Anal Cancer

Kelly Knudson, MD
UCHSC Surgery Grand Rounds
3/3/08
The Malignant Hemorrhoid
 Anal Canal= 4 cm
Anal Anatomy mucosa lined region
from junction of the
puborectalis portion
of the levator ani
Rectal
muscle and the
glandular
external anal
mucosa
sphincter, and
extends distally to
the anal verge
Transitional

Squamous

Anal Margin- begins at the

anal verge. It represents
the transition from the Transitional zone- from
squamous mucosa to the True Epidermis glandular (columnar) to
epidermis-lined perianal squamous mucosa- at
skin. dentate line
 WHO Classification of Anal Cancer
Anal canal Anal margin
 Squamous cell carcinoma
 Keratinizing (below dentate) Squamous cell carcinoma
 Nonkeratinizing (above dentate) Giant condyloma
 Basaloid (transitional)
Basal cell carcinoma
 Adenocarcinoma
 Rectal type Others (Melanoma)
 Of anal glands Bowen's disease (SCC in situ)
 Within anorectal fistula
Paget's disease (Intraepithelial
 Small cell carcinoma
adenocarcinoma)
 Undifferentiated
Classification of tumor is determined by the pathology/histology
of the tumor not the anatomic location as determined by the
surgeon or endoscopist.
“Anal Cancer” = squamous cell cancer arising in the mucosa of the anal canal.
 Epidemiology and Risk Factors
 Squamous cell carcinoma of the anus is rare and
accounts for only 1.5% of cases of GI cancer in the U.S.
 (SEER) data
 4,660 patients have been diagnosed with anal cancer in 2006
 660 individuals died of anal cancer
 incidence is rising from 1975 to 2003 (2% every year)
 The age-adjusted incidence rate is 1.5 per 100,000.
 Risk Factors
 HPV infection with high risk genotypes or multiple genotypes
 HPV dna in 90% of tumors. Subtype 16 associated with 70%
 Cervical dysplasia, cervical cancer, or genital warts
 HIV seropositivity and low CD 4 count
 Cigarette smoking (OR 3-9)
 Anoreceptive intercourse
 Immune suppresion following transplant (100x increase in KTX)
Human Papilloma Virus
Anal cancer = Cervical cancer of the anus
 90 genotypes of HPV
 HPV6 and HPV11
 associated with condylomata acuminata (genital
warts) and low-grade squamous intraepithelial lesions
 benign or low-risk HPV types
 HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52,
56, 58, 59, 68, 73, and 82
 high-risk types -associated with pre-malignant high-
grade squamous intraepithelial lesions and cancers of
the uterine cervix, vagina, vulva, anus, and penis.
 transformation zone in the cervix or anus = the
area of columnar epithelium that is susceptible
to metaplasia and transformation into squamous
epithelium
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.
 Physical exam- rectal and nodes
 Biopsy- used to differentiate squamous cell (anal ca)
from adenocarcinoma (rectal ca) does not have to be
excisional
 CT scan to evaluate for metastatic disease
 Consider EUS to evaluate for sphincter involvement and
perianal lymph nodes
 Consider PET scan since 25% of patients have
metastatic disease by PET not seen on CT and 20% of
inguinal nodes negative by CT are PET positive.
 AJCC anal cancer TNM staging system
Primary tumor (T)

T Primary tumor cannot be assessed

X

T Carcinoma in situ
i
s
T No evidence of primary tumor
0

T Tumor 2 cm or less in greatest dimension

1

T Tumor more than 2 cm but not more than 5 cm in greatest dimension

2

T Tumor more than 5 cm in greatest dimension

3

T Tumor of any size invades adjacent organ(s), eg, vagina, urethra, bladder
4
(involvement of sphincter muscle(s) alone is not classified as T4)
Lymph node (N)

N Regional lymph nodes cannot be assessed

x

N No regional lymph node metastasis

0

N Metastasis in perirectal lymph node(s)

1

N Metastasis in unilateral internal iliac and/or inguinal lymph node(s)

