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20 Anal Intraepithelial Neoplasia
283
– May interfere with proper dysplasia dif-
ferentiation (i.e., AIN I versus AIN II or
III).
• The equipment used for the evaluation of AIN
is expensive, and the high-resolution microscopy procedure is time intensive and difcult
to learn.
• Others have taken to diagnose AIN with simple anoscopy or endoscopic methods.
• At this time, data have not demonstrated that
high-resolution anoscopy is superior to other
methods.
– Interestingly, a recent study from Ohio
revealed no difference in anal cancer progression with simple observation versus
high-resolution anoscopy.
– Others have demonstrated a very low rate
of anal cancer progression with an intense
surveillance strategy involving anal cytology, digital anorectal examination, and
oncogenic HPV testing in men who have
sex with men.
Treatment
• It should be clear that there is no proven treatment for HPV infection.
• As stated earlier, the infection is self-limited
such that treatment is directed only to the
macroscopic (i.e., genital warts) or pathologic
(i.e., precancerous) lesions caused by
infection.
• It is thought that all subclinical HPV infections resolve without treatment, and thus, any
attempt at antiviral therapies is not
indicated.
• When dysplasia is present, whether in the
anus, vulva, or cervix, there are a number of
methods to manage or treat these neoplastic
tissues ranging from no intervention to very
aggressive care.
• At this time there is no clear best treatment
option for all types of patients and all degrees
of anal dysplasia.
• Ultimately the best method of treatment must
be efcacious in preventing the progression of
anal intraepithelial neoplasia to cancer while
reducing the morbidity of treatment and preserving function (Table20.1).
• Observation may be the best option for
patients with low-grade dysplasia.
– Management would consist of surveillance
every 4–12months.
– Overall low rates of disease progression
and malignant potential (especially for
low-grade disease) and the increased morbidity associated with excision and
repeated focal destruction.
• Topical treatments with imiquimod and 5-FU
have demonstrated effectiveness for both
high- and low-grade dysplasia.
– Imiquimod is one of the most tested agents
although there is a high rate of recurrence
when treatment is discontinued.
Table 20.1 Common options used in the treatment of anal dysplasia
Treatment Advantages Disadvantages Cure Recurrence
Observation Cost cheap
No side effects
Imiquimod Minimal pain
Easy to use
5-FU Easy to use Burning
Infrared coagulation Clinic use Need equipment Good Moderate in immunosuppressed
Ablation One application Painful
Wide local excision Removes all tissue Disguring
Low cure rate
Time intensive
Burning
Moderate cost
Moderate cost
Costly
Painful
Poor High
Poor High with DC
Poor High with DC
Good Moderate in immunosuppressed
Good Low
284
R. Ricciardi
• Interestingly a recent meta-analysis
failed to demonstrate any statistically
signicant effect of imiquimod in the
management of anal intraepithelial neoplasia, but there was a trend for imiquimod to downgrade high-grade AIN to a
lower risk stage.
– 5-FU has fewer trials but is similarly effec-
tive in reducing dysplasia with complete
response in 39%.
• Unfortunately, patients treated with
5-FU similarly had high rates of recurrence (50%) and even higher rates of
side effects.
• Surgery is an effective option to treat anal
neoplasia.
– Electrocautery is highly effective in induc-
ing complete response of AIN especially in
immunocompetent individuals (72%) as
compared to immunosuppressed individuals (51%).
– Ablation is generally performed in the
operating room with electrocautery in conjunction with high-resolution anoscopy;
yet others perform the procedure in clinic
with local anesthesia.
– The technique is highly selective with tar-
geting of only those areas with evidence of
dysplasia.
– The operating surgeon should remember
that the disease is limited to the epidermis
and does not require destruction of deeper
dermal tissues.
– During ablation, the surgeon should be
mindful of potential scarring, stricture
formation, and the need to preserve as
much healthy tissue as possible.
• In addition to ablation or excision, infrared
coagulation can also be used to destroy
lesions.
– The infrared beam can be pulsed at varying
intervals to prevent trauma to deeper tissues with a tissue to a depth of approximately 1mm targeting the epithelium and
destroying dysplastic tissue.
