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330
Fig. 19.3 PET/CT demonstrating distal anal canal
carcinoma
characteristics of tissue, such as cell density,
cell membrane integrity, and ultimately cell
viability [17].
Evaluation for distant metastatic disease can be
performed either via CT scan of the chest, abdomen,
and pelvis or via FDG PET/CT, which is being
used with increasing frequency in both the initial
staging of anal cancer as well as in assessment of
response to treatment. Approximately 98% of anal
tumors are FDG avid (Fig.19.3), making PET/CT
an extremely useful imaging modality [11].
Advantages of PET/CT over traditional CT include
its ability to identify the primary tumor as well as
potential lymph node metastases. PET/CT has
been shown to be able to identify the primary tumor
in over 90% of cases of anal cancer, compared with
less than 60% for conventional CT [18]; PET/CT
has also been shown to be able to detect inguinal
lymph node involvement in 17–23% of patients in
which CT was deemed to show no lymph node
involvement [18, 19].
PET/CT is most useful in patients with clinically suspicious lymph node involvement and
larger (T2-T4) tumors to assist with initial staging and to establish a pre-treatment baseline. The
primary impact of PET/CT on therapy seems to
be its superiority in identifying involved pelvic or
inguinal lymph nodes, prompting inclusion of
these areas in the radiation eld [20–22]. Wells
etal reported that PET/CT ndings in the initial
staging of anal cancer altered patient management in 29% of cases [23]. A systematic review
published by Jones etal found that PET/CT led to
B. R. Kann
changes in nodal status compared with conventional imaging in 28% of patients; when only
studies performing contemporary PET/CT were
considered, the TNM stage was altered in 41% of
patients [24].
Treatment
Local excision may be considered for the smallest
of tumors (usually <1cm in size) without sphincter involvement or in high-risk patients. Postexcision combined modality treatment (CMT)
may be utilized when margins are positive or
threatened, with the understanding that healing of
the excision site will be hampered by radiotherapy, potentially leading to a chronic non-healing
ulcer that can be extremely painful.
Until the 1970s, radical surgery in the form of
an abdominoperineal resection (APR) and
permanent end colostomy was the standard of
care for potentially curable anal squamous cell
carcinoma not amenable to local resection.
Mortality rates, local failure rates, and the
incidence of major complications with this
procedure were quite high compared with current
surgical standards. In 1974, Norman Nigro published the rst in a series of manuscripts that
would dramatically alter the means by which anal
squamous cell carcinoma would come to be
managed. His rst report was a series of three
patients with anal cancer treated with a combination of pre-operative 5-uorouricil (5-FU) and
mitomycin-C (MMC) given in conjunction with
3000 rads of external beam radiation. Two
patients underwent APR and were found to have
no residual malignancy in the resected specimens; the remaining patient refused surgery and
was disease-free at a follow-up of 14 months
[25]. A follow-up report in 1977 added clinical
data from an additional 7 patients to the original
3 patients. Of the 9 patients who underwent surgery, 6 had no residual malignancy, 2 had locally
advanced (“Duke’s B”) residual malignancy, and
1 was found to have hepatic metastases at the
time of laparotomy [26].
In 1983, Nigro published an expanded report
of 28 patients managed similarly [27]. Twelve
19 Anal Neoplasms
331
underwent subsequent APR; 7 had no residual
disease in the specimen and 1 had microscopic
disease only. The remaining 16 patients all had a
complete treatment response and did not undergo
surgery; 14 of these underwent excision of the
residual scar and were found to have no residual
disease. Four patients ultimately died of cancer;
all had undergone APR after initial treatment and
all had gross residual tumor. Additionally, all had
tumors >7cm in size at the time of initial diagnosis. By 1987, Nigro’s cohort had grown to 104
patients; 97 had a complete clinical response
after chemoradiation, and 24 followed treatment
by undergoing APR—22 had no residual tumor
in the specimen. Biopsy of the post-treatment
scar was performed in 62 patients, 61 of whom
had no residual tumor. The 5-year overall survival rate was 83% [28]. This combined modality
treatment (CMT) regimen, termed the “Nigro
Protocol,” paved the way for future research and
led to a major paradigm shift in the management
of anal squamous cell carcinoma.
