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ANAL AND PERIANAL REGION 61
Electrocautery is then used for the remainder of the warts.
e aim is to produce a white coagulum, which is the equivalent
of a supercial second-degree burn. Aer adequate anesthesia is
achieved, the cautery tip is placed near, but not into, the wart and
a “spark gap” is created, producing a white coagulum. One must be
careful not to allow too deep a burn or brous scarring may result.
A wheal can be created with a local anesthetic to elevate the warty
tissue and spare normal skin. Intense pain and sphincter spasm may
occur both during and aer the procedure, requiring oral analgesics.
Patients are usually seen 4 to 6 weeks later. ey are followed up until
they remain recurrence free for 1 year. Anal stenosis is a potential
complication.
Electrocautery is a rapid method for treating multiple small warts
(i.e., those that measure less than 5 mm). is method is oen combined with scissor excision of larger warts. Recurrence rates range
from 10% to 25%.
For patients with extensive recurrent disease, a single injection of
10 million International Units of interferon alpha 2b is used in combination with electrocautery. e injection is made into the dermis
of the operative bed. Imiquimod 5% cream can be used as an adjunct
to surgical treatment in patients with recurrent disease and can be a
treatment option for AIN in HIV-positive MSM. It is applied once
daily at bedtime, three times per week for up to 16 weeks. e product should be washed o with mild soap and water 6 to 10 hours aer
application. Imiquimod induces the production of local cytokines
(interferon, tumor necrosis factor, and interleukins) from predominantly T helper lymphocytes, thus stimulating both acquired and cellular immunity, which is important for ghting virus-infected and
tumor cells.
Cidofovir, a nucleotide analog with antiviral activity against
DNA viruses, including HPV, has been used for the treatment of severe recurrent disease, dysplastic lesions, and as an
adjuvant treatment. Cidofovir can be used topically or injected
intralesionally.
OTHER DISORDERS
Several infectious diarrheal disorders are seen with impressive
regularity in MSM. ey include amebiasis, giardiasis, shigellosis,
campylobacter, cryptosporidiosis, isosporiasis, and mycobacterium
avium–intracellulare. e mode of transmission is fecal-oral. Discussion of these disorders is beyond the scope of this chapter.
ACKNOWLEDGMENT
We thank Radu Clincea, MD, infectious disease consultant, for his
assistance with this chapter.
S u g g e S t e d R e a d i n g
Centers for Disease Control and Prevention. 2015 Sexually transmitted diseases
treatment guidelines. MMWR Recomm Rep. 2015;64(No. RR-3):1–137.
Lamb CA, Lamb EIM, Manseld JC, Sankar KN. Sexually transmitted infec-
tions manifesting as proctitis. Frontline Gastroenterol. 2013;4:32–40.
Modesto VL, Gottesman L. Sexually transmitted diseases. In: Wexner SD,
Vernava AM III, eds. Clinical Decision Making in Colorectal Surgery. New
York: IGAKU-SHOIN; 1995:195–198.
Whitlow CB. Bacterial sexually transmitted diseases. Clin Colon Rectal Surg.
2004;17(4):209–214.
Whitlow CB, Gottesman L, Bernstein MA. Sexually transmitted diseases. In:
Beck DE, Roberts PL, Saclarides TJ, etal., eds. e ASCRS Textbook of Co-
lon and Rectal Surgery. 2nd ed. Berlin: Springer Science + Business Media,
LLC; 2011:295–307.
M H-G
S I
L (F B
D) P D
Nicholas La Gamma and John Procaccino
INTRODUCTION
Malignancies of the anus, anal canal, and perianal skin include epidermoid carcinoma, malignant melanoma, squamous cell carcinoma,
adenocarcinoma, and basal cell carcinoma. From 2006 to 2010, the
number of new cases of anal cancer was 1.7 per 100,000 men and
women per year. e number of deaths was 0.2 per 100,000 men
and women per year. is chapter focuses on perianal intraepithelial squamous cell carcinoma and perianal intraepithelial adenocarcinoma. ese conditions present subtly, and aected patients may
present with other diagnoses aer protracted medical therapy has
failed to relieve their symptoms. Prompt diagnosis requires awareness of these conditions and a high index of suspicion.
e symptoms produced by neoplasms of the perianal and anal
skin frequently mimic those of more common benign inammatory
conditions. Patients may be asymptomatic or may report pruritus,
burning, pain, bleeding, drainage, or a sensation of a mass. Failure
to investigate these common symptoms may result in a delay in the
diagnosis of a malignant tumor. Performing a biopsy of all nonhealing
lesions, atypical rashes, or perianal growths is important, with subsequent cytologic and histologic examination by a skilled pathologist.
HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (FORMERLY BOWEN DISEASE)
When Bowen rst described this entity in 1913, he designated it as
a “precancerous dermatosis.” Now the term “Bowen disease” is synonymous with “squamous cell carcinoma in situ,” “high-grade anal
intraepithelial neoplasia,” and “high-grade squamous intraepithelial
lesion” (HSIL). In this chapter, to consolidate terminology and eliminate confusion, these entities will all be referred to as HSIL.
HSIL of the perianal skin and anal canal is a rare, slow-growing,
intraepithelial squamous cell carcinoma that occurs most oen in
patients in their fourth to h decade of life. ese lesions are commonly caused by human papilloma virus (HPV) infection, specically with serotypes HPV-6, -11, -16, and -18. Risk factors include
medical immunosuppression (e.g., in patients who have undergone a
kidney transplant), human immunodeciency virus (HIV) seropositivity, cigarette smoking, and anal receptive intercourse. Prevention
strategies include vaccination against these HPV strains.
