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ANATOMY Anal Canal= 4 cm mucosa lined
region from junction of the puborectalis
portion of the levator ani muscle and
the external anal sphincter, and extends
distally to the anal verge
Transitional zone- from glandular
(columnar) to squamous mucosa- at
Anal Margin- begins at the anal
verge. It represents the transition from
the squamous mucosa to the epidermis-
lined perianal skin.
The anal canal is a 4-cm-long structure that passes downward
and backward from the rectal ampulla (level of pelvic ﬂoor) to
the anus (anal verge).
The proximal border of the anal canal clinically corresponds
to the anal sphincter at the level of the puborectalis muscle
(palpable as the anorectal ring on digital rectal examination).
This is where the rectum enters the puborectalis sling, made
by ﬁbers from both sides.
The distal end of the anal canal is at the level of the anal
verge, where the groove between the internal sphincter and
the subcutaneous part of the external sphincter is palpable.
This also is the level of the squamous-mucocutaneous
junction and the perianal skin.
Epidemiology and Risk Factors
Squamous cell carcinoma of the anus is rare and least prevalent GI
malignancy & accounts for only 1 – 2 % of all large bowel malignancy.
Ratio of 1:2 for men to women with median age at diagnosis is 60 yrs.
Geographical variation- heighest in caucasian female
lowest in asian males
- HPV infection.
- HIV seropositivity and low CD 4 count (twice)
- Cigarette smoking
- Anoreceptive intercourse (homosexual male 15 times)
- Immune suppresion following transplant
- anal warts.
Most anal cancers are believed to arise from precancerous
changes(i.e. AIN) of the anal canal and peri anal skin
High-grade AIN Squamous cell cancers in most instances.
However, it has been estimated that approximately 5% of
cases with AIN III progress to invasive cancer over multiyear
Squamous cell cancers spread.
Clinical Presentation and Workup
Rectal bleeding- 45% of patients
Pain or sensation of mass- 30%
No symptoms- 20%
Pruritus ani or bleeding plaques associated with anal margin
skin cancers- Paget’s disease.
Sensation of mass or fullness and tenesmus
Physical exam- perrectal and nodes.
Biopsy- used to differentiate squamous cell (anal ca) from
adenocarcinoma (rectal ca) .
Vaccine prevention- two vaccines- best long term approach
for reducing long term risk.
Boys 11-12 yrs
Girls 13 to 26 yrs
EUS or MRI
It follows that two distinct categories of tumors
arise in the anal region.
Tumors that develop from mucosa (columnar,
transitional, or squamous) are true anal canal
that arise from skin at or distal to the squamous-
mucocutaneous junction are termed anal margin
WHO Classification of Anal Cancer
Squamous cell carcinoma
- Keratinizing (below dentate)
- Nonkeratinizing (above dentate)
- Basaloid (transitional)
- Rectal type
- Of anal glands
- Within anorectal fistula
Small cell carcinoma
Squamous cell carcinoma
Basal cell carcinoma
Bowen's disease (SCC in situ)
Paget's disease (Intraepithelial
PRIMARY TUMOR (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor =2 cm in greatest dimension
T2 Tumor >2 cm but =5 cm in greatest dimension
T3 Tumor >5 cm in greatest dimension
T4 Tumor of any size invades adjacent organ(s) (e.g., vagina,
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 perirectal lymph node(s)
N2 Metastasis in unilateral internal iliac and/or inguinal
N3 Metastasis in perirectal and inguinal lymph nodes and/or
bilateral internal iliac and/or inguinal lymph node
AJCC stage groups
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage IIIA T1 N1 M0
T2 N1 M0
T3 N1 M0
T4 N0 M0
Stage IIIB T4 N1 M0
Any T N3 M0
Any T N2 M0
Stage IV Any T Any N M1
5 y survival-
T1 — 86 percent
T2 — 86 percent
T3 — 60 percent
T4 — 45 percent
N0 — 76 percent
N+ — 54 percent
Tumor size >5 cm , lymph nodes involvement, male sex are
associated with poor prognosis.
High expression of p53 associated with decreased DFS.
Also local control rates are lower with increased p53 expression.
High level of Ki 67 – longer DFS.
Combined-modality therapy was described initially by Nigro
This was a preoperative regimen inspired by reports that 5-ﬂ
uorouracil (5-FU) potentiated the effects of radiotherapy on
This regimen consisted of delivering 30 Gy in 15 fractions to
the primary tumor and pelvic lymph nodes with concurrent 5-
FU (1000 mg/m2 as a 4-day continuous infusion) and
mitomycin C (MTC) (15 mg/m2 bolus injection)
chemotherapy, and APR 6 weeks after completion of the
Promising early results, however, suggested that surgery may
not be necessary.