A number of other studies have helped to better
dene the role of CMT in the management of anal
squamous cell cancer. The UK Coordinating
Committee on Cancer Research (UKCCCR)
prospective randomized trial of radiotherapy alone
compared with CMT found a 59% local failure
rate with radiotherapy alone compared with a 36%
local failure rate with CMT at 42month follow-up;
CMT imparted a 46% reduction in the risk of local
failure compared with radiotherapy alone, and the
risk of death from anal cancer was signicantly
reduced in the CMT arm [29]. Twelve-year
follow-up of the patients from this study (ACT I
Trial) showed that for every 100 patients treated
with CMT, there are an expected 25.3 fewer
patients with locoregional relapse and 12.5 fewer
anal cancer deaths, compared with 100 patients
given radiotherapy alone [30].
Similarly, the European Organization for
Research and Treatment of Cancer Radiotherapy
and Gastrointestinal Cooperative Groups phase
III randomized trial of CMT vs. radiotherapy
alone found that the addition of chemotherapy to
radiotherapy resulted in an increase in the complete remission rate from 54% for radiotherapy
alone to 80% for radiotherapy and chemotherapy,
and an increase from 85% to 96%, respectively, if
results were considered after surgical resections.
CMT provided signicant improvement in both
locoregional control (18% improvement at
5 years) and colostomy-free interval (increased
by 32%) [31].
The Radiation Therapy Oncology Group
(RTOG)/Eastern Cooperative Oncology Group
(ECOG) 87-04 trial, published in 1996, was a
phase III randomized trial in which treatment
with 5-FU, MMC, and radiotherapy was compared with treatment with 5-FU and radiotherapy.
While there was no signicant difference in overall survival at 4-year follow-up, colostomy rates
were lower (9% v 22%; P= 0.002), colostomyfree survival was higher (71% v 59%; P=0.014),
and disease-free survival was higher (73% v
51%; P = 0.0003) in the treatment arm that
included MMC [32].
Other studies have investigated the use of cisplatin in lieu of MMC.The US Gastrointestinal
Intergroup trial RTOG 98-11 was a multicenter,
phase III, randomized controlled trial comparing
treatment with 5-FU plus MMC and radiotherapy
vs treatment with 5-FU plus cisplatin and radiotherapy. The 5-year disease-free survival rate was
60% in the MMC-based group compared with
54% in the cisplatin-based group (p= 0.17) and
the 5-year overall survival rate was 75% in the
MMC-based group and 70% in the cisplatinbased group (P=0.10). However, the cumulative
rate of colostomy was signicantly better for
MMC-based than cisplatin-based treatment (10%
vs 19%; P=0.02) [33].
The ACT II trial was another randomized
phase III trial that compared MMC- or cisplatinbased CMT chemoradiation with or without
maintenance chemotherapy (5-FU and cisplatin
at weeks 11 and 14). No difference was seen in
the rates of achieving complete response between
the MMC-based arm and the cisplatin-based arm
(90.5% vs 89.6% at 26 weeks; p = 0.64).
Additionally, maintenance chemotherapy did not
improve progression-free survival [34].
The ACCORD-03 trial, published in 2012,
sought to determine if there was an advantage to
using induction chemotherapy with 5-FU and
cisplatin prior to a standard course of CMT or to
332
B. R. Kann
using a high-dose radiation boost. The authors
reported no difference in colostomy free-survival
rates between groups treated with induction chemotherapy and standard radiotherapy (45 Gy)
with 5-FU/MMC, induction chemotherapy and
high-dose boost radiotherapy (additional
20–25 Gy) with 5-FU/MMC, standard dose
radiotherapy with 5-FU/cisplatin, and high-dose
boost radiotherapy with 5-FU/cisplatin [35].
The dosage of external beam radiotherapy and
means of delivery have evolved signicantly
since Nigro’s initial reports. The dosage varies
based on the size of the tumor and presence or
absence of suspected lymph node involvement.
Typically, larger tumors will require larger doses
of radiation. While Nigro’s initial protocol used
30Gy, patients with anal cancer typically receive
a minimum dose of 45–54Gy to the primary cancer. Current NCCN Guidelines (Version 1.2017)
call for a minimum dose of 45Gy in 1.8Gy fractions (25 fractions over 5weeks) to the primary
cancer. The inguinal nodes, pelvis, anus, and
perineum should be included in the initial radiation elds, with the superior eld border at L5-S1
and the inferior border at the anus with a minimum 2.5-cm margin around the anus and tumor.