Grossly, HSIL appears as discrete, erythematous, occasionally pigmented, noninltrating, scaly or crusted plaques. HSIL is sometimes
identied incidentally on histopathologic examination of specimens
removed in the treatment of other perianal and anal diseases. Biopsies
of all nonhealing perianal lesions should be performed. Histologic
features of HSIL show multinucleated giant cells with some vacuolization, giving a “halo” eect. e distinction between low- and highgrade anal intraepithelial neoplasm (AIN) is based on the percentage
62
of epithelial cells replaced by abnormal basaloid cells; low-grade AIN
has less than 50% replacement, and high-grade AIN has greater than
50% replacement. Although more common in women, the incidence
of low-grade squamous intraepithelial lesions and HSIL is increasing in both sexes; the group most at risk is HIV-positive men who
have sex with men (MSM). Although low-grade lesions may regress
or progress to high-grade lesions, HSIL rarely regresses regardless of
appropriate treatment and control of HIV and HPV.
e relationship between HSIL and concomitant systemic and
cutaneous cancers has been controversial. However, it is now generally accepted that, unlike with Paget disease, HSIL is not directly
associated with other malignancies.
Screening programs for the general population are not cost-eective because of the rarity of the disease. However, in certain high-risk
groups such as MSM, annual screening and screening every 2 to 3
years have been shown to have benets in life expectancy and costeectiveness, respectively.
Management
Inspection and biopsy of gross lesions underestimate the local extent of
disease. Traditionally, mapping of the perianal region is carried out using
full-thickness punch biopsies around a superimposed clock face at the
3-, 6-, 9-, and 12-o’ clock positions to plan resection margins (Fig. 13-1).
Subsequent wide local excision (WLE) of areas of positive HSIL with
1-cm margins has been used. However, this method has led to signicant morbidity, including pain, chronic wounds, anal stricture, and the
necessity of advancement or rotational skin aps to cover tissue defects.
Healing by secondary intention is an alternative. Unfortunately, WLE is
associated with a rate of persistent disease as high as 63% at 1 year and
local recurrence rates as high as 34% over the same period.
A less invasive approach involving anal cytologic testing and highresolution anoscopy (HRA) has recently been adopted for screening
and treating patients with suspected HSIL. Anal cytologic testing is
carried out using a Dacron swab inserted 3 to 5 cm into the unlubricated anal canal; the swab is then withdrawn in a circular motion to
sample cells from the region. Specimens are rapidly preserved on slides
or in a liquid medium. Positive identication of atypical cells warrants
further investigation using HRA. Topical 3% or 5% acetic acid and
Lugol solution improves detection the local extent of disease. e acetic
acid identies areas of disease by staining them white, whereas Lugol
solution identies interposed areas of normal mucosa by staining them
brown. is dierentiation of pathologic tissue for targeted destruction
is further augmented by the use of a high- resolution operating microscope. Patients considered to be in high-risk populations such as HIVpositive MSM should be referred for HRA at the outset.
e initial treatment strategy includes topical therapies such as trichloroacetic acid, 5-uorouracil cream, and imiquimod cream. ese
topical therapies show modest ecacy. When topical therapy fails to
COCCYX
D3
D2
D1
C3 C2 C1 A1 A2 A3
B1
B2
B3
ANAL AND PERIANAL REGION 63
in situ arising from the epidermal apocrine glands of the perineum.
When occurring in this location, it is associated with concomitant
colon or rectal adenocarcinoma in approximately 50% of the cases.
Perianal Paget disease has a higher rate of progression to invasive carcinoma (40%) than does HSIL (5%).
Grossly, perianal and anal Paget disease appears as an erythematous, eczematous rash mimicking many other common perianal diseases such as pruritus ani, allergic dermatitis, eczema, Crohn disease,
and HSIL. A biopsy should be performed for all nonhealing perianal
lesions. Basic hematoxylin and eosin staining is usually sucient to
dierentiate Paget disease from the other dierential diagnoses. On
microscopy, classic Paget cells appear large and round, with a pale
vacuolated cytoplasm and hyperchromatic eccentric nuclei. Histologic examination reveals strong positive mucin staining by periodic
acid–Schi, as well as positivity for cytokeratin (CK)7 and CK20
staining. CK7 and CK20 positivity help dierentiate Paget cells from
the downward spread of anorectal carcinoma, which tends to stain
negative for these markers.
Once the diagnosis has been made, anoscopy and complete colonoscopy are performed prior to treatment. Furthermore, anterior
involvement or involvement of the genitalia requires a urologicgynecologic consultation and investigation. In women with Paget
disease of the vulva, 20% to 30% may have malignancies involving
the breast, rectum, bladder, urethra, cervix, or ovary.
V
A
G
I
N
A
FIGURE 13-1 Quadrant biopsy of the perineum.
control the disease, a more invasive approach is necessary. Targeted
destruction using photodynamic therapy, infrared coagulation, a carbon dioxide laser, and electrocautery all have similar ecacy, with
increasing postoperative pain proles, respectively. Although the
gold standard and most widely performed therapy continues to be
anal mapping with WLE of areas testing positive, HRA and targeted
destruction have become more popular at specialized centers. Multiple treatments are oen required, but patients experience decreased
morbidity compared with WLE.