– The technique is reportedly as effective as
electrocautery and considered to be associated with less pain.
• In the past, mapping biopsies with wide local
excision was recommended for patients with
anal intraepithelial neoplasia.
– Unfortunately, much healthy and unin-
volved tissue was removed with the dysplastic tissues, and this treatment option
was associated with high rates of recurrence between 13% and 63%.
– In addition, because of the extensive tissue
destruction, wide local excision was associated with high rates of local wound complications such as stenosis and incontinence.
• When selecting which of the above options is
best for an individual patient, the physician
should consider patient treatment goals, symptoms, history of immunosuppression, past history of dysplasia, and bowel function.
• An attempt at Cochrane Review failed to provide guidelines for treatment in anal intraepithelial neoplasia because of lack of
high-quality randomized controlled trials.
Management Strategies
• For AIN I, a minimalist approach may be the
most effective strategy (Fig.20.6).
Progression
• Progression of anal intraepithelial neoplasia to
squamous cell cancer of the anus parallels the
pathway of cervical dysplasia to cervical
cancer.
• Once established in the anal epithelium, dysplasia of the anus rarely regresses.
• The high rate of progression to cancer is particularly true for immunosuppressed patients
as compared to immunocompetent patients.
Prevention
• As with all infectious diseases that are transmissible by sexual contact, the best method of
prevention is safe sexual practices or limiting
sexual contact.
Disease Status
20 Anal Intraepithelial Neoplasia
Fig. 20.6 Algorithm for
the treatment of AIN
based on immune status
and biopsy results
AIN I
Immune
Competent
Immune
Competent
285
AIN II/III
High Risk
PMHx of AIN
Immune-sup
HRA every
3-6 months
Ablation/annual cytology
• In addition to monogamy, proper and consistent use of prophylactic condoms has been
shown to reduce the transmission of HPV.
• Educational interventions do have the potential to reduce the transmission of HPV and
possibly reduce the incidence of squamous
carcinoma.
• In addition to primary prevention techniques,
vaccines have also been efcacious in reducing the incidence of HPV infection.
– In the general screening population, HPV
vaccine efcacy was almost 100% for cervical intraepithelial neoplasia, vulvar and
vaginal intraepithelial neoplasia, and anogenital condyloma.
Annual HRA
or
Ablate
Immune-sup
HRA every 3-6 months
with topical agent
Ablation
– In men who have sex with men, use of
quadrivalent HPV vaccine signicantly
reduced the rates of moderate and highgrade anal intraepithelial neoplasia.
– Although the vaccinated populations
were HPV naïve, there are some data
indicating effectiveness of HPV vaccines
in preventing reinfection or reactivation
of disease.
– Along the same reasoning, a nonconcurrent
cohort study of HPV-vaccinated men who
had been previously treated with highgrade anal intraepithelial neoplasia noted a
reduction in anal intraepithelial neoplasia
recurrence.
OR
Part III
Malignant Disease
Anal Cancer
TusharSamdani andGarrettM.Nash
21
Key Concepts
• Chemoradiotherapy (CRT) is the primary
treatment for patient with anal squamous cell
carcinoma (mitomycin + 5-FU + radiotherapy). The dosage of radiotherapy varies based
on the size of the tumor and presence of lymph
node involvement.
• Surgery (local excision) can be used to remove
some small squamous cell carcinomas (usually measuring <1 cm or ½ in.) that do not
involve the anal sphincter musculature.
• Following primary treatment with chemoradiotherapy, patients are evaluated with repeat
physical examination of the anal area at
approximately 8–12 weeks after completion
of treatment and then at 6- to 8-week intervals
until resolution of any suspicious ndings.
Patients with persistent but nonprogressive
disease may be followed up to 6months after
chemoradiotherapy for assessment of complete remission.
• Patients with progressive disease or recurrence after chemoradiotherapy are considered
T. Samdani
Department of Colorectal Surgery, Medstar Saint
Mary’s Hospital, Leonardo Town, MD, USA
G. M. Nash (*)
Department of Surgery, Memorial Sloan Kettering
Cancer Center, New York, NY, USA
e-mail: nashg@mskcc.org
for salvage abdominoperineal resection
(APR).