The lateral borders should include the lateral
inguinal lymph nodes, but attempt to reduce the
radiation dose to the femoral heads. After 17
fractions (30.6Gy), an additional 14.4Gy should
be given in 8 fractions, with the superior eld
reduced to the bottom of the sacroiliac joints.
Additional eld reduction off the inguinal nodes
should occur after 36 Gy for node-negative
lesions. For T2 lesions, T3/4 lesions, or N1
lesions, an additional boost of 9–14 Gy in
1.8–2Gy fractions to the original primary tumor
volume and involved nodes plus a 2 to 2.5-cm
margin is usually delivered [13].
Toxicity with radiotherapy is common but fortunately, adverse effects are typically minor and
usually self-limited. Short-term and long-term
side effects are listed in Table19.5. Local toxicity, namely dermatitis and pain, may necessitate
“breaks” in radiotherapy protocols, delaying
completion of treatment and potentially affecting
outcomes. Intensity-modulated radiation therapy
(IMRT) is a modality utilized to reduce toxicity
Table 19.5 Side effects of radiotherapy for anal cancer
Short term Dermatitis
Pain
Local tissue edema
Increased fecal urgency and frequency
Weakness, fatigue
Nausea
Vaginal discomfort/discharge
Long term Anal stenosis
Fecal incontinence
Radiation proctitis
Vaginal stenosis
Dyspareunia
Infertility
Lymphedema
to surrounding structures and potentially
eliminate toxicity-related treatment delays.
IMRT utilizes detailed shaping of radiation
beams, allowing for more precise delivery to
target tissues and sparing normal tissues,
including the perianal/perineal skin, external
genitalia, and bladder. A retrospective study from
Memorial Sloan Kettering Cancer Center found
no differences in 2-year local recurrence-free
survival, distant metastasis-free survival,
colostomy-free survival, and overall survival,
comparing patients with squamous cell anal
cancer treated with IMRT compared with conventional 3-dimensional radiotherapy (3DRT)
[36]. The RTOG 0529 trial prospectively assessed
the utility of IMRT in reducing acute morbidity
of CMT for anal cancer, and found that IMRT
was associated with signicant sparing of acute
grade 2+ hematologic and grade 3+ dermatologic
and gastrointestinal toxicity [37]. Current NCCN
guidelines (Version 1.2017) indicate that IMRT is
preferred over conventional radiotherapy in the
management of anal squamous cell cancer [13].
In terms of chemotherapy dosing, current
NCCN Guidelines (Version 1.2017) for the
management of localized, non-metastatic
squamous cell cancer of the anus recommend
CMT with 5-FU (continuous infusion 100mg/
2
m
/day on days 1–4 and 29–32) and MMC
(10 mg/m2 IV bolus days 1 and 29) with
concurrent radiotherapy. Alternatively, oral
capecitabine may be substituted for 5-FU,
19 Anal Neoplasms
333
though it must be taken twice daily throughout
the duration of radiotherapy and is typically
associated with a higher incidence of adverse
effects and treatment interruption. Similarly,
cisplatin may be used in lieu of MMC, though it
is generally associated with higher rates of
toxicity. For the management of metastatic
disease, NCCN Guidelines recommend CMT
with 5-FU, cisplatin, and concurrent
radiotherapy [13].
Cetuximab, an anti-epidermal growth factor
receptor 1 (EGFR-1) monoclonal antibody, was
studied in combination with CMT utilizing radiotherapy, 5 FU and cisplatin in a phase 1 trial.
Despite a response rate of 95%, the study was
closed early due to severe toxicity, including
thromboembolism (26%), grade 3/4 radiation
dermatitis (52%), and grade 3/4 diarrhea (44%)
[38]. The ACCORD-16 trial was a phase II trial
evaluating concurrent use of cetuximab with
CMT for the treatment of anal cancer that also
was closed early due to excessive toxicity [39].