In a recent review of 246 patients presenting with HSIL who were
treated with HRA and targeted destruction with routine follow-up,
Pineda etal have shown superiority over expectant management, as
well as traditional mapping and excision. Comparable results were
found in another study that was similar in both size and scope.
Treatment strategies for HSIL are evolving. It is important for
both the patient and treating physician to anticipate the need for multiple treatments to gain control of the condition. HRA with targeted
destruction is superior to topical therapy while equivalent to WLE
with regard to control of disease. e decreased procedural morbidity
of HRA makes it an attractive option for clinicians and patients alike.
Routine follow-up, regardless of treatment modality, is crucial to
avoid progression to invasive cancer. Although no guidelines for follow-up have been established, most studies quote a routine 6-month
interval to monitor for recurrence or progression.
PERIANAL PAGET DISEASE
Darrier and Coulillaud rst described perianal Paget disease in 1893.
To date, approximately 200 cases have been reported in the literature.
Perianal Paget disease is more common in women and usually presents in the sixth to seventh decades of life. It is an adenocarcinoma
Management
Surgery is the mainstay of therapy for perianal Paget disease. Invasive
disease warrants abdominoperineal resection, whereas noninvasive
disease requires WLE. Standard resection margins have not been
established for WLE because of the rarity of the disease. Reports in
the literature describe gross margins from 1 to 5 cm. Unfortunately,
recurrence rates are still high as a result of invisible lateral spread and
multicentric disease.
e most widespread technique for guiding surgical resection
margins has been described by Beck and Fazio. Full-thickness punch
biopsies are taken at a 1-cm distance around the lesion in all four quadrants. Additionally, full-thickness skin biopsy specimens are obtained
at the dentate line, anal verge, and anal margin in all four quadrants as
shown in Fig. 13-1. is technique maps out the proposed resection
margins. If lesions are small or less than 25% of the circumference of
the anus, WLE to negative microscopic margins with primary closure
or healing by secondary intention is a reasonable approach. However,
if the aected area is greater than 25% circumference, this method can
lead to large tissue defects requiring myocutaneous ap for closure. Use
of skin gras is discouraged because of the dicult anatomic location
and gra failure rates that have been unacceptably high. Fecal diversion
may be necessary if the area of resection is greater than 50% of the circumference of the anus. Once the specimen is excised, frozen sections
should be sent to conrm clear margins. Unfortunately, the local recurrence rate is high, even with clear microscopic margins.
Marchesa etal of the Cleveland Clinic established that the best
long-term outcomes can be expected from WLE with greater than
1 cm of microscopically clear margins. e largest and most recent
study of perianal Paget disease was by McCarter etal of Memorial
Sloan-Kettering. In this 50-year study, 27 patients were identied
with perianal Paget disease. Most patients underwent wide local excision, and 30% had local recurrence requiring a repeat excision. e
overall and disease-free survival at 5 years was 59% and 64%, and at
10 years it was 33% and 39%, respectively.
Adjuvant chemotherapy and radiation have not been shown to be
eective in controlling local disease or recurrence. Case reports of treatment with targeted destruction or radiation alone have been published.
is approach should be reserved for patients who are not candidates
for surgery. Newer techniques for identifying areas of involvement
such as uorescence-guided demarcation and biopsy and targeted
destruction are still experimental and not currently recommended.
64 MANAGEMENT OF HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (FORMERLY BOWEN DISEASE) AND PAGET DISEASE
S u g g e S t e d R e a d i n g
Beck DE, Fazio VW. Perianal Paget’s disease. Dis Colon Rectum. 1987;30:
263–266.
Marchesa P, Fazio VW, Oliart S, etal. Long-term outcome of patients with
perianal Paget’s disease. Ann Surg Oncol. 1997;4:475–480.
Marks DK, Goldstone SE. Electrocautery ablation of high-grade anal
squamous intraepithelial lesions in HIV-negative and HIV-positive
men who have sex with men. J Acquir Immune Defic Syndr. 2012;59:
259–265.
McCarter MD, Quan SH, Busam K, etal. Long-term outcome of perianal
Paget’s disease. Dis Colon Rectum. 2003;46:612–616.
Mengjun B, Zheng-Qiang W, Tasleem MM. Extramammary Paget’s disease of
the perianal region: a review of the literature emphasizing management.
Dermatol Surg. 2013;39:69–75.
Pineda CE, Berry JM, Jay N, etal. High-resolution anoscopy targeted surgical
destruction of anal high-grade squamous intraepithelial lesions: a ten-year
experience. Dis Colon Rectum. 2008;51:829–835. discussion 835–837.
Steele SR, Varma MG, Melton GB, et al. Practice parameters for anal squa-
mous neoplasms. Dis Colon Rectum. 2012;55:735–749.
A M
B C C
P R
INTRODUCTION
Anorectal melanoma is a rare disease with a poor prognosis. It can
be found anywhere in the anal canal or distal rectum and can spread
anywhere in the body. Standard chemotherapy and radiation options
are not eective, and thus surgery is the primary treatment. Debate
is ongoing about whether the treatment of choice is local excision or
radical resection.
EPIDEMIOLOGY AND RISK FACTORS
Anorectal melanoma represents approximately 0.5% of all anal malignancies and accounts for 0.3% of all melanomas, making it the second
most common site for mucosal-based melanoma aer the head and neck.