The series of Nigro and colleagues included 31 patients who
underwent surgery and 73 who received chemoradiotherapy
Twenty-two of the 31 surgical specimens had no evidence of
disease (NED) on histopathologic examination, and on long-
term follow-up evaluation, an NED rate of 79% was found for
the surgical patients, compared with 82% NED for patients
receiving combined-modality treatment.
Overall death rates were 6% in patients with tumors smaller
than 4 cm and 26% for those larger than 4 cm
The trials conducted by the
( combined modality therapy Vs radiation alone )
- United Kingdom Coordinating Committee for Cancer
- European Organization for Research on Treatment of
- Both showed statistically significant advantages in
-- the rate of control of the primary cancer
-- colostomy-free survival rates
UKCCCR ACT I trial
585 patients with SCC of anal canal & perianal skin were
randomized between radiation alone and radiation
combined with chemotherapy.
The radiation dose was 45 Gy , with a boost dose of 15 to
20 GY following 6-weeks break, based on response.
5-FU (1,000 mg/m2
per 24 hours for 4 days or 750 mg/m2
per 24 hours for 5 days) by continuous peripheral
intravenous infusion in the first and final weeks of
radiation treatment, plus mitomycin (12 mg/m2
) by bolus
intravenous injection on day 1 of the first course of
3 year local Failure in the primary tumor or regional lymph
nodes -(39%) of chemoradiation , (61%) of radiation alone.
Acute toxicity, particularly hematologic, skin, gastrointestinal,
and genitourinary, was increased in the combined modality
Late morbidity was comparable in each group.
No statistically significant advantage was seen in terms of
Included 103 patients with T3-4N0-3 or T1-2N1-3
The radiation dose was 45 Gy , with a boost dose of 15 to 20
GY following 6-weeks break, based on response
Chemotherapy consisted of 5-FU (750 mg/m2
per 24 hours by
continuous infusion for 5 days) in the first and fifth week of
radiation, and a single bolus injection of mitomycin (15
) on day 1 of the first course of 5-FU only.
Surgery was reserved for the patients with less than a partial
Concurrent CTRT group has higher complete response(80 vs
54%),locoregional control(68 vs 50%),colostomy free (72 vs
Acute and late toxicity rates were similar
U.S. RTOG–ECOG trial (RTOG 87–04/
The need for MMC in combined-modality therapy of anal
cancers was evaluated
This was the ﬁrst study comparing two methods of
chemoradiotherapy in patients with anal cancer. One study
arm used 5-FU alone with radiotherapy, and the other arm
used 5-FU and MMC with radiotherapy.
showed that colostomy free survival (71 vs 59%) and disease free survival
rate(73 vs 51%) were significantly higher in patient receiving MMC and
significantly lower colostomy (9 vs 22%) and local failure rate(16 vs 34%)
The investigators concluded that despite the greater toxicity,
the use of MTC in a deﬁnitive complete response regimen for
anal cancer was justiﬁed.
ACT II trial
randomized trial of 950 non-HIV infected patients with anal
Treatment consisted of RT in both arms (50.4 Gy in 28
fractions) with concurrent infusional 5-FU (1000 mg/m2 per
day on days 1 to 4 and 29 to 32) and either cisplatin (60
mg/m2 on days 1 and 29) or mitomycin (12 mg/m2 day 1 only).
There was a second randomization to receive or not receive
maintenance chemotherapy starting four weeks after
chemoradiotherapy (two courses of cisplatin plus 5-FU,
administered four weeks apart).
patients receiving mitomycin had more acute grade 3 or 4
hematologic toxicity (25 versus 13 percent), but no higher rates of
febrile neutropenia (3.1 versus 3.2 percent) during
Rates of grade 3 or 4 nonhematologic toxicity were similar (61
versus 65 percent).
The complete response rate at six months (the primary endpoint)
was 95 percent with both cisplatin and mitomycin, and
the three-year colostomy rate was not significantly different (13.7
versus 11.3 percent).
Three year RFS was similar with or without the use of
maintenance therapy (75 percent for both arms) as was overall
survival (84 versus 85 percent).