Evaluation ofTreatment Response
andSurveillance
Clinical follow-up by careful physical examination and regular imaging is critical in the assessment of response to treatment with CMT and in
ongoing surveillance. Digital rectal exam, anoscopy, and evaluation of inguinal nodes should initially be performed 8–12weeks after completion
of CMT.If no residual tumor or suspicious inguinal adenopathy is identied, the patient is considered to be in remission; surveillance should include
DRE every 3–6 months for 5 years, anoscopy
every 6–12 months for 3 years, and contrastenhanced CT of the chest/abdomen/pelvis or PET/
CT annually for 3 years if the initial tumor was
T3-4 and/or inguinal node positive. Routine posttreatment biopsy of scar at the previous tumor site
is not indicated.
If persistent disease is noted at the time of initial post-treatment evaluation, one should resist
the urge to biopsy the residual lesion at rst, as
the effects of radiotherapy typically continue to
cause tumor regression for weeks to months after
completion of therapy. The patient should be reevaluated in 4weeks, and if there is regression or
lack of progression, continued observation and
re-evaluation of the patient in 3months is recommended. If persistent disease is noted at 6months
following completion of CMT or if progressive
disease arises, the suspicious lesion should be
biopsied; a positive biopsy indicates that at that
point the patient has progressive disease and
should be restaged. In the absence of metastatic
disease, APR is indicated, if the patient is medically t to undergo surgery. Alternatively,
depending on the initial radiation dose, the
patient may be a candidate for an additional radiation boost. If re-staging reveals the presence of
metastatic disease, chemotherapy with 5-FU and
cisplatin is indicated.
MRI after completion of CMT has been advocated by some for the evaluation of response to
treatment. Kochhar etal assessed the use of an
MRI-determined tumor regression grading
(TRG), in which scores ranged from 1 (complete
response) to 5 (no response), in the assessment of
local response and detection of salvageable early
relapse after CMT for anal squamous cell carcinoma. They found that on post-CMT MRI’s performed 3 and 6 months after completion of
treatment, TRG 1/2 scores had a 100% negative
predictive value, whereas TRG 4/5 scores on
MRI 6 months post-CMT had a 100% positive
predictive value. All patients with TRG 4/5 score
on MRI 6months post-CMT underwent salvage
R0 resections [40].
Post-CMT PET/CT may also be helpful in
determining response to treatment. Vercillino
etal reported that during post-treatment followup, PET/CT had a sensitivity of 93% and specicity of 81% on a per-examination basis, with a
negative predictive value of 94% [41]. Teagle
et al similarly reported a sensitivity of 100%,
specicity of 74%, and negative predictive value
of 100% [42].
If, during the course of surveillance, local
recurrence is detected, APR is indicated in the
absence of metastatic disease. Inguinal node
recurrence may be managed with inguinal node
dissection, with consideration for radiotherapy, if
not previously administered, and/or chemotherapy
334
B. R. Kann
with 5-FU (or capecitabine) and MMC.Patients
found to have distant metastatic disease during
thecourse of follow-up should be offered chemotherapy with 5-FU and cisplatin.
Salvage Treatment
Persistent or recurrent disease can be seen in up
to 30% of patients following initial CMT [11].
Risk factors include HIV-positivity, high T and/
or N stage at time of initial diagnosis, and interruption of treatment during CMT.After conrming progressive or recurrent disease by biopsy
and excluding distant metastatic disease, salvage
surgery is generally indicated. Some advocate for
an additional 9 Gy of radiotherapy prior to
surgery [11]. The extent of salvage surgery may
range from local excision to APR to pelvic exenteration, depending on the extent of disease present. Salvage APR is associated with 5-year
locoregional control rates of 30–77% [43–45].
Wound complications occur commonly, owing to
large perineal incisions involving previously
radiated tissue. A number of studies have shown
that ap reconstruction of the perineum, using
either the rectus abdominus or gracilus muscle,
results in signicantly fewer wound healing complications [46–50].
Functional Results After Radiotherapy
While the vast majority of patients with anal squamous cell cancer treated with CMT will have
excellent oncologic outcomes, functional outcomes
are often overlooked. Long-term complications,
such as anal ulcers, strictures, brosis, stenosis, and
stulae are being seen less frequently with
increased utilization of IMRT. Other long-term
effects of pelvic radiotherapy include urinary
dysfunction (including frequency, urgency,
incomplete bladder emptying, incontinence, and
dysuria), and sexual dysfunction (including
impotence, dyspareunia, and vaginal stenosis).