• Dosage of radiotherapy and chemotherapy
may be modied based on CD4 count and
blood count in immunocompromised patients.
• Anal melanoma is very aggressive and is generally treated with local excision (LE).
• Anal adenocarcinoma is treated with APR and
usually with neoadjuvant chemoradiotherapy,
as in treatment for distal rectal
adenocarcinoma.
• Anal cancer accounts for only 4% of all cancers of the lower alimentary tract. However,
the incidence is rising – possibly due to the
higher incidence of persons engaging in analreceptive intercourse.
Anal Squamous Cell Carcinoma
• Risk factors: sexually transmitted disease;
anal-receptive intercourse; more than 10 sexual partners; the presence of precancerous
anal lesions such as condylomas or high-grade
anal intraepithelial neoplasia and cervical,
vulvar, or vaginal cancers; immunosuppression secondary to solid organ transplantation
or chronic glucocorticoid therapy; HIV seropositivity, low CD4 count; and smoking.
• Anatomic Location Guides Treatment
– Surgery alone (local excision) can be used
to remove select small squamous cell
© ASCRS (American Society of Colon and Rectal Surgeons) 2019
S. R. Steele et al. (eds.), The ASCRS Manual of Colon and Rectal Surgery,
https://doi.org/10.1007/978-3-030-01165-9_21
289
290
T. Samdani and G. M. Nash
Combined preoperative radiation and chemotherapy for squamous cell
carcinoma of anal cancer (Cancer 1983): Nigro protocol (23)
Radiotherapy should be initial treatment in anal carcinoma (Int J Colorectal
Use of mitomycin C in a definitive chemoradiotherapy regimen for anal cancer is
justified, particularly in patients with large primary tumors (J Clin Oncol 1996): Phase
Combined chemoradiotherapy s better than radiation with significantly improved
locoregional control rate and reduction of the need for colostomy: Phase III
randomized trial of the European Organization for Research and Treatment of Cancer
Radiotherapy and Gastrointestinal Cooperative Groups (J Clin Oncol 1997) and
Dis 1989): Swedish study (± chemotherapy) (24)
III randomized intergroup study (25)
UKCCR Anal Cancer Trial (ACT I) (Br J Cancer 2010) (26,27)
Induction chemotherapy with cisplatin-based therapy not only failed to improve
disease-free survival compared with mitomycin-based therapy, but cisplatin-based
therapy also resulted in a significantly higher colostomy rate (JAMA 2008) (28)
Fig. 21.1 Evolution of management of anal cancer (algorithm)
carcinomas of the perianal skin that do not
involve the anal sphincter musculature and
tumors of the buttock skin.
– Chemoradiotherapy (CRT, mitomycin
+5-ourouracil + radiotherapy) is the primary treatment for patient with squamous
cell carcinoma that involves the anal canal or
anal sphincter musculature. The dosage and
elds of radiotherapy vary based on the size
of the tumor and presence of lymph node
involvement. There has been an evolution of
treatment philosophy over time (Fig.21.1).
21 Anal Cancer
Fig. 21.2 Algorithm for anal mass evaluation and work-up
291
Anal Mass
Detailed History including sexual history
Physical examination including digital rectal
examination and proctoscopy
(Gynecological examination in females)
Tissue biopsy to prove anal cancer
• Anal Canal Tumors: Staging/Prognosis
– A thorough exam including assessing the
primary tumor and the groins should be
performed in patients with anal canal
tumors (Fig.21.2).
– A CT of the chest, abdomen, and pelvis or
whole body FDG-PET-CT should be performed to rule out distant metastasis.
PET- CT is often used to assess response to
therapy; thus a pretreatment PET-CT may
be of value as a baseline examination
(Fig.21.3). MR of the pelvis can provide
information regarding adjacent organ invasion and/or regional lymphadenopathy
(Fig. 21.4). Transanal/transrectal ultrasound can occasionally be helpful with
assessment of primary tumor and/or mesorectal lymph nodes.