However, mucosal melanomas represent only 1.2% of all melanomas,
with cutaneous melanoma accounting for the majority. e average age
at diagnosis of anorectal melanomas is approximately 60 to 70 years, with
males presenting at a slightly younger age. Females are more commonly
aected than males with a ratio of 1.7:1. It is estimated that 1 in 1.7 million
Americans will be diagnosed with anorectal melanoma. Unlike in cutaneous melanomas, exposure to ultraviolet-B radiation and a Caucasian
background are not risk factors. A review from 1999 reported an indirect
link to human immunodeciency virus disease. is link was inferred
mainly from a spike in the disease in the 1980s and 1990s in young males
from San Francisco. ese intriguing results have not been followed up.
PATHOPHYSIOLOGY
Anal melanoma develops from the melanocytes found in the anal
transition zone. Mutations in KIT are more commonly seen in mucosal than in cutaneous melanoma, which might play a role in future
adjuvant therapies.
e disease is most commonly seen in the anal canal at or below
the dentate line. However, up to 35% of tumors are found in the distal
rectal mucosa. Rectal lesions tend to be more advanced than their
anal counterparts. Anorectal melanoma is aggressive and penetrates
the muscularis in 79% of cases. Approximately 20% of patients present with lymphatic involvement and 7% to 25% present with metastases. Disseminated disease develops in 90% of patients with nodal
disease. e most common site of metastatic involvement is the liver.
Other common sites include the lungs, bone, and brain.
CLINICAL PRESENTATION AND DIAGNOSIS
e most common symptom associated with anorectal melanoma
is bleeding. An anal mass, tenesmus, and pain are other frequent
sequelae. Melanomas are oen misdiagnosed as hemorrhoids because
Kurt Melstrom and Joseph Martz
they share the same symptom prole. e rate of missed diagnosis is
55%, which can lead to a delay in treatment. Approximatey 25% of
melanomas are amelanotic, which also contributes to the diculty in
diagnosis. Anorectal melanoma is rarely found incidentally in hemorrhoidectomy specimens. Workup includes a biopsy of the tumor
along with a colonoscopy and computed tomography scans of the
brain, chest, abdomen, and pelvis. Magnetic resonance imaging scans
of the pelvis and positron emission tomography scans can be helpful
but are not routinely necessary.
TNM staging for anorectal melanoma has not been developed,
given its rarity. e following simple staging system has been used
since the 1970s: stage I, local disease; stage II, regional lymph node
spread; and stage III, disseminated disease. A recent article has suggested that this system should be amended to a four-stage system
(stage I, local disease not in the muscularis; stage II, local disease into
the muscularis; stage III, regional lymph node spread; and stage IV,
disseminated spread) because patients with deeper local disease have
been found to have a worse prognosis.
SURGERY
Management of the Primary Tumor
e surgical management of anorectal melanoma oen occurs in the
context of widely metastatic disease. Lymph node metastases may
involve the mesenteric, pelvic/iliac, and inguinal nodes, and distant
metastasis occurs in 90% of aected patients. e variable biological
drainage and the potential for synchronous involvement of multiple
nodal regions has led to a shi in the classic paradigm for the surgical
management of anorectal melanoma.
Historically, it was believed that patients with anorectal melanoma were optimally managed with a radical abdominoperineal
resection (APR). is approach has never been prospectively studied.
erefore, as a result of the high morbidity of this procedure (including a permanent colostomy, infection, hernia, and sexual and urinary
dysfunction) and the lack of documented survival benet, a focus on
wide local excision (WLE) has increased. Multiple single-center retrospective review studies and a review of 17 of these case series were
unable to nd a survival benet for patients who underwent an APR
compared with those who had a WLE. According to a recent Surveillance, Epidemiology, and End Results (SEER) database review of 143
patients undergoing curative surgery, 60% presented with localized
disease, 19% with concurrent regional lymph node metastasis, and
21% with synchronous distant metastasis. e 5-year survival rate
was 26.7%, 9.8%, and 0%, respectively. No survival advantage was
observed for patients treated with WLE compared with APR. e
authors concluded that the extent of surgical resection does not correlate with survival. Lymph node status at presentation is signicant
for its prognostic value.
65
AnAl MelAnoMA And BAsAl Cell CAnCer of the PeriAnAl region66
TABLE 14-1: Clinical Series of Anorectal Melanoma
Author Year No. of Patients Treatment Results Comments
Ballo etal 2002 23 WLE + RTx, 23 5-yr overall survival, 31%;
DSS, 36%;
DFS, 37%;
5-yr local control, 74%;
5-yr regional control, 84%
WLE + RTx well toler-
ated and controlled
local-regional disease while avoiding
the morbidity of an
APR
Pessaux etal 2004 30 WLE, 21;
APR, 9
Droesch etal 2005 301 (review of 14 studies) WLE, 129;
APR, 172
Yeh etal 2006 46 WLE, 27;
APR, 19
Ramakrishnan 2008 8 WLE, 5;
APR, 3
Kiran etal 2010 109 (SEER database) WLE, 60;
RR, 49
5-yr overall survival:
WLE, 16%;
APR, 33%
(P = NS)
Local recurrence:
WLE, 47%;
APR, 23%
Median survival:
WLE, 21 mo;
APR, 17 mo
Local recurrence:
WLE, 26%;
APR, 24%
5-year DSS:
WLE, 35%;
APR, 34%
Median overall survival (mo):
WLE, 12;
APR, 10
Local recurrence:
WLE, 80%;
APR, 0%
Median survival:
WLE, 28 mo;
RR, 17 mo (P = .3)
Survival for RR with localized
disease similar to patients
who underwent WLE
WLE is recommended
if a negative resection margin can be
obtained
No stage-specic sur-
vival advantage for
APR; WLE should
be considered the
initial choice of
treatment
Local excision should
be oered when
technically feasible
WLE with adjuvant
radiation therapy
for small, supercial
tumors; APR for
locally advanced
disease or salvage
for recurrence
Survival is similar aer
WLE or RR irrespective of whether
patients have
localized or regional
stage of disease
Che etal 2011 56 WLE, 20;
APR, 36
Local recurrence:
WLE, 69%;
APR, 16%
Median survival:
WLE, 21 mo;
APR, 22 mo
Surgical method of
treatment does not
aect prognosis;
depth of invasion
is an independent
prognostic factor
inuencing survival
APR, Abdominoperineal resection; DFS, disease-free survival; DSS, disease-specic survival; NS, not signicant; RR, rectal resection; RTx, radiation therapy;
SEER, Surveillance, Epidemiology, and End Results; WLE, wide local excision.
