
umbrella platform trial including ACT3, 4, and 5 trials. The
ACT4 trial looks at different radiotherapy doses for early
anal cancer (Stage I-IIA) (ISRCTN – ISRCTN88455282:
PLATO – Personalising anal cancer radiotherapy dose).
13 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF ANAL CANCER 241
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The role of surgery:
• Defunctioning colostomy
A pre-treatment defunctioning colostomy can be required in
10–20% of anal cancer patients to relieve their anorectal pain,
fecal incontinence, or both. Patients should be warned that half
of these colostomies are not reversed with high rates of fecal
incontinence or anal stenosis due to the effect of radiotherapy
on the anal sphincter (Glynne-Jones et al. 2014). End colostomy is recommended over loop colostomy as the latter has a
higher rate of parastomal hernia. CRT can be started two weeks
after the creation of colostomy (Rao etal. 2021).
• Fistulating disease
Perianal fistulas, either malignant or benign, can lead to the
development of perianal sepsis during CRT. This can delay
treatment and have an unfavorable effect on long-term outcomes. Pre-treatment clinical and radiological assessment of
anal cancer should detect the presence of a perianal fistula. In
patients with fistulas, a seton should be inserted before stating
CRT to reduce the risk of infection. The seton will need to stay
in for the duration of treatment, and definitive treatment of the
fistula should be delayed until the effect of CRT has subsided
(Rao etal. 2021).
• APR as primary treatment
CRT has replaced abdominoperineal resection of the rectum
and anal canal (APR) as the primary treatment for most anal
cancers. APR might be considered the primary treatment
option in some patients. Examples include patients who had
previous pelvis radiation, transplant patients on immunosuppressants due to the high risk of interrupted CRT, patients with
adenocarcinoma or adenosquamous carcinoma of the anal
canal, which are more resistant to radiotherapy, and patients
refusing CRT (Rao etal. 2021).
• APR as salvage treatment
After CRT, 5–15% of patients will still have a visible or microscopic disease and need an abdominoperineal resection.
Similarly, 10–30% of patients will experience locoregional disease relapse. It is unclear whether residual or recurrent disease
carries the worse prognosis, and both groups have a skeptical
outcome.
• Local excision for anal margin cancer
Early anal margin cancer (T1N0), representing around 5%
of anal cancers, is suitable for local excision. A microscopic
>1 mm clear margin is required for “complete excision.” This
requires a macroscopic resection margin of 0.5–1 cm. Primary
closure is associated with an increased risk of wound dehiscence, and plastic surgery reconstruction is usually preferable
(Rao et
al. 2021). Re-excision of a positive margin is associated
with a high recurrence rate and is not recommended.
• Postoperative CRT
Postoperative CRT should be considered through MDT
discussion in patients who had local excision of anal canal cancers, patients with a histological margin less than or equal to
mm, patients who had a piecemeal excision of anal margin
1
cancers, and patients with high radiological or pathological
risks of nodal involvement.
Figures 3 and 4 summarize the recommended algorithm for
the management of localized and advanced anal cancer as recommended by the European society of medical oncology
(ESMO) (Rao etal. 2021).
Follow-up and Prognosis
• CRT response evaluation
Anal cancer response to CRT is slow, and the optimum
interval to evaluate treatment response is 26 weeks based on
the data from ACT II trial (James et al. 2013). Complete
clinical response is defined as the absence of tumor and/or
ulceration on DRE. Examination under general anesthesia
might be required in some patients. The assessment also
includes clinical evaluation of the inguinal regions and radiological assessment using pelvic MRI and CT scans. While it
can be challenging to distinguish treatment-induced edema
and fibrosis from persistent disease clinically, tissue biopsies
are not routinely recommended 8–12 weeks after CRT. It can
be challenging to pathologically determine the treatmentrelated effects from active disease. The lack of clinical
response at three months post CRT does not indicate that
salvage surgery is indicated as reassessment at six months,
which often reveals a late clinically significant regression
(Rao et al. 2021). There is insufficient evidence to recommend routine PET-CT in assessing treatment response
(Mahmud etal. 2017).
Persistent or recurrent diseases usually occur within the first
24 months from the completion of CRT. Histological confirmation is required, along with radiological assessment and
discussion in specialist MDT. Salvage surgery for residual or
recurrent disease will require beyond total mesorectal excision
(TME) surgery, and surgical planning should include a thorough radiological assessment of all pelvic compartments. The
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Figure 3 Treatment algorithm for localized anal cancer. (Rao etal. 2021/with permission of Elsevier).