Locoregional: MRI ± Endoscopic ultrasound
Staging of anal cancer
Systemic staging: CT chest abdomen and pelvis ± PET scan
Colonoscopy to rule out any other colorectal cancer
Treatment based on TNM staging
– Clinical/histologic staging: Unlike colorec-
tal adenocarcinoma, anal squamous cell
carcinoma T staging is based on the size of
the tumor and nodal (N) staging based on
the anatomic location of the nodes
(Table21.1).
– Lymph node involvement: Studies have
shown that the chance of LN involvement
with a T1 primary is extremely low.
However, the chance of LN involvement
with a T2 primary is 24% and as high as
67% with a T3 primary.
– The size of the primary tumor and the pres-
ence of nodal or distant metastases are the
principal determinates of outcome. Patients
with de novo tumors >5 cm (T3) are at
increased risk of ultimately requiring APR
with permanent colostomy, and such
292
Fig. 21.3 Anal cancer: left inguinal adenopathy and
mesorectal adenopathy seen on PET-CT
T. Samdani and G. M. Nash
Table 21.1 TNM classication for anal cancer
Primary tumor(T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ (Bowen’s disease, high-grade
squamousintraepitheliallesion(HISL),
AIN II–III)
T1 Tumor 2cm or less in greatest dimension
T2 Tumor more than 2cm but not more than 5cm
in greatest dimension
T3 Tumor more than 5cm in greatest dimension
T4 Tumor of any size invades adjacent organ(s),
e.g., vagina, urethra, bladder (direct invasion of
rectal wall, perirectal skin, subcutaneous tissue,
or sphincter muscle is not classied as T4)
Regional lymph node (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in perirectal lymph nodes(s)
N2 Metastasis in unilateral internal iliac and/or
unilateral inguinal lymph node(s)
N3 Metastasis in perirectal and inguinal lymph
nodes and/or bilateral internal iliac and/or
inguinal lymph nodes
Distant metastases (M)
M0 No distant metastasis
M1 Distant metastasis
Source: AJCC Cancer Staging Manual plus EZTNM, 6th
edition
Fig. 21.4 Anal cancer: pretreatment MRI T2 oblique,
suspicion for focal tumor invasion into the right lateral
internal anal sphincter
tumors are associated with inferior diseasefree and overall survival, compared to T1/
T2 primary tumors. Male gender and HIVpositive status may portend an unfavorable
long-term outcome.
• Anal Canal Tumors: Surveillance
– Following primary treatment with chemo-
radiotherapy, patients are evaluated with
repeat physical examination of the anal
area at approximately 8–12 weeks after
completion of treatment and then at 6- to
8-week intervals until resolution of any
suspicious ndings. Patients with persistent but nonprogressive disease may be fol-
lowed for up to 6 months after
chemoradiotherapy for assessment of complete remission.
– Patients with complete remission should
undergo clinical evaluation every
3–6months for 5years. This should include
examination of the primary tumor site and
the groin. CT scan of the chest, abdomen,
and pelvis, or PET/CT, is performed annually for 3years.
• Anal Canal Tumors: Persistent/Recurrent
Disease
– Approximately 10–30% of patients have
persistent or recurrent disease after initial
CRT.Risk factors associated with failure of
initial treatment include HIV-positive status, high T and N stage at original
presentation, and interruption of treatment
during CRT.
– If the patient has persistent disease at
6months, or progressive disease develops
21 Anal Cancer
Fig. 21.5 Anal melanoma with epithelioid morphology
in the meantime, biopsy may be done to
conrm cancer. Biopsy is recommended
earlier when there is tumor mass progression or unsatisfactory response to treatment. However, unnecessary biopsy should
be avoided to minimize the risk of soft tissue infections, tissue necrosis, or impairment of anal function.
– Patients who fail initial chemoradiother-
apy, or those with local recurrence following initial response to therapy, should be
restaged with PET-CT.
– Patients with isolated local disease should
be considered for salvage abdominoperineal resection (APR). Salvage APR is associated with 5-year locoregional control in
30–77% of patients; overall survival at
5years ranges from 30% to 60%. Wound
complications are common, and muscle
ap reconstruction of the perineum may be
considered.