Das et al surveyed patients who had been
treated for anal squamous cell cancer with
denitive radiotherapy, with or without
chemotherapy, using the Functional Assessment
of Cancer Therapy-Colorectal (FACT-C) and
Medical Outcomes Study (MOS) Sexual
Problems Scale. The authors found that the
median FACT-C score was 108 of a best possible
score of 136. Lower scores were more commonly
seen in younger patients and those reporting
depression or anxiety. The median score on the
MOS Sexual Problems Scale was 67 out of a best
possible 100 [51].
Joseph etal surveyed patients with anal squamous cell cancer undergoing CMT utilizing
IMRT at baseline, after treatment, and during
follow-up, using EORTC core (QLQ-C30) and
colorectal (QLQ-CR29) questionnaires. They
found that all C30 functional symptoms, except
emotional and cognitive functioning, were
impaired at end of treatment but recovered by
3-month follow-up. The majority of CR29 symptom scores were worse at end of treatment but
recovered by 3 months, except fecal incontinence, diarrhea, urinary incontinence, and dyspareunia. Fecal incontinence returned to baseline at
12months, while diarrhea, urinary incontinence,
and dyspareunia persisted [52].
A Danish study looking at quality of life after
radiotherapy for anal cancer found that, at a
median 33months after radiotherapy, incontinence
to solid stool, liquid stool, and gas occurred at least
monthly in 31%, 54%, and 79% of patients. Forty
percent of patients reported “great distress” from
fecal incontinence at least monthly, and fecal
urgency occurred at least once monthly in 87% of
patients. Urinary incontinence occurred at least
once monthly in 48% of patients. Sexual desire
was severely decreased in 58% and only 24% were
satised with their sexual function [53].
Bentzen etal. compared quality of life scores
in anal cancer survivors treated with CMT to
those of a reference group using normative data,
and found statistically signicant impairment of
function, including increased stool frequency,
fatigue, diarrhea, fecal incontinence, atulence,
impotence in males, and dyspareunia and
decreased sexual interest in females. Global quality of life was signicantly reduced in anal cancer
survivors [54].
19 Anal Neoplasms
335
Treatment ofHIV-Positive Patients
HIV infection is a known risk factor for the
development of anal canal, due to immunosuppression and HPV co-infection from anal-receptive intercourse [55, 56]. A low CD4 count may
necessitate an altered CMT regimen in certain
individuals. A CD4 count >200 is generally felt
to be acceptable in terms of minimizing treatment-related toxicity with a standard CMT regimen of 5-FU, MMC, and 45Gy of radiotherapy.
While patients with a CD4 count <200 have a
higher incidence of treatment-related morbidity,
this has not been found to be associated with
decreased overall survival [11].
Anal Adenocarcinoma
Adenocarcinoma of the anal canal is extremely
rare, accounting for 3% of all anal cancers. These
tumors tend to be mucinous adenocarcinomas that
are slow growing but locally very aggressive.
While the majority arises from the columnar
epithelium of the upper anal canal proximal to the
anal transition zone, they may also originate from
the stratied columnar epithelium in the ducts of
anal glands or from chronic anal stulae. Anal
adenocarcinomas that arise from the proximal
anal canal are clinically indistinguishable from
traditional colorectal adenocarcinoma, but have a
higher risk of metastases along the inguinal and
femoral lymph node chains. Immunohistochemical
staining of adenocarcinomas arising from the
proximal anal canal shows CK20 positivity and
CK7 negativity, whereas anal adenocarcinomas
arising from the anal glands are typically CK7
positive.
Anal canal adenocarcinoma presents in a similar fashion to anal canal squamous cell cancer;
typical symptoms include rectal bleeding, pain,
tenesmus, and altered bowel patterns. Thorough
examination, including digital rectal examination, anoscopy, and palpation of inguinal nodes
should be performed. A biopsy should be performed to conrm the diagnosis (Fig.19.4), and
colonoscopy should be performed to exclude
concomitant colonic pathology. Clinical staging
via imaging studies is similar to that for anal
squamous cell carcinoma, and a similar staging
system, based on tumor size and furthest extent
of involved lymph nodes, is used.