With regard to local control, most groups have identied equivalent rates of local recurrence between patients managed with WLE
and APR (Table 14-1). Although some authors have found an
increased rate of local recurrence in patients treated with WLE, disease-free survival is mostly aected by systemic metastasis. Although
APR has a role for large and/or circumferential tumors, when technically feasible, WLE is generally recommended.
e optimal margins for excision of anorectal melanoma are still
debated. Some recommendations are dependent on the thickness or
the size of the tumor: tumors less than 1 mm thickness require WLE
with 1-cm margins, tumors between 1 and 4 mm should be excised with
a WLE with a 2-cm margin, and tumors greater than 4 cm in size or
with involvement of the anal sphincters require an APR. However, many
surgeons propose a 2-cm margin independent of tumor size or depth of
invasion. e Swedish National Cancer registry showed the importance
of obtaining clear margins. Patients who had an R0 resection had a 5-year
survival of 19% compared with patients with involved margins of 6%
(P <.001). Melanoma in situ, in the absence of an invasive component,
should be excised with a 5-mm margin. Patients with large obstructing
and bleeding tumors are usually best served with a palliative APR.
ANAL AND PERIANAL REGION 67
Management of Lymph Nodes
e role of lymphadenectomy in patients with anorectal melanoma
remains controversial. Variable approaches have been advocated,
including bilateral groin dissection, total mesorectal excision, and
pelvic lymphadenectomy. ese procedures have been performed in
a therapeutic, prophylactic, and delayed manner. As a result of the
varied lymphatic drainage and the elevated risk of systemic disease
at time of presentation along with the lack of documented benet
obtained with surgical lymphatic resection, prophylactic lymphadenectomy is not recommended. e morbidity of the groin dissection (lower extremity edema and wound complications) is signicant.
Sentinel lymph node biopsy and inguinal lymphadenectomy may
assist in determining prognosis, and in lesions with a documented
lymph node metastasis determined by imaging or sentinel lymph
node biopsy, a therapeutic lymph node dissection should be considered. However, the benet of this approach remains to be determined.
SURVIVAL
e prognosis of anorectal melanoma is poor. It is believed that the
early systemic spread of disease with the establishment of micrometastases at the time of diagnosis contributes to this prognosis. Most
studies report 5-year survival rates of 12% to 18%, and long-term survival is rare. Recurrence aer curative surgery is seen in more than
80% of patients. e Mayo Clinic and Memorial Sloan-Kettering
Cancer Center reported an overall 5-year survival of 22% and 17%,
respectively. In a large review of 17 case series, Yap and Neary etal
reported a median survival of 20 months, with 30 months for stage
I disease and 10 months for stage III disease. Variable predictors of
outcome have been identied, including lymph node status, perineural invasion, tumor thickness, and size, but these predictors have
not been consistently signicant among the many case series.
BASAL CELL CANCER OF THE PERIANAL REGION
Although basal cell cancer remains the most common cancer found
in humans, it very rarely presents in the anus. Basal cell cancer represents approximately 0.2% of all anal tumors, and anal basal cell
cancers are 0.27% of all basal cell cancers. e main reason for their
rarity stems from the lack of sun exposure of the perianal area. Basal
cell cancers of the anus behave the same way as basal cell cancers
found elsewhere. ey are slow growing and rarely metastasize. ey
present as an ulcerated mass with sharp, raised margins. Because
basal cell cancer forms from the basal cell layer of the epidermis,
these cancers arise in the hair-bearing skin of the anal margin. However, if allowed to grow, they can advance into the anal canal. As with
melanoma, cases are oen misdiagnosed as hemorrhoids, and common symptoms include a mass, anal bleeding, and a change in bowel
habits. is lesion should be dierentiated from the more aggressive
basosquamous variant that does recur and metastasizes more oen.
Treatment should consist of WLE with negative microscopic
margins. e National Comprehensive Cancer Network suggests at
least 4-mm gross margins with a negative microscopic margin of
any distance for all basal cell cancers. Depending on the size of the
defect, the wound may be closed primarily, with skin gras, or with
an advancement ap, or it may be allowed to heal by secondary intention. Mohs surgery is also a viable option. Abdominoperineal resection should be reserved only for very advanced cases with extension
into the anal canal and sphincter muscle complex.
e most recent review of this disease came from the Mayo Clinic
in 1999. A total of 21 cases (15 males and 6 females) of basal cell cancer of the perianal region were reviewed; the average age of onset was
67 years. Results of excision were excellent, as no one had a recurrence in the 72-month follow-up window. However, 33% of patients
had multiple areas of basal cell cancer on other areas of the body. For
this reason, patients should undergo a complete skin examination
when they present with perianal basal cell cancer.
