Anal Neoplasms- Dysplasia to
Cancer
Paul A. Lucha Jr., D.O., FACOS,
FAOCPr
VAMC Salisbury, NC
Introduction





Histology
Muscles of the
anorectal region
Anorectal spaces
Vascular anatomy
Lymphatic drainage
Anatomy

Surgical Anal Canal
– differs from
anatomists
description
– 4 cm length
– arises from anorectal
junction
– terminates at anal
verge




Anatomists Anal
Canal
2-3 cm in length
begins at the
pectinate line
terminates at the
anal verge
Anatomy
Anatomy

Anal Margin
– area caudal to anal canal
– Intersphinceric groove to approximately 5
cm circumference on the perineum
– non keratinized squamous epithelium
keratinized squamous epithelium
– hair follicles and apocrine glands present
Histology

6-14 Columns of
Morgagni
– 4-10 anal glands at
crypts
– Pathogenesis of fistula/
abcess (Parks 1961)
– 2/3 glands enter internal
sphincter
– 1/3 cross into
intersphincteric plane
– none penetrate the
external sphincter
Histology

Transition from
columnar
epithelium to
squamous
epithelium (6-12 cm
above dentate line)
– transition zone
(cloacogenic anal
cancer)

Anal verge
– hair follicles present
– apocrine glands
Muscles of the Anorectal
Region

Internal Sphincter
– thickening of the
circular smooth
muscle fibers of
the rectum
– extends 1-1.5 cm
below the dentate
line
– inervated by the
pelvic autonomic
plexus
Muscles of the Anorectal
Region  Conjoined
Longitudinal
Muscle
– longitudinal
muscle layer of the
rectum
– joins with levator
ani muscle
complex
– descends between
the internal and
external sphincters
Muscles of the Anorectal
Region
 External
Sphincter
– somatic
inervation


perineal
branch of the
4th sacral
nerve
Inferior rectal
nerve
Muscles of the Anorectal
Region  Levator Ani
complex
– Puborectalis
– Iliococcygeus
– Pubococcygeus

Inervated by 4th
sacral nerve
Muscles of the
Anorectal Region
Muscles of the Anorectal
 anorectal ring
Region
– junction of the
rectum and anal
canal
– composed of
internal
sphincter and
puborectalis
– division results
in incontinence
Anorectal Spaces






ischiorectal
perianal
intersphincteric
Postanal
supralevator
retrorectal
Anorectal Spaces

Postanal space
connects with
ischiorectal
fossa bilaterally
Vascular anatomy


anorectum has a
profuse
intramural
vascular
anastomotic
network
this prevents
necrosis of the
anus in low rectal
resections
Vascular anatomy

Portal and
systemic
venous
drainage
Lymphatic drainage



Important in
rectal cancer
Important in
anal cancer
Important in
anal margin
cancer
Innervation

Sympathetic innervation
– L1, L2, L3
– preganglionic

preaortic plexus
– postganglionic
follow branches of the IMA
 enter via “lateral stalks” of the rectum

Innervation

Parasympathetic innervation
–
–
–
–
S2, S3, S4
also called nervi erigenti
upward path via IMA
downward path follows the sympathetic
postganglionic nerves
Innervation

Sexual function
– erection

parasympathetic and sympathetic
– ejaculation

parasympathetic
– emission

sympathetic
Innervation

Internal anal
sphincter
– Sympathetic

L5
– Parasympathetic

S2, S3, S4

Levator Ani
complex
– S2, S3, S4
– perineal branch of
the pudendal nerve
– inferior rectal nerves
(puborectalis)
Innervation

External Anal Sphincter
– Inferior rectal branch of the pudendal nerve (S2,
S3) and perineal branch of S4

Sensory- Inferior Branch Pudendal Nerve
–
–
–
–
–
Meissner’s Corpuscles (touch)
Krause’s bulbs (cold)
Golgi-Mazzoni bodies (pressure)
genital corpuscles (friction)
Concentrated at anal valve area
ANAL CANCER OVERVIEW
Carcinomas in the anal canal account for about
1.5% of gastrointestinal cancers in the United
States, and approximately 80% of these are
squamous cell carcinomas (SCCs).
 SCCs of the anus are frequently related to
chronic infection with human papilloma virus
(HPV)

ANAL CANCER OVERVIEW
Usually occur in the sixth to seventh decade of
life, occur in younger patients when they are
immunocompromised
 Male:Female=2:1
 HIV/AIDS, and the increasing use of
immunosuppressive therapy for solid organ
transplantation, inflammatory bowel disease and
collagen vascular diseases has meant an
increasing incidence of HPV infection and anal
SCC.