2

N Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac
3
and/or inguinal lymph nodes
 Anal Cancer Staging At Presentation-
AJCC anal cancer stage grouping
 T1 — 9 percent
Stage
 T2 — 51 percent
Stage 0 Tis N0 M0
 T3 — 30 percent
Stage I T1 N0 M0
 T4 — 10 percent
Stage II T2 N0 M0
 N+ — 13 percent
T3 N0 M0
Stage IIIA T1 N1 M0
5 y survival-
T2 N1 M0
 T1 — 86 percent
T3 N1 M0
 T2 — 86 percent
T4 N0 M0
 T3 — 60 percent
Stage IIIB T4 N1 M0
 T4 — 45 percent
Any T N2 M0
Any T N3 M0
 N0 — 76 percent
Stage IV Any T Any N M1  N+ — 54 percent
Treatment
 The Nigro Protocol
 Developed as preop regimen before APR
 5-FU + mitomycin with 30-54 Gy radiation
 5-year overall survival rates of 72 to 89%
 5-year colostomy-free survival of 70 to 86%
 local failure rates of 14 to 37%
 Increased Radiation Dose > 54 Gy
 Increased survival and local control
 Increased complications including colostomy for
stricture etc.
 6-12% require colostomy for radiation complications
 No evidence for survival advantage with cisplatin
over mitomycin
 Higher colostomy rate (19% vs 10%) but lower severe
hematologic toxicity
 Locoregional failure in 30%
 ½ recurrence, ½ progression
 Salvage APR is associated with five-year
survival rates from 24 to 58%
Salvage Surgery
 LAR = low anterior resection
 APR = abdominoperineal resection
 Pelvic exenteration = multiviseral resection
 NOT exoneration
 Urinary and fecal diversion
Salvage APR
 MD Anderson – 31 patients – 1990-2002
 11 patients= persistent; 20 = recurrent
 Actuarial 5 y survival = 64%
Salvage APR- MD Anderson
 Patients who received an initial radiation dose of less
than 55 Gy had a significantly worse survival than
those who received at least 55 Gy as part of their
initial treatment
 5-year overall survival 37.5% vs. 75%
Salvage APR- MD Anderson
 At last follow-up 7 pts had died as a result of
disease progression,3 pts were alive with disease,
and 21 pts were alive without evidence of recurrent
disease.
 12 recurrences (40%)- 6 locoregional, 3 distant, 3 both
 All are alive with disease or dead x 1 patient (salvage
inguinal LND)
 Mean survival 33 months after 2º failure
 Positive lymph nodes at presentation adversely
affected survival (P < .05). Majority recurred.
 Factors not impacting survival include
 Tumor stage
 Margin status of resection
 Perineal wound complications in 35%
 Salvage APR- Mt Sinai
 40 patients -29 women, 11 men, med age 57-
curative intent resection
 APR in 14, multivisceral resection in 24, local 2
 Mortality = 5%, morbidity = 72%
 Median Survival 41 months
 Actuarial 5 year survival = 39%
 52% overall recurrence rate
 Predictors for poor overall/disease free survival
 Male gender; comorbity score; Tumor size
 Positive margins, lymphovascular invasion
 All 6 patients with + margins went on to recur locally
 High grade tumors and + lymph nodes also associated
with recurrence and progression
 Salvage APR- MSKCC
 62 patients with APR or LAR for epidermoid anal ca
 Actuarial 5y survival for APR/LAR pts = 33%
 Actuarial 5 y survival after potentially curative
resection for recurrence after chemoradiation was
51% as opposed to 31 % for persistence
 Negative nodes/margins improved OS/DFS
Lymphatic Drainage
 Lymphatic drainage of anal cancers depends on
the location of the tumor in relation to the
dentate line.
 Regional nodes are considered to be the inguinal,
internal iliac, and perirectal (anorectal, perirectal, and
lateral sacral) nodes.
 Tumors below the dentate line drain to the inguinal
and femoral nodes.
 Tumors above the dentate line drain to the perirectal
and paravertebral nodes, a pattern similar to that
seen with rectal cancers.
 Tumors in the most proximal portion of the canal drain to the
nodes of the inferior mesenteric system.
 Lymph Node Management
 Chemoradiation is the treatment of choice for
inguinal lymph node disease
 cure rates approach 90 percent for synchronous
disease
 Bilateral groins should be incorporated into the
radiation fields with the addition of a boost for
clinically positive lymph nodes.
 Metachronous lymph nodes + in 10 to 20%
 usually appearing w/in six months after treatment
 respond well to CRT
 LND considered in patients who have persistent nodal
disease after CRT.
Sentinel Lymph Node Bx
 SLNB identifies inguinal metastases in 10–40% of anal
cancer patients with limited morbidity ranging between
3% and 7%
 The clinical impact of this procedure on the therapeutic
approach is unclear as long as the inguinal nodes are
included in the radiation field.
 The Standards Practice Task Force of The American
Society of Colon and Rectal Surgeons
Anal Margin Cancers
 Anal margin -distal end of the anal canal to a 5-cm
margin surrounding the verge.
 Treat similar to skin cancer
 WLE for T1 and early T2 lesions that can be excised with
a 1-cm margin.
 Larger T2 cancers -add prophylactic radiation to the
inguinal lymph nodes along with radiation or excision of
the primary tumor.
 T3 and T4 lesions- radiation to both inguinal regions and
the pelvis, along with 5-FU and mitomycin C.
 APR for bulky tumors extending into the sphincter or
surrounding structures.
Anal Intraepithelial Neoplasia (AIN)
 Precursor to anal SCC
 parallelobservations in the cervix in which
HPV infection causes the development of
CIN, the precursor lesion to invasive cervical
cancer.
 AIN = squamous intraepithelial lesion (SIL)
 Alsocalled carcinoma in situ and Bowen’s dz
 AIN 1 = LSIL AIN 2&3 = HSIL
AIN & HIV
 Limited data for HIV negatve pts
 AIN 1 (LSIL)
 LSIL progresses to HSIL in more than 50 percent of
HIV-positive homosexual males within two years.
 AIN 2&3 (HSIL)
 risk for progression to invasive cancer ranges from 10
to 50 percent among HIV positive patients
 Among HPV-infected individuals, the prevalence
of HSIL and anal carcinoma is higher in those
with concomitant HIV infection compared to
those who are HIV-negative
 Anal pap smears -69 to 93% and specificity
ranges from 32 to 59%, but no trials showing
survival benefit etc.
Management of AIN
 Excision is for clinically definable lesions.
 WLE guided by frozen sections.
 1 cm margins
 large defects closed with local flaps
 WLE is associated with high rates of disease recurrence and
anal incontinence/stenosis
 Targeted destruction guided by high-resolution
anoscopy
 Decreased morbidity compared to WLE
 high risk for persistent or recurrent disease among HIV+
 Surveillance examinations performed at six-month
intervals as long as dysplasia is present
 Treatment with imiquimod or 5-fluorouracil has
initial 50-90% response rates.
 Recurrence limited with long duration therapy
 Compliance limited by significant skin irritation
Take Home Points
 Think of anal cancer
 Nigro protocol (5-FU + mitomycin with
XRT)
 APR for salvage 30-40% 5 y survival
 HPV vaccine- near 100% effective for the
strains it covers