S u g g e S t e d R e a d i n g
Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local exci-
sion and adjuvant radiation for anal-rectal melanoma. J Clin Oncol.
2002;23:4555–4558.
Bello DM, Smyth E, Perez D, etal. Anal versus rectal melanoma: does site of
origin predict outcome? Dis Colon Rectum. 2013;56:150–157.
Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experi-
ence at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum.
1995;38:146–151.
Cagir B, Whiteford MH, Topham A, Rakinic J, Fry RD. Changing epidemiol-
ogy of anorectal melanoma. Dis Colon Rectum. 1999;42:1203–1208.
Chang AE, Karnell LH, Menck HR. e National Cancer Data Base report
on cutaneous and noncutaneous melanoma. Cancer. 1998;83:1664–1678.
Falch C, Stojadinovic A, Hann-von-Weyhern C, et al. Anorectal malignant
melanoma: extensive 45-year review and proposal for a novel staging clas-
sication. J Am Coll Surg. 2013;217:324–335.
Gibson GE, Ahmed I. Perianal and genital basal cell carcinoma: a clinico-
pathologic review of 51 cases. J Am Acad Dermatol. 2001;45:68–71.
Iddings DM, Fleisig AJ, Chen SL, etal. Practice patterns and outcomes for
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A C
Timothy J. Ridolfi and Kirk A. Ludwig
INTRODUCTION
Anal cancer is relatively rare, accounting for only 1.5% of gastrointestinal malignancies. However, its incidence is on the rise. Although
chemotherapy/radiotherapy is the primary mode of treatment of
anal squamous cell cancer (SCC), abdominoperineal resection is still
required at times. e cornerstones of successful therapy are timely
diagnosis, accurate staging, and routine surveillance. Although major
advances have been made in the treatment of anal cancer, many challenges still exist, especially in patients who have recurrent or metastatic disease and are immunocompromised. In this chapter we oer
a management scheme for both anal canal and perianal SCC.
ANATOMIC CONSIDERATIONS
e anal region is composed of the anal canal and the perianal skin.
e “surgical” or “functional” anal canal extends from the anal
verge to the anorectal ring. e perianal skin extends an additional
5 cm from the anal verge. e latest version of the American Joint
Committee on Cancer Staging manual suggests a classication of
anal cancers based on where they are located. e system divides
the region into three easily identiable regions: anal canal, perianal region, and skin. Anal canal lesions are lesions that cannot be
visualized at all or are incompletely visualized with gentle traction
placed on the buttocks. In contrast, perianal lesions are completely
visible and fall within a 5-cm radius of the anal opening. Finally,
skin lesions fall outside the 5-cm radius of the anal opening. e
strength of this classication system is that it allows all clinicians,
including gastroenterologists, surgeons, advanced practice providers, and medical and radiation oncologists, to perform this simple
examination in the oce without the need for an anoscope or a
clear understanding of the anatomic landmarks of the region. Accurate classication of anal cancers is important because true anal
canal lesions may have a more aggressive biology requiring chemotherapy/radiotherapy, whereas lesions of the perianal skin may be
treated simply with local excision.
e arterial supply of the anus is derived from branches of the
superior rectal artery, the inferior rectal branch of the pudendal
artery, and branches of the median sacral artery. e venous drainage of the anal canal has two patterns. Above the dentate line, the
venous blood drains through the terminal branches of the superior
rectal vein into the inferior mesenteric vein and portal system, and
below the dentate line it drains via the inferior rectal vein into the
pudendal vein, which itself drains into the internal iliac vein. Lymphatic drainage of anal cancers is dependent upon the location of the
lesion with respect to the dentate line. Cancers arising proximal to
the dentate line drain to perirectal and paravertebral lymph nodes in
tandem with rectal carcinomas, whereas cancers distal to the dentate
line drain to inguinal and femoral nodes.
68
EPIDEMIOLOGY
Multiple studies have shown that the incidence of anal carcinoma
is increasing. In the United States between 1973 and 1979, the incidence per 100,000 was 1.06 in men and 1.39 in women. From 1994 to
2000 this incidence almost doubled, with a rate of 2.04 per 100,000
in males and 2.06 per 100,000 in females. Similarly, in 2011 there
were an estimated 6230 new cases and 780 related deaths, whereas
in 2008, the number was 5000 new cases and 680 related deaths,
demonstrating a signicant increasing trend from 2003 when
approximately 4000 new cases and 500 related deaths were recorded.
In Denmark, similar trends were documented, and age-adjusted
incidence rates per 100,000 person-years showed an increase from
around 0.2 among both men and women to 0.5 among men and 1.0
among women during the period 1943-1997. A peak in incidence is
noted in the seventh decade, with women more commonly aected
than men. Risk factors for developing anal cancer include human
immunodeciency virus (HIV) seropositivity, low CD4 count, persistent infection with high-risk human papillomavirus genotypes
(16, 18, 31, 33, and 35), infection with multiple genotypes, cigarette smoking, anal receptive intercourse, immunosuppression, and
female gender.