ANAL CANCER OVERVIEW
Rare in general population, but high and growing in at-risk populations1
•Men who have sex with men (HIV+/-)
•Women (HIV)
Incidence Rates2, 3
•Men who have sex with men (MSM)
•HIV35/100,000
•HIV+ est 70/100,000
•General Population
•<1/100,000
1 Bean,
Anal Cancer 2010 cases4
Cases
Deaths
Men
2,000
280
Women
3,260
440
Total
5,260
720
SM, Chhieng, DC, Anal-Rectal Cytology: A Review. Diagnostic Cytopathology 2009; Vol 38 No 7, 538-546
Palefsky, J. Screening for Anal and Cervical Dysplasia in HIV-Infected Patients. The PRN Notebook. Volume 6, No. 3, Sept. 2001. 24-31.
3 Darragh, TM. Anal Cytology for Anal Cancer Screening: Is it Time Yet? Diagnostic Cytopathology, 2004; Vol 30, No 6, 371-374
4 American Cancer Society, Cancer Facts and Figures, 2010
2
ANAL CANCER OVERVIEW
•Morphologic & biologic similarities between anal intraepithelial neoplasia
(AIN) and cervical intraepithelial neoplasia (CIN)1
•Association with sexual transmission of oncogenic HPV, especially type 161
•Gardasil® HPV-vaccine approved to prevent anal cancer2
2001 Bethesda guidelines
includes appendix for
anal cytology
1
Darragh, TM. Anal Cytology for Anal Cancer Screening: Is it Time Yet? Diagnostic Cytopathology, 2004; Vol 30, No 6, 371-374
News Release , Dec 22, 2010 (http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm237941.htm)
Gardasil® is a registered trademark of Merck, Sharp, & Dohme Corp.
2 FDA
Anal cancer
Approx 4200 new cases annually in US
 May be an overestimation due to
misclassification of perianal or anal
margin cancers as anal canal cancers
 Anal canal lesions may have more
aggressive biology

Three Regions
•
Intraanal lesions
– Cannot be visualized or only slightly
visualized with gentle traction on the buttocks
•
Perianal lesions
– Completely visible
– Within a 5-cm radius of anal opening with
gentle traction
•
Skin lesions
– Outside of the 5-cm radius
Transformation Zone
0-12 mm in length
 Beginning at the dentate line
 “Transitional urothelium-like” epithelium
in rectal mucosa instead of columnar
mucosa
 Squamous metaplasia may be found
overlying the normal columnar mucosa
involving up to 10 cm or more of distal
rectal mucosa

Terminology
SCC in situ (CIS), anal intraepithelial
neoplasia (AIN), anal dysplasia, squamous
intraepithelial lesion (SIL), and Bowen’s
disease are all used to refer to the same
histopathology
 Normal, low-grade squamous
intraepithelial lesions (LSIL), high-grade
squamous intraepithelial lesions (HSIL),
or invasive cancer

Lymphatic Drainage

Above the dentate line
– Superior rectal lymphatics to inferior
mesenteric lymph nodes and laterally to
internal iliac nodes

Below the dentate line
– Inguinal nodes
– May also involve the inferior or superior
rectal lymph nodes
HPV
•
•
•
•
•
Necessary but not sufficient cause for
development of anal cancer
DNA papovavirus with 8-kb genome
Most common viral sexually transmitted
infection
Most patients clear virus with only 1%
developing genital warts with low oncogenic
potential (serotypes 6 &11)
10-46% develop subclinical infections that may
harbor malignant potential (serotypes 16, 18, 31,
33, 35)
HPV

Not prevented by condoms
– Virus pools at the base of the penis and
scrotum
In women, may pool and extend from
vagina to anus
 Anoreceptive intercourse associated with
intraanal disease but condylomata or
dysplasia within the anus does not
mandate that it has occurred

HPV
•
After developing chronic infection, virus
enters basal and parabasal cells
– Disruption in normal mucosal barrier
•
•
•
•
•
Anoreceptive intercourse
Other STD’s (ulcers from syphilis, gonorrhea)
Friable prolapsing hemorrhoid
Firm bowel movement
Can become widespread and persistent
(for decades) if viral DNA gains access to
nucleus of replicating cells
– Increased risk of cancer
•
HPV
Cell-mediated immunity important to cellular response
prohibiting the virus from establishing prolonged presence
– Oncogenic viruses lead to cellular proliferation in latency phase
•
Interferes with cell cycle control mechanisms through p53
binding and degradation
– Leads to accumulation of genetic errors
•
These cells then proliferate, accumulate, and involve the entire
thickness of epithelium
– Disease progression from low-grade to high-grade dysplasia
– Increased proliferation and angiogenesis, decreased apoptosis