Historically, primary surgical management
was the mainstay of therapy, either via local
excision for high-risk patients or for palliation in
patients with metastatic disease, or via APR for
Fig. 19.4 Anal canal
adenocarcinoma
336
B. R. Kann
those being treated with curative intent. With
theadvent of neoadjuvant chemoradiation for
rectal adenocarcinoma, most have adopted the
practice of offering neoadjuvant therapy, followed
by radical surgical excision (APR). Observation
of patients who have a complete clinical response
to CMT, as is being practiced more commonly
with rectal adenocarcinoma, is generally not
advocated due to the aggressive nature of anal
adenocarcinoma. Alternatively, local excision
followed by adjuvant therapy (chemoradiation or
radiation alone) may be feasible in certain cases.
Data regarding outcomes is sparse given the
rarity of the condition, and the majority of
published literature consists of case reports and
small retrospective series. Chang etal reported a
series of 34 patients treated over a 20-year period,
28 of which were treated with curative intent.
Local excision followed by chemoradiotherapy or
radiotherapy alone was performed in 13 patients,
and 15 patients underwent APR with either
neoadjuvant or adjuvant chemoradiotherapy.
Median disease-free survival and overall 5-year
survival did not differ signicantly between local
excision and APR (13% vs. 32%, p=0.055 and
43% vs. 63%, p=0.3, respectively), though APR
was found on multivariate analysis to be predictive
of both disease free survival (p = 0.004) and
overall survival (p=0.045) [57].
Bertelson etal. published a series of 18 patients
over a period of 15years, half of which were stage
III/IV at the time of diagnosis. One patient refused
treatment, 3 were given palliative chemotherapy, 1
underwent initial APR, and the remaining 13
patients underwent initial chemoradiation therapy.
Of the 13 patients who received neoadjuvant
therapy, 8 underwent subsequent radical resection,
3 progressed during neoadjuvant treatment and
became unresectable, 1 had a complete pathologic
response and was observed, and 1 did not complete
neoadjuvant treatment and was lost to follow-up.
Two patients with stage II disease were disease
free over eight years, and 1 was disease free after
26months; four patients had persistent or recurrent
local disease, and 10 developed metastatic disease.
Seven patients died with disease at a median
16 months, and the other seven were alive with
disease at a median follow-up of 10months [58].
Anal Melanoma
Anal melanoma accounts for less than 1% of all
melanomas and represents 1–4% of all anorectal
malignancies [59, 60]. Mean age at presentation
is 60years, and there is a female predominance
[61]. Anal melanomas may arise from a number
of sites, including the transitional epithelium of
the anal canal, the anoderm, or the mucocutaneous junction. Tumors may be pigmented or nonpigmented; early pigmented lesions of the
anoderm can be mistaken for thrombosed externalhemorrhoids. Approximately 30% of lesions
are amelanotic, and diagnosis depends on
immunohistochemical evidence of melanin pigment [62].
Anorectal melanomas exhibit biologic behaviors different from those of cutaneous melanomas, as they demonstrate a more aggressive
nature, tend to be more locally advanced and/or
metastatic at the time of diagnosis, and are associated with poorer long-term survival rates [63].
The most common presenting symptoms are rectal bleeding, pain, change in bowel habits, tenesmus, and the presence of a palpable mass.
Morphologically they tend to appear polypoid or
ulcerated, and satellite lesions are not uncommon. Biopsy is indicated to conrm the diagnosis
(Fig.19.5). Staging should include a CT scan of
the chest, abdomen, and pelvis or PET/CT to
evaluate for distant metastatic disease.
The overall prognosis is quite grim for anal
melanoma. Surgical excision is the mainstay of
treatment, as these tumors tend to be chemo- and
radio-resistant. Tumors >1-cm in size are unlikely
to be cured. APR may offer some survival advantage for early stage lesions, though given that the
majority of lesions are locally advanced or metastatic at the time of diagnosis, local excision may
be a more appropriate means of achieving
palliation.
Brady etal published one of the largest retrospective series, which included 71 patients with
anal melanoma over a 64-year period, reporting a
17% 5-year survival and a median survival of
19months. While there was no signicant difference in 5-year survival rates between patients
treated with APR and wide local excision (27%
ab
19 Anal Neoplasms
Fig. 19.5 (a) Epithelioid anal melanoma, H&E stain; (b) Anal melanoma, S-100 immunostain
337
vs. 5%, p=0.11), 9 of 10 long-term survivors had
undergone treatment with APR.The median size
Sarcoma/Gastrointestinal Stromal Tumor (GIST)
of the tumor in long-term survivors was 2.5cm,
compared with 4.0-cm in non-long-term survivors [64].