Purple: general categories or stratification; red: surgery; turquoise: combination of treatments or other systemic treatments; white: other aspects of management.
5-FU, 5-fluorouracil; CRT, chemoradiotherapy; M, metastasis; N, node; MMC, mitomycin C; RT, radiotherapy; T, tumor.
(a) Optimum timepoint to assess clinical tumor response after CRT is 26 weeks [II, B].
(b) In cases where surgery cannot be carried out.
mainstay of salvage surgery for tumors involving the anal
sphincter complex is APR, and more radical exenterative surgery might be required to achieve an R0 resection. APR for
relapsed anal cancer is different from the procedure performed
for rectal cancer and plastic perineal reconstruction with musculocutaneous flaps is usually required.
• Advanced/Metastatic disease management
Distant metastatic disease occurs in around 20% of patients.
Chemotherapy is commonly a part of treatment because the
tumor is typically chemosensitive. Based on the findings from
The International Multicentre Study in Advanced Anal Cancer
(InterAACT), Carboplatin-paclitaxel is currently recommended as the new standard of care in patients with chemotherapy-naive advanced anal cancer and has replaced the
cisplatin – 5FU regimen (Rao etal. 2020).
• Immunotherapy for advanced anal cancer
In addition to HPV viruses’ oncogenic abilities, HPV proteins E6 and E7 are known to encourage tumor-infiltrating
13 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF ANAL CANCER 243
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Figure 4 Treatment algorithm for advanced anal cancer. (Rao etal. 2021/with permission of Elsevier).
Purple: general categories or stratification; blue: systemic anticancer therapy; white: other aspects of management.
5-FU, 5-fluorouracil; BSC, best supportive care; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.
lymphocyte (TILs) recruitment which turns on the immune
system’s anti-cancer defenses. Given that HPV infection is a
known cause of anal cancer, the interest in the role of immunotherapy in advanced anal cancer is growing, especially in
patients who progressed while on first-line chemotherapy.
The KEYNOTE-028 study reported encouraging results with
pembrolizumab, a monoclonal antibody directed against
programmed cell death protein 1 (PD-1), in managing a cohort
of patients with refractory anal cancer and no other options for
standard systemic therapy (Ott et
al. 2017). Similar outcomes
were reported on the safety and efficacy of nivolumab (Morris
et al. 2017). Programmed cell death protein 1 (PD-1)/PD-L1
inhibitor testing and other immunotherapy-based strategies
are currently being conducted.
Treatment Complications
As with any chemotherapy regimen, side effects are possible,
and a 1–2% mortality risk is present (often from neutropenic
sepsis). Up to 30% of individuals who receive radiation therapy
or CRT may experience significant late adverse effects such as
bleeding, anal necrosis, skin ulceration, stenosis or fibrosis, and
diarrhea. Under these circumstances, some individuals might
have a colostomy created, either with or without anal resection.
Prognosis
For local control and overall survival in anal cancer, gender,
tumor stage, nodal status, and response to chemoradiation are
independent prognostic variables (Salmon etal. 1986). Little predictive significance is attached to the histologic subtype. Patients
who have malignancies that are well differentiated do better than
those who have tumors that are not well differentiated.
Anorectal Malignant Melanoma
Anorectal malignant melanoma is a rare, highly lethal tumor
with an incidence of 2.7 per 10 million per year in the United
States (Coté and Sobin 2009), and it accounts for 4% of all anal
canal tumors (Klas etal. 1999). Delayed diagnosis is common,
and almost 60% of patients have distant metastasis on diagnosis
(van Schaik etal. 2008) as clinical presentation in the form of
perianal itching and bleeding is similar to some common
benign proctology conditions such as hemorrhoids. Tumors
can look like benign polypoid lesions on endoscopy, especially
in the amelanotic melanomas, representing 20–30% of anorectal melanoma.
The pathogenesis of anorectal melanomas is not well
established, and there are several theories for the development
of melanomas in the gastrointestinal tract, including their
development from intestinal Schwann cells and the migration
from the neural crest during embryogenesis (Malaguarnera
etal. 2018).