Increased anal cancer rates observed in kidney transplant and
HIV (+) patients, both populations with blunted cell-mediated
responses
HPV



As the infection with oncogenic viruses persists, the anal tissues
may progress through low-grade to high-grade dysplasia and
cancer
With this disease progression is an associated increased
proliferation and angiogenesis, and decreased apoptosis
In the cervix, angiogenic changes have long been recognized as an
important and visible step in the progression of dysplasia to cancer
– Colposcopy with the aid of acetic acid and Lugol’s solution, allows for direct
visualization of characteristic vascular patterns seen with LSIL and HSIL
– Therapeutic intervention, in combination with screening Pap smears, has led to
the belief that cervical cancer is a largely preventable cancer

Fortunately, the angiogenic changes associated with development of
anal HSIL can also be visualized with the aid of acetic acid and
Lugol’s solution in the perianal skin, anus, and distal rectum
through an operative microscope, colposcope, or loops in the office
or operating room
– Targeted destruction is safe and may result in the same decrease in anal cancer
incidence
Bowen’s disease

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


SCCA in situ and HSIL
Is frequently found as an incidental histologic finding
after surgery for an unrelated problem, often
hemorrhoids
Clinically unapparent but histologically reveals SCC in
situ
May present with complaints of perianal burning,
pruritus, or pain
Physical examination may reveal scaly, discrete,
erythematous, or pigmented lesions
In the immunocompetent, <10% will progress to cancer
Bowen’s disease

Standard recommendation for lesions found after
hemorrhoidectomy is to return the patient to the OR for random
biopsies taken at 1-cm intervals starting at the dentate line and
around the anus in a clock-like manner
– Frozen sections establish the presence of Bowen’s disease and these areas are
widely locally excised with 1-cm margins
– Large defects are covered with flaps of gluteal and perianal skin

A less radical approach involves taking patients to the OR and using
an operating microscope, acetic acid, and Lugol’s solution to
visualize and target for electrocautery destruction
– May also simply be locally excised
– The deep margin is kept equally close because wide local excision seems of
limited benefit and increases morbidity

Other therapeutic modalities include topical 5-fluorouracil (5-FU)
cream, imiquimod, photodynamic therapy, radiation therapy, laser
therapy, and combinations of the above
SCC of the Anal Margin



Arises from both the anal margin and the anal
canal
Immunohistochemical studies of squamous cell
tumors from the anal margin and anal canal
demonstrate differences in expression of
cadherin, cytokeratins, and p53 confirming that
these tumors are of distinct histogenetic origin
The anal margin is defined as the skin starting at
the distal end of the anal canal to a 5-cm margin
surrounding the anal verge

Clinical Characteristics
Tumors of the anal margin resemble SCC of other areas of skin
 Staged and often treated in a similar manner

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Rolled, everted edges with central ulceration
May have a palpable component in the subcutaneous tissues
Sphincter complex is not usually involved
Patients present in the seventh decade of life, M=F
Presenting symptoms include a painful lump, bleeding,
pruritus, tenesmus, discharge, or even fecal incontinence
Anal margin tumors may have a delay in diagnosis because of
their location and indistinct features
 Almost one-third are misdiagnosed at their first physician visit
 Patients were given erroneous diagnoses of hemorrhoids, anal
fissures, fistulas, eczema, abscesses, or benign tumors
 No significant difference in survival between correctly diagnosed
and misdiagnosed patients
Staging
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
Based on size of the tumor and lymph node involvement
 Both correlate with prognosis
Lymphatic drainage of the anal margin extends to the femoral and
inguinal nodes and then to the external and common iliac nodes
 Lymph node involvement is associated with the size and
differentiation of the tumor
Incidence of inguinal lymph node metastasis
 0% for tumors <2 cm, 23% for tumors 2–5 cm in size, and 67% in
tumors >5 cm
Distal visceral mets at presentation is rare but should be evaluated
with CT of the abdomen and pelvis to assess for liver metastases, as
well as the presence of nodal disease
Chest X-ray can be performed for lung mets
These tumors are generally slow growing and histologically are well
differentiated with well-developed patterns of keratinization
Treatment Options
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Traditionally consisted of surgical resection with wide local excision for
smaller-sized tumors and APR for larger, invasive tumors
Wide local excision alone results in high locoregional recurrence rates (18%–
63%)
 Should be reserved for those lesions that can be excised with a 1-cm
margin, are Tis or T1, and do not involve enough sphincter to
compromise function
Since it was introduced in the early 1970s, radiation therapy has become the
mainstay of therapy for SCC of the anal canal and its application to tumors
of the anal margin is increasing
Local control rates for radiation therapy reported by T stage: T1, 50%–
100%; T2, 60%–100%; T3, 37%–100%
In patients with T1 or early T2 lesions, local excision or radiation therapy
provides similar local control rates (60%–100%)
For less favorable lesions, chemoradiation is now used as the first-line
therapy using a perineal field and inguinal fields, even without clinically
detectable disease in the groin
 Pelvic lymph nodes are also treated for those patients with T3 and T4
tumors