Podnos et al reviewed the Surveillance,
Epidemiology, and End Results (SEER) database
and found a total of 126 patients diagnosed with
anal melanoma from 1973 to 2001. Mean age
was 69.2years and 61% were females. Median
survival was 34months in patients with localized
disease, 13 months in patients with regional
spread, and 10months for those with distant disease. Five-year survival was 32% for localized
disease, 17% for regional disease, and 0% for
distant disease. Survival was unaffected by age at
diagnosis, operation performed, or use of radiation therapy [65].
A more recent review of the SEER database
from the Cleveland Clinic reported 160 patients,
55% of who underwent local excision and 45%
of who underwent radical resection. The median
survival of the 2 groups was similar (17 vs 28
months, p = 0.3); rectal resection and local
excision were associated with similar survival
for patients with both regional and localized
stages of disease at presentation. The authors
argued for a limited role for radical resection
given lack of superior survival [66]. An even
more recent review of the SEER database
reported a 2.5% 10-year survival for patents
with anal melanoma [67].
Anal sarcomas are exceedingly rare and produce
symptoms similar to other anal malignancies.
Biopsy and imaging are essential in establishing a
diagnosis and extent of disease. Anal sarcomas
may be either intra- or extra-luminal and may show
differentiation resembling any tissue of mesodermal
origin. Variations include rhabdomyosarcoma,
leiomyosarcoma, brosarcoma, and liposarcoma.
These tumors tend to be advanced at the time of
diagnosis. In the absence of metastatic disease,
treatment is generally surgical, either by local
excision or APR. These tumors are generally
radioresistant. Recurrence rates are high, and longterm survival is quite poor.
Gastrointestinal stromal tumors (GISTs) are
the most common mesenchymal neoplasms of
the gastrointestinal tract. While they most commonly occur in the stomach and small bowel, rare
cases of anal canal GISTs have been reported.
GISTs arise in the smooth muscle pacemaker
interstitial cell of Cajal, and their behavior is
driven by mutations in c-KIT, platelet-derived
growth factor receptor alpha, (PDRFRA), or
BRAF kinase. For localized primary GIST’s surgical resection is the mainstay of treatment, if
feasible. Imatinib, a tyrosine kinase inhibitor, can
be used as adjuvant therapy for high-risk lesions
or as neoadjuvant therapy for larger lesions where
downsizing of the tumor may be necessary before
338
surgical resection. Tumor size and mitotic index
are the two most important factors in determining
risk stratication. Tumor size <2 cm and/or a
mitotic rate of <5 mitoses/50 high power elds
(hpf) is considered low risk, while tumor size
>5cm and/or a mitotic rate of >10/50hpf is considered high risk for developing metastatic
disease, and adjuvant treatment with imatinib
should be considered. In patients with tumors
between 2 and 5cm or with 5–10mitoses/hpf, a
decision regarding adjuvant therapy should be
made on an individual basis [68].
Paget’s Disease
Paget’s disease, initially described in association
with breast cancer, can occur in a number of
extramammary locations, including the anogenital region, where it is thought to arise from apocrine sweat glands. Perianal Paget’s disease was
rst reported by Darier and Coulillaud in 1893
[69]; it represents approximately 6.5% of all
cases of Paget’s disease and less than 1% of all
anal diseases [70]. It is more commonly seen in
Caucasians, with a median age at presentation of
60 years and a strong female predominance
(3–4:1) [71].
When present in the perianal region, Paget’s
disease typically presents as an erythematous,
eczematous rash that often weeps uid (Fig.19.6);
clinically it is often confused with other perianal
skin conditions, such as Bowen’s disease, pruritis
ani, hidradenitis supporitiva, or Crohn’s disease.
Symptoms on presentation are non-specic, and
include pruritis, pain with defecation, bleeding,
and discharge. The non-specic nature of
presenting symptoms and the ambiguous nature
of its gross appearance often lead to signicant
delays in diagnosis. Patients often give a history
of a number of unsuccessful trials of topical
corticosteroids and other local measures.