SQUAMOUS CELL CARCINOMA OF THE ANAL CANAL
Squamous cell carcinoma of the anal canal is ve times more common than perianal SCC. Epidermoid cancers collectively include all
variants of SCC (cloacogenic cancer)—keratinizing, nonkeratinizing, and basaloid. For the most part, no distinction needs to be made
between the subtypes of epidermoid cancer when considering treatment. Symptoms include anal bleeding, discharge, a palpable lump,
or discomfort upon defecation, but these symptoms are common and
nonspecic. Patients are frequently misdiagnosed with a benign condition such as hemorrhoids or an anal ssure prior to the diagnosis of
anal cancer. Because diagnosis is oen delayed, epidermoid cancers
are found to have inltrated the sphincter muscles or beyond in up to
90% of patients, and lymph node metastases are present in one third
of patients. Evaluation should include a complete anorectal examination with external inspection of the anoderm, digital examination,
anoscopy, proctoscopy, and examination of inguinal nodes. Careful
notation should be made of the size, location, and mobility of the
mass and associated perirectal and inguinal lymphadenopathy, and
in women, a pelvic examination should be performed to look for any
associated lesions or invasion of tumor into the vagina. A complete
examination and biopsy may require use of an anesthetic for patients
with signicant pain but oen can be completed in the oce setting. HIV testing should be considered, along with a CD4 count, if
indicated.
ANAL AND PERIANAL REGION 69
Staging is completed once diagnosis is conrmed by biopsy.
According to the seventh edition of the cancer staging manual of the
American Joint Committee on Cancer, a TNM system is utilized. T
level is determined by tumor size in the greatest dimension, as follows: T1 lesions are less than 2 cm, T2 tumors are more than 2 cm but
no more than 5 cm, T3 tumors are more than 5 cm, and T4 tumors
are those of any size that invade adjacent organ(s)—for example, the
vagina, urethra, and bladder. It is important to note that direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or sphincter muscle is not classied as T4 disease.
Nodal level is based on location of positive nodes, as follows:
N0, no regional lymph node metastasis; N1, metastasis in perirectal lymph nodes; N2, metastasis in unilateral internal iliac and/or
inguinal lymph nodes; and N3, metastasis in perirectal and inguinal
lymph nodes and/or bilateral internal iliac and/or inguinal lymph
nodes. e most current version of the National Comprehensive Cancer Network Guidelines (version 2.2014) suggests that all
patients who are found to have anal cancer should undergo a computed tomography (CT) scan of the chest, abdomen, and pelvis or
pelvic magnetic resonance imaging (MRI). Further staging workup
is dictated by T level and physical examination ndings of suspicious lymph nodes. A positron emission tomography (PET) scan is
reserved for persons with T2-T4 or N
+
disease, and biopsy or neneedle aspiration is suggested in persons with suspicious nodes.
However, in our practice, all newly diagnosed patients with anal cancer undergo CT of the chest, abdomen, and pelvis, as well as pelvic
MRI. We routinely request a PET scan for all patients regardless of
clinical T and N stages. In most cases we forgo biopsy or ne-needle
aspiration of suspicious nodes and consider positive PET avidity to
indicate nodal metastasis.
e goals of therapy in patients with SCCs of the anal canal are to
ablate the neoplasm and preserve anal sphincter function. Originally,
treatment of anal canal SCC was surgical, with abdominoperineal
resection (APR) the standard of care. However, local recurrence rates
were high, 5-year survival was only 40% to 70%, and the morbidity
with a permanent colostomy was considerable. In 1974, Nigro and
coworkers rst described treatment with radiation and concurrent
5-uorouracil (5-FU) and mitomycin C (MTC). is combination
revolutionized the treatment of anal canal SCC. Chemotherapy/
radiotherapy alone results in a complete response in 70% (64% to
86%) of patients and an overall survival rate at 5 years of 75% (66%
to 92%). Two randomized trials, one conducted in the United
Kingdom and the other in Europe, have conrmed the superiority
of combined modality treatment over radiation alone. Nigro and
colleagues described using 30-Gy external beam radiation with 5-FU
and MTC and demonstrated a complete pathologic response in 21
of 26 patients treated (81%). Since that time, various radiation doses
(30 to 60 Gy) and chemotherapeutic regimens have been used with
similar complete pathologic responses (45% to 100%) and survival
rates (70% to 90%). As a result, surgery for anal canal SCC has been
reserved for patients with persistent or recurrent disease aer chemotherapy/radiotherapy. We treat all newly diagnosed epidermoid anal
canal cancers with chemotherapy/radiotherapy regardless of stage. In
patients with frank incontinence or a malignant stula, it is our practice to rst perform laparoscopic fecal diversion before chemotherapy/radiation is used. e results of the treatment are then assessed
and consideration is given to APR for persistent disease.
Patients are re-evaluated 8 to 12 weeks aer completion of chemotherapy and radiation treatments and classied according to whether
they have a complete remission, persistent disease, or progressive
disease. e primary cancer will generally regress by about 6 to 12
weeks aer the completion of treatment but sometimes may take longer. A pale, irregular scar is usually visible at the site of the primary
tumor. e base and edges of this brotic scar have a rubbery texture,
whereas any hard, tender, or ulcerated area is suspicious for residual cancer. Patients can be classied as having a complete remission
without biopsy verication if they have no clinical evidence of disease. However, a clinical assessment of progressive disease requires a
biopsy. When residual or recurrent cancer is identied, further radiation and chemotherapy occasionally may be eective, provided the
initial radiation dose had not been to the limit of normal tissue tolerance. However, APR is oen necessary.
A salvage APR is required in approximately 30% of cases as a
result of either primary nonresponse or recurrence. In the majority
of such cases, long-term survival can be achieved aer salvage surgical operations. Prognosis is worse in persons who initially presented
with lymph node metastasis or who received a radiation dose of less
than 55 Gy during initial combined chemotherapy/radiation therapy.
Another important prognostic factor of survival aer resection is
the margin status. For patients in whom a negative margin can be
achieved, the 5-year overall survival rate approaches 75%. Other predictors of a poor outcome aer salvage surgery include tumor size
greater than 5 cm, adjacent organ involvement, male gender, and
associated comorbidities. Salvage surgery is also reported to be associated with substantial morbidity in up to 72% of patients, including
delayed perineal wound healing, pelvic abscess, perineal wound hernia, urinary retention, and impotence. A treatment algorithm for anal
canal cancer is outlined in Fig. 15-1.
e technique of anal excision by the combined abdominoperineal route includes a wider perianal excision than that used for lowlying adenocarcinomas of the rectum based on the fact that many of
these cancers exhibit extensive subcutaneous lymphatic involvement
and are oen accompanied by an in situ component. A preliminary
diverting stoma is usually not necessary unless signicant anorectal sepsis is present. Care is taken to stay away from any stulas or
sinuses in the ischiorectal space. Posteriorly, the coccyx can easily
be removed if necessary. Anteriorly, the dissection is carried immediately posterior to the urethra in males. When malignant inltration of the prostatic capsule is suspected, exenteration is considered.
In females, a posterior vaginectomy is performed if the lesion is in
the anterior half of the anal circumference. e levator muscles are
taken as far laterally as possible. e abdominal portion of the procedure is similar in technique and extent to an excision for rectal
cancer, including a total mesorectal excision down to the coccyx.
e internal iliac nodes are not dissected unless they appear to be
involved with cancer. Although primary wound closure is at times
feasible, preoperative radiation and large size defects created aer
complete excision of the tumor make primary wound healing difcult. Reconstruction with a myocutaneous ap is oen required.
e reconstruction can be completed with various aps, including a
pedicled omental ap, a unilateral or bilateral gracilis ap, a gluteus
maximus ap, an inferior pedicle rectus abdominis ap, and a vertical rectus abdominis myocutaneous ap. Myocutaneous aps have
the double advantage of bringing in fresh nonradiated tissue and lling the pelvic cavity.
Preoperative imaging studies such as CT or MRI are helpful in
determining the extent of disease, but radiation-induced changes
may aect the interpretation of these studies and also make assessment dicult during surgery. Intraoperative frozen-section histologic examination is frequently obtained. However, scattered
islands of apparently viable cancer may be identied in the nal
pathologic specimen, and it is dicult to be condent of tumorfree margins.
Surveillance
No consensus has been reached on appropriate follow-up aer the
treatment of SCC. It is 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 anoscopy every 3 months in the rst 2 years
and every 6 months until 5 years has been recommended. Annual
chest, abdominal, and pelvic imaging is recommended for 3 years for
patients with slow disease regression and for those who initially had
T3/T4 or node-positive cancers.
AnAl CArCinomA70
Epidermoid cancer
plus postoperative RT,
Observe APR
Complete
Adenocarcinoma
Undifferentiated carcinoma
Incontinent
or malignant fistula
APR
5-FU, MTC
Continent
No fistula
Medically able to receive
RT, 5-FU, MTC
No
RT alone
or APR
Negative Positive
Observe
Incomplete
response
persists or enlarges
No Yes
APR
Yes
Able to receive
further conservative
treatment
Incomplete
response
persists or enlarges
From
perianal cancer
algorithm
Complete
response
ObserveBiopsy if mass
response
ObserveBiopsy if mass
Negative Positive
FIGURE 15-1 Treatment algorithm for anal canal cancer. APR, Abdominoperineal resection and colostomy;
5-FU, 5-fluorouracil; MTC, mitomycin C; RT, radiation therapy.
Local Excision
Local excision is rarely considered for carcinomas of the anal canal.
Limited excision is appropriate only when the risk of regional nodal
metastasis is low and local excision will not compromise anal function. e likelihood of nodal metastasis is related to the histologic
subtype, size, and depth of inltration of the primary cancer. Local
excision is recommended by some authors for supercial or moderate to well-dierentiated SCCs of the distal canal that are less than
2 cm in diameter. We do not use this treatment in patients who are
medically able to undergo radiation and chemotherapy. Local excision is said to be adequate treatment for occasional patients who
are found to have histologically supercial cancer as an incidental
nding at the time of treatment of a benign anal condition. However,
oen it is not possible to identify the site from which the malignant
tissue was removed and to assess the surgical margins properly. Usually, the entire surgical eld is at risk of implantation if the cancer was
transected; therefore, wide local re-excision is rarely practical. ese
patients may be treated with combined radiation and chemotherapy
as described previously, but the total radiation dose is limited.
Inguinal Lymph Node Management
e current management options for inguinal lymph nodes in patients
with squamous cell carcinoma of the anal canal vary according to
protocols and preferences of institutions. e conventional approach
of prophylactic bilateral inguinal radiation for persons with clinically
negative nodes and the addition of a radiation boost for patients with
clinically positive nodes are still widely followed in many centers. At
our institution we use PET avidity to determine who will receive a
radiation boost to inguinal lymph nodes. Surgical lymph node dissection is reserved for primary failure of chemotherapy/radiation
(residual disease) and for recurrent disease.