307 patients with stage II and III anal cancers randomized to
one of four treatment arms:
-Group 1- 5FU & cisplatin f/b EBRT 45 GY+ 5FU & Cisplatin
->rest ->15 GY
-Group 2- 5FU & cisplatin f/b EBRT 45 GY+ 5FU & Cisplatin
->rest ->20 -25 GY
-Group 3- EBRT 45 GY+ 5FU & Cisplatin ->rest ->15 GY
-Group 4- EBRT 45 GY+ 5FU & Cisplatin ->rest ->20 -25
Results-no significant difference in 5 yr colostomy free
survival (70 to 82%), no significant differences were seen
between the arms in terms of LRF and OS.
Conclusion-induction CT does not improve outcomes, with
the role of radiation dose escalation remaining uncertain, but
the combination of induction CT and radiation dose
escalation should be explored further.
For intermediate-stage primary anal canal cancer who -
- Cannot tolerate radiation therapy or chemoradiation
- Incontinent because of irreversible damage of the
- Anovaginal fistula
- Prior pelvic radiation treatment (most frequently for
carcinoma of the cervix)
- Active inflammatory bowel disease affecting the rectum
or anal region
- Failure of chemoradiation or radiation and less
frequently, complications of the initial treatment.
APR = abdominoperineal resection
Pelvic exenteration = multiviseral resection with urinary and
Salvage surgery is recommended in patient with chronically
persistent disease or recurrence.
Salvage APR is associated with five-year survival rates from
30 to 70%,with DFS ranging from 30 to 40%.
Tumor size >5 cm, inguinal lymph node involvement, positive
surgical margin, male sex, adjacent organ involvement are the
factors associated with poor overall survival after salvage
Reported in up to about 10-17% of patients
Median survival time - 8 to 12 months
The combination studied most extensively, and the most
effective, is 5-FU and cisplatin.
The usual regimen is a 4- or 5-day continuous infusion of 5-
FU (1,000 mg/m2
per 24 hours) plus a bolus infusion of
cisplatin (100 mg/m2
) on day 1 or 2, repeated at 4 weekly
intervals as tumor response and toxicity permit.
A patient with metastatic cancer who received 12 cycles of
5-FU and cisplatin had been free of cancer for more than 3
years at the time of reporting.
Other combinations, including mitomycin and 5-FU, and
bleomycin, vincristine, and high-dose methotrexate
produced few responses.
Comprise about 5% of cancers of the anal canal.
Small female preponderance.
The majority develop in rectal mucosa, which extends
below the upper muscular boundary of the canal.
No recognized association with high-risk HPV or
The most useful prognostic factors are T category and N
Overall 5-year survival rates following all treatments have
generally been less than 50%.
Locoregional control is problematic.
Risk of distant metastases higher than for squamous cell
Treated similarly to adenocarcinomas which arise in the
rectum with surgery remaining as a cornerstone therapy and
neoadjuvant radiation therapy or combined modality therapy
generally implimented in patients with T3 or T4 and/or N+
Melanoma of anal canal
It’s a rare disease, 1% of all malignant melanoma & 0.5%of
all anal malignancy.
Bleeding perrectum is most common c/f.
Surgery is the cornerstone for the treatment of anal
melanoma, traditionally surgeons use more redical approach
in form of APR with radical lymphnodes dissection
Kiran et al 109 patients , reported no significant difference
b/w patient treated by APR or local resection.
Anal Margin Cancers
Anal margin cancers includes the area extending from the
anal verge radially 5cm outward on perianal skin.
More common in 7th
decade with slight female
Treat similar to skin cancer.
WLE for T1 and N0 can be excised with a 1-cm margin.
T3 and T4 lesions- radiation to both inguinal regions and
the pelvis, along with 5-FU and mitomycin C.
APR should be reserved for patients with recurrent
disease following CTRT or recurrence not amenable to
The regional nodes for the perianal skin are the inguinal
Perirectal or pelvic node metastases are very uncommon.
The risk of inguinal node metastases is about 10%,
associated mainly with category T3 or T4 tumors, or
poorly differentiated cancers.
Elective inguinal nodal irradiation has been suggested for
those categories only.
Bowen's Disease and Paget's Disease
About half the cases of anal Paget's disease are associated
with a synchronous or metachronous internal malignancy,
often a colorectal adenocarcinoma.
High local recurrence rate .
May become invasive .
Wide local excision, with intraoperative microscopic control
Local recurrence can often be managed by further local
Other less-established treatments
-- Topical chemotherapy
-- Topical immune modifiers such as imiquimod
-- Photodynamic therapy.
Radiation therapy, or radiation and chemotherapy -
reserved for patients with recurrent or invasive disease in
whom adequate excision would entail sacrifice of anorectal
Abdominoperineal resection may be necessary to control
extensive or recurrent disease.