The symptoms associated with anorectal melanoma are nonspecific and similar to those related to other more common
benign or malignant conditions of the anorectum, like hemorrhoids and rectal cancer. This includes anal pain or discomfort,
bleeding, tenesmus, feeling of anal/rectal fullness or mass,
244 2 COLORECTAL AND ANAL CANCER
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change in bowel habits, and even inguinal masses from enlarged
LN (Malaguarnera etal. 2018).
Colonoscopy with biopsies followed by histological and
immunochemistry assessment is the gold standard diagnostic
test for anorectal melanoma. The different forms of melanocytes in anorectal melanomas, including pleomorphic, epithelioid, spindle cells, etc., can resemble other anorectal tumors
such as gastrointestinal tumors and sarcomas, indicating the
need for immunohistochemical assessment to differentiate between those tumors (Malaguarnera etal. 2018).
The clinical and radiological assessment of anorectal melanomas is similar to the anal squamous cell cancer assessment
discussed earlier in this chapter. EUA is helpful for the
assessment of tumor site, size, and extent. Radiological tests
used for tumor staging include endoanal USS and MRI scans
for local staging, while CT scans, MRI liver, and PET/CT are
used to detect distal metastasis (Malaguarnera et al. 2018).
Anorectal melanoma is staged based on disease spread into
stage I (local disease), stage II (spread into regional LN), and
stage III (tumors with distant metastasis).
The treatment options for anorectal melanomas include surgical excision, radiotherapy, chemotherapy, immunotherapy,
and targeted therapy. While surgery proved to add survival
benefit in patients with stage I and Stage II disease, there were
no significant survival benefits from surgery in patient with
metastatic (stage III) disease (Chen etal. 2016).
Surgical excision in the form of radical abdominoperineal
resection (APR) or more conservative wide local excision
(WLE), or even endoscopic mucosal resection (EMR), are
offered for patients with anorectal melanomas. No clinical
trials were performed to compare the outcomes of the radical
versus local excision approach. However, recent meta-analyses
have shown no survival benefits with more radical excision
(APR) than with wide local excision. A less is more approach
is recommended to avoid the significant comorbidities associated with APR (Smith etal. 2020; Wanebo etal. 1981). APR is
more selectively used now for more local advanced resectable,
nonmetastatic tumors not amenable for wide local excision.
None of the reported studies compared the quality of life following those two treatment options (Table 4).
Cutaneous melanomas are known to respond well to
Immune checkpoint inhibitors such as CTLA-4 (Cytotoxic Tlymphocyte-associated antigen, Ipilimumab) and PD-1
(Programmed-death, Nivolumab, and Pembrolizumab) targeted therapy. However, the evidence of survival benefits in
anorectal melanoma still requires more investigation (Adileh
etal. 2021).
Patients with anorectal melanomas experience a high rate of
disease recurrence with a 5-year disease-free survival of
16–17%, and overall 5-year survival is estimated between 6 and
20% and a median survival of 24 months (Coté and Sobin 2009;
van Schaik etal. 2008). Patients with stage I disease (LN negative disease) has significantly better survival (Nusrath et al.
2018). Survival after surgery has not improved over the last
three decades (Wanebo etal. 1981). This indicates the need for
more studies on other different treatment approaches, such as
the potential role of adjuvant targeted therapy and immunotherapy in the management of anorectal melanoma.
Study No. of
patients
(Jutten etal. 2021) 103 I 13.7% 21.7% 17 / 25 m
(Ford etal. 2018) 570 NS 20.2% 17.3%
(Nusrath etal. 2018) 20 I 75% 80% 56 m
(Chen etal. 2016) 317 I 18.5% 14.9% 35 / 30 m
(Wang etal. 2013) 43 NS 27% 0% 28 m
(Zhang etal. 2010) 53 NS 30.7% 16% 25 / 13 m
(Belli etal. 2009) 31 NS 30.7% 22.2% 17 m
(Pessaux etal. 2004) 30 NS 33% 19% 16 m
(Bullard etal. 2003) 15 NS 25% 63.6% –
(Thibault etal. 1997) 37 NS 23% 36.4% 29 m
(Wanebo etal. 1981) 33 NS 18% 0% 21.5 m
(Pack and Martins 1960) 14 I 11% 100% –
Stage Extensive resection
5 years survival
II 8.7% 11.1% 14 / 17 m
II 19% – 13 m
II 14% 22.2% 18 / 23 m
II 0% 0% –
Local excision 5
years survival
median survival
in months
Overall survival of the
Table 4
surgical treatment (extensive
versus local excision) of stage I
and II anal melanoma.
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