Diagnosis is conrmed by biopsy, which reveals
intraepithelial adenocarcinoma characterized by
the presence of large, rounded, multi-vacuolated
“Pagetoid” cells containing abundant mucin
(Fig.19.7); cells are typically CK7, CK19, and
c-erb B2 positive on immunohistochemical
B. R. Kann
Fig. 19.6 Perianal Paget’s disease
Fig. 19.7 Perianal Paget’s disease
staining [72]. The diagnosis of Paget’s disease
should prompt an evaluation of the colon via
endoscopy, as upwards of 50% of patients with
Paget’s disease will also have a concomitant
colorectal neoplasm [73].
Wide local excision is the preferred means of
treating perianal Paget’s disease, when it can be
19 Anal Neoplasms
339
accomplished without debilitating effects on
anorectal function. Historically, pre-operative
anal “mapping” with perianal biopsies was
recommended to delineate the extent of disease
and achieve microscopically negative resection
margins [74]. However, in light of the high
recurrence rate after surgery for perianal Paget’s
disease, the value of such extensive mapping
procedures has been questioned [75], especially
given the resulting large tissue defects that are
frequently too large to close primarily and require
cutaneous advancement aps, myocutaneous
rotational aps, or split-thickness skin grafts
[76–78].
While data regarding long-term outcomes is
limited to a number of case reports and small retrospective series, the problems frequently
encountered post-operatively include recurrence
and the presence of concomitant invasive cancer.
Marchesa etal published a series of 14 patients
with perianal Paget’s disease and follow-up longer than 5 years, which differentiated between
local excision (with macroscopic clearance) and
wide local excision (with >1 cm microscopic
clearance of margins). Actuarial 8-year survival
was 0% in the local excision group and 40%
(SE=21.9) in the wide local excision group. All
patients who had recurrence after wide local
excision were treated with repeat wide local excision, with no further recurrences [79].
McCarter etal reported a series of 27 patients
from Memorial Sloan-Kettering Cancer Center
with perianal Paget’s disease, 74% of which were
treated with wide excision. Local recurrence
occurred in 37% of all patients and 30% of these
treated with wide excision. An invasive component was seen in almost half (44%) of all patients.
A colostomy was required in 22% of patients,
and adjuvant chemoradiotherapy was used in
22% of patients. At a median follow-up of 67
months, 56% had no evidence of disease, while 2
patients had died of metastatic disease. Overall
and disease-free survival at ve years was 59%
and 64%, respectively; these dropped signicantly to 33% and 3% by ten years [80].
A more recent series from Memorial SloanKettering Cancer Center described 65 patients
with perianal Paget’s disease, 63% of which had
invasive disease. Synchronous malignancies
unrelated to the primary were noted in 8 patients.
Non-invasive disease was treated with wide local
excision, while invasive disease was treated by
wide local excision (78%) or abdominoperineal
resection (22%). At a median follow-up of
5.3 years, local recurrence was seen in 29% of
those with non-invasive disease and 56% of those
with invasive disease; 63% of patients required
multiple operations for tumor clearance. In
patients with invasive disease, the means of surgical resection (wide local excision vs. abdominoperineal resection) did not alter recurrence or
disease-specic survival [75].
Another series, reported by Isik et al.,
described 25 patients with perianal Paget’s disease, 4 of whom had concurrent anorectal adenocarcinoma at the time of diagnosis. After index
procedures (local excision, wide local excision,
abdominoperineal resection, and radiotherapy), 5
patients developed invasive carcinoma, and 13
patients required reoperation for recurrent Paget’s
disease or invasive cancer. Overall survival did
not differ in patients treated with local excision
based on margin status at index excision, indicating that local recurrences can be successfully
treated with further surgery [81].
A series from the Mayo Clinic refuted the
aggressive nature of Paget’s disease, in spite of
its high recurrence rate. In this series of 13 patents with perianal Paget’s disease, there was a
61% 5-year recurrence rate, with most recurrences managed with wider local excision.
Overall ve-year and ten-year survival was 67%,
which was no different from an age-matched
control population [82].
Functional outcomes after wide excision and
reconstructive procedures must be carefully considered, particularly in terms of fecal continence.
Another study from the Mayo Clinic surveyed
patients who had undergone repair of a perianal
defect following surgery for Paget’s disease or
Bowen’s disease using the fecal incontinence
quality of life scale and SF-36. While SF-36
scores did not differ from the normative population, 9 of 14 patients reported some degree of
altered continence [83]. Given the potential functional consequences of extensive local resection