SCC of the Anal Canal
All large-cell keratinizing, large-cell nonkeratinizing
(transitional), and basaloid histologies
Terms epidermoid, cloacogenic, and mucoepidermoid
carcinoma are all encompassed in the SCC group
SCC of the anal canal is 5 times more common than SCC of the
anal margin
 Incidence is 1/10 that of rectal cancer

The most common presenting symptom is bleeding
 occurs in >50% of patients with many complaining of anal pain
 Other symptoms include palpable lump, pruritus, discharge,
tenesmus, change in bowel habits, fecal incontinence, and rarely,
inguinal lymphadenopathy
 A small number of patients will be asymptomatic

Unfortunately, most patients are diagnosed late, with up to
55% of patients being misdiagnosed at the time of presentation

Evaluation
PE should include a complete anorectal examination with external inspection of the
anoderm, digital examination, anoscopy and proctoscopy and exam of inguinal areas




Additional workup should include an endoanal/endorectal ultrasound to assess the depth
of the tumor, presence of perirectal lymph nodes, and invasion of adjacent organs as an
adjunct to the physical examination
Enlarged lymph nodes can be reactive to secondary inflammation and should be biopsied
with direct FNA or ultrasound-guided FNA






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Notation should be made of size, location, and mobility of the mass, associated perirectal
lymphadenopathy
In women, a pelvic exam should be done to look for any associated lesions or invasion of tumor into
the vagina
Studies of sentinel lymph node biopsy may result in more accurate staging but the actual impact on
initial and subsequent management remains unclear
CT scan or MRI of the A/P can add to locoregional staging as well as evaluating for liver
metastasis
CXR is used as a screening tool for lung lesions and, if suspicious, a chest CT should be
performed.
Positron emission tomography (PET) scans are useful for assessing persistent or residual
disease after treatment
Colonoscopy can exclude any associated lesions proximal to the anal canal
HIV test should be performed for those at higher risk
HIV-positive patients with CD4 counts <200 need better monitoring of opportunistic
infections,


Radiation
Therapy
Quite effective because this tumor is extremely radiosensitive
Can be given as external beam radiation, brachytherapy, or in combination
 Response is dose dependent--best chance of tumor eradication with at least 54 Gy of
external beam radiation


Benefit is lost when administered in a split-course manner
Local control and cure can be achieved in 70%–90% of selected patients with
60%–70% retaining sphincter function
 When tumors are >5 cm or lymph nodes are involved, the cure rate decreases to 50%



Better results with higher doses of radiation must be exchanged with
increased radiation-induced complications (when >40 Gy is administered)
Serious late complications: anal necrosis, stenosis, and ulcerations, diarrhea,
urgency, and fecal incontinence, cystitis, urethral stenosis, and sbo
Dose-dependent effect on morbidity
 Requirement of a colostomy in 6%–12% of patients--tumor size was the only risk factor

Brachytherapy used alone with external beam is also effective
 Local control rates of 75%–79% and 5-year survival of 61%–65%
 3%–6% of patients had serious complications that required surgery
Chemoradiation Therapy

Introduction of by Nigro et al. in 1974 revolutionized the
treatment of anal canal SCC
 demonstrated equivalent local control and survival rates with
preservation of sphincter function and thus avoidance of a
colostomy
 Described using 30-Gy external beam radiation with 5-FU and
mitomycin C
 Complete pathologic response in 21 of 26 patients (81%)

Since that time, has become the standard therapy for SCC of
the anal canal
 Operative treatment for anal canal SCC was largely abandoned
and reserved for those patients with persistent or recurrent
disease after chemoradiation

Cisplatin has replaced mitomycin C because it is a radiation
sensitizer, is less myelosuppressive, and has been used for
those patients who failed to respond to mitomycin C