– Isolated recurrence in an inguinal node may
be treated with RT to the groin, with or without chemotherapy, if there is no history of
previous RT to the groin. If isolated recurrence develops in an inguinal node despite
previous RT, inguinal node dissection may
be performed without an APR. Morbidity
from groin dissection may be high.
– Patients with metastatic anal cancer are
treated with cisplatin-based chemotherapy
with or without radiotherapy (or surgery)
to control the primary tumor. Cetuximab-
293
based treatment may be used in patients
with metastatic anal cancer (KRAS wild
type) after failure of cisplatin-based
chemotherapy.
• Anal Canal Tumors in HIV-Positive Patients
– Increased incidence, likely due to human
papillomavirus infection and
immunosuppression.
– Dose of radiotherapy and chemoradiother-
apy may need to be adjusted in patients
with CD4 counts <200, due to increased
toxicity.
– Otherwise, treatment is the same as for
HIV-negative patients.
Anal Melanoma
• Anal melanoma represents 1–4% of all anorectal malignancies. It is the third most common site of melanoma, after the skin and
retina, accounting for less than 1% of all melanomas. These tumors arise from the transitional epithelium of the anal canal, the
anoderm or the mucocutaneous junction.
• The most common symptom of anal melanoma is bleeding per rectum. Early lesions
may be mistaken for hemorrhoids.
• A thorough physical exam, including assessment of the groin, should be done. Anal melanoma may be pigmented, and either polypoid
or ulcerated, with raised edges. Satellite
lesions may also be present. Biopsy is
conrmatory.
• Histopathological Diagnosis: The features of
anal melanoma resemble those of cutaneous
melanomas (Fig.21.5). The majority show a
junctional component adjacent to the invasive
tumor, which proves that the lesion is primary
in nature. Perineural invasion is an important
prognostic factor.
• Staging: Metastatic disease is common (up to
35% of patients at initial presentation). CT of
the chest, abdomen, and pelvis or whole body
PET-CT should be considered.
• Treatment/Prognosis. The overall prognosis of
anal melanoma is dismal, with a median survival of 10–19 months after diagnosis.
294
T. Samdani and G. M. Nash
Melanoma does not respond well to chemotherapy or radiotherapy; thus, surgery is the
principal treatment when disease is localized.
The extent of surgical resection is a matter of
debate.
– Patients with tumors >1cm are unlikely to
be cured by any type of treatment. Thus,
most authors advocate for local excision as
the only surgical treatment which should
be considered. Local excision may be curative for small tumors, which are often incidentally found in hemorrhoidectomy
specimens.
– Palliative local excision can be considered
for patients with local symptoms due to
anal melanoma.
– APR can be considered. However, as most
patients with anal melanoma die of distant
metastasis, radical resection is unlikely to
offer a survival advantage.
Anal Adenocarcinoma
• Primary mucinous adenocarcinoma of the
anus is a rare malignancy, accounting for
approximately 3% of anal cancers. Most anal
adenocarcinomas originate from the colorec-
tal zone in the upper portion of the anal canal,
or from the glandular cells of the ATZ mucosa.
• Adenocarcinoma of the anal canal can be categorized based on origin:
– Colorectal-type adenocarcinoma:
Macroscopically and histologically, these
lesions are indistinguishable from typical
rectal adenocarcinoma. However, they
carry a higher risk of nodal disease along
the inguinal and femoral nodal chains.
– Adenocarcinoma within an anorectal
stula.
– Adenocarcinoma of the anal glands: This
diagnosis is given if the tumor is primary to
the anal canal and centered within the wall
of the anorectal area, without a pre-existing
stula and without surface mucosa dysplasia, irrespective of the extent of mucin
production.
• Anal adenocarcinomas are staged and treated as
one would for a distal rectal adenocarcinoma.
• Historically, these tumors have been considered aggressive with poor prognosis. However,
the rarity of the tumors and the difculty of
making the distinction between distal rectal
adenocarcinoma and anal gland adenocarcinoma has made it difcult to draw rm conclusions in this regard.