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Follow-up
No consensus has been reached on appropriate follow-up after
treatment of SCC
Generally agreed that early intervention for persistent disease
and recurrent locoregional disease can lead to successful
salvage therapy
Routine examination with digital rectal examination and
proctoscopy every 2 months in the first year, every 3 months
in the second year, and every 6 months thereafter has been
recommended
Ultrasound examination has also become popular in detecting
recurrence although the literature is mixed on its benefit
CT scan or MRI performed after completion of chemoradiation
may also be useful as a baseline for future comparison
MRI is useful for distinguishing surrounding tissues and
detecting persistent or recurrent disease





Treatment of Residual or
Recurrent Disease
Patients need to be restaged with a CT of the chest, abdomen, and pelvis
MRI may be useful to assess resectability of pelvic recurrence
PET may help differentiate tumor from radiation-induced tissue changes or other
undetectable metastases
APR can be performed for tumor localized to the pelvis with a 5-year survival of 24%–47%
Positive margins, nodal disease at salvage, and persistent disease after chemoradiation have
poorer outcomes




Clinically evident inguinal disease after chemoradiation of the primary tumor can be treated
with radical groin dissection if radiation has already been administered




Morbidity for APR in this setting is significant with an increased risk of perineal wound complications
This has prompted the use of plastic surgery reconstruction using rotational or advancement flaps to
promote healing
The benefit of adjuvant chemotherapy after APR is currently unknown
Additional radiotherapy can be considered if maximal doses of radiation were not delivered
Radical groin dissection in selected patients can result in a 5-year survival of 55%
Distant metastases have been found in 10%–17% of patients treated with chemoradiation,
and are usually treated with systemic chemotherapy such as cisplatin or 5-FU for palliation
If the metastases are isolated in the liver or lung and the primary disease is controlled,
resection can be considered
AJCC staging of SCC
Primary tumor (T)
Anal margin
Anal canal
Tx
Tumor cannot be assessed
Tumor cannot be assessed
T0
No evidence of primary tumor
No evidence of primary
tumor
Tis
Carcinoma in situ
Carcinoma in situ
T1
Tumor ≤2 cm in greatest dimension
Tumor ≤2 cm in greatest
dimension
T2
Tumor 2–5 cm in greatest
dimension
Tumor 2–5 cm in greatest
dimension
T3
Tumor ≥5 cm in greatest dimension
Tumor ≥5 cm in greatest
dimension
T4
Tumor invades deep structures
(muscle, bone, cartilage)
Tumor invades deep
structures (vagina, urethra,
bladder, but not sphincter)
AJCC staging of SCC
Nodal status (N)
Anal margin
Anal canal
Nx
Regional lymph nodes
cannot be assessed
Regional lymph nodes
cannot be assessed
N0
No regional lymph node
metastasis
No regional lymph node
metastasis
N1
Regional lymph node
metastasis present
Perirectal lymph node
metastasis present
N2
Unilateral internal
iliac/inguinal lymph node
metastasis present
N3
N1 and N2 and/or
bilateral internal iliac
and/or inguinal lymph
node metastasis
AJCC staging of SCC
Distant metastasis (M)
Anal margin
Anal canal
Mx
Distant metastasis cannot be
assessed
Distant metastasis cannot be
assessed
M0
No distant metastasis
No distant metastasis
M1
Distant metastasis present
Distant metastasis present
AJCC staging of SCC

Stage grouping (3b does not exist for anal
margin)
Stage 0 Tis N0 M0
 Stage 1 T1 N0 M0
 Stage 2 T2,3 N0 M0
 Stage 3a T1,2,3 N1 M0 or T4 N0 M0
 Stage 3b
Any T N2,3 M0 or T4 N1 M0
 Stage 4 Any T Any N M1

Perianal squamous cell
carcinoma
- treatment

Wide local excision – well
differentiated, up to 3 cm

Less favourable lesions- chemoradiation
(40-70 Gy)
Perianal basal cell carcinoma






Uncommon
1-2 cm
Rarely metastasize
Misdiagnosed in 33%
Delayed diagnosis
Rx – local excision
with adequate
margins
Perianal Paget’s disease




Extramammary
Paget’s found in axilla
and anogenital region
Uncommon
Eczematous lesions
Visceral carcinomas
in 50%
Perianal Paget’s disease
- biopsy & identify Paget’s cells
APR for local failure of
treatment

Not easy
Technical tips

Fill the hole

Tackle pelvic side wall involvement

Sacral invasion
Rectus abdominus flap
Sidewall vessel involvement
vessels
Pelvic side wall

BLEEDING
Suture
 Fibrillar surgicell
 Argon beamer
 Be prepared to pack

Direct invasion of the sacrum

Choose level of sacrectomy carefully

Frozen section

Beware bleeding from pre-sacral veins
APR+S vs TPE